U.S. patent application number 15/385612 was filed with the patent office on 2017-12-14 for methods for treating atrial fibrillation.
This patent application is currently assigned to Armetheon, Inc.. The applicant listed for this patent is Armetheon, Inc.. Invention is credited to David J. Ellis, Peter J. Milner.
Application Number | 20170354635 15/385612 |
Document ID | / |
Family ID | 48524443 |
Filed Date | 2017-12-14 |
United States Patent
Application |
20170354635 |
Kind Code |
A1 |
Milner; Peter J. ; et
al. |
December 14, 2017 |
METHODS FOR TREATING ATRIAL FIBRILLATION
Abstract
The subject invention provides methods for reducing stroke rate,
methods for preventing atrial remodeling, and methods for reversing
atrial remodeling by administering budiodarone to reduce atrial
fibrillation (AF) episode duration and an anticoagulant (AC).
According to some methods of the invention, the average AF episode
duration can be reduced to less than about 24, 5, 3 or 1 hour(s),
and the maximum AF episode duration may be reduced to less than
about 20, 10 or 5 hours. According to some methods of the
invention, the reduced stroke rate upon administration of
budiodarone and AC is less than the age-adjusted overall stroke
rate. Further, some methods provide that patients who were
refractory to one or more anti-arrhythmic drugs prior to
administration of budiodarone may also be treated. Some methods
provide for prevention of atrial remodeling and others provide for
the reversal of atrial remodeling, including methods to quantify
the reversal of atrial remodeling. In some methods of the
invention, budiodarone is administered 400 mg BID or more
preferably 600 mg BID.
Inventors: |
Milner; Peter J.; (Los Altos
Hills, CA) ; Ellis; David J.; (Los Altos,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Armetheon, Inc. |
Milpitas |
CA |
US |
|
|
Assignee: |
Armetheon, Inc.
Milpitas
CA
|
Family ID: |
48524443 |
Appl. No.: |
15/385612 |
Filed: |
December 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13758687 |
Feb 4, 2013 |
9549912 |
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15385612 |
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12952683 |
Nov 23, 2010 |
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13758687 |
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12952666 |
Nov 23, 2010 |
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13758687 |
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12952696 |
Nov 23, 2010 |
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13758687 |
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61263564 |
Nov 23, 2009 |
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61263465 |
Nov 23, 2009 |
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61263567 |
Nov 23, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/343 20130101;
A61K 31/4184 20130101; A61K 31/444 20130101; A61K 31/444 20130101;
A61K 31/397 20130101; A61K 31/40 20130101; A61K 31/445 20130101;
A61K 31/4184 20130101; A61K 31/37 20130101; A61K 45/06 20130101;
A61K 31/343 20130101; A61K 31/37 20130101; A61K 31/4418 20130101;
A61K 31/439 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/4709 20130101; A61K 2300/00 20130101; A61K
31/5377 20130101; A61K 31/445 20130101; A61K 31/4439 20130101; A61K
31/4402 20130101; A61K 31/439 20130101; A61K 31/4545 20130101; A61K
31/4402 20130101; A61K 31/40 20130101; A61K 31/5377 20130101; A61K
31/4709 20130101; A61K 31/397 20130101; A61K 31/4439 20130101; A61K
31/4418 20130101; A61K 31/4545 20130101 |
International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 31/4439 20060101 A61K031/4439; A61K 31/445
20060101 A61K031/445; A61K 31/4545 20060101 A61K031/4545; A61K
31/397 20060101 A61K031/397; A61K 45/06 20060101 A61K045/06; A61K
31/40 20060101 A61K031/40; A61K 31/4709 20060101 A61K031/4709; A61K
31/4184 20060101 A61K031/4184; A61K 31/4418 20060101 A61K031/4418;
A61K 31/37 20060101 A61K031/37; A61K 31/4402 20060101 A61K031/4402;
A61K 31/5377 20060101 A61K031/5377; A61K 31/444 20060101
A61K031/444; A61K 31/439 20060101 A61K031/439 |
Claims
1. A method for treating a refractory atrial fibrillation patient
comprising administering to patient refractory to one or more
anti-arrhythmic drugs an amount of budiodarone effective to reduce
atrial fibrillation burden (AFB).
2. The method of claim 1, further comprising administration of an
effective amount of anticoagulant (AC) selected from the group
consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin.
3. The method of claim 1, wherein average atrial fibrillation
episode duration is reduced.
4. The method of claim 1, wherein said patient is identified as at
risk for stroke.
5. The method of claim 4, wherein said patient has a CHADS.sub.2
(Cardiac failure, Hypertension, Age, Diabetes, Stroke/transient
ischemic event [doubled]) score of 1 or more.
6. The method of claim 1, wherein said atrial fibrillation is
paroxysmal atrial fibrillation (PAF).
7. The method of claim 1, wherein said atrial fibrillation is
persistent atrial fibrillation.
8. The method of claim 1, wherein average atrial fibrillation
episode duration is greater than about 5 hours prior to
administration of budiodarone.
9. The method of claim 1, wherein average atrial fibrillation
episode duration is reduced to less than about 5 hours.
10. The method of claim 1, wherein average atrial fibrillation
episode duration is reduced to less than about 3 hours.
11. The method of claim 1, wherein average atrial fibrillation
episode duration is reduced to less than about 1 hour.
12. The method of claim 2, wherein average atrial fibrillation
episode duration is decreased by more than 50% after treatment.
13. The method of claim 2, wherein average atrial fibrillation
episode duration is decreased by more than 70% after treatment.
14. The method of claim 1, wherein AFB is decreased by at least 70%
after treatment.
15. The method of claim 1, wherein the amount of budiodarone is 400
mg BID.
16. The method of claim 1, wherein the amount of budiodarone is 600
mg BID.
17. The method of claim 2, wherein said anticoagulant is
warfarin.
18. The method of claim 2, wherein said anticoagulant is
tecarfarin.
19. The method of claim 1, wherein mean duration of normal sinus
rhythm (NSR) between episodes of atrial fibrillation is
increased.
20. The method of claim 1, wherein said one or more anti-arrhythmic
drugs is a class III anti-arrhythmic drug.
21. The method of claim 19, wherein said one or more class III
anti-arrhythmic drug is dofetilide or ibutilide.
22. The method of claim 1, wherein said one or more anti-arrhythmic
drugs is amiodarone.
23. The method of claim 1, wherein said one or more anti-arrhythmic
drugs is a class I anti-arrhythmic drug.
24. The method of claim 9, wherein said one or more class I
anti-arrhythmic drug is flecanide or quinidine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/758,687, filed Feb. 4, 2013, which is a
continuation-in-part of U.S. patent application Ser. No.
12/952,683, filed Nov. 23, 2010, which claims priority to U.S.
Provisional Application No. 61/263,564, filed Nov. 23, 2009; U.S.
patent application Ser. No. 13/758,687 is also a
continuation-in-part of U.S. patent application Ser. No.
12/952,666, filed Nov. 23, 2010, which claims priority to U.S.
Provisional Application No. 61/263,465, filed Nov. 23, 2009; and
U.S. patent application Ser. No. 13/758,687 is also a
continuation-in-part of U.S. patent application Ser. No.
12/952,696, filed Nov. 23, 2010, which claims priority to U.S.
Provisional Application No. 61/263,567, filed Nov. 23, 2009; the
contents of each of which are incorporated herein by reference in
their entirety.
BACKGROUND
[0002] Atrial fibrillation (AF) is a common cardiac disorder
characterized transient to permanent replacement of the normal,
coordinated electrical impulses generated by the sinoatrial (SA)
node by disorganized electrical impulses originating in the atria
and pulmonary veins. An irregular heartbeat results.
[0003] AF is classified into three classes after the first detected
AF event, each with a greater proportion of time spent in AF.
Paroxysmal atrial fibrillation (PAF) patients have multiple
self-terminating episodes of arrhythmia that can span from >30
seconds to days, but they must self-terminate in less than seven
days. PAF is typically responsive to chemical or electrical
cardioversion, or the reestablishment of sinus rhythm. Persistent
AF is characterized by episodes that can last more than 7 days, but
are generally still responsive to cardioversion. Permanent AF is
characterized by continuous AF that is unresponsive to efforts to
reestablish sinus rhythm. The natural tendency of AF is to become a
chronic condition, advancing from PAF to persistent and eventually
to permanent AF.
[0004] The process whereby AF advances from first event to PAF to
persistent and finally permanent AF is called atrial remodeling.
Remodeling is broadly comprised of electrical remodeling and
structural remodeling though thrombotic remodeling is often
considered a separate part of the progression and dependent upon
electrical remodeling. Electrical remodeling refers to the changes
primarily affecting the excitability and electrical activity of the
atrial myocytes. Such remodeling is fairly rapid, happening on the
hours to days timescale. Structural remodeling refers to the
changes in myocyte number, chamber size, interstitial collagen
deposition, and fibroblast proliferation, which is a slower process
that occurs on the months to years timescale. All types of
remodeling have adverse medical consequences such as an increased
risk of clot formation and stroke. Remodeling can lead to loss of
the primary mechanical function of the atrium, the properly
coordinated diastolic filling of the left and right ventricles,
which in turn can lead to congestive heart failure.
[0005] Thrombotic remodeling refers to increase in thrombogenicity
of the atria in AF patients. AF is associated with the upregulation
of thrombogenic factors, for example fibrinogen, fibrin D-dimer,
and von Willebrand factor, that, when combined with decreased blood
flow and left atrial stasis in AF, promotes thrombogenesis (Marin,
F, et al., Heart. 2004 October; 90(10):1162-6; Lip G Y, et al., Br
Heart J. 1995 June; 73(6):527-33). Patients with first onset AF,
PAF, as well as persistent and permanent AF exhibit such
upregulation (Marin, F, et al., supra; Lip, G Y, et al., Am Heart
J. 1996 April; 131(4):724-30). The presence of such upregulation
for first onset AF suggests that thrombogenic remodeling takes
place in the hours timescale, similar to electrical remodeling. It
is thought that these are important early biomarkers of increased
risk of clot formation and stroke. It has only recently been
recognized, counter to prior conventional wisdom, that PAF or new
onset AF carries a significant stroke risk.
[0006] Remodeling, particularly electrical remodeling, appears to
be reversible, and the greater the time a patient spends in normal
sinus rhythm after some atrial remodeling has occurred, the greater
the reversal of remodeling, and the lower the probability of AF
recurrence (Hobbs et al., Circulation Hobbs et al. 101 (10): 1145.
(2000)). Several parameters can be measured to determine the level
of remodeling or reversal of remodeling, including atrial
fibrillation cycle length (AFCL). AFCL decreases as a patient
spends more time in AF and, conversely, AFCL increases with
increased time spent in normal sinus rhythm. Longer AFCLs reflect
greater atrial refractoriness and, in general, resistance to AF. It
is accepted in clinical practice that "AF begets AF". This may be
because increased time in AF is associated with decreased AFCL
making it more difficult over time for the AF to either terminate
sponateously, or be to cardioverted back to normal sinus rhythm by
direct current or drugs. Hobbs et al., (supra) found that AFCL at
the right atrial appendage increased an average of 6 milliseconds
when a patient was cardioverted from AF and spent time in NSR,
which was a statistically significant change in AFCL (and atrial
refractoriness) that represented greater resistance to AF. At the
distal coronary sinus, a statistically significant increase in AFCL
of 6 milliseconds was observed after the first cardioversion and
time spent in NSR. Thus, measurement of a patient's AFCL before
treatment and over time can reflect the extent of reversal of
electrical remodeling. Similarly, other measures of refractoriness,
such as the shortest coupling interval of atrial premature beats
and directly measured refractory periods after cardioversion, can
indicate the extent of electrical remodeling and remodeling
reversal.
[0007] While there are many factors that influence stroke risk,
such as age, heredity, race, sex, prior stroke, hypertension,
cardiac failure, diabetes, and others, a significant risk factor
for stroke is AF. The characteristic lack of coordinated atrial
contraction can result in clot formation in the atrium, and
particularly the left atrial appendage (assisted by the localized
prothrombotic state due to thrombotic remodeling). The increased
stasis of blood in the atrium due to loss of mechanical function
(i.e. contraction), combined with poorly understood changes in the
thrombogenicity of the atrial endocardial surface in AF is thought
to be the primary basis for clot formation in the left atrium and
left atrial appendage in AF. There is good precendent for this. For
example the combination of stasis and increased thromogenicity of
the underlying surface when they occur in the veins of the calf are
well accepted to be the eitiology of clot formation in the legs
known as deep venous thrombosis (DVT).
[0008] If the blood clot leaves the atria and becomes lodged in an
artery in the brain, a stroke results. This is known as an embolic
or more precisely as a thromboembolic cerebrovascular accident
(CVA). If the clot travels to the periphery, other damage can
occur, such as bowel ischemia. This event is known as systemic
thromboembolic event. Approximately 15% of strokes occur in people
with AF, a number that is likely artificially low due to
cryptogenic stroke, or stroke whose cause is indeterminate,
actually being caused by formerly undiagnosed or unrecognized AF.
Approximately one third of strokes are classified as cryptogenic,
of which nearly one quarter were associated with undiagnosed AF
(Tayal, et al., Neurology. 2008 Nov. 18; 71(21):1696-701).
Diagnosed AF is associated with a four- to five-fold increase in
stroke risk (Wolf P A, Abbott R D, Kannel W B, Arch Intern Med.
1987 September; 147(9):1561-4; Stroke. 1991 August;
22(8):983-8).
[0009] Regarding the relative risk of the subtypes of AF, the
benchmark study is known as ACTIVE W (Hohnloser S H, et al., J Am
Coll Cardiol. 2007 Nov. 27; 50(22):2156-61). ACTIVE W investigated
the incidence of stroke in 1202 paroxysmal AF patients versus a
combined group of 5495 patients with either persistent or permanent
(i.e., "sustained") AF. The investigators found that patients with
paroxysmal AF have a similar risk of stroke as those with sustained
AF, and that despite the statistically significantly lower
CHADS.sub.2 score in the paroxysmal AF population (CHADS.sub.2 of
1.79 versus 2.04, p<0.00001). CHADS.sub.2 is a clinical
prediction rule for estimating the risk of stroke in AF patients
comprising Cardiac failure, Hypertension, Age, Diabetes, and Stroke
or transient ischemic event (TIA) [doubled], wherein the higher a
patient's score, the greater their risk of stroke. In an
observational study, Capucci et al (J Am Coll Cardiol. 2005 Nov.
15; 46(10):1913-20) reported in PAF an increased risk of stroke for
patients with episodes longer than 24 hours and suggested that such
information be used to guide anticoagulation regimen. The reference
fails to offer any teaching or suggestion that a drug could or
should intervene and modulate AF episode duration thereby offering
therapeutic intervention for stroke as with the instant invention.
Again, Capucci's teaching relates to guiding anticoagulation
therapy in AF not antiarrhythmic therapy. In fact the conventional
accepted medical belief, as a result of multiple antiarrhythmic
drug studies over many years that failed to shown any reduction in
stroke rate with antiarrhytmic drug therapy, has been that, an
antiarrhythmic drug would have no benefit or role in reducing
stroke risk in AF.
[0010] Atrial fibrillation can be symptomatic or asymptomatic.
Symptomatic AF can be characterized by, for example, palpitations,
dyspnea, chest discomfort, fatigue, dizziness, syncope, exercise
intolerance, and transient ischemic attack (TIA), and is often
found upon examination for such symptoms. Asymptomatic AF, due to
its lack of symptoms, is generally found by happenstance, such as
during a routine examination or preoperative assessment. Page et
al. (Circulation. 1994 January; 89(1):224-7), found that
asymptomatic AF is more than 12-fold more prevalent than
symptomatic AF, which is particularly significant given that
asymptomatic AF is thought to confer no less risk than symptomatic
AF with regard AF-related complications (Savelieva, I. Camm, I.
John, J Intery Card Electrophysiol. 2000 June; 4(2):369-82). From
the results of Tayal et al on the etiology of cryptogenic stroke
described above (Tayal, et al., Neurology. 2008 Nov. 18;
71(21):1696-701) it is clear that asymptomatic PAF or undiagnosed
PAF can prose a major threat of stroke in often otherwise seemingly
health people.
[0011] Two primary chemotherapeutic paradigms are utilized to treat
AF, one to address the AF itself, and the other addresses stroke.
Chemotherapeutic treatment of AF includes heart rate control drugs
(such as digoxin), beta-blockers, and calcium channel blockers
(such as verapamil and diltiazem), which seek to reduce the heart
rate to one that is closer to normal to reduce symptoms, and rhythm
control drugs (such as amiodarone, dronedarone, budiodarone,
vernakalant, celivarone and AZD-1305), which seek to restore and
maintain the regular heart rhythm. It has been widely accepted for
many years that these treatment strategies offer no protection from
stroke in AF, and that the only effective stroke prevention
treatment for patients with AF is to administer an effective dose
of an (oral) anticoagulant (blood thinner) on a chronic basis as
described later.
[0012] Regarding the relative effectiveness of rhythm control and
rate control drugs on AF, the benchmark study is known as AFFIRM
(Wyse D G, et al., N Engl J Med. 2002 Dec. 5; 347(23):1825-33).
AFFIRM compared rhythm control and rate control in 4060 AF patients
with an endpoint of overall mortality. The study demonstrated that
management of AF with rhythm control offers no survival advantage
over rate control, and that rate control potentially offers
advantages, such as a lower risk of adverse events. Regarding
stroke, the AFFIRM study showed similar numbers (rate control: 77
events among 2027 patients; rhythm control: 80 events among 2033
patients), indicating, like ACTIVE W, that more time spent in AF
does not correlate with a greater risk of stroke and that
antiarrhythmic drug therapy fails to prevent strokes in AF.
Additional studies came to the same conclusion, such as PIAF
(Hohnloser S H, et al. Lancet 2000; 356:1789-94), STAF (Carlsson J,
et al. J Am Coll Cardiol 2003; 41:1690-6), RACE (Van Gelder I C, et
al., N Engl J Med 2002; 347:1834-40), HOT CAFE (Opolski G., et al,
Chest 2004; 126: 476-86) and AF-CHF (Roy D, et al., N Engl J Med
2008; 358:2667-77).
[0013] A standard study design for new anti-arrhythmic drugs
involves TTFR, or time to first recurrence of AF. Two examples of
such a study are EURIDIS and ADONIS for dronedarone (Singh B N, et
al., N Engl J Med. 2007 Sep. 6; 357(10):987-99). In EURIDIS and
ADONIS, 1237 (combined) AF patients were given placebo (409) or
dronedarone (828), and followed for a year. Follow-up consisted of
two 12-lead electrocardiograms, 10 minutes apart on days 2, 3, and
5, as well as at months 3, 5, 7, and 10 post-randomization, or
whenever they had symptomatic AF. The primary end point was the
time from randomization to the first documented recurrence of AF,
defined as an episode lasting for at least 10 minutes and confirmed
by two consecutive recordings taken 10 minutes apart. EURIDIS and
ADONIS demonstrated a significant increase in TTFR compared to
placebo.
[0014] Nevertheless, EURIDIS and ADONIS, as well as other TTFR
trials, have weaknesses. Increased TTFR assumes less overall AF,
but detection still occurs by chance, i.e., on preplanned days 2,
3, and 5, after months 3, 5, 7, and 10, or when AF is symptomatic
(the only non-chance identification of AF). However, asymptomatic
AF accounts for at least 12.times. more AF than symptomatic AF, and
stroke risk of both is thought to be the same. Thus, TTFR trials
like EURIDIS and ADONIS may quantify an increase in TTFR, but they
significantly under represent the amount of time a patient spends
in AF. That is, they fail, except by chance, to identify and
account for the significant amount of asymptomatic AF, and they
fail to characterize AF and how AF might change under influence of
study drug or comparator. As a consequence, one of ordinary skill
in the art has no guidance regarding the present invention.
[0015] A recent outcome study, ATHENA, followed the EURIDIS and
ADONIS TTFR studies on dronedarone (Hohnloser S H, et al., N Engl J
Med. 2009 Feb. 12; 360(7):668-78. Erratum in: N Engl J Med. 2009
Jun. 4; 360(23):2487; Connolly S J, et al., Circulation. 2009 Sep.
29; 120(13):1174-80). In ATHENA, of 4628 total patients, 2327 were
given placebo and 2301 were given dronedarone, and the primary
study outcome was time to first hospitalization due to
cardiovascular events or death from any cause. Contrary to the vast
body of clinical studies and literature, treatment with an
anti-arrhythmic was correlated with a reduction in stroke. However,
confounding that observation was the inexplicable finding in ATHENA
that patients with only AF or atrial flutter on all ECGs through
out the 2 years of the study (i.e., those who had degraded into
permanent AF, which is unresponsive to anti-arrhythmics),
experienced 2 strokes versus 8 for the placebo, suggesting a
possible undetermined imbalance between the treatment groups.
Moreover, the study authors describe how study drug reduced blood
pressure and that reductions in blood pressure are correlated with
decreased stroke. It is well known that blood pressure reduction
reduces stroke risk due to non-embolic cerebrovascular accidents.
The failure to properly ajudicate the cause of these strokes in AF
in the ATHENA study fails to teach or suggest whether the cause of
the reduction in strokes was due to preventing embolic strokes from
the left atrium, hypertensive strokes, strokes due to in situ
thrombosis in the cerebral arteries, some other cause, or a
combination of some or all of the above. The study authors also
describe that study drug reduced heart rate and that such an effect
could directly reduce stroke risk by preventing hypotension. To the
extent that the study authors say that a reduction in overall AF
could have influenced stroke risk, they provide no teaching or
suggestion regarding how reduced AF may exert this effect (which is
contrary to the vast body of knowledge in the art that
anti-arrhythmics have no effect on stroke, e.g., AFFIRM), or how
their drug may specifically affect AF. They even summarize their
study by stating "the results of the present study should not be
interpreted to indicate that dronedarone might be a replacement for
AC therapy or a treatment for stroke prevention." (supra). Thus,
ATHENA provides no teaching or suggestion regarding how an
anti-arrhythmic could affect stroke risk, beyond blood pressure and
heart rate, and in particular no teaching or suggestion of the
present invention.
[0016] The other primary AF treatment paradigm is anticoagulation
as a means to reduce stroke risk. Anticoagulation is the only
proven and currently accepted drug therapy known to reduce stoke
risk in AF. In patients with AF, warfarin prevents 64% of strokes
(Hart R G, Pearce L A, Aguilar M I. Ann Intern Med. 2007 June 19;
146(12):857-67). Warfarin, despite being effective, is inconvenient
to use and is susceptible to a significant number of drug-drug
interactions, which complicate its use. As a consequence, other
anticoagulants are being developed that are vitamin-K epoxide
reductase inhibitors (for example, tecarfarin), direct thrombin
inhibitors (for example, AZD-0837; dabigatran etexilate,
dabigatran, ximelagatran; melagatran, and argatroban), or Factor Xa
inhibitors (for example, apixaban, rivaroxaban, YM466, betrixaban,
and edoxaban).
[0017] In a phase 2 clinical trial, tecarfarin (ATI-5923)
demonstrated an statistically significant increase in time in
therapeutic range (TTR), defined as an International Normalized
Ratio (INR) of between 2.0 and 3.0, as compared to warfarin
(p=0.0009). TTR was 71.5% versus 59.3% for the same exact patient
population when they were previously on warfarin. The proportion of
time spent in more thrombogenic INR ranges were also reduced
compared to warfarin. On warfarin, patients had INR ratios between
1.5 and 1.9 22.4% of the time versus 14.2% for tecarfarin. On
warfarin, patients had INR ratios below 1.5 3.9% of the time versus
1.2% for tecarfarin. Similar results were seen for higher INR
ratios, which are representative of higher risk of hemorrhage.
Greater time in therapeutic range correlates with increased life
expectancy, from approximately 50% life expectancy at 5 years for
32% TTR, to about 65% at 59% TTR, to about 75% at 72% TTR and about
85% at 84% TTR (Currie et al., Heart 2006(92)196-200). Regarding
outcomes, a 10% decrease in TTR results in a 29% increase in
mortality, a 10% increase in ischemic stroke risk and a 12%
increase in all thromboembolic events (Jones et al., Heart
2005(91)472-477). Thus, tecarfarin should be an important AC for
use in AF patients to reduce stroke.
[0018] The results of an outcome trial for a direct thrombin
inhibitor (DTI), dabigatran etexilate, were recently published
(Connolly S J, et al., N Engl J Med. 2009 Sep. 17; 361(12):1139-51;
Gage B F, N Engl J Med. 2009 Sep. 17; 361(12):1139-51). The RE-LY
trial followed over 18000 patients for an average of two years,
with a primary outcome of systemic embolism or stroke. Dabigatran
at 150 mg proved superior to warfarin with respect to stroke and
noninferior with respect to major bleeding; whereas, dabigatran at
110 mg proved noninferior to warfarin with respect to stroke and
superior with respect to major bleeding. Amiodarone was being used
concomitantly in approximately 2000 of the 18000 enrolled patients,
and those patients appeared to show a trend toward lower stroke
risk in contrast to other trials, but the trend was not
statistically significant. Moreover, dabigatran is a P-glycoprotein
(P-gp) substrate, and amiodarone is a P-gp inhibitor, so the trend
was attributed to a pharmacokinetic interaction between amiodarone
and dabigatran through P-gp resulting in an increased serum
concentration of dabigatran and hence greater efficacy in reducing
stroke risk in AF. Further bolstering this explanation is the fact
that quinidine, another anti-arrhythmic that was originally
permitted in the study, was later removed because the combination
of dabigatran and quinidine was unfavorable to patient health.
Quinidine is a particularly potent P-gp inhibitor and because it is
a more potent inhibitor of P-gp than amiodarone, it raised
dabigatran blood levels to unacceptably high levels. Quinidine is
now specifically contraindicated in dabigatran product
literature.
[0019] Clarfication of the recommended and accepted current
treatments for preventing stroke in AF can be found in practice
guidelines. There are three professional bodies in the US that
issue guidelines to physicians on how to reduce stroke risk in AF;
the ACC (American College of Cardiology), the AHA (American Heart
Association), and the ACCP (American College of Chest Physicians).
All three concur that an anticoagulant can, and should be used to
prevent stroke in AF especially in patients who have a CHADS.sub.2
score of 1 or greater. As of the date of application none of the
current guidelines from these three professional bodies recommend,
or even suggest that, an antiarrhythmic drug can be used to reduce
stroke risk in AF.
[0020] Given the above, the prior art fails to teach or suggest
that budiodarone can serve as a therapeutic intervention for stroke
by reducing AF episode duration. Likewise, there is no teaching or
suggestion than AF episode duration can be lowered as substantially
as described herein, or that budiodarone can prevent or reverse
atrial remodeling through reduction in AF episode duration.
[0021] Given the above, the prior art fails to teach or suggest
that the administration of an anti-arrhythmic and an anticoagulant
can serve as a synergistic therapeutic intervention for stroke by
reducing AF episode duration and inhibiting thrombogenesis.
Likewise, there is no teaching or suggestion than AF episode
duration can be lowered as substantially as described herein, or
that the administration of an anti-arrhythmic and an anticoagulant
can prevent or reverse atrial remodeling through reduction in AF
episode duration.
[0022] Given the above, the prior art fails to teach or suggest
that the administration of budiodarone and an anticoagulant can
serve as a synergistic therapeutic intervention for stroke by
reducing AF episode duration and inhibiting thrombogenesis.
Likewise, there is no teaching or suggestion than AF episode
duration can be lowered as substantially as described herein, or
that the administration of budiodarone and an anticoagulant can
prevent or reverse atrial remodeling through reduction in AF
episode duration.
SUMMARY OF THE INVENTION
[0023] The present invention provides methods for reducing atrial
fibrillation (AF) episode duration comprising administering an
amount of budiodarone effective to reduce AF episode duration.
Average AF episode duration can be reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours and less
than about 1 hour. The invention also provides methods for reducing
maximum AF episode duration to less than about 20 hours, less than
about 10 hours and less than about 5 hours.
[0024] The subject invention provides methods for reducing atrial
fibrillation (AF) episode duration, methods for reducing stroke
rate, methods for increasing time in normal sinus rhythm (NSR),
methods for preventing atrial remodeling, and methods for reversing
atrial remodeling, all comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0025] The subject invention provides methods for reducing stroke
rate, methods for preventing atrial remodeling, and methods for
reversing atrial remodeling by administering a multiple ion channel
blocker anti-arrhythmic to reduce atrial fibrillation (AF) episode
duration and an anticoagulant (AC). According to some methods of
the invention, the average AF episode duration can be reduced to
less than about 24, 5, 3 or 1 hour(s), and the maximum AF episode
duration may be reduced to less than about 20, 10 or 5 hours.
According to some methods of the invention, the reduced stroke rate
upon administration of multiple ion channel blocker and AC is less
than the age-adjusted overall stroke rate. Further, some methods
provide that patients who were refractory to one or more
anti-arrhythmic drugs prior to administration of the multiple ion
channel blocker may also be treated. Some methods provide for
prevention of atrial remodeling and others provide for the reversal
of atrial remodeling, including methods to quantify the reversal of
atrial remodeling. In some methods of the invention, budiodarone is
administered 400 mg BID or more preferably 600 mg BID.
[0026] The present invention provides methods for reducing stroke
rate comprising administering an amount of multiple ion channel
blocker selected from the group consisting of amiodarone,
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce atrial fibrillation (AF) episode duration and
an effective amount of anticoagulant (AC) selected from the group
consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin.
According to the invention, the average AF episode duration can be
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, and less than about 1 hour. The methods of the
invention also provide for the reduction of maximum AF episode
duration to less than about 20 hours, less than about 10 hours and
less than about 5 hours.
[0027] The present invention provides methods for reducing stroke
rate comprising administering an amount of budiodarone effective to
reduce atrial fibrillation (AF) episode duration and an effective
amount of anticoagulant (AC) selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin. According to the
invention, the average AF episode duration can be reduced to less
than about 24 hours, less than about 5 hours, less than about 3
hours, and less than about 1 hour. The methods of the invention
also provide for the reduction of maximum AF episode duration to
less than about 20 hours, less than about 10 hours and less than
about 5 hours.
[0028] The present invention also provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration. As above, average AF
episode duration can be reduced to less than about 24, 5, 3, and 1
hours, as well as reducing maximum AF episode duration to less than
about 20, 10 and 5 hours.
[0029] The invention also provides methods for increasing time in
normal sinus rhythm (NSR) comprising administering an amount of
budiodarone effective to reduce AF episode duration. Certain
methods provide for the reduction of average and maximum AF episode
duration according to the time spans recited above.
[0030] According to certain methods of the invention, the reduced
stroke rate upon administration of multiple ion channel blocker and
AC is less than the age-adjusted overall stroke rate. Certain other
methods of the invention provide for the administration of multiple
ion channel blocker and AC in patients who were refractory to one
or more anti-arrhythmic drugs prior to administration of
budiodarone.
[0031] According to certain methods of the invention, the reduced
stroke rate upon administration of budiodarone and AC is less than
the age-adjusted overall stroke rate. Certain other methods of the
invention provide for the administration of budiodarone and AC in
patients who were refractory to one or more anti-arrhythmic drugs
prior to administration of budiodarone.
[0032] The invention also provides methods for preventing atrial
remodeling comprising administering an amount of budiodarone
effective to reduce AF episode duration. Again, certain methods of
the invention provide for the reduction of average and maximum AF
episode duration according to the time spans recited above.
[0033] The invention also provides methods for preventing atrial
remodeling comprising administering an amount of multiple ion
channel blocker effective to reduce atrial fibrillation (AF)
episode duration and an effective amount of anticoagulant (AC)
selected from the group listed above. Some methods provide for the
reduction in average and maximum AF episode duration according to
the times recited above. Certain methods also provide for the
administration of multiple ion channel blocker and AC in patients
who were refractory to one or more anti-arrhythmic drugs prior to
administration of budiodarone.
[0034] The invention also provides methods for preventing atrial
remodeling comprising administering an amount of budiodarone
effective to reduce atrial fibrillation (AF) episode duration and
an effective amount of anticoagulant (AC) selected from the group
consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin. Some
methods provide for the reduction in average and maximum AF episode
duration according to the times recited above. Certain methods also
provide for the administration of budiodarone and AC in patients
who were refractory to one or more anti-arrhythmic drugs prior to
administration of budiodarone.
[0035] The invention further provides methods for reversing atrial
remodeling comprising administering an amount of budiodarone
effective to reduce AF episode duration. Some methods provide for
reductions in average and maximum AF episode duration as recited
above. Further some methods provide for quantifying the reversal of
remodeling.
[0036] The present invention also provides methods for reversing
atrial remodeling comprising administering an amount of multiple
ion channel blocker effective to reduce atrial fibrillation (AF)
episode duration and an effective amount of anticoagulant (AC)
selected from the group listed above. Some methods also provide for
the reduction in average and maximum AF episode duration according
to the times recited above. Some methods also provide for the
administration of multiple ion channel blocker and AC in patients
who were refractory to one or more anti-arrhythmic drugs prior to
administration of multiple ion channel blocker. Additional methods
provide for quantifying the reversal of atrial remodeling.
[0037] The present invention also provides methods for reversing
atrial remodeling comprising administering an amount of budiodarone
effective to reduce atrial fibrillation (AF) episode duration and
an effective amount of anticoagulant (AC) selected from the group
consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin. Some
methods also provide for the reduction in average and maximum AF
episode duration according to the times recited above. Some methods
also provide for the administration of budiodarone and AC in
patients who were refractory to one or more anti-arrhythmic drugs
prior to administration of budiodarone. Additional methods provide
for quantifying the reversal of atrial remodeling.
[0038] In each case above, the invention also provides methods
wherein the patient was refractory to one or more anti-arrhythmic
drugs prior to the administration of budiodarone. Further methods
are provided wherein budiodarone is administered 400 mg or 600 mg
BID.
[0039] In each case above, the invention also provides methods
wherein budiodarone is administered 400 mg or 600 mg BID.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 shows a dose-dependent decrease in atrial
fibrillation burden (AFB) on budiodarone, with overall burden
decreasing 54% on 400 mg and 75% on 600 mg. AFB is the duration of
time a subject's cardiac rhythm was AF divided by the total time
recorded for the study period, expressed as a percent.
[0041] FIG. 2 shows the reduction of AFB on budiodarone, as well as
a return to pre-treatment burden state after washout.
[0042] FIG. 3 shows the median percent change from baseline for
three parameters on 600 mg budiodarone. Top left graph: number of
AT/AF episodes decrease by more than 60% in all three treatment
months. Top right: duration of episodes decreases by more than 50%
in treatment month 1, followed by a decrease of more than 70% in
treatment month 2 and nearly 70% in treatment month 3.
[0043] FIG. 4 shows the duration of AF episodes at baseline, after
treatment months 1, 2 and 3, and after washout for placebo and for
200, 400 and 600 mg of budiodarone.
[0044] FIG. 5 shows the median duration of AF episodes in hours for
placebo and budiodarone at 200, 400 and 600 mg at baseline, after
treatment months 1, 2 and 3, and after washout.
[0045] FIG. 6 shows the cumulative time of all episodes over 24
hours for placebo and budiodarone at 200, 400 and 600 mg, at
baseline, after treatment months 1-3, and after washout.
[0046] FIG. 7 shows the results of a Phase 2 pilot study of
budiodarone. Mean absolute AFB, relative reductions in burden and
changes in episode number and duration are described. Significant
reductions in AFB and episode duration were observed on drug.
DETAILED DESCRIPTION OF THE INVENTION
[0047] In one aspect, the invention provides methods for reducing
atrial fibrillation (AF) episode duration comprising administering
an amount of budiodarone effective to reduce AF episode
duration.
[0048] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 24 hours.
[0049] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 5 hours.
[0050] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 3 hours.
[0051] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 1 hour.
[0052] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 20 hours.
[0053] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 10 hours.
[0054] In another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 5 hours.
[0055] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0056] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF average episode duration to less
than about 24 hours.
[0057] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF average episode duration to less
than about 5 hours.
[0058] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF average episode duration to less
than 3 hours.
[0059] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF average episode duration to less
than about 1 hour.
[0060] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce maximum AF episode duration to less
than about 20 hours.
[0061] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce maximum AF episode duration to less
than about 10 hours.
[0062] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce maximum AF episode duration to less
than about 5 hours.
[0063] In yet another aspect, the invention provides methods for
increasing time in normal sinus rhythm (NSR) comprising
administering an amount of budiodarone effective to reduce AF
episode duration.
[0064] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 24 hours.
[0065] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 5 hours.
[0066] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than 3 hours.
[0067] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 1 hour.
[0068] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 20 hours.
[0069] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 10 hours.
[0070] In another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 5 hours.
[0071] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0072] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 24 hours.
[0073] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 5 hours.
[0074] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than 3 hours.
[0075] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 1 hour.
[0076] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 20 hours.
[0077] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 10 hours.
[0078] In another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 5 hours.
[0079] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0080] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 24 hours.
[0081] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 5 hours.
[0082] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than 3 hours.
[0083] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 1 hour.
[0084] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 20 hours.
[0085] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 10 hours.
[0086] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 5 hours.
[0087] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration, wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0088] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 24 hours, wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0089] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 5 hours, wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0090] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than 3 hours, wherein the reversal of atrial remodeling is defined
as a measured increase in AFCL at the right atrial appendage or
distal coronary sinus of at least 6 milliseconds.
[0091] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration to less
than about 1 hour, wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0092] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 20 hours, wherein the reversal of atrial remodeling
is defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0093] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 10 hours, wherein the reversal of atrial remodeling
is defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0094] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce the maximum AF episode duration to
less than about 5 hours, wherein the reversal of atrial remodeling
is defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0095] In yet another aspect, the invention provides methods for
reducing atrial fibrillation (AF) episode duration comprising
administering an amount of budiodarone effective to reduce average
AF episode duration, wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0096] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0097] In yet another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0098] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0099] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0100] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0101] In yet another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0102] In yet another aspect, the invention provides methods for
reducing AF episode duration comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 600 mg BID.
[0103] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0104] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 600 mg BID.
[0105] In yet another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0106] In yet another aspect, the invention provides methods for
increasing time in NSR comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 600 mg BID.
[0107] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0108] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 600 mg BID.
[0109] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0110] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce average AF episode duration,
wherein the effective amount of budiodarone is 600 mg BID.
[0111] In yet other aspects, the invention provides for all of the
above methods in patients with severe heart failure.
[0112] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of multiple ion
channel blocker anti-arrhythmic selected from the group consisting
of amiodarone, dronedarone, budiodarone, vernakalant, celivarone,
and AZD1305 effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[0113] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0114] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0115] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
budiodarone, dronedarone, celivarone, AZD1305 or vernakalant
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin.
[0116] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0117] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0118] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin.
[0119] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour.
[0120] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0121] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of multiple ion
channel blocker selected from the group consisting of amiodarone,
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban.
[0122] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0123] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0124] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
budiodarone, dronedarone, celivarone, AZD1305 or vernakalant
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban.
[0125] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the average AF episode duration is reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours, or less
than about 1 hour.
[0126] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours.
[0127] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban.
[0128] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0129] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours.
[0130] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0131] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0132] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0133] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0134] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0135] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0136] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the average AF episode duration is reduced to less
than about 24 hours, less than about 5 hours, less than about 3
hours, or less than about 1 hour.
[0137] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the maximum AF episode duration is reduced to less
than about 20 hours, less than about 10 hours, or less than about 5
hours.
[0138] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the average AF episode duration is reduced to less than
about 24 hours, less than about 5 hours, less than about 3 hours,
or less than about 1 hour.
[0139] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours.
[0140] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour.
[0141] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours.
[0142] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0143] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0144] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0145] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0146] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0147] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0148] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0149] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0150] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0151] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0152] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0153] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0154] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0155] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0156] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0157] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0158] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0159] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0160] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of multiple ion
channel blocker selected from the group consisting of amiodarone,
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the reduced stroke rate is less
than the age-adjusted overall stroke rate.
[0161] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0162] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0163] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0164] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0165] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0166] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0167] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of multiple ion
channel blocker selected from the group consisting of amiodarone,
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0168] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0169] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0170] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
budiodarone, dronedarone, celivarone, AZD1305 or vernakalant
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0171] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the average AF episode duration is reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours, or less
than about 1 hour, and wherein the reduced stroke rate is less than
the age-adjusted overall stroke rate.
[0172] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0173] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0174] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate.
[0175] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0176] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, wherein
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0177] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0178] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0179] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0180] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0181] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0182] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the average AF episode duration is reduced to less
than about 24 hours, less than about 5 hours, less than about 3
hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0183] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the maximum AF episode duration is reduced to less
than about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0184] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the average AF episode duration is reduced to less than
about 24 hours, less than about 5 hours, less than about 3 hours,
or less than about 1 hour, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0185] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0186] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0187] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0188] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0189] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0190] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0191] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0192] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0193] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0194] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0195] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0196] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0197] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0198] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0199] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0200] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0201] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0202] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0203] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0204] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0205] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0206] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0207] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0208] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0209] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0210] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0211] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0212] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0213] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0214] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0215] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0216] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0217] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0218] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the average AF episode duration is reduced to less
than about 24 hours, less than about 5 hours, less than about 3
hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0219] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the maximum AF episode duration is reduced to less
than about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0220] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the average AF episode duration is reduced to less than
about 24 hours, less than about 5 hours, less than about 3 hours,
or less than about 1 hour, and wherein the patient was refractory
to one or more anti-arrhythmic drugs.
[0221] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0222] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0223] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0224] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0225] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0226] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0227] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0228] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0229] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0230] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0231] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0232] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0233] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0234] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0235] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0236] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0237] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0238] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0239] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0240] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0241] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0242] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of multiple ion
channel blocker selected from the group consisting of amiodarone,
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the reduced stroke rate is less
than the age-adjusted overall stroke rate, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0243] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0244] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0245] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0246] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0247] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0248] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0249] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0250] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0251] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the average AF episode duration is reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours, or less
than about 1 hour, and wherein the reduced stroke rate is less than
the age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0252] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0253] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0254] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0255] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, wherein
the reduced stroke rate is less than the age-adjusted overall
stroke rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0256] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0257] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0258] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0259] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0260] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0261] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the average AF episode duration is reduced to less
than about 24 hours, less than about 5 hours, less than about 3
hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0262] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of ximelagatran and
AZD0837, wherein the maximum AF episode duration is reduced to less
than about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0263] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the average AF episode duration is reduced to less than
about 24 hours, less than about 5 hours, less than about 3 hours,
or less than about 1 hour, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0264] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0265] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0266] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of ximelagatran and AZD0837,
wherein the maximum AF episode duration is reduced to less than
about 20 hours, less than about 10 hours, or less than about 5
hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0267] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0268] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0269] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0270] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0271] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0272] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0273] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0274] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0275] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0276] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0277] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0278] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0279] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0280] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0281] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0282] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of multiple
ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0283] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0284] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount budiodarone
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0285] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[0286] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0287] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0288] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone, dronedarone, celivarone, AZD1305 and vernakalant
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin.
[0289] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0290] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0291] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin.
[0292] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour.
[0293] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours.
[0294] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban.
[0295] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0296] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0297] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone, dronedarone, celivarone, AZD1305 and vernakalant
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban.
[0298] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the average AF episode duration is reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours, or less
than about 1 hour.
[0299] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours.
[0300] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban.
[0301] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0302] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0303] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0304] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0305] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0306] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0307] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0308] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0309] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AZD0837 or ximelagatran, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0310] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AZD0837 or ximelagatran, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0311] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AZD0837 or ximelagatran, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0312] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AZD0837 or ximelagatran, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0313] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837 or ximelagatran, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0314] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837 or ximelagatran, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0315] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0316] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0317] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0318] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0319] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0320] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0321] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0322] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0323] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0324] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0325] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0326] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0327] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0328] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0329] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0330] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0331] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0332] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0333] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0334] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0335] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0336] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0337] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0338] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0339] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0340] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0341] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0342] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0343] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0344] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0345] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AZD0837 or ximelagatran, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0346] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AZD0837 or ximelagatran, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0347] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AZD0837 or ximelagatran, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0348] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AZD0837 or ximelagatran, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0349] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837 or ximelagatran, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0350] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837 or ximelagatran, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0351] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0352] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0353] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0354] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0355] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0356] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0357] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0358] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0359] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0360] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0361] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0362] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0363] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0364] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0365] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0366] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0367] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0368] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0369] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin.
[0370] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0371] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0372] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin.
[0373] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0374] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0375] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin.
[0376] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour.
[0377] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours.
[0378] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban.
[0379] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0380] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of tecarfarin,
dabigatran etexilate, ximelagatran, AZD0837, apixaban and
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0381] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban.
[0382] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the average AF episode duration is reduced to less than about 24
hours, less than about 5 hours, less than about 3 hours, or less
than about 1 hour.
[0383] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of tecarfarin, dabigatran
etexilate, ximelagatran, AZD0837, apixaban and rivaroxaban, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours.
[0384] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban.
[0385] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0386] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0387] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0388] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0389] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0390] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0391] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0392] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0393] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0394] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0395] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0396] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0397] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0398] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0399] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0400] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0401] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0402] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0403] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0404] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0405] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0406] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0407] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0408] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0409] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0410] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0411] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour.
[0412] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0413] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour.
[0414] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0415] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0416] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0417] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0418] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0419] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0420] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0421] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0422] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0423] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0424] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0425] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0426] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0427] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0428] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0429] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0430] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0431] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0432] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0433] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0434] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0435] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0436] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0437] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0438] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0439] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0440] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0441] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0442] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0443] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0444] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0445] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0446] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0447] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0448] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0449] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0450] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0451] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0452] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of AC selected from the group consisting of AZD0837,
dabigatran etexilate, dabigatran, ximelagatran, melagatran,
argatroban, apixaban, rivaroxaban, YM466, betrixaban, edoxaban,
otamixaban, tecarfarin and warfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0453] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0454] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0455] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0456] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0457] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0458] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of dabigatran etexilate, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0459] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0460] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
dabigatran etexilate, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0461] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0462] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0463] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0464] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of ximelagatran or AZD0837, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0465] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0466] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
ximelagatran or AZD0837, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0467] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0468] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of ximelagatran or AZD0837, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0469] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0470] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of apixaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0471] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0472] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
apixaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0473] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0474] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0475] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0476] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of rivaroxaban, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0477] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0478] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
rivaroxaban, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0479] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0480] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0481] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the average AF episode duration is
reduced to less than about 24 hours, less than about 5 hours, less
than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0482] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce AF episode duration and an effective
amount of tecarfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0483] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the average AF episode duration is reduced to
less than about 24 hours, less than about 5 hours, less than about
3 hours, or less than about 1 hour, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0484] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
dronedarone, budiodarone, vernakalant, celivarone, and AZD1305
effective to reduce AF episode duration and an effective amount of
tecarfarin, wherein the maximum AF episode duration is reduced to
less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0485] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reversal of atrial remodeling is defined as a measured
increase in AFCL at the right atrial appendage or distal coronary
sinus of at least 6 milliseconds.
[0486] In yet another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0487] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce atrial fibrillation (AF) episode duration and
an effective amount of anticoagulant (AC) selected from the group
consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin.
[0488] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, comprising administering an amount of budiodarone effective
to reduce AF episode duration and an effective amount of AC
selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the maximum AF episode duration is
reduced to less than about 20 hours, less than about 10 hours, or
less than about 5 hours.
[0489] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0490] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0491] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0492] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0493] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0494] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour.
[0495] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours.
[0496] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0497] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0498] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0499] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0500] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour.
[0501] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours.
[0502] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate.
[0503] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0504] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours or less than about 5 hours, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0505] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate.
[0506] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate.
[0507] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours or less than about 1 hour,
and wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0508] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate.
[0509] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0510] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate.
[0511] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0512] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0513] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0514] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0515] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate.
[0516] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate.
[0517] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0518] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0519] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0520] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0521] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0522] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0523] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AZD0837, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0524] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0525] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0526] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0527] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0528] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours or less than about 1 hour, and
wherein the patient was refractory to one or more anti-arrhythmic
drugs.
[0529] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0530] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin.
[0531] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour.
[0532] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours.
[0533] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0534] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0535] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0536] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate.
[0537] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour.
[0538] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours.
[0539] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran.
[0540] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour.
[0541] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours.
[0542] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban.
[0543] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0544] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0545] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban.
[0546] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0547] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0548] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin.
[0549] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0550] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0551] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0552] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0553] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0554] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0555] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0556] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban, and wherein the patient was refractory to
one or more anti-arrhythmic drugs.
[0557] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0558] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0559] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0560] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0561] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0562] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0563] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the patient was refractory
to one or more anti-arrhythmic drugs.
[0564] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0565] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0566] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0567] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0568] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0569] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0570] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin.
[0571] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour.
[0572] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours.
[0573] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban.
[0574] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour.
[0575] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours.
[0576] A method for reversing atrial remodeling comprising
administering an amount of budiodarone effective to reduce AF
episode duration and an effective amount of AC that is dabigatran
etexilate.
[0577] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour.
[0578] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours.
[0579] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837.
[0580] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour.
[0581] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours.
[0582] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban.
[0583] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0584] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0585] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban.
[0586] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0587] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0588] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin.
[0589] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1
hour.
[0590] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours.
[0591] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0592] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0593] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0594] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0595] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0596] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the patient was refractory to one or
more anti-arrhythmic drugs.
[0597] A method for reversing atrial remodeling comprising
administering an amount of budiodarone effective to reduce AF
episode duration and an effective amount of AC that is dabigatran
etexilate, wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0598] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour, and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0599] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours, and wherein
the patient was refractory to one or more anti-arrhythmic
drugs.
[0600] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the patient was refractory to one
or more anti-arrhythmic drugs.
[0601] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
patient was refractory to one or more anti-arrhythmic drugs.
[0602] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the patient was refractory
to one or more anti-arrhythmic drugs.
[0603] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0604] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0605] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0606] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0607] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0608] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0609] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the patient was
refractory to one or more anti-arrhythmic drugs.
[0610] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the patient was refractory to one or more
anti-arrhythmic drugs.
[0611] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the patient
was refractory to one or more anti-arrhythmic drugs.
[0612] In one aspect, the invention provides methods for reducing
stroke rate comprising administering an amount of budiodarone
effective to reduce AF episode duration and an effective amount of
AC selected from the group consisting of AZD0837, dabigatran
etexilate, dabigatran, ximelagatran, melagatran, argatroban,
apixaban, rivaroxaban, YM466, betrixaban, edoxaban, otamixaban,
tecarfarin and warfarin, wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0613] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the effective amount of budiodarone is 600 mg
BID.
[0614] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0615] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0616] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0617] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0618] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0619] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0620] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0621] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0622] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0623] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the effective amount
of budiodarone is 400 mg BID or more preferably 600 mg BID.
[0624] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0625] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the effective amount
of budiodarone is 400 mg BID or more preferably 600 mg BID.
[0626] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0627] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the effective amount
of budiodarone is 400 mg BID or more preferably 600 mg BID.
[0628] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0629] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the effective amount
of budiodarone is 400 mg BID or more preferably 600 mg BID.
[0630] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours or less than about 5 hours, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the effective amount of budiodarone is 400 mg BID
or more preferably 600 mg BID.
[0631] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0632] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours or less than
about 5 hours, and wherein the reduced stroke rate is less than the
age-adjusted overall stroke rate, and wherein the effective amount
of budiodarone is 400 mg BID or more preferably 600 mg BID.
[0633] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours or less than about 1 hour,
and wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0634] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of dabigatran etexilate, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the reduced
stroke rate is less than the age-adjusted overall stroke rate, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0635] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
reduced stroke rate is less than the age-adjusted overall stroke
rate, and wherein the effective amount of budiodarone is 400 mg BID
or more preferably 600 mg BID.
[0636] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the reduced stroke rate is
less than the age-adjusted overall stroke rate, wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0637] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0638] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of apixaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0639] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0640] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of rivaroxaban, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0641] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the average AF episode
duration is reduced to less than about 24 hours, less than about 5
hours, less than about 3 hours, or less than about 1 hour, and
wherein the reduced stroke rate is less than the age-adjusted
overall stroke rate, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0642] In another aspect, the invention provides methods for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of tecarfarin, wherein the maximum AF episode
duration is reduced to less than about 20 hours, less than about 10
hours, or less than about 5 hours, and wherein the reduced stroke
rate is less than the age-adjusted overall stroke rate, and wherein
the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0643] In other aspects, the invention provides methods wherein the
patient was refractory to one or more anti-arrhythmic drugs prior
to treating with each above recited 400 mgBID or more preferably
600 mg BID dose of budiodarone.
[0644] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0645] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0646] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the effective amount of budiodarone is 400 mg BID
or more preferably 600 mg BID. In yet another aspect, the invention
provides methods for preventing atrial remodeling comprising
administering an amount of budiodarone effective to reduce AF
episode duration and an effective amount of AC selected from the
group consisting of AZD0837, dabigatran etexilate, dabigatran,
ximelagatran, melagatran, argatroban, apixaban, rivaroxaban, YM466,
betrixaban, edoxaban, otamixaban, tecarfarin and warfarin, wherein
the maximum AF episode duration is reduced to less than about 20
hours, less than about 10 hours, or less than about 5 hours, and
wherein the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0647] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0648] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0649] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0650] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0651] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours, and wherein
the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0652] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0653] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0654] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837 and ximelagatran, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0655] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0656] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0657] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0658] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0659] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0660] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0661] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0662] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0663] In yet another aspect, the invention provides methods for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0664] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0665] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the effective amount of budiodarone is 400 mg BID
or more preferably 600 mg BID.
[0666] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0667] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the effective amount of budiodarone is 400
mg BID or more preferably 600 mg BID.
[0668] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0669] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0670] A method for reversing atrial remodeling comprising
administering an amount of budiodarone effective to reduce AF
episode duration and an effective amount of AC that is dabigatran
etexilate, wherein the effective amount of budiodarone is 400 mg
BID or more preferably 600 mg BID.
[0671] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour, and wherein the effective amount of budiodarone is
400 mg BID or more preferably 600 mg BID.
[0672] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours, and wherein
the effective amount of budiodarone is 400 mg BID or more
preferably 600 mg BID.
[0673] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0674] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0675] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the effective amount of
budiodarone is 400 mg BID or more preferably 600 mg BID.
[0676] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0677] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0678] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0679] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0680] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0681] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0682] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the effective
amount of budiodarone is 400 mg BID or more preferably 600 mg
BID.
[0683] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the effective amount of budiodarone is 400 mg BID or
more preferably 600 mg BID.
[0684] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
effective amount of budiodarone is 400 mg BID or more preferably
600 mg BID.
[0685] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the reversal
of atrial remodeling is defined as a measured increase in AFCL at
the right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0686] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the average
AF episode duration is reduced to less than about 24 hours, less
than about 5 hours, less than about 3 hours, or less than about 1
hour, and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0687] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
AZD0837, dabigatran etexilate, dabigatran, ximelagatran,
melagatran, argatroban, apixaban, rivaroxaban, YM466, betrixaban,
edoxaban, otamixaban, tecarfarin and warfarin, wherein the maximum
AF episode duration is reduced to less than about 20 hours, less
than about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0688] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
and rivaroxaban, wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0689] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the average AF episode duration is reduced
to less than about 24 hours, less than about 5 hours, less than
about 3 hours, or less than about 1 hour, and wherein the reversal
of atrial remodeling is defined as a measured increase in AFCL at
the right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0690] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban, wherein the maximum AF episode duration is reduced
to less than about 20 hours, less than about 10 hours, or less than
about 5 hours, and wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0691] 315. A method for reversing atrial remodeling comprising
administering an amount of budiodarone effective to reduce AF
episode duration and an effective amount of AC that is dabigatran
etexilate, wherein the reversal of atrial remodeling is defined as
a measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0692] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
average AF episode duration is reduced to less than about 24 hours,
less than about 5 hours, less than about 3 hours, or less than
about 1 hour, and wherein the reversal of atrial remodeling is
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0693] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is dabigatran etexilate, wherein the
maximum AF episode duration is reduced to less than about 20 hours,
less than about 10 hours, or less than about 5 hours, and wherein
the reversal of atrial remodeling is defined as a measured increase
in AFCL at the right atrial appendage or distal coronary sinus of
at least 6 milliseconds.
[0694] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the reversal of atrial remodeling
is defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[0695] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the average AF episode duration
is reduced to less than about 24 hours, less than about 5 hours,
less than about 3 hours, or less than about 1 hour, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0696] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC selected from the group consisting of
ximelagatran and AZD0837, wherein the maximum AF episode duration
is reduced to less than about 20 hours, less than about 10 hours,
or less than about 5 hours, and wherein the reversal of atrial
remodeling is defined as a measured increase in AFCL at the right
atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0697] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0698] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0699] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is apixaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0700] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the reversal of
atrial remodeling is defined as a measured increase in AFCL at the
right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0701] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0702] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is rivaroxaban, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0703] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, and wherein the reversal
of atrial remodeling is defined as a measured increase in AFCL at
the right atrial appendage or distal coronary sinus of at least 6
milliseconds.
[0704] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the average AF
episode duration is reduced to less than about 24 hours, less than
about 5 hours, less than about 3 hours, or less than about 1 hour,
and wherein the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[0705] In another aspect, the invention provides methods for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration and an
effective amount of AC that is tecarfarin, wherein the maximum AF
episode duration is reduced to less than about 20 hours, less than
about 10 hours, or less than about 5 hours, and wherein the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0706] In yet other aspects, the invention provides for all of the
above methods in patients with severe heart failure.
[0707] The term "effective amount" for a direct thrombin inhibitor
(DTI) refers to an amount effective to provide adequate
anticoagulation according to the common coagulation tests activated
partial thromboplastin time (aPTT) and activated clotting time
(ACT). The aPTT is a measure of the intrinsic or "contact
activation" pathway and the common coagulation pathway. Under
common test conditions, clotting times below about 25 seconds or
above about 39 seconds are considered abnormal. The ACT is a test
of the intrinsic or common pathway of coagulation, using
diatomaceous earth as an activating agent to hasten coagulation of
whole blood, the time being measured.
[0708] Alternatively, for fixed or one-size-fits-most DTIs like
dabigatran etexilate and dabigatran, about 110 to 300 mg daily can
comprise an effective amount. For ximelagatran and melagatran,
about 40 to 120 mg daily can comprise an effective amount. For
AZD0837, about 100 to 500 mg daily can comprise an effective
amount. For argatroban, about 2 mcg/kg/min infused for 1 minute per
every 10 kg body mass, starting at 6 minutes for 50 kg patient can
comprise an effective amount.
[0709] For a Factor Xa inhibitor, the term refers to an amount
effective to reduce coagulation according to U.S. Pat. No.
7,220,553. Alternatively, for fixed or one-size-fits-most Xa
inhibitors like apixaban, about 2.5 to 20 mg daily can comprise an
effective amount. For rivaroxaban, about 5 to 60 mg daily can
comprise an effective amount. For betrixaban, about 20 to 120 mg
daily can comprise an effective amount. For edoxaban, about 15 to
120 mg daily can comprise an effective amount. For YM466, about 2
to 300 mg daily can comprise an effective amount. For otamixaban,
about 0.05 to 0.20 mg/kg bolus followed by infusions of about 0.050
to 0.180 mg/kg/h can comprise an effective amount.
[0710] For VKOR inhibitors, like tecarfarin and warfarin, an
effective amount refers to an amount of drug sufficient to maintain
an International Normalized Ratio (INR) between 2-3.
[0711] The term "International Normalized Ratio" or INR refers to
the ratio of a patient's prothrombin time to a normal (control)
sample, raised to the power of the International Sensitivity Index
(ISI) value for the analytical system used. The ISI value indicates
how a particular batch of tissue factor compares to an
internationally standardized sample, and is usually between 1.0 and
2.0. Prothrombin time is a measure of the extrinsic pathway of
coagulation, and it is used to determine the clotting tendency of
blood. Prothrombin time indirectly measures factors II, V, VII, X
and fibrinogen.
[0712] The terms "AF episode" refers to a period wherein the heart
in not in normal sinus rhythm (NSR) but is in atrial fibrillation.
The term "AF episode duration" refers to the length of time,
typically in hours, that an AF episode persists before reverting to
NSR. "Average episode duration" is the mean length of a patient's
AF episodes, typically in hours.
[0713] The term "refractory to one or more anti-arrhythmic drugs"
refers to the failure of a non-budiodarone anti-arrhythmic drug,
for example, amiodarone, sotolol, ibutilide, dofetilide,
flecainide, propafenone, dronedarone, vernakalant, celivarone,
AZ1305 and quinidine, to restore and or maintain NSR in an AF
patient.
[0714] The term "age-adjusted overall stroke rate" refers to the
annual, age-adjusted stroke rates as defined in Lloyd-Jones D, et
al., "Heart disease and stroke statistics--2009 update"
Circulation. 2009 Jan. 27; 119(3):480-6. According to Chart 5-2 of
page 65, for ages 65-74, the overall (annual) stroke rates for
white females, white males, black females and black makes are
0.56%, 0.76%, 0.56% and 0.72%, respectively. For ages 75-84, the
overall (annual) stroke rates for white females, white males, black
females and black makes are 1.24%, 1.25%, 1.25% and 0.84%,
respectively. For ages 85+, the overall (annual) stroke rates for
white females, white males, black females and black makes are
1.96%, 3.21%, 2.02% and 1.47%, respectively.
Exemplary Embodiments
[0715] I-1. In one embodiment, the invention provides a method for
reducing atrial fibrillation (AF) episode duration comprising
administering an amount of budiodarone effective to reduce AF
episode duration.
[0716] I-2. In a further embodiment of embodiment I-1, the average
AF episode duration is reduced to less than about 24 hours.
[0717] I-3. In a further embodiment of embodiment I-1, the average
AF episode duration is reduced to less than about 5 hours.
[0718] I-4. In a further embodiment of embodiment I-1, the average
AF episode duration is reduced to less than about 3 hours.
[0719] I-5. In a further embodiment of embodiment I-1, the average
AF episode duration is reduced to less than about 1 hour.
[0720] I-6. In a further embodiment of embodiment I-1, the maximum
AF episode duration is reduced to less than about 20 hours.
[0721] I-7. In a further embodiment of embodiment I-1, the maximum
AF episode duration is reduced to less than about 10 hours.
[0722] I-8. In a further embodiment of embodiment I-1, the maximum
AF episode duration is reduced to less than about 5 hours.
[0723] I-9. In one embodiment, the invention provides a method for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0724] I-10. In a further embodiment of embodiment I-9, the average
AF episode duration is reduced to less than about 24 hours.
[0725] I-11. In a further embodiment of embodiment I-9, the average
AF episode duration is reduced to less than about 5 hours.
[0726] I-12. In a further embodiment of embodiment I-9, the average
AF episode duration is reduced to less than 3 hours.
[0727] I-13. In a further embodiment of embodiment I-9, the average
AF episode duration is reduced to less than about 1 hour.
[0728] I-14. In a further embodiment of embodiment I-9, the maximum
AF episode duration is reduced to less than about 20 hours.
[0729] I-15. In a further embodiment of embodiment I-9, the maximum
AF episode duration is reduced to less than about 10 hours.
[0730] I-16. In a further embodiment of embodiment I-9, the maximum
AF episode duration is reduced to less than about 5 hours.
[0731] I-17. In one embodiment, the invention provides a method for
increasing time in normal sinus rhythm (NSR) comprising
administering an amount of budiodarone effective to reduce AF
episode duration.
[0732] I-18. In a further embodiment of embodiment I-17, the
average AF episode duration is reduced to less than about 24
hours.
[0733] I-19. In a further embodiment of embodiment I-17, the
average AF episode duration is reduced to less than about 5
hours.
[0734] I-20. In a further embodiment of embodiment I-17, the
average AF episode duration is reduced to less than 3 hours.
[0735] I-21. In a further embodiment of embodiment I-17, the
average AF episode duration is reduced to less than about 1
hour.
[0736] I-22. In a further embodiment of embodiment I-17, the
maximum AF episode duration is reduced to less than about 20
hours.
[0737] I-23. In a further embodiment of embodiment I-17, the
maximum AF episode duration is reduced to less than about 10
hours.
[0738] I-24. In a further embodiment of embodiment I-17, the
maximum AF episode duration is reduced to less than about 5
hours.
[0739] I-25. In one embodiment, the invention provides a method for
preventing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0740] I-26. In a further embodiment of embodiment I-25, the
average AF episode duration is reduced to less than about 24
hours.
[0741] I-27. In a further embodiment of embodiment I-25, the
average AF episode duration is reduced to less than about 5
hours.
[0742] I-28. In a further embodiment of embodiment I-25, the
average AF episode duration is reduced to less than 3 hours.
[0743] I-29. In a further embodiment of embodiment I-25, the
average AF episode duration is reduced to less than about 1
hour.
[0744] I-30. In a further embodiment of embodiment I-25, the
maximum AF episode duration is reduced to less than about 20
hours.
[0745] I-31. In a further embodiment of embodiment I-25, the
maximum AF episode duration is reduced to less than about 10
hours.
[0746] I-32. In a further embodiment of embodiment I-25, the
maximum AF episode duration is reduced to less than about 5
hours.
[0747] I-33. In one embodiment, the invention provides a method for
reversing atrial remodeling comprising administering an amount of
budiodarone effective to reduce AF episode duration.
[0748] I-34. In a further embodiment of embodiment I-33, the
average AF episode duration is reduced to less than about 24
hours.
[0749] I-35. In a further embodiment of embodiment I-33, the
average AF episode duration is reduced to less than about 5
hours.
[0750] I-36. In a further embodiment of embodiment I-33, the
average AF episode duration is reduced to less than 3 hours.
[0751] I-37. In a further embodiment of embodiment I-33, the
average AF episode duration is reduced to less than about 1
hour.
[0752] I-38. In a further embodiment of embodiment I-33, the
maximum AF episode duration is reduced to less than about 20
hours.
[0753] I-39. In a further embodiment of embodiment I-33, the
maximum AF episode duration is reduced to less than about 10
hours.
[0754] I-40. In a further embodiment of embodiment I-33, the
maximum AF episode duration is reduced to less than about 5
hours.
[0755] I-41. In a further embodiment of embodiment I-33, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0756] I-42. In a further embodiment of embodiment I-34, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0757] I-43. In a further embodiment of embodiment I-35, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0758] I-44. In a further embodiment of embodiment I-36, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0759] I-45. In a further embodiment of embodiment I-37, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0760] I-46. In a further embodiment of embodiment I-38, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0761] I-47. In a further embodiment of embodiment I-39, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0762] I-48. In a further embodiment of embodiment I-40, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[0763] I-49. In a further embodiment of embodiment I-1, the patient
was refractory to one or more anti-arrhythmic drugs.
[0764] I-50. In a further embodiment of embodiment I-9, the patient
was refractory to one or more anti-arrhythmic drugs.
[0765] I-51. In a further embodiment of embodiment I-17, the
patient was refractory to one or more anti-arrhythmic drugs.
[0766] I-52. In a further embodiment of embodiment I-25, the
patient was refractory to one or more anti-arrhythmic drugs.
[0767] I-53. In a further embodiment of embodiment I-33, the
patient was refractory to one or more anti-arrhythmic drugs.
[0768] I-54. In a further embodiment of embodiment I-41, the
patient was refractory to one or more anti-arrhythmic drugs.
[0769] I-55. In a further embodiment of embodiment I-1, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0770] I-56. In a further embodiment of embodiment I-55, the
effective amount of budiodarone is 600 mg BID.
[0771] I-57. In a further embodiment of embodiment I-9, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0772] I-58. In a further embodiment of embodiment I-57, the
effective amount of budiodarone is 600 mg BID.
[0773] I-59. In a further embodiment of embodiment I-17, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0774] I-60. In a further embodiment of embodiment I-59, the
effective amount of budiodarone is 600 mg BID.
[0775] I-61. In a further embodiment of embodiment I-25, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0776] I-62. In a further embodiment of embodiment I-61, the
effective amount of budiodarone is 600 mg BID.
[0777] I-63. In a further embodiment of embodiment I-33, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0778] I-64. In a further embodiment of embodiment I-64, the
effective amount of budiodarone is 600 mg BID.
[0779] I-65. In a further embodiment of embodiment I-41, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0780] I-66. In a further embodiment of embodiment I-65, the
effective amount of budiodarone is 600 mg BID.
[0781] II-1. In one embodiment, the invention provides a method for
reducing stroke rate comprising administering an amount of
budiodarone effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[0782] II-2. In a further embodiment of embodiment II-1, the
average AF episode duration is reduced to less than about 24
hours.
[0783] II-3. In a further embodiment of embodiment II-1, the
average AF episode duration is reduced to less than about 5
hours.
[0784] II-4. In a further embodiment of embodiment II-1, the
average AF episode duration is reduced to less than 3 hours.
[0785] II-5. In a further embodiment of embodiment II-1, the
average AF episode duration is reduced to less than about 1
hour.
[0786] II-6. In a further embodiment of embodiment II-1, the
maximum AF episode duration is reduced to less than about 20
hours.
[0787] II-7. In a further embodiment of embodiment II-1, the
maximum AF episode duration is reduced to less than about 10
hours.
[0788] II-8. In a further embodiment of embodiment II-1, the
maximum AF episode duration is reduced to less than about 5
hours.
[0789] II-9. In a further embodiment of embodiment II-1, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0790] II-10. In a further embodiment of embodiment II-2, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0791] II-11. In a further embodiment of embodiment II-3, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0792] II-12. In a further embodiment of embodiment II-4, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0793] II-13. In a further embodiment of embodiment II-5, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0794] II-14. In a further embodiment of embodiment II-6, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0795] II-15. In a further embodiment of embodiment II-7, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0796] II-16. In a further embodiment of embodiment II-8, the AC is
tecarfarin, dabigatran etexilate, ximelagatran, AZD0837, apixaban
or rivaroxaban.
[0797] II-17. In a further embodiment of embodiment II-10, the AC
is dabigatran etexilate.
[0798] II-18. In a further embodiment of embodiment II-11, the AC
is dabigatran etexilate.
[0799] II-19. In a further embodiment of embodiment II-12, the AC
is dabigatran etexilate.
[0800] II-20. In a further embodiment of embodiment II-13, the AC
is dabigatran etexilate.
[0801] II-21. In a further embodiment of embodiment II-14, the AC
is dabigatran etexilate.
[0802] II-22. In a further embodiment of embodiment II-15, the AC
is dabigatran etexilate.
[0803] II-23. In a further embodiment of embodiment II-16, the AC
is dabigatran etexilate.
[0804] II-24. In a further embodiment of embodiment II-10, the AC
is ximelagatran or AZD0837.
[0805] II-25. In a further embodiment of embodiment II-11, the AC
is ximelagatran or AZD0837.
[0806] II-26. In a further embodiment of embodiment II-12, the AC
is ximelagatran or AZD0837.
[0807] II-27. In a further embodiment of embodiment II-13, the AC
is ximelagatran or AZD0837.
[0808] II-28. In a further embodiment of embodiment II-14, the AC
is ximelagatran or AZD0837.
[0809] II-29. In a further embodiment of embodiment II-15, the AC
is ximelagatran or AZD0837.
[0810] II-30. In a further embodiment of embodiment II-16, the AC
is ximelagatran or AZD0837.
[0811] II-31. In a further embodiment of embodiment II-10, the AC
is apixaban.
[0812] II-32. In a further embodiment of embodiment II-11, the AC
is apixaban.
[0813] II-33. In a further embodiment of embodiment II-12, the AC
is apixaban.
[0814] II-34. In a further embodiment of embodiment II-13, the AC
is apixaban.
[0815] II-35. In a further embodiment of embodiment II-14, the AC
is apixaban.
[0816] II-36. In a further embodiment of embodiment II-15, the AC
is apixaban.
[0817] II-37. In a further embodiment of embodiment II-16, the AC
is apixaban.
[0818] II-38. In a further embodiment of embodiment II-10, the AC
is rivaroxaban.
[0819] II-39. In a further embodiment of embodiment II-11, the AC
is rivaroxaban.
[0820] II-40. In a further embodiment of embodiment II-12, the AC
is rivaroxaban.
[0821] II-41. In a further embodiment of embodiment II-13, the AC
is rivaroxaban.
[0822] II-42. In a further embodiment of embodiment II-14, the AC
is rivaroxaban.
[0823] II-43. In a further embodiment of embodiment II-15, the AC
is rivaroxaban.
[0824] II-44. In a further embodiment of embodiment II-16, the AC
is rivaroxaban.
[0825] II-45. In a further embodiment of embodiment II-10, the AC
is tecarfarin.
[0826] II-46. In a further embodiment of embodiment II-11, the AC
is tecarfarin.
[0827] II-47. In a further embodiment of embodiment II-12, the AC
is tecarfarin.
[0828] II-48. In a further embodiment of embodiment II-13, the AC
is tecarfarin.
[0829] II-49. In a further embodiment of embodiment II-14, the AC
is tecarfarin.
[0830] II-50. In a further embodiment of embodiment II-15, the AC
is tecarfarin.
[0831] II-51. In a further embodiment of embodiment II-16, the AC
is tecarfarin.
[0832] II-52. In a further embodiment of embodiment II-1, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0833] II-53. In a further embodiment of embodiment II-10, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0834] II-54. In a further embodiment of embodiment II-11, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0835] II-55. In a further embodiment of embodiment II-12, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0836] II-56. In a further embodiment of embodiment II-13, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0837] II-57. In a further embodiment of embodiment II-14, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0838] II-58. In a further embodiment of embodiment II-15, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0839] II-59. In a further embodiment of embodiment II-16, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0840] II-60. In a further embodiment of embodiment II-17, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0841] II-61. In a further embodiment of embodiment II-18, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0842] II-62. In a further embodiment of embodiment II-19, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0843] II-63. In a further embodiment of embodiments II-20-II-22,
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0844] II-64. In a further embodiment of embodiment II-23, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0845] II-65. In a further embodiment of embodiment II-24, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0846] II-66. In a further embodiment of embodiment II-25, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0847] II-67. In a further embodiment of embodiment II-26, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0848] II-68. In a further embodiment of embodiments II-27-II-29,
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0849] II-69. In a further embodiment of embodiment II-30, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0850] II-70. In a further embodiment of embodiment II-31, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0851] II-71. In a further embodiment of embodiment II-32, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0852] II-72. In a further embodiment of embodiment II-33, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0853] II-73. In a further embodiment of embodiments II-34-II-36,
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0854] II-74. In a further embodiment of embodiment II-37, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0855] II-75. In a further embodiment of embodiment II-38, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0856] II-76. In a further embodiment of embodiment II-39, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0857] II-77. In a further embodiment of embodiment II-40, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0858] II-78. In a further embodiment of embodiments II-41-II-43,
the reduced stroke rate is less than the age-adjusted overall
stroke rate.
[0859] II-79. In a further embodiment of embodiment II-44, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0860] II-80. In a further embodiment of embodiment II-45, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0861] II-81. In a further embodiment of embodiment II-46, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0862] II-82. In a further embodiment of embodiment II-47, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0863] II-83. In a further embodiment of embodiment II-48, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0864] II-84. In a further embodiment of embodiment II-51, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[0865] II-85. In a further embodiment of embodiment II-1, the
patient was refractory to one or more anti-arrhythmic drugs.
[0866] II-86. In a further embodiment of any of embodiments
II-2-II-5, the patient was refractory to one or more
anti-arrhythmic drugs.
[0867] II-87. In a further embodiment of any of embodiments
II-6-II-9, the patient was refractory to one or more
anti-arrhythmic drugs.
[0868] II-88. In a further embodiment of any of embodiments
II-10-II-13, the patient was refractory to one or more
anti-arrhythmic drugs.
[0869] II-89. In a further embodiment of any of embodiments
II-14-II-16, the patient was refractory to one or more
anti-arrhythmic drugs.
[0870] II-90. In a further embodiment of any of embodiments
II-17-II-20, the patient was refractory to one or more
anti-arrhythmic drugs.
[0871] II-91. In a further embodiment of any of embodiments
II-21-II-23, the patient was refractory to one or more
anti-arrhythmic drugs.
[0872] II-92. In a further embodiment of any of embodiments
II-24-II-27, the patient was refractory to one or more
anti-arrhythmic drugs.
[0873] II-93. In a further embodiment of any of embodiments
II-28-II-30, the patient was refractory to one or more
anti-arrhythmic drugs.
[0874] II-94. In a further embodiment of any of embodiments
II-31-II-34, the patient was refractory to one or more
anti-arrhythmic drugs.
[0875] II-95. In a further embodiment of any of embodiments
II-35-II-37, the patient was refractory to one or more
anti-arrhythmic drugs.
[0876] II-96. In a further embodiment of any of embodiments
II-38-II-41, the patient was refractory to one or more
anti-arrhythmic drugs.
[0877] II-97. In a further embodiment of any of embodiments
II-42-II-44, the patient was refractory to one or more
anti-arrhythmic drugs.
[0878] II-98. In a further embodiment of any of embodiments
II-45-II-48, the patient was refractory to one or more
anti-arrhythmic drugs.
[0879] II-99. In a further embodiment of any of embodiments
II-49-II-51, the patient was refractory to one or more
anti-arrhythmic drugs.
[0880] II-100. In one embodiment, the invention provides a method
for preventing atrial remodeling comprising administering an amount
of budiodarone effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[0881] II-101. In a further embodiment of embodiment II-100, the
average AF episode duration is reduced to less than about 24
hours.
[0882] II-102. In a further embodiment of embodiment II-100, the
average AF episode duration is reduced to less than about 5
hours.
[0883] II-103. In a further embodiment of embodiment II-100, the
average AF episode duration is reduced to less than 3 hours.
[0884] II-104. In a further embodiment of embodiment II-100, the
average AF episode duration is reduced to less than about 1
hour.
[0885] II-105. In a further embodiment of embodiment II-100, the
maximum AF episode duration is reduced to less than about 20
hours.
[0886] II-106. In a further embodiment of embodiment II-100, the
maximum AF episode duration is reduced to less than about 10
hours.
[0887] II-107. In a further embodiment of embodiment II-100, the
maximum AF episode duration is reduced to less than about 5
hours.
[0888] II-108. In a further embodiment of embodiment II-100, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[0889] II-109. In a further embodiment of any of embodiments
II-101-II-104, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[0890] II-110. In a further embodiment of any of embodiments
II-105-II-107, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[0891] II-111. In a further embodiment of embodiment II-107, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[0892] II-112. In a further embodiment of embodiment II-100, the AC
is dabigatran etexilate.
[0893] II-113. In a further embodiment of any of embodiments
II-101-II-104, the AC is dabigatran etexilate.
[0894] II-114. In a further embodiment of any of embodiments
II-105-II-107, the AC is dabigatran etexilate.
[0895] II-115. In a further embodiment of embodiment II-107, the AC
is dabigatran etexilate.
[0896] II-116. In a further embodiment of embodiment II-100, the AC
is ximelagatran or AZD0837.
[0897] II-117. In a further embodiment of any of embodiments
II-101-II-104, the AC is ximelagatran or AZD0837.
[0898] II-118. In a further embodiment of any of embodiments
II-105-II-107, the AC is ximelagatran or AZD0837.
[0899] II-119. In a further embodiment of embodiment II-107, the AC
is ximelagatran or AZD0837.
[0900] II-120. In a further embodiment of embodiment II-100, the AC
is apixaban.
[0901] II-121. In a further embodiment of any of embodiments
II-101-II-104, the AC is apixaban.
[0902] II-122. In a further embodiment of any of embodiments
II-105-II-107, the AC is apixaban.
[0903] II-123. In a further embodiment of embodiment II-107, the AC
is apixaban.
[0904] II-124. In a further embodiment of embodiment II-100, the AC
is rivaroxaban.
[0905] II-125. In a further embodiment of any of embodiments
II-101-II-104, the AC is rivaroxaban.
[0906] II-126. In a further embodiment of any of embodiments
II-105-II-107, the AC is rivaroxaban.
[0907] II-127. In a further embodiment of embodiment II-107, the AC
is rivaroxaban.
[0908] II-128. In a further embodiment of embodiment II-100, the AC
is tecarfarin.
[0909] II-129. In a further embodiment of any of embodiments
II-101-II-104, the AC is tecarfarin.
[0910] II-130. In a further embodiment of any of embodiments
II-105-II-107, the AC is tecarfarin.
[0911] II-131. In a further embodiment of embodiment II-107, the AC
is tecarfarin.
[0912] II-132. In a further embodiment of embodiment II-100, the
patient was refractory to one or more anti-arrhythmic drugs.
[0913] II-133. In a further embodiment of any of embodiments
II-101-II-104, the patient was refractory to one or more
anti-arrhythmic drugs.
[0914] II-134. In a further embodiment of any of embodiments
II-105-II-107, the patient was refractory to one or more
anti-arrhythmic drugs.
[0915] II-135. In a further embodiment of embodiment II-107, the
patient was refractory to one or more anti-arrhythmic drugs.
[0916] II-136. In a further embodiment of embodiment II-108, the
patient was refractory to one or more anti-arrhythmic drugs.
[0917] II-137. In a further embodiment of embodiment II-109, the
patient was refractory to one or more anti-arrhythmic drugs.
[0918] II-138. In a further embodiment of embodiment II-110, the
patient was refractory to one or more anti-arrhythmic drugs.
[0919] II-139. In a further embodiment of embodiment II-111, the
patient was refractory to one or more anti-arrhythmic drugs.
[0920] II-140. In a further embodiment of embodiment II-113, the
patient was refractory to one or more anti-arrhythmic drugs.
[0921] II-141. In a further embodiment of embodiment II-114, the
patient was refractory to one or more anti-arrhythmic drugs.
[0922] II-142. In a further embodiment of embodiment II-117, the
patient was refractory to one or more anti-arrhythmic drugs.
[0923] II-143. In a further embodiment of embodiment II-118, the
patient was refractory to one or more anti-arrhythmic drugs.
[0924] II-144. In a further embodiment of embodiment II-121, the
patient was refractory to one or more anti-arrhythmic drugs.
[0925] II-145. In a further embodiment of embodiment II-122, the
patient was refractory to one or more anti-arrhythmic drugs.
[0926] II-146. In a further embodiment of embodiment II-125, the
patient was refractory to one or more anti-arrhythmic drugs.
[0927] II-147. In a further embodiment of embodiment II-126, the
patient was refractory to one or more anti-arrhythmic drugs.
[0928] II-148. In a further embodiment of embodiment II-129, the
patient was refractory to one or more anti-arrhythmic drugs.
[0929] II-149. In a further embodiment of embodiment II-130, the
patient was refractory to one or more anti-arrhythmic drugs.
[0930] II-150. In one embodiment, the invention provides a method
for reversing atrial remodeling comprising administering an amount
of budiodarone effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[0931] II-151. In a further embodiment of embodiment II-150, the
average AF episode duration is reduced to less than about 24
hours.
[0932] II-152. In a further embodiment of embodiment II-150, the
average AF episode duration is reduced to less than about 5
hours.
[0933] II-153. In a further embodiment of embodiment II-150, the
average AF episode duration is reduced to less than 3 hours.
[0934] II-154. In a further embodiment of embodiment II-150, the
average AF episode duration is reduced to less than about 1
hour.
[0935] II-155. In a further embodiment of embodiment II-150, the
maximum AF episode duration is reduced to less than about 20
hours.
[0936] II-156. In a further embodiment of embodiment II-150, the
maximum AF episode duration is reduced to less than about 10
hours.
[0937] II-157. In a further embodiment of embodiment II-150, the
maximum AF episode duration is reduced to less than about 5
hours.
[0938] II-158. In a further embodiment of embodiment II-150, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[0939] II-159. In a further embodiment of any of embodiments
II-151-II-154, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[0940] II-160. In a further embodiment of any of embodiments
II-154-II-157, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[0941] II-161. In a further embodiment of embodiment II-157, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[0942] II-162. In a further embodiment of embodiment II-150, the AC
is dabigatran etexilate.
[0943] II-163. In a further embodiment of any of embodiments
II-151-II-154, the AC is dabigatran etexilate.
[0944] II-164. In a further embodiment of any of embodiments
II-155-II-157, the AC is dabigatran etexilate.
[0945] II-165. In a further embodiment of embodiment II-157, the AC
is dabigatran etexilate.
[0946] II-166. In a further embodiment of embodiment II-150, the AC
is ximelagatran or AZD0837.
[0947] II-167. In a further embodiment of any of embodiments
II-151-II-154, the AC is ximelagatran or AZD0837.
[0948] II-168. In a further embodiment of any of embodiments
II-155-II-157, the AC is ximelagatran or AZD0837.
[0949] II-169. In a further embodiment of embodiment II-157, the AC
is ximelagatran or AZD0837.
[0950] II-170. In a further embodiment of embodiment II-150, the AC
is apixaban.
[0951] II-171. In a further embodiment of any of embodiments
II-151-II-154, the AC is apixaban.
[0952] II-172. In a further embodiment of any of embodiments
II-155-II-157, the AC is apixaban.
[0953] II-173. In a further embodiment of embodiment II-157, the AC
is apixaban.
[0954] II-174. In a further embodiment of embodiment II-150, the AC
is rivaroxaban.
[0955] II-175. In a further embodiment of any of embodiments
II-151-154, the AC is rivaroxaban.
[0956] II-176. In a further embodiment of any of embodiments
II-155-II-157, the AC is rivaroxaban.
[0957] II-177. In a further embodiment of embodiment II-157, the AC
is rivaroxaban.
[0958] II-178. In a further embodiment of embodiment II-150, the AC
is tecarfarin.
[0959] II-179. In a further embodiment of any of embodiments
II-151-II-154, the AC is tecarfarin.
[0960] II-180. In a further embodiment of any of embodiments
II-155-II-157, the AC is tecarfarin.
[0961] II-181. In a further embodiment of embodiment II-157, the AC
is tecarfarin.
[0962] II-182. In a further embodiment of embodiment II-150, the
patient was refractory to one or more anti-arrhythmic drugs.
[0963] II-183. In a further embodiment of any of embodiments
II-151-II-154, the patient was refractory to one or more
anti-arrhythmic drugs.
[0964] II-184. In a further embodiment of any of embodiments
II-155-II-157, the patient was refractory to one or more
anti-arrhythmic drugs.
[0965] II-185. In a further embodiment of embodiment II-157, the
patient was refractory to one or more anti-arrhythmic drugs.
[0966] II-186. In a further embodiment of embodiment II-158, the
patient was refractory to one or more anti-arrhythmic drugs.
[0967] II-187. In a further embodiment of embodiment II-159, the
patient was refractory to one or more anti-arrhythmic drugs.
[0968] II-188. In a further embodiment of embodiment II-160, the
patient was refractory to one or more anti-arrhythmic drugs.
[0969] II-189. In a further embodiment of any of embodiments
II-161-II-163, the patient was refractory to one or more
anti-arrhythmic drugs.
[0970] II-190. In a further embodiment of any of embodiments
II-164-II-167, the patient was refractory to one or more
anti-arrhythmic drugs.
[0971] II-191. In a further embodiment of embodiment II-167, the
patient was refractory to one or more anti-arrhythmic drugs.
[0972] II-192. In a further embodiment of embodiment II-168, the
patient was refractory to one or more anti-arrhythmic drugs.
[0973] II-193. In a further embodiment of any of embodiments
II-169-II-170, the patient was refractory to one or more
anti-arrhythmic drugs.
[0974] II-194. In a further embodiment of embodiment II-171, the
patient was refractory to one or more anti-arrhythmic drugs.
[0975] II-195. In a further embodiment of any of embodiments
II-172-II-174, the patient was refractory to one or more
anti-arrhythmic drugs.
[0976] II-196. In a further embodiment of embodiment II-175, the
patient was refractory to one or more anti-arrhythmic drugs.
[0977] II-197. In a further embodiment of any of embodiments
II-176-II-178, the patient was refractory to one or more
anti-arrhythmic drugs.
[0978] II-198. In a further embodiment of embodiment II-179, the
patient was refractory to one or more anti-arrhythmic drugs.
[0979] II-199. In a further embodiment of embodiment II-180, the
patient was refractory to one or more anti-arrhythmic drugs.
[0980] II-200. In a further embodiment of embodiment II-1, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0981] II-201. In a further embodiment of embodiment II-2, the
effective amount of budiodarone is 600 mg BID.
[0982] II-202. In a further embodiment of embodiment II-3, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0983] II-203. In a further embodiment of embodiment II-4, the
effective amount of budiodarone is 600 mg BID.
[0984] II-204. In a further embodiment of embodiment II-5, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0985] II-205. In a further embodiment of embodiment II-6, the
effective amount of budiodarone is 600 mg BID.
[0986] II-206. In a further embodiment of embodiment II-7, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0987] II-207. In a further embodiment of embodiment II-8, the
effective amount of budiodarone is 600 mg BID.
[0988] II-208. In a further embodiment of embodiment II-9, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0989] II-209. In a further embodiment of any of embodiments
II-10-II-12, the effective amount of budiodarone is 600 mg BID.
[0990] II-210. In a further embodiment of any of embodiments
II-13-II-15, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[0991] II-211. In a further embodiment of embodiment II-16, the
effective amount of budiodarone is 600 mg BID.
[0992] II-212. In a further embodiment of any of embodiments
II-17-II-19, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[0993] II-213. In a further embodiment of any of embodiments
II-20-II-22, the effective amount of budiodarone is 600 mg BID.
[0994] II-214. In a further embodiment of embodiment II-23, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[0995] II-215. In a further embodiment of any of embodiments
II-24-II-26, the effective amount of budiodarone is 600 mg BID.
[0996] II-216. In a further embodiment of any of embodiments
II-27-II-29, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[0997] II-217. In a further embodiment of embodiment II-30, the
effective amount of budiodarone is 600 mg BID.
[0998] II-218. In a further embodiment of any of embodiments
II-31-II-33, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[0999] II-219. In a further embodiment of any of embodiments
II-34-II-36, the effective amount of budiodarone is 600 mg BID.
[1000] II-220. In a further embodiment of embodiment II-37, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1001] II-221. In a further embodiment of any of embodiments
II-38-II-40, the effective amount of budiodarone is 600 mg BID.
[1002] II-222. In a further embodiment of any of embodiments
II-41-II-43, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[1003] II-223. In a further embodiment of embodiment II-44, the
effective amount of budiodarone is 600 mg BID.
[1004] II-224. In a further embodiment of any of embodiments
II-45-II-47, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[1005] II-225. In a further embodiment of any of embodiments
II-48-II-50, the effective amount of budiodarone is 600 mg BID.
[1006] II-226. In a further embodiment of embodiment II-51, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1007] II-227. In a further embodiment of embodiment II-52, the
effective amount of budiodarone is 600 mg BID.
[1008] II-228. In a further embodiment of any of embodiments
II-53-II-55, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[1009] II-229. In a further embodiment of any of embodiments
II-56-II-58, the effective amount of budiodarone is 600 mg BID.
[1010] II-230. In a further embodiment of embodiment II-59, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1011] II-231. In a further embodiment of any of embodiments
II-60-II-62, the effective amount of budiodarone is 600 mg BID.
[1012] II-232. In a further embodiment of embodiment II-63, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1013] II-233. In a further embodiment of embodiment II-64, the
effective amount of budiodarone is 600 mg BID.
[1014] II-234. In a further embodiment of any of embodiments
II-65-II-67, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[1015] II-235. In a further embodiment of embodiment II-68, the
effective amount of budiodarone is 600 mg BID.
[1016] II-236. In a further embodiment of embodiment II-69, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1017] II-237. In a further embodiment of any of embodiments
II-70-II-72, the effective amount of budiodarone is 600 mg BID.
[1018] II-238. In a further embodiment of embodiment II-73, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1019] II-239. In a further embodiment of embodiment II-74, the
effective amount of budiodarone is 600 mg BID.
[1020] II-240. In a further embodiment of any of embodiments
II-75-II-77, the effective amount of budiodarone is 400 mg BID or
600 mg BID.
[1021] II-241. In a further embodiment of embodiment II-78, the
effective amount of budiodarone is 600 mg BID.
[1022] II-242. In a further embodiment of embodiment II-79, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1023] II-243. In a further embodiment of any of embodiments
II-80-II-82, the effective amount of budiodarone is 600 mg BID.
[1024] II-244. In a further embodiment of embodiment II-83, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1025] II-245. In a further embodiment of embodiment II-84, the
effective amount of budiodarone is 600 mg BID.
[1026] II-246. In a further embodiment of embodiment II-100, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1027] II-247. In a further embodiment of embodiment II-101, the
effective amount of budiodarone is 600 mg BID.
[1028] II-248. In a further embodiment of embodiment II-102, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1029] II-249. In a further embodiment of embodiment II-103, the
effective amount of budiodarone is 600 mg BID.
[1030] II-250. In a further embodiment of embodiment II-104, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1031] II-251. In a further embodiment of embodiment II-105, the
effective amount of budiodarone is 600 mg BID.
[1032] II-252. In a further embodiment of embodiment II-106, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1033] II-253. In a further embodiment of embodiment II-107, the
effective amount of budiodarone is 600 mg BID.
[1034] II-254. In a further embodiment of embodiment II-109, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1035] II-255. In a further embodiment of embodiment II-110, the
effective amount of budiodarone is 600 mg BID.
[1036] II-256. In a further embodiment of embodiment II-111, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1037] II-257. In a further embodiment of embodiment II-112, the
effective amount of budiodarone is 600 mg BID.
[1038] II-258. In a further embodiment of embodiment II-113, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1039] II-259. In a further embodiment of embodiment II-114, the
effective amount of budiodarone is 600 mg BID.
[1040] II-260. In a further embodiment of embodiment II-115, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1041] II-261. In a further embodiment of embodiment II-116, the
effective amount of budiodarone is 600 mg BID.
[1042] II-262. In a further embodiment of embodiment II-117, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1043] II-263. In a further embodiment of embodiment II-118, the
effective amount of budiodarone is 600 mg BID.
[1044] II-264. In a further embodiment of embodiment II-119, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1045] II-265. In a further embodiment of embodiment II-120, the
effective amount of budiodarone is 600 mg BID.
[1046] II-266. In a further embodiment of embodiment II-121, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1047] II-267. In a further embodiment of embodiment II-122, the
effective amount of budiodarone is 600 mg BID.
[1048] II-268. In a further embodiment of embodiment II-123, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1049] II-269. In a further embodiment of embodiment II-124, the
effective amount of budiodarone is 600 mg BID.
[1050] II-270. In a further embodiment of embodiment II-125, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1051] II-271. In a further embodiment of embodiment II-126, the
effective amount of budiodarone is 600 mg BID.
[1052] II-272. In a further embodiment of embodiment II-127, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1053] II-273. In a further embodiment of embodiment II-128, the
effective amount of budiodarone is 600 mg BID.
[1054] II-274. In a further embodiment of embodiment II-129, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1055] II-275. In a further embodiment of embodiment II-130, the
effective amount of budiodarone is 600 mg BID.
[1056] II-276. In a further embodiment of embodiment II-131, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1057] II-277. In a further embodiment of embodiment II-150, the
effective amount of budiodarone is 600 mg BID.
[1058] II-278. In a further embodiment of embodiment II-151, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1059] II-279. In a further embodiment of embodiment II-152, the
effective amount of budiodarone is 600 mg BID.
[1060] III-280. In a further embodiment of embodiment II-153, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1061] II-281. In a further embodiment of embodiment II-154, the
effective amount of budiodarone is 600 mg BID.
[1062] II-282. In a further embodiment of embodiment II-155, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1063] II-283. In a further embodiment of embodiment II-156, the
effective amount of budiodarone is 600 mg BID.
[1064] II-284. In a further embodiment of embodiment II-157, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1065] II-285. In a further embodiment of embodiment II-159, the
effective amount of budiodarone is 600 mg BID.
[1066] II-286. In a further embodiment of embodiment II-160, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1067] II-287. In a further embodiment of embodiment II-161, the
effective amount of budiodarone is 600 mg BID.
[1068] II-288. In a further embodiment of embodiment II-162, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1069] II-289. In a further embodiment of embodiment II-163, the
effective amount of budiodarone is 600 mg BID.
[1070] II-290. In a further embodiment of embodiment II-164, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1071] II-291. In a further embodiment of embodiment II-165, the
effective amount of budiodarone is 600 mg BID.
[1072] II-292. In a further embodiment of embodiment II-166, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1073] II-293. In a further embodiment of embodiment II-167, the
effective amount of budiodarone is 600 mg BID.
[1074] II-294. In a further embodiment of embodiment II-168, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1075] II-295. In a further embodiment of embodiment II-169, the
effective amount of budiodarone is 600 mg BID.
[1076] II-296. In a further embodiment of embodiment II-170, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1077] II-297. In a further embodiment of embodiment II-171, the
effective amount of budiodarone is 600 mg BID.
[1078] II-298. In a further embodiment of embodiment II-172, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1079] II-299. In a further embodiment of embodiment II-173, the
effective amount of budiodarone is 600 mg BID.
[1080] II-300. In a further embodiment of embodiment II-174, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1081] II-301. In a further embodiment of embodiment II-175, the
effective amount of budiodarone is 600 mg BID.
[1082] II-302. In a further embodiment of embodiment II-176, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1083] II-303. In a further embodiment of embodiment II-177, the
effective amount of budiodarone is 600 mg BID.
[1084] II-304. In a further embodiment of embodiment II-178, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1085] II-305. In a further embodiment of embodiment II-179, the
effective amount of budiodarone is 600 mg BID.
[1086] II-306. In a further embodiment of embodiment II-180, the
effective amount of budiodarone is 400 mg BID or 600 mg BID.
[1087] II-307. In a further embodiment of embodiment II-181, the
effective amount of budiodarone is 600 mg BID.
[1088] II-308. In a further embodiment of embodiment II-150, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1089] II-309. In a further embodiment of any of embodiments
II-151-II-154, the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[1090] II-310. In a further embodiment of any of embodiments
II-155-II-157, the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[1091] II-311. In a further embodiment of embodiment II-157, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1092] II-312. In a further embodiment of embodiment II-158, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1093] II-313. In a further embodiment of embodiment II-159, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1094] II-314. In a further embodiment of embodiment II-160, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1095] II-315. In a further embodiment of any of embodiments
II-161-II-162, the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[1096] II-316. In a further embodiment of embodiment II-163, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1097] II-317. In a further embodiment of any of embodiments
II-164-II-167, the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[1098] II-318. In a further embodiment of any of embodiments
II-165-II-168, the reversal of atrial remodeling is defined as a
measured increase in AFCL at the right atrial appendage or distal
coronary sinus of at least 6 milliseconds.
[1099] II-319. In a further embodiment of embodiment II-168, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1100] II-320. In a further embodiment of embodiment II-171, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1101] II-321. In a further embodiment of embodiment II-172, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1102] II-322. In a further embodiment of embodiment II-175, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1103] II-323. In a further embodiment of embodiment II-176, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1104] II-324. In a further embodiment of embodiment II-179, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1105] II-325. In a further embodiment of embodiment II-180,
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1106] III-1. In one embodiment, the invention provides a method
for reducing stroke rate comprising administering an amount of
multiple ion channel blocker selected from the group consisting of
amiodarone, dronedarone, budiodarone, vernakalant, celivarone, and
AZD1305 effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[1107] III-2. In a further embodiment of embodiment III-1, the
average AF episode duration is reduced to less than about 24
hours.
[1108] III-3. In a further embodiment of embodiment III-1, the
average AF episode duration is reduced to less than about 5
hours.
[1109] III-4. In a further embodiment of embodiment III-1, the
average AF episode duration is reduced to less than 3 hours.
[1110] III-5. In a further embodiment of embodiment III-1, the
average AF episode duration is reduced to less than about 1
hour.
[1111] III-6. In a further embodiment of embodiment III-1, the
maximum AF episode duration is reduced to less than about 20
hours.
[1112] III-7. In a further embodiment of embodiment III-1, the
maximum AF episode duration is reduced to less than about 10
hours.
[1113] III-8. In a further embodiment of embodiment III-1, the
maximum AF episode duration is reduced to less than about 5
hours.
[1114] III-9. In a further embodiment of embodiment III-1, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1115] III-10. In a further embodiment of embodiment III-2, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1116] III-11. In a further embodiment of embodiment III-3, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1117] III-12. In a further embodiment of embodiment III-4, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1118] III-13. In a further embodiment of embodiment III-5, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1119] III-14. In a further embodiment of embodiment III-6, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1120] III-15. In a further embodiment of embodiment III-7, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1121] III-16. In a further embodiment of embodiment III-8, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1122] III-17. In a further embodiment of embodiment III-1, the
multiple ion channel blocker is budiodarone.
[1123] III-18. In a further embodiment of embodiment III-2, the
multiple ion channel blocker is budiodarone.
[1124] III-19. In a further embodiment of embodiment III-3, the
multiple ion channel blocker is budiodarone.
[1125] III-20. In a further embodiment of embodiment III-4, the
multiple ion channel blocker is budiodarone.
[1126] III-21. In a further embodiment of embodiment III-5, the
multiple ion channel blocker is budiodarone.
[1127] III-22. In a further embodiment of embodiment III-6, the
multiple ion channel blocker is budiodarone.
[1128] III-23. In a further embodiment of embodiment III-7, the
multiple ion channel blocker is budiodarone.
[1129] III-24. In a further embodiment of embodiment III-8, the
multiple ion channel blocker is budiodarone.
[1130] III-25. In a further embodiment of embodiment III-1, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1131] III-26. In a further embodiment of any of embodiments
III-2-III-5, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1132] III-27. In a further embodiment of embodiment III-5, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1133] III-28. In a further embodiment of any of embodiments
III-6-III-8, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1134] III-29. In a further embodiment of embodiment III-8, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1135] III-30. In a further embodiment of embodiment III-9, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1136] III-31. In a further embodiment of any of embodiments
III-10-III-12, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1137] III-32. In a further embodiment of embodiment III-13, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1138] III-33. In a further embodiment of any of embodiments
III-14-III-16, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1139] III-34. In a further embodiment of embodiment III-16, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1140] III-35. In a further embodiment of embodiment III-17, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1141] III-36. In a further embodiment of embodiment III-18, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1142] III-37. In a further embodiment of any of embodiments
III-19-III-20, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1143] III-38. In a further embodiment of embodiment III-21, the AC
is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1144] III-39. In a further embodiment of any of embodiments
III-22-III-24, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1145] III-40. In a further embodiment of any of embodiments
III-26-III-27, the AC is dabigatran etexilate.
[1146] III-41. In a further embodiment of embodiment III-28, the AC
is dabigatran etexilate.
[1147] III-42. In a further embodiment of any of embodiments
III-29-III-30, the AC is dabigatran etexilate.
[1148] III-43. In a further embodiment of embodiment III-31, the AC
is dabigatran etexilate.
[1149] III-44. In a further embodiment of embodiment III-33, the AC
is dabigatran etexilate.
[1150] III-45. In a further embodiment of embodiment III-34, the AC
is dabigatran etexilate.
[1151] III-46. In a further embodiment of embodiment III-36, the AC
is dabigatran etexilate.
[1152] III-47. In a further embodiment of embodiment III-38, the AC
is dabigatran etexilate.
[1153] III-48. In a further embodiment of embodiment III-39, the AC
is dabigatran etexilate.
[1154] III-49. In a further embodiment of embodiment III-26, the AC
is ximelagatran or AZD0837.
[1155] III-50. In a further embodiment of embodiment III-28, the AC
is ximelagatran or AZD0837.
[1156] III-51. In a further embodiment of embodiment III-29, the AC
is ximelagatran or AZD0837.
[1157] III-52. In a further embodiment of embodiment III-31, the AC
is ximelagatran or AZD0837.
[1158] III-53. In a further embodiment of embodiment III-33, the AC
is ximelagatran or AZD0837.
[1159] III-54. In a further embodiment of embodiment III-34, the AC
is ximelagatran or AZD0837.
[1160] III-55. In a further embodiment of embodiment III-36, the AC
is ximelagatran or AZD0837.
[1161] III-56. In a further embodiment of embodiment III-38, the AC
is ximelagatran or AZD0837.
[1162] III-57. In a further embodiment of embodiment III-39, the AC
is ximelagatran or AZD0837.
[1163] III-58. In a further embodiment of embodiment III-26, the AC
is apixaban.
[1164] III-59. In a further embodiment of embodiment III-28, the AC
is apixaban.
[1165] III-60. In a further embodiment of embodiment III-29, the AC
is apixaban.
[1166] III-61. In a further embodiment of embodiment III-31, the AC
is apixaban.
[1167] III-62. In a further embodiment of embodiment III-33, the AC
is apixaban.
[1168] III-63. In a further embodiment of embodiment III-34, the AC
is apixaban.
[1169] III-64. In a further embodiment of embodiment III-36, the AC
is apixaban.
[1170] III-65. In a further embodiment of embodiment III-38, the AC
is apixaban.
[1171] III-66. In a further embodiment of embodiment III-39, the AC
is apixaban.
[1172] III-67. In a further embodiment of embodiment III-26, the AC
is rivaroxaban.
[1173] III-68. In a further embodiment of embodiment III-28, the AC
is rivaroxaban.
[1174] III-69. In a further embodiment of embodiment III-29, the AC
is rivaroxaban.
[1175] III-70. In a further embodiment of embodiment III-31, the AC
is rivaroxaban.
[1176] III-71. In a further embodiment of embodiment III-33, the AC
is rivaroxaban.
[1177] III-72. In a further embodiment of embodiment III-34, the AC
is rivaroxaban.
[1178] III-73. In a further embodiment of embodiment III-36, the AC
is rivaroxaban.
[1179] III-74. In a further embodiment of embodiment III-38, the AC
is rivaroxaban.
[1180] III-75. In a further embodiment of embodiment III-39, the AC
is rivaroxaban.
[1181] III-76. In a further embodiment of embodiment III-26, the AC
is tecarfarin.
[1182] III-77. In a further embodiment of embodiment III-28, the AC
is tecarfarin.
[1183] III-78. In a further embodiment of embodiment III-29, the AC
is tecarfarin.
[1184] III-79. In a further embodiment of embodiment III-31, the AC
is tecarfarin.
[1185] III-80. In a further embodiment of embodiment III-33, the AC
is tecarfarin.
[1186] III-81. In a further embodiment of embodiment III-34, the AC
is tecarfarin.
[1187] III-82. In a further embodiment of embodiment III-36, the AC
is tecarfarin.
[1188] III-83. In a further embodiment of embodiment III-38, the AC
is tecarfarin.
[1189] III-84. In a further embodiment of embodiment III-39, the AC
is tecarfarin.
[1190] III-85. In a further embodiment of embodiment III-1, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1191] III-86. In a further embodiment of embodiment III-2, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1192] III-87. In a further embodiment of embodiment III-3, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1193] III-88. In a further embodiment of embodiment III-4, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1194] III-89. In a further embodiment of embodiment III-5, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1195] III-90. In a further embodiment of embodiment III-6, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1196] III-91. In a further embodiment of embodiment III-7, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1197] III-92. In a further embodiment of embodiment III-8, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1198] III-93. In a further embodiment of embodiment III-10, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1199] III-94. In a further embodiment of embodiment III-13, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1200] III-95. In a further embodiment of embodiment III-16, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1201] III-96. In a further embodiment of embodiment III-18, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1202] III-97. In a further embodiment of embodiment III-21, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1203] III-98. In a further embodiment of embodiment III-24, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1204] III-99. In a further embodiment of embodiment III-25, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1205] III-100. In a further embodiment of embodiment III-26, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1206] III-101. In a further embodiment of embodiment III-27, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1207] III-102. In a further embodiment of embodiment III-28, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1208] III-103. In a further embodiment of embodiment III-29, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1209] III-104. In a further embodiment of embodiment III-30, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1210] III-105. In a further embodiment of embodiment III-31, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1211] III-106. In a further embodiment of embodiment III-32, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1212] III-107. In a further embodiment of embodiment III-33, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1213] III-108. In a further embodiment of embodiment III-34, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1214] III-109. In a further embodiment of embodiment III-35, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1215] III-110. In a further embodiment of embodiment III-36, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1216] III-111. In a further embodiment of embodiment III-37, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1217] III-112. In a further embodiment of embodiment III-38, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1218] III-113. In a further embodiment of embodiment III-39, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1219] III-114. In a further embodiment of embodiment III-40, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1220] III-115. In a further embodiment of embodiment III-41, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1221] III-116. In a further embodiment of embodiment III-42, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1222] III-117. In a further embodiment of embodiment III-43, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1223] III-118. In a further embodiment of embodiment III-44, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1224] III-119. In a further embodiment of embodiment III-45, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1225] III-120. In a further embodiment of embodiment III-46, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1226] III-121. In a further embodiment of embodiment III-47, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1227] III-122. In a further embodiment of embodiment III-48, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1228] III-123. In a further embodiment of embodiment III-49, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1229] III-124. In a further embodiment of embodiment III-50, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1230] III-125. In a further embodiment of embodiment III-51, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1231] III-126. In a further embodiment of embodiment III-52, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1232] III-127. In a further embodiment of embodiment III-53, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1233] III-128. In a further embodiment of embodiment III-54, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1234] III-129. In a further embodiment of embodiment III-55, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1235] III-130. In a further embodiment of embodiment III-56, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1236] III-131. In a further embodiment of embodiment III-57, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1237] III-132. In a further embodiment of embodiment III-58, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1238] III-133. In a further embodiment of embodiment III-59, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1239] III-134. In a further embodiment of embodiment III-60, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1240] III-135. In a further embodiment of embodiment III-61, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1241] III-136. In a further embodiment of embodiment III-62, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1242] III-137. In a further embodiment of embodiment III-63, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1243] III-138. In a further embodiment of embodiment III-64, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1244] III-139. In a further embodiment of embodiment III-65, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1245] III-140. In a further embodiment of embodiment III-66, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1246] III-141. In a further embodiment of embodiment III-67, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1247] III-142. In a further embodiment of embodiment III-68, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1248] III-143. In a further embodiment of embodiment III-69, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1249] III-144. In a further embodiment of embodiment III-70, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1250] III-145. In a further embodiment of embodiment III-71, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1251] III-146. In a further embodiment of embodiment III-72, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1252] III-147. In a further embodiment of embodiment III-73, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1253] III-148. In a further embodiment of embodiment III-74, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1254] III-149. In a further embodiment of embodiment III-75, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1255] III-150. In a further embodiment of embodiment III-76, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1256] III-151. In a further embodiment of embodiment III-77, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1257] III-152. In a further embodiment of embodiment III-78, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1258] III-153. In a further embodiment of embodiment III-79, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1259] III-154. In a further embodiment of embodiment III-80, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1260] III-155. In a further embodiment of embodiment III-81, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1261] III-156. In a further embodiment of embodiment III-82, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1262] III-157. In a further embodiment of embodiment III-83, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1263] III-158. In a further embodiment of embodiment III-84, the
reduced stroke rate is less than the age-adjusted overall stroke
rate.
[1264] III-159. In a further embodiment of embodiment III-2, the
patient was refractory to one or more anti-arrhythmic drugs.
[1265] III-160. In a further embodiment of embodiment III-5, the
patient was refractory to one or more anti-arrhythmic drugs.
[1266] III-161. In a further embodiment of embodiment III-10, the
patient was refractory to one or more anti-arrhythmic drugs.
[1267] III-162. In a further embodiment of embodiment III-13, the
patient was refractory to one or more anti-arrhythmic drugs.
[1268] III-163. In a further embodiment of embodiment III-18, the
patient was refractory to one or more anti-arrhythmic drugs.
[1269] III-164. In a further embodiment of embodiment III-21, the
patient was refractory to one or more anti-arrhythmic drugs.
[1270] III-165. In a further embodiment of embodiment III-41, the
patient was refractory to one or more anti-arrhythmic drugs.
[1271] III-166. In a further embodiment of embodiment III-44, the
patient was refractory to one or more anti-arrhythmic drugs.
[1272] III-167. In a further embodiment of embodiment III-47, the
patient was refractory to one or more anti-arrhythmic drugs.
[1273] III-168. In a further embodiment of embodiment III-50, the
patient was refractory to one or more anti-arrhythmic drugs.
[1274] III-169. In a further embodiment of embodiment III-53, the
patient was refractory to one or more anti-arrhythmic drugs.
[1275] III-170. In a further embodiment of embodiment III-56, the
patient was refractory to one or more anti-arrhythmic drugs.
[1276] III-171. In a further embodiment of embodiment III-59, the
patient was refractory to one or more anti-arrhythmic drugs.
[1277] III-172. In a further embodiment of embodiment III-62, the
patient was refractory to one or more anti-arrhythmic drugs.
[1278] III-173. In a further embodiment of embodiment III-65, the
patient was refractory to one or more anti-arrhythmic drugs.
[1279] III-174. In a further embodiment of embodiment III-68, the
patient was refractory to one or more anti-arrhythmic drugs.
[1280] III-175. In a further embodiment of embodiment III-71, the
patient was refractory to one or more anti-arrhythmic drugs.
[1281] III-176. In a further embodiment of embodiment III-74, the
patient was refractory to one or more anti-arrhythmic drugs.
[1282] III-177. In a further embodiment of embodiment III-77, the
patient was refractory to one or more anti-arrhythmic drugs.
[1283] III-178. In a further embodiment of embodiment III-80, the
patient was refractory to one or more anti-arrhythmic drugs.
[1284] III-179. In a further embodiment of embodiment III-83, the
patient was refractory to one or more anti-arrhythmic drugs.
[1285] III-180. In a further embodiment of embodiment III-85, the
patient was refractory to one or more anti-arrhythmic drugs.
[1286] III-181. In a further embodiment of embodiment III-86, the
patient was refractory to one or more anti-arrhythmic drugs.
[1287] III-182. In a further embodiment of embodiment III-87, the
patient was refractory to one or more anti-arrhythmic drugs.
[1288] III-183. In a further embodiment of embodiment III-88, the
patient was refractory to one or more anti-arrhythmic drugs.
[1289] III-184. In a further embodiment of embodiment III-89, the
patient was refractory to one or more anti-arrhythmic drugs.
[1290] III-185. In a further embodiment of embodiment III-90, the
patient was refractory to one or more anti-arrhythmic drugs.
[1291] III-186. In a further embodiment of embodiment III-91, the
patient was refractory to one or more anti-arrhythmic drugs.
[1292] III-187. In a further embodiment of embodiment III-92, the
patient was refractory to one or more anti-arrhythmic drugs.
[1293] III-188. In a further embodiment of embodiment III-93, the
patient was refractory to one or more anti-arrhythmic drugs.
[1294] III-189. In a further embodiment of embodiment III-94, the
patient was refractory to one or more anti-arrhythmic drugs.
[1295] III-190. In a further embodiment of embodiment III-97, the
patient was refractory to one or more anti-arrhythmic drugs.
[1296] III-191. In a further embodiment of embodiment III-102, the
patient was refractory to one or more anti-arrhythmic drugs.
[1297] III-192. In a further embodiment of embodiment III-107, the
patient was refractory to one or more anti-arrhythmic drugs.
[1298] III-193. In a further embodiment of embodiment III-112, the
patient was refractory to one or more anti-arrhythmic drugs.
[1299] III-194. In a further embodiment of embodiment III-115, the
patient was refractory to one or more anti-arrhythmic drugs.
[1300] III-195. In a further embodiment of embodiment III-118, the
patient was refractory to one or more anti-arrhythmic drugs.
[1301] III-196. In a further embodiment of embodiment III-121, the
patient was refractory to one or more anti-arrhythmic drugs.
[1302] III-197. In a further embodiment of embodiment III-124, the
patient was refractory to one or more anti-arrhythmic drugs.
[1303] III-198. In a further embodiment of embodiment III-127, the
patient was refractory to one or more anti-arrhythmic drugs.
[1304] III-199. In a further embodiment of embodiment III-130, the
patient was refractory to one or more anti-arrhythmic drugs.
[1305] III-200. In a further embodiment of embodiment III-133, the
patient was refractory to one or more anti-arrhythmic drugs.
[1306] III-201. In a further embodiment of embodiment III-136, the
patient was refractory to one or more anti-arrhythmic drugs.
[1307] III-202. In a further embodiment of embodiment III-139, the
patient was refractory to one or more anti-arrhythmic drugs.
[1308] III-203. In a further embodiment of embodiment III-142, the
patient was refractory to one or more anti-arrhythmic drugs.
[1309] III-204. In a further embodiment of embodiment III-145, the
patient was refractory to one or more anti-arrhythmic drugs.
[1310] III-205. In a further embodiment of embodiment III-148, the
patient was refractory to one or more anti-arrhythmic drugs.
[1311] III-206. In a further embodiment of embodiment III-151, the
patient was refractory to one or more anti-arrhythmic drugs.
[1312] III-207. In a further embodiment of embodiment III-154, the
patient was refractory to one or more anti-arrhythmic drugs.
[1313] III-208. In a further embodiment of embodiment III-157, the
patient was refractory to one or more anti-arrhythmic drugs.
[1314] III-209. In one embodiment, the invention provides a method
for preventing atrial remodeling comprising administering an amount
of multiple ion channel blocker selected from the group consisting
of amiodarone, dronedarone, budiodarone, vernakalant, celivarone,
and AZD1305 effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[1315] III-210. In a further embodiment of embodiment III-209, the
average AF episode duration is reduced to less than about 24
hours.
[1316] III-211. In a further embodiment of embodiment III-209, the
average AF episode duration is reduced to less than about 5
hours.
[1317] III-212. In a further embodiment of embodiment III-209, the
average AF episode duration is reduced to less than 3 hours.
[1318] III-213. In a further embodiment of embodiment III-209, the
average AF episode duration is reduced to less than about 1
hour.
[1319] III-214. In a further embodiment of embodiment III-209, the
maximum AF episode duration is reduced to less than about 20
hours.
[1320] III-215. In a further embodiment of embodiment III-209, the
maximum AF episode duration is reduced to less than about 10
hours.
[1321] III-216. In a further embodiment of embodiment III-209, the
maximum AF episode duration is reduced to less than about 5
hours.
[1322] III-217. In a further embodiment of embodiment III-209, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1323] III-218. In a further embodiment of embodiment III-210, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1324] III-219. In a further embodiment of embodiment III-211, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1325] III-220. In a further embodiment of embodiment III-212, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1326] III-221. In a further embodiment of embodiment III-213, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1327] III-222. In a further embodiment of embodiment III-214, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1328] III-223. In a further embodiment of embodiment III-215, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1329] III-224. In a further embodiment of embodiment III-216, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1330] III-225. In a further embodiment of embodiment III-209, the
multiple ion channel blocker is budiodarone.
[1331] III-226. In a further embodiment of embodiment III-210, the
multiple ion channel blocker is budiodarone.
[1332] III-227. In a further embodiment of embodiment III-211, the
multiple ion channel blocker is budiodarone.
[1333] III-228. In a further embodiment of embodiment III-212, the
multiple ion channel blocker is budiodarone.
[1334] III-229. In a further embodiment of embodiment III-213, the
multiple ion channel blocker is budiodarone.
[1335] III-230. In a further embodiment of embodiment III-214, the
multiple ion channel blocker is budiodarone.
[1336] III-231. In a further embodiment of embodiment III-215, the
multiple ion channel blocker is budiodarone.
[1337] III-232. In a further embodiment of embodiment III-216, the
multiple ion channel blocker is budiodarone.
[1338] III-233. In a further embodiment of embodiment III-209, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1339] III-234. In a further embodiment of embodiment III-210, the
AC is tecarfarin, dabigatran etexilate, AZD0837, apixaban or
rivaroxaban.
[1340] III-235. In a further embodiment of embodiment III-211, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1341] III-236. In a further embodiment of embodiment III-213, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1342] III-237. In a further embodiment of any of embodiments
III-214-III-216, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1343] III-238. In a further embodiment of embodiment III-217, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1344] III-239. In a further embodiment of embodiment III-218, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1345] III-240. In a further embodiment of embodiment III-219, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1346] III-241. In a further embodiment of embodiment III-221, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1347] III-242. In a further embodiment of any of embodiments
III-222-III-224, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1348] III-243. In a further embodiment of embodiment III-225, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1349] III-244. In a further embodiment of embodiment III-226, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1350] III-245. In a further embodiment of embodiment III-227, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1351] III-246. In a further embodiment of embodiment III-229, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1352] III-247. In a further embodiment of embodiment III-232, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1353] III-248. In a further embodiment of embodiment III-234, the
AC is dabigatran etexilate.
[1354] III-249. In a further embodiment of embodiment III-236, the
AC is dabigatran etexilate.
[1355] III-250. In a further embodiment of embodiment III-237, the
AC is dabigatran etexilate.
[1356] III-251. In a further embodiment of embodiment III-239, the
AC is dabigatran etexilate.
[1357] III-252. In a further embodiment of embodiment III-241, the
AC is dabigatran etexilate.
[1358] III-253. In a further embodiment of embodiment III-242, the
AC is dabigatran etexilate.
[1359] III-254. In a further embodiment of embodiment III-244, the
AC is dabigatran etexilate.
[1360] III-255. In a further embodiment of embodiment III-246, the
AC is dabigatran etexilate.
[1361] III-256. In a further embodiment of embodiment III-247, the
AC is dabigatran etexilate.
[1362] III-257. In a further embodiment of embodiment III-234, the
AC is ximelagatran or AZD0837.
[1363] III-258. In a further embodiment of embodiment III-236, the
AC is ximelagatran or AZD0837.
[1364] III-259. In a further embodiment of embodiment III-237, the
AC is ximelagatran or AZD0837.
[1365] III-260. In a further embodiment of embodiment III-239, the
AC is ximelagatran or AZD0837.
[1366] III-261. In a further embodiment of embodiment III-241, the
AC is ximelagatran or AZD0837.
[1367] III-262. In a further embodiment of embodiment III-242, the
AC is ximelagatran or AZD0837.
[1368] III-263. In a further embodiment of embodiment III-244, the
AC is ximelagatran or AZD0837.
[1369] III-264. In a further embodiment of embodiment III-246, the
AC is ximelagatran or AZD0837.
[1370] III-265. In a further embodiment of embodiment III-247, the
AC is ximelagatran or AZD0837.
[1371] III-266. In a further embodiment of embodiment III-234, the
AC is apixaban.
[1372] III-267. In a further embodiment of embodiment III-236, the
AC is apixaban.
[1373] III-268. In a further embodiment of embodiment III-237, the
AC is apixaban.
[1374] III-269. In a further embodiment of embodiment III-239, the
AC is apixaban.
[1375] III-270. In a further embodiment of embodiment III-241, the
AC is apixaban.
[1376] III-271. In a further embodiment of embodiment III-242, the
AC is apixaban.
[1377] III-272. In a further embodiment of embodiment III-244, the
AC is apixaban.
[1378] III-273. In a further embodiment of embodiment III-246, the
AC is apixaban.
[1379] III-274. In a further embodiment of embodiment III-247, the
AC is apixaban.
[1380] III-275. In a further embodiment of embodiment III-234, the
AC is rivaroxaban.
[1381] III-276. In a further embodiment of embodiment III-236, the
AC is rivaroxaban.
[1382] III-277. In a further embodiment of embodiment III-237, the
AC is rivaroxaban.
[1383] III-278. In a further embodiment of embodiment III-239, the
AC is rivaroxaban.
[1384] III-279. In a further embodiment of embodiment III-241, the
AC is rivaroxaban.
[1385] III-280. In a further embodiment of embodiment III-242, the
AC is rivaroxaban.
[1386] III-281. In a further embodiment of embodiment III-244, the
AC is rivaroxaban.
[1387] III-282. In a further embodiment of embodiment III-246, the
AC is rivaroxaban.
[1388] III-283. In a further embodiment of embodiment III-247, the
AC is rivaroxaban.
[1389] III-284. In a further embodiment of embodiment III-234, the
AC is tecarfarin.
[1390] III-285. In a further embodiment of embodiment III-236, the
AC is tecarfarin.
[1391] III-286. In a further embodiment of embodiment III-237, the
AC is tecarfarin.
[1392] III-287. In a further embodiment of embodiment III-239, the
AC is tecarfarin.
[1393] III-288. In a further embodiment of embodiment III-241, the
AC is tecarfarin.
[1394] III-289. In a further embodiment of embodiment III-242, the
AC is tecarfarin.
[1395] III-290. In a further embodiment of embodiment III-244, the
AC is tecarfarin.
[1396] III-291. In a further embodiment of embodiment III-246, the
AC is tecarfarin.
[1397] III-292. In a further embodiment of embodiment III-247, the
AC is tecarfarin.
[1398] III-293. In a further embodiment of embodiment III-210, the
patient was refractory to one or more anti-arrhythmic drugs.
[1399] III-294. In a further embodiment of any of embodiments
III-213-216, the patient was refractory to one or more
anti-arrhythmic drugs.
[1400] III-295. In a further embodiment of embodiment III-218, the
patient was refractory to one or more anti-arrhythmic drugs.
[1401] III-295. In a further embodiment of embodiment III-221, the
patient was refractory to one or more anti-arrhythmic drugs.
[1402] III-297. In a further embodiment of embodiment III-226, the
patient was refractory to one or more anti-arrhythmic drugs.
[1403] III-298. In a further embodiment of any of embodiments
III-229-III-232, the patient was refractory to one or more
anti-arrhythmic drugs.
[1404] III-299. In a further embodiment of embodiment III-249, the
patient was refractory to one or more anti-arrhythmic drugs.
[1405] III-300. In a further embodiment of embodiment III-252, the
patient was refractory to one or more anti-arrhythmic drugs.
[1406] III-301. In a further embodiment of embodiment III-255, the
patient was refractory to one or more anti-arrhythmic drugs.
[1407] III-302. In a further embodiment of embodiment III-258, the
patient was refractory to one or more anti-arrhythmic drugs.
[1408] III-303. In a further embodiment of embodiment III-261, the
patient was refractory to one or more anti-arrhythmic drugs.
[1409] III-304. In a further embodiment of embodiment III-264, the
patient was refractory to one or more anti-arrhythmic drugs.
[1410] III-305. In a further embodiment of embodiment III-267, the
patient was refractory to one or more anti-arrhythmic drugs.
[1411] III-306. In a further embodiment of embodiment III-270, the
patient was refractory to one or more anti-arrhythmic drugs.
[1412] III-307. In a further embodiment of embodiment III-273, the
patient was refractory to one or more anti-arrhythmic drugs.
[1413] III-308. In a further embodiment of embodiment III-276, the
patient was refractory to one or more anti-arrhythmic drugs.
[1414] III-309. In a further embodiment of embodiment III-279, the
patient was refractory to one or more anti-arrhythmic drugs.
[1415] III-310. In a further embodiment of embodiment III-282, the
patient was refractory to one or more anti-arrhythmic drugs.
[1416] III-311. In a further embodiment of embodiment III-285, the
patient was refractory to one or more anti-arrhythmic drugs.
[1417] III-312. In a further embodiment of embodiment III-288, the
patient was refractory to one or more anti-arrhythmic drugs.
[1418] III-313. In a further embodiment of embodiment III-291, the
patient was refractory to one or more anti-arrhythmic drugs.
[1419] III-314. In one embodiment, the invention provides a method
for reversing atrial remodeling comprising administering an amount
of multiple ion channel blocker selected from the group consisting
of amiodarone, dronedarone, budiodarone, vernakalant, celivarone,
and AZD1305 effective to reduce atrial fibrillation (AF) episode
duration and an effective amount of anticoagulant (AC) selected
from the group consisting of AZD0837, dabigatran etexilate,
dabigatran, ximelagatran, melagatran, argatroban, apixaban,
rivaroxaban, YM466, betrixaban, edoxaban, otamixaban, tecarfarin
and warfarin.
[1420] III-315. In a further embodiment of embodiment III-314, the
average AF episode duration is reduced to less than about 24
hours.
[1421] III-316. In a further embodiment of embodiment III-314, the
average AF episode duration is reduced to less than about 5
hours.
[1422] III-317. In a further embodiment of embodiment III-314, the
average AF episode duration is reduced to less than 3 hours.
[1423] III-318. In a further embodiment of embodiment III-314, the
average AF episode duration is reduced to less than about 1
hour.
[1424] III-319. In a further embodiment of embodiment III-314, the
maximum AF episode duration is reduced to less than about 20
hours.
[1425] III-320. In a further embodiment of embodiment III-314, the
maximum AF episode duration is reduced to less than about 10
hours.
[1426] III-321. In a further embodiment of embodiment III-314, the
maximum AF episode duration is reduced to less than about 5
hours.
[1427] III-322. In a further embodiment of embodiment III-314, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1428] III-323. In a further embodiment of embodiment III-315, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1429] III-324. In a further embodiment of embodiment III-316, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1430] III-325. In a further embodiment of embodiment III-317, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1431] III-326. In a further embodiment of embodiment III-318, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1432] III-327. In a further embodiment of embodiment III-319, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1433] III-328. In a further embodiment of embodiment III-320, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1434] III-329. In a further embodiment of embodiment III-321, the
multiple ion channel blocker is budiodarone, dronedarone,
celivarone, AZD1305 or vernakalant.
[1435] III-330. In a further embodiment of embodiment III-314, the
multiple ion channel blocker is budiodarone.
[1436] III-331. In a further embodiment of embodiment III-315, the
multiple ion channel blocker is budiodarone.
[1437] III-332. In a further embodiment of embodiment III-316, the
multiple ion channel blocker is budiodarone.
[1438] III-333. In a further embodiment of embodiment III-317, the
multiple ion channel blocker is budiodarone.
[1439] III-334. In a further embodiment of embodiment III-318, the
multiple ion channel blocker is budiodarone.
[1440] III-335. In a further embodiment of embodiment III-319, the
multiple ion channel blocker is budiodarone.
[1441] III-336. In a further embodiment of embodiment III-320, the
multiple ion channel blocker is budiodarone.
[1442] III-337. In a further embodiment of embodiment III-321, the
multiple ion channel blocker is budiodarone.
[1443] III-338. In a further embodiment of embodiment III-314, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1444] III-339. In a further embodiment of embodiment III-315, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1445] III-340. In a further embodiment of any of embodiments
III-316-317, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1446] III-341. In a further embodiment of embodiment III-318, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1447] III-342. In a further embodiment of any of embodiments
III-319-321, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1448] III-343. In a further embodiment of embodiment III-322, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1449] III-344. In a further embodiment of embodiment III-323, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1450] III-345. In a further embodiment of any of embodiments
III-324-325, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1451] III-346. In a further embodiment of any of embodiments
III-326-328, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1452] III-347. In a further embodiment of embodiment III-329, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1453] III-348. In a further embodiment of embodiment III-330, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1454] III-349. In a further embodiment of embodiment III-331, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1455] III-350. In a further embodiment of any of embodiments
III-332-III-333, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1456] III-351. In a further embodiment of any of embodiments
III-334-III-336, the AC is tecarfarin, dabigatran etexilate,
ximelagatran, AZD0837, apixaban or rivaroxaban.
[1457] III-352. In a further embodiment of embodiment III-337, the
AC is tecarfarin, dabigatran etexilate, ximelagatran, AZD0837,
apixaban or rivaroxaban.
[1458] III-353. In a further embodiment of embodiment III-339, the
AC is dabigatran etexilate.
[1459] III-354. In a further embodiment of embodiment III-341, the
AC is dabigatran etexilate.
[1460] III-355. In a further embodiment of embodiment III-342, the
AC is dabigatran etexilate.
[1461] III-356. In a further embodiment of embodiment III-344, the
AC is dabigatran etexilate.
[1462] III-357. In a further embodiment of embodiment III-346, the
AC is dabigatran etexilate.
[1463] III-358. In a further embodiment of embodiment III-347, the
AC is dabigatran etexilate.
[1464] III-359. In a further embodiment of embodiment III-349, the
AC is dabigatran etexilate.
[1465] III-360. In a further embodiment of embodiment III-351, the
AC is dabigatran etexilate.
[1466] III-361. In a further embodiment of embodiment III-352, the
AC is dabigatran etexilate.
[1467] III-362. In a further embodiment of embodiment III-339, the
AC is ximelagatran or AZD0837.
[1468] III-363. In a further embodiment of embodiment III-341, the
AC is ximelagatran or AZD0837.
[1469] III-364. In a further embodiment of embodiment III-342, the
AC is ximelagatran or AZD0837.
[1470] III-365. In a further embodiment of embodiment III-344, the
AC is ximelagatran or AZD0837.
[1471] III-366. In a further embodiment of embodiment III-346, the
AC is ximelagatran or AZD0837.
[1472] III-367. In a further embodiment of embodiment III-347, the
AC is ximelagatran or AZD0837.
[1473] III-368. In a further embodiment of embodiment III-349, the
AC is ximelagatran or AZD0837.
[1474] III-369. In a further embodiment of embodiment III-351, the
AC is ximelagatran or AZD0837.
[1475] III-370. In a further embodiment of embodiment III-352, the
AC is ximelagatran or AZD0837.
[1476] III-371. In a further embodiment of embodiment III-339, the
AC is apixaban.
[1477] III-372. In a further embodiment of embodiment III-341, the
AC is apixaban.
[1478] III-373. In a further embodiment of embodiment III-342, the
AC is apixaban.
[1479] III-374. In a further embodiment of embodiment III-344, the
AC is apixaban.
[1480] III-375. In a further embodiment of embodiment III-346, the
AC is apixaban.
[1481] III-376. In a further embodiment of embodiment III-347, the
AC is apixaban.
[1482] III-377. In a further embodiment of embodiment III-349, the
AC is apixaban.
[1483] III-378. In a further embodiment of embodiment III-351, the
AC is apixaban.
[1484] III-379. In a further embodiment of embodiment III-352, the
AC is apixaban.
[1485] III-380. In a further embodiment of embodiment III-339, the
AC is rivaroxaban.
[1486] III-381. In a further embodiment of embodiment III-341, the
AC is rivaroxaban.
[1487] III-382. In a further embodiment of embodiment III-342, the
AC is rivaroxaban.
[1488] III-383. In a further embodiment of embodiment III-344, the
AC is rivaroxaban.
[1489] III-384. In a further embodiment of embodiment III-346, the
AC is rivaroxaban.
[1490] III-385. In a further embodiment of embodiment III-347, the
AC is rivaroxaban.
[1491] III-386. In a further embodiment of embodiment III-349, the
AC is rivaroxaban.
[1492] III-387. In a further embodiment of embodiment III-351, the
AC is rivaroxaban.
[1493] III-388. In a further embodiment of embodiment III-352, the
AC is rivaroxaban.
[1494] III-389. In a further embodiment of embodiment III-339, the
AC is tecarfarin.
[1495] III-390. In a further embodiment of embodiment III-341, the
AC is tecarfarin.
[1496] III-391. In a further embodiment of embodiment III-342, the
AC is tecarfarin.
[1497] III-392. In a further embodiment of embodiment III-344, the
AC is tecarfarin.
[1498] III-393. In a further embodiment of embodiment III-346, the
AC is tecarfarin.
[1499] III-394. In a further embodiment of embodiment III-347, the
AC is tecarfarin.
[1500] III-395. In a further embodiment of embodiment III-349, the
AC is tecarfarin.
[1501] III-396. In a further embodiment of embodiment III-351, the
AC is tecarfarin.
[1502] III-397. In a further embodiment of embodiment III-352, the
AC is tecarfarin.
[1503] III-398. In a further embodiment of embodiment III-315, the
patient was refractory to one or more anti-arrhythmic drugs.
[1504] III-399. In a further embodiment of embodiment III-318, the
patient was refractory to one or more anti-arrhythmic drugs.
[1505] III-400. In a further embodiment of embodiment III-323, the
patient was refractory to one or more anti-arrhythmic drugs.
[1506] III-401. In a further embodiment of embodiment III-326, the
patient was refractory to one or more anti-arrhythmic drugs.
[1507] III-402. In a further embodiment of embodiment III-331, the
patient was refractory to one or more anti-arrhythmic drugs.
[1508] III-403. In a further embodiment of embodiment III-334, the
patient was refractory to one or more anti-arrhythmic drugs.
[1509] III-404. In a further embodiment of embodiment III-354, the
patient was refractory to one or more anti-arrhythmic drugs.
[1510] III-405. In a further embodiment of embodiment III-357, the
patient was refractory to one or more anti-arrhythmic drugs.
[1511] III-406. In a further embodiment of embodiment III-360, the
patient was refractory to one or more anti-arrhythmic drugs.
[1512] III-407. In a further embodiment of embodiment III-363, the
patient was refractory to one or more anti-arrhythmic drugs.
[1513] III-408. In a further embodiment of embodiment III-366, the
patient was refractory to one or more anti-arrhythmic drugs.
[1514] III-409. In a further embodiment of embodiment III-369, the
patient was refractory to one or more anti-arrhythmic drugs.
[1515] III-410. In a further embodiment of embodiment III-372, the
patient was refractory to one or more anti-arrhythmic drugs.
[1516] III-411. In a further embodiment of embodiment III-375, the
patient was refractory to one or more anti-arrhythmic drugs.
[1517] III-412. In a further embodiment of embodiment III-378, the
patient was refractory to one or more anti-arrhythmic drugs.
[1518] III-413. In a further embodiment of embodiment III-381, the
patient was refractory to one or more anti-arrhythmic drugs.
[1519] III-414. In a further embodiment of embodiment III-384, the
patient was refractory to one or more anti-arrhythmic drugs.
[1520] III-415. In a further embodiment of embodiment III-387, the
patient was refractory to one or more anti-arrhythmic drugs.
[1521] III-416. In a further embodiment of embodiment III-390, the
patient was refractory to one or more anti-arrhythmic drugs.
[1522] III-417. In a further embodiment of embodiment III-393, the
patient was refractory to one or more anti-arrhythmic drugs.
[1523] III-418. In a further embodiment of embodiment III-396, the
patient was refractory to one or more anti-arrhythmic drugs.
[1524] III-419. In a further embodiment of embodiment III-315, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1525] III-420. In a further embodiment of embodiment III-318, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1526] III-421. In a further embodiment of embodiment III-323, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1527] III-422. In a further embodiment of embodiment III-326, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1528] III-423. In a further embodiment of embodiment III-331, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1529] III-424. In a further embodiment of embodiment III-334, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1530] III-425. In a further embodiment of embodiment III-354, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1531] III-426. In a further embodiment of embodiment III-357, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1532] III-427. In a further embodiment of embodiment III-360, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1533] III-428. In a further embodiment of embodiment III-363, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1534] III-429. In a further embodiment of embodiment III-366, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1535] III-430. In a further embodiment of embodiment III-369, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1536] III-431. In a further embodiment of embodiment III-372, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1537] III-432. In a further embodiment of embodiment III-375, the
defined as a measured increase in AFCL at the right atrial
appendage or distal coronary sinus of at least 6 milliseconds.
[1538] III-433. In a further embodiment of embodiment III-378, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1539] III-434. In a further embodiment of embodiment III-381, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1540] III-435. In a further embodiment of embodiment III-384, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1541] III-436. In a further embodiment of embodiment III-387, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1542] III-437. In a further embodiment of embodiment III-390, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1543] III-438. In a further embodiment of embodiment III-393, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
[1544] III-439. In a further embodiment of embodiment III-396, the
reversal of atrial remodeling is defined as a measured increase in
AFCL at the right atrial appendage or distal coronary sinus of at
least 6 milliseconds.
Example 1: Budiodarone (ATI-2042) and AF
[1545] The primary objective of the study was to assess the
efficacy of budiodarone, (s)-sec-butyl
2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl)acetat-
e, in treating AF, as measured by a reduction in AF burden (AFB) in
subjects with paroxysmal atrial fibrillation who had implanted
pacemakers (Arya A, et al., Europace. 2009 April; 11(4):458-64.
Epub 2009 Jan. 26).
[1546] This study was a proof of concept design seeking preliminary
information on the pharmacodynamic effects, safety, and
tolerability of the investigational drug ATI-2042 at a variety of
doses, in patients with PAF. Patients with advanced DDDRP
pacemakers were selected because of the pacemaker's sophisticated
diagnostics and the ability to record continuously and log
asymptomatic as well as symptomatic episodes.
[1547] The molecular structure of budiodarone is identical to that
of amiodarone, except for the presence of a sec-butyl acetate side
chain at position 2 of the benzofuran moiety. The core of the
molecule is a benzofuranyl ring system, to which an iodinated
diiodophenyl group, a tertiary amine, and the chiral centre of the
molecule, an (S)-2-butanyl group, are added over the course of the
synthesis. The final drug substance is provided as a tartrate
salt.
[1548] ATI-2042 is not a prodrug of amiodarone, nor is amiodarone a
metabolite of ATI-2042. The electrophysiological activity of
ATI-2042 in animals includes inhibition comparable with amiodarone
of sodium, potassium, and calcium ion channels, increased left and
right atrial refractoriness comparable with amiodarone, atrial
effects (increased St-A and A-H intervals), and ventricular effects
(increased MAPD90 and QT-interval). The major metabolite (ATI-2000)
is electrophysiologically inactive.
[1549] Only post-menopausal or surgically sterile females with a
significant PAF burden and pacemakers were included in this study.
The pacemakers had to have been in situ for at least 1 month prior
to the study and have appropriate arrhythmia diagnostics. In this
study, Vitatron pacemakers, models Selection 9000 or T70
pacemakers, were used. Non-specific but potentially toxic findings
were observed in canine testes during pre-clinical safety testing.
Although this finding was explored further, it was prudent to
commence clinical testing in a population not at risk for this
effect. Hence, the study described in Example 1 was limited to
post-menopausal or surgically sterile females; the use of the drug
in males has been addressed in the study described in Example
2.
[1550] The patients underwent screening assessments to assess
suitability for the study and to obtain a baseline medical history
and examination. The value of this cohort was that the pacemaker
was not inserted for bradycardia but for the treatment of AF using
various prevention pacing and rate control techniques. The
inclusion criteria were as follows: age 18-85 years; AF burden
(AFB) of 1-50%; able to have pacemaker anti-arrhythmic algorithms
turned off or remain at a stable setting; stable warfarin regimen;
be generally healthy and free from significant comorbid illnesses;
and able to understand study requirements.
[1551] The exclusion criteria were significant structural heart
disease (ejection fraction <45% and congestive heart failure);
abnormal QTc interval (i.e. >470 ms); an abnormal 12-lead
electrocardiogram (ECG); known hypersensitivity to amiodarone or
iodine; chronic treatment with amiodarone within 3 months;
demonstrated lack of efficacy with amiodarone treatment; treatment
with any other investigational drug within 30 days; treatment with
any anti-arrhythmic medication (exclusive of a stable dose of
digoxin or a beta-blocker or calcium blocker) within five
half-lives prior to study entry; major surgery within 3 months
prior to study entry or any surgery within 2 weeks prior to study
entry; or any laboratory assay result that was out of the normal
reference range at screening from a standard battery of blood
chemistry, haematology, and urinalysis tests.
[1552] Patients were enrolled within 8 weeks of screening. During
the study, they were reviewed on days 1, 2, and 8 of each study
period. ATI-2042 was increased on day 1 of each 2-week study
period, following routine bloods for haematology, biochemistry, and
coagulation screens. Plasma samples for pharmacokinetic analysis of
ATI-2042 and its metabolites were taken at steady state at the end
of each study period just prior to the first escalated dose of the
subsequent period and within 15 min prior to the pre-dose ECG for
that dose.
[1553] Patients were then monitored for at least 3 h continuously
post-dose; this included telemetry, vital signs, and oxygen
saturations. Electrocardiograms were taken, and the pacemaker data
were downloaded prior to drug administration on day 8 and day 14 of
each study period.
[1554] Criteria for drug discontinuation included a fall in
systolic blood pressure (BP) to <90 mmHg systolic, an increase
in BP >200 mmHg, intolerable side-effects, a change in rhythm
that in the opinion of the investigator constituted a risk to
safety, or a QRS increase >50%. Where possible, ECGs of
intrinsic rhythm rather than ventricular-paced rhythm were
obtained, as paced complexes can be difficult to interpret for QT
prolongation. An increase in QT interval >470 ms for intrinsic
and >550 ms for paced beats or an increase of 30% was considered
significant.
[1555] The study consisted of six 2-week periods: a baseline period
(p1), four treatment periods (p2-p5), and a washout period where
return to baseline was observed (p6).
[1556] The initial ATI-2042 dosage for all subjects was 200 mg
orally bid, and it was then increased by 200 mg bid for each
subsequent study period. Patients received 200 mg bid of ATI-2042
during period 2, 400 mg bid during period 3, 600 mg bid during
period 4 and 800 mg bid during period 5, and no drug was
administered during baseline and washout periods.
[1557] "Selection 9000" and "T70" pacemakers (Vitatron, Arnhem, The
Netherlands) are dual-chamber pacemakers with sophisticated and
similar algorithms for AF detection and prevention. Atrial
fibrillation detection is based on atrial rate; atrial
tachyarrhythmias are detected when the median atrial cycle length
is less than that programmed for AT or AF detection. In all
patients, atrial fibrillation was detected if the atrial rate was
>200 bpm for six consecutive beats, and its end logged if the
atrial rate dropped below 200 bpm for 10 beats. An arrhythmia diary
of up to 400 episodes and 15 detailed onset reports (DORs) were
recorded with rate profile, interval plots, and electrograms to
confirm diagnosis. Pacemaker anti-arrhythmic algorithms were turned
off prior to entry into the baseline period and remained turned off
until after washout.
[1558] Pacemaker data, for the primary outcome measure AFB, were
downloaded on days 8 and 14 of each 2-week period to allow up to
800 episodes of AF to be recorded.
[1559] The primary outcome measure, AFB, was defined as the
duration of time the subject's cardiac rhythm was AF divided by the
total time recorded for that study period, expressed as percent.
The total duration of time that the rhythm was AF is a function of
the number of PAF episodes and the duration of each episode.
Therefore, a reduction in AFB can occur through reduction in either
or both of these variables. Atrial fibrillation burden was compared
with baseline during the treatment periods. Secondary outcome
measures were the number of AF episodes, the safety of ATI-2042,
and the incidence and severity of adverse events (AEs).
[1560] The minimum study interval was 2 weeks; data were acquired
from the pacemaker and averaged to give a final value. Atrial
fibrillation burden is given as the percentage of total storage
duration.
[1561] The sample size for this study was selected empirically. All
patients who received any amount of study medication were included
in the efficacy and safety analysis. Efficacy variables for the
study group are described as mean and standard deviation for each
study period. Due to the small number of subjects, comparisons of
periods 2-6 with baseline were made using estimates from a
mixed-effects regression model. This model had a fixed, categorical
effect of period and a random patient effect to account for
correlations over time. A P-value of <0.05 was considered
significant.
[1562] Electrocardiogram parameters (ventricular HR, PR, QRS, QT,
QTc interval) were summarized by baseline, dosing period, and
washout using descriptive statistics. Changes from baseline in ECG
values at day 8 of dosing and day 14 of washout were also
summarized. Baseline values of ECG parameters are defined as the
mean of three values recorded prior to the first dose of
ATI-2042.
[1563] An AE was defined as any untoward medical occurrence in a
study subject administered a medicinal product (either study drug
or marketed product), whether or not the event had a causal
relationship with this product.
[1564] Trough concentrations of ATI-2042 and its metabolites
(ATI-2000, ATI-2100, and ATI-2142), measured at pre-dose on day 1
of each of the four treatment periods and on days 1 and 8 of the
washout period, were summarized by time point. Spearman's rank
correlation was used to examine the relationship between trough
concentrations of ATI-2042 and AFB.
[1565] Levels of pacemaker malsensing of AF or over- and
under-sensing were evaluated by the manual examination of each DOR;
this was performed for all patients and or every pacemaker download
throughout the study and confirmed by an independent observer.
[1566] Six females, mean age (SD) 70.8+7.1 years with PAF of mean
duration 4.7+2.3 years, were recruited. One patient withdrew in
period 3 due to gastric AEs (nausea, flatulence, and loose stools)
and for logistical reasons.
[1567] Patients were treated with a mean of 1.8+1.0 AADs, range
1-3, for PAF prior to study entry. Three patients had Vitatron T70
pacemakers and three had Selection 9000s. All patients had
echocardiographic assessments prior to the study; mean (SD) left
atrial diameter 3.66+0.54 cm and mean fractional shortening
41.4+10.7%.
[1568] All patients were compliant with study medication. Mean
trough levels of ATI-2042 were 0.0+0.0 ng/mL at baseline, 2.4+0.9
ng/mL at 200 mg bid, 5.2+1.7 ng/mL at 400 mg bid, 13.1+5.6 ng/mL at
600 mg bid, and 19.8+17.9 ng/mL at 800 mg bid, indicating some dose
proportionality. In washout, trough levels of ATI-2042 were 0.3+0.4
ng/mL, and its metabolites were low or undetectable.
[1569] A summary of ATI-2042 efficacy measures is shown in FIG. 7.
Mean AFB at baseline ranged from 4.6 to 45.3%, mean (SD)
20.3+14.6%. Absolute values of AFB decreased between baseline and
all doses; mean AFB (SD) at 200 mg bid was 5.2+4.2%, at 400 mg bid
5.2+5.2%, at 600 mg bid 2.8+3.4%, and at 800 mg bid 1.5+0.5%. There
was a 71.2+31.3% relative reduction (RR) in p2 from baseline
(P=0.0045), 71.7+20.6% in p3 (P=0.0047), 79.9+26.4% in p4
(P=0.0023), and 86.8+9.8% in p5 (P=0.0013). Atrial fibrillation
burden increased towards baseline in washout; mean (SD) 11.7+14.0%,
range 0.8-38.4 (P=0.1880 compared with baseline).
[1570] The number of AF episodes increased initially with ATI-2042
and remained elevated in washout (FIG. 7). Mean episode duration
(SD) decreased from baseline at 4.8+5.2 to 1.7+2.5 h in p2, to
0.6+0.7 h in p3, to 0.1+0.2 h in p4, to 0.5+0.7 h in p5. Mean
episode duration increased in washout to 2.4+3.0 h, but did not
reach baseline values.
[1571] There were no significant changes in HR, QRS, QT, or QTc
between baseline and dosing or washout. There were no clinically
significant changes in overall ECG interpretation. The PR interval
showed a trend towards decreasing: reductions from baseline were
16.6+23.9% at 200 mg bid, 11.4+22.6% at 400 mg bid, 27.0+32.1% at
600 mg bid, 35.1+30.9% at 800 mg bid, and 30.7+24.3% at washout.
There were no group or individual trends to QT or QTc prolongation
with dosing. One patient exhibited a 30-60 ms change in QTc from
baseline at 400 mg bid; this patient had had a previous
atrioventricular (AV) node ablation and had permanently paced
rhythm. A change in the paced QTc amounted to 15% from baseline. No
patient exhibited >30% change from baseline QT or QTc with
dosing, despite the presence or absence of pacing.
[1572] The drug was generally well tolerated. There were no serious
AEs related to study drug. The number of subjects with AEs was
similar in all groups, and most were of mild severity. The highest
number of AEs was in period 5 (800 mg bid) and the fewest in period
4 (600 mg bid); gastric AEs, including transient nausea,
flatulence, and loose stools, were more prevalent at 800 mg bid,
clinically insignificant biochemical abnormalities at 400 mg bid,
and cardiac AEs (transient palpitations) while taking 200 mg bid of
ATI-2042.
[1573] There were no cases of proarrhythmia, clinical
hypothyroidism, or hyperthyroidism. Three patients demonstrated
dose-responsive increases in thyroid-stimulating hormone, which
were outside the normal range. The level in one patient increased
from 2.53 to 4.82 mU/L (normal range 0.27-4.2), another increased
from 3.51 to 9.49 mU/L, and a third increased from 0.68 to 16.12
mU/L. None was associated with clinical abnormalities, and all
returned towards normal after drug discontinuation in washout.
There were minor fluctuations in free T4 and free T3, which were
felt not to be clinically significant.
[1574] A total of 524 DORs were manually overread for accuracy,
mean 87+69 per patient. A total of 10.9% of the DORs exhibited
under- or over-sensing, and 6.3% of the DORs were undersensed
almost exclusively due to blanking of P waves during AV delay as
opposed to P wave fallout. Over-sensing was entirely due to
farfield R sensing (4.6%) and was present in one patient; this
patient had an excessive inter-electrode distance of 17 mm on the
atrial pacing lead. The mean number of malsensed DORs/patient was
10+12.
[1575] During anti-arrhythmic drug (AAD) development, establishing
human drug efficacy in phase I to III studies is often hindered by
problems of proarrhythmia and tolerability. In addition, arrhythmic
conditions are challenging to treat and evaluate because of
heterogeneous temporal patterns of arrhythmia behavior.
[1576] This study was novel in using the sophisticated data logs of
pacemakers to monitor drug efficacy continuously throughout the
study and to record all episodes of AF including those that were
asymptomatic. Patients with refractory PAF, i.e., those who had
failed at least one AAD therapy were included in this study.
ATI-2042 was significantly effective in reducing AFB at all doses
in this group of patients. The endpoint of AFB can be affected by a
reduction in the number of episodes of AF, indicating an effect on
AF initiation, or by a reduction in the duration of episodes,
indicating an effect on the sustainability of the episodes. In this
study, therapy with ATI-2042 was associated with a mild trend for
the number of episodes to increase with doses up to 600 mg bid, but
this was offset by a substantial shortening of mean AF episode
duration at all doses that reached statistical significance. The
overall effect was a clinically and statistically significant
reduction in AFB.
[1577] It was also apparent that the effects of ATI-2042, despite
its short half-life, have a prolonged cardiac effect after
discontinuation of the drug. Even in washout, AF parameters did not
completely return to baseline. Trough levels of ATI-2042 and its
metabolite were low or negligible within days of drug
discontinuation, making drug persistence unlikely. Results indicate
that even relatively short courses of this drug may promote atrial
reverse-remodeling, which have a carry-over effect longer than its
metabolism.
[1578] Overall, the drug was well tolerated. The absence of the
electrocardiographic changes that were seen in animal testing may
be due to the small sample size and/or the inclusion of patients
with prior AV nodal ablation procedures with paced rhythms. One
patient withdrew due to moderate gastric side effects and
logistical reasons. There were no serious AEs related to study drug
and no cases of proarrhythmia. Minor changes in thyroid function
studies were likely reflective of the iodine content of ATI-2042.
These resolved during continued study drug administration or after
discontinuing the study medication. This pattern of thyroid
function study changes is consistent with those reported for
amiodarone. These findings require additional evaluation in future
studies.
[1579] Paroxysmal atrial fibrillation is a common, distressing
arrhythmia, which is often difficult to treat due to its
heterogeneity and the tendency for AADs with class III action to
exhibit reverse-use dependency. Drugs with multiple classes of
action rather than specific class action, such as amiodarone, are
the most efficacious in treating AF, but many drugs are limited to
low-risk patients because of concerns regarding proarrhythmia.
Amiodarone has been shown to be superior to other AADs in the
maintenance of sinus rhythm post-cardioversion, but it is less
effective in preventing recurrence in PAF than chronic AF. It has a
pharmacokinetic and metabolic profile that contributes to its slow
onset and offset of action and its toxicity. Prescribing class I
agents, such as flecanide and quinidine, tends to be limited to
patients without ischemic heart disease, who have preserved left
ventricular function. This is due to the observation of increased
mortality of post-myocardial infarction patients in the Cardiac
Arrhythmia Suppression Trial (CAST; Echt D S, et al. "Mortality and
morbidity in patients receiving encainide, flecainide or placebo:
the Cardiac Arrhythmia Suppression Trial."
[1580] N Engl J Med 1991; 324:781-8) and concerns regarding
Torsades de Pointes extending to `pure` class III agents such as
dofetilide and ibutilide. New atrio-selective drugs that prolong
atrial refractoriness without significant effects on ventricular
refractoriness or the QT interval appear promising, but are early
in development. In the present study, ATI-2042 was well tolerated
and effective in reducing AFB, with decreases of at least 70% in
AFB at all doses. Its short half-life, rapid onset and offset,
small volume of distribution, and cytochrome P450-independent
elimination represent attractive drug features of an AAD.
[1581] This study used the sophisticated monitoring capacity of
pacemakers to record all episodes of AF and differed from the
conventional means of assessing drug efficacy by the `time to first
recurrence` of AF. `Time to first recurrence` is the time taken for
an atrial tachyarrhythmia to recur post-chemical or electrical
cardioversion. This measure makes the assumption that AF episodes
are uniformly random, i.e. the risk of having an episode at any
given time is uniform. However, recent data from pacemaker and
defibrillator studies suggest a tendency to clustering of
fibrillation episodes with the highest instantaneous risk of AF
being immediately after termination. Human arrhythmia patterns vary
between patients and the majority of episodes are asymptomatic,
making assessment of drug efficacy in PAF patients challenging even
with frequent study follow-up or trans-telephonic monitoring.
Despite the complexities and heterogeneous nature of PAF, we
propose that pacemaker data logs provide a comprehensive
documentation of arrhythmia events. The degree of accuracy of the
pacemaker diagnostics as determined by manual overreading supports
the use of this method to measure AFB. Pacemaker logs may also
monitor for proarrhythmia and can be used with handheld activators
to correlate symptoms with events.
[1582] This study suggests that ATI-2042 is safe, well tolerated
and may reduce AFB in patients with PAF. It has a promising
electrophysiological and pharmacokinetic profile that makes it an
attractive alternative to amiodarone. This study provides support
for further clinical trials that evaluate the use of this
investigational drug in an expanded cohort of patients with PAF and
supports the concept of using implanted pacemaker devices to
monitor AAD efficacy. Such a randomized, double-blind,
placebo-controlled clinical trial of ATI-2042 is described in
Example 2.
Example 2: Budiodarone (ATI-2042) and AF, Round 2
[1583] The objective of the study is to determine the efficacy of
budiodarone in reducing atrial tachyarrhythmia (AT/AF) burden in
patients with paroxysmal atrial fibrillation (PAF) compared to
placebo, for 12 weeks of treatment, and the safety and tolerability
of budiodarone for up to 12 weeks of treatment.
[1584] Secondary: to study the effect of budiodarone versus placebo
on the number and duration of AT/AF episodes, duration of normal
sinus rhythm (NSR) between episodes of AT/AF and on symptoms
associated with PAF.
[1585] Example 2 describes a multicenter, multinational,
randomized, double-blind, placebo-controlled, parallel-group study
of the efficacy and safety of budiodarone in patients with PAF.
Planned enrollment was up to 140 patients (with eventually 110
enrolled) with proven PAF who had permanently implanted pacemakers
with appropriate AT/AF diagnostic and recording capabilities.
Potential study participants underwent screening assessments,
including the optimization of pacemaker programming for accurate
AT/AF detection. Within 30 days after screening assessments began,
eligible patients entered a 4-week baseline period (Period 1) when
baseline atrial fibrillation burden (AFB) was established followed
by randomization to one of three active treatment regimens or
placebo for a 12-week treatment period (Period 2), followed by a
4-week washout period (Period 3). During the treatment period,
patients received twice-daily (BID) oral doses of 200 mg ATI-2042,
400 mg ATI-2042, 600 mg ATI-2042, or placebo. No study drug was
given during the baseline and washout periods.
[1586] 110 patients were enrolled. Of 72 randomized and analyzed:
72 were treated and included in the intent-to-treat (ITT) and
safety population; 60 were in the modified ITT (mITT) population;
and 45 in the efficacy evaluable (EE) population
[1587] Inclusion Criteria were the following: age 18 and above;
proven PAF (electrocardiogram, Holter monitor, or pacemaker
diagnosis obtained by the clinical site or patient's prior medical
record documenting clear evidence of a diagnosis of PAF); pacemaker
with appropriate AF diagnostic and recording capabilities implanted
for at least 6 weeks (additional pacemaker requirements included:
dual chamber with bipolar leads, able to diagnose and log AT/AF
events, able to have AT/AF treatment algorithms turned off, capable
of storing at least 4 weeks AT/AF data between downloads, and able
to record and store electrograms); atrial P waves of adequate
amplitude to allow accurate sensing and assessment of AT/AF
episodes and no obvious indications of frequent oversensing or
undersensing; Able to have pacemaker AT/AF treatment algorithms
turned off for the duration of the study; able to understand study
requirements and willing to follow instructions, attend all
required study visits, and undergo all planned tests; women: unable
to bear children, that is, post-menopausal (absence of vaginal
bleeding or spotting) for at least one year or surgically sterile;
men: starting at the time of study drug administration until
completion of the 12-week treatment period, must have been willing
to use an approved method of contraception (which included use of a
condom with spermicide or use by partner of oral, implantable, or
injectable contraceptives, intrauterine device (IUD), diaphragm
with spermicide) or had a sterile sex partner.
[1588] To be randomized, study participant must have had: an AT/AF
burden between 5% and 70% during the baseline period; no evidence
of persistent AF (i.e., 7 or more consecutive days of AT/AF with
episodes lasting >23 hours); able to have pacemaker atrial
antitachyarrhythmia treatment algorithms turned off for the
remaining duration of the study.
[1589] Efficacy outcome measures were AT/AF burden (total time
spent in AT/AF as a percentage of total observation time), number
and mean duration of AT/AF episodes, mean duration of NSR, patient
global clinical impression (GCI) questionnaire, and University of
Toronto Atrial Fibrillation Severity Scale (AFSS).
[1590] Safety: treatment-emergent adverse event (TEAE) type,
severity, and incidence; clinical laboratory assessments, including
thyroid function and testicular function (males); coagulation
tests; vital signs; physical examinations; ECGs; eye examinations;
chest X-rays; and pulmonary function tests.
[1591] Three analysis populations were used, which were: intent to
treat (ITT; all randomized patients who had at least one assessment
of AT/AF burden during the treatment period); modified intent to
treat (mitt; all randomized patients who had a baseline AT/AF
burden >3%, completed at least the first 4 weeks of treatment,
and had been assessed as usable by the core lab and/or had
over/undersensing detected by core lab adjudication but no gross
violations of pacemaker programming guidelines); and efficacy
evaluable (EE; all randomized patients who had a baseline AT/AF
burden of 3% to 70%, completed at least the first 4 weeks of
treatment, and had been assessed as usable by the core lab).
[1592] Statistical methods for efficacy: The primary efficacy
analysis was the percent change in the AT/AF burden from baseline
to the 12-week treatment period. Pairwise comparisons between each
ATI-2042 dose group and the placebo group were performed using the
Wilcoxon rank sum test. The primary analysis was based on the mITT
population.
[1593] For all variables based on the pacemaker data, the Wilcoxon
rank sum test was used to compare each ATI-2042 dose group to the
placebo group. The Jonckheere-Terpstra test was used to test for a
dose response. The Wilcoxon signed rank test was used to test for a
significant change from baseline within each treatment group. An
analysis of covariance (ANCOVA) was used to compare the percent
change from baseline in AT/AF burden among the treatment groups
after adjusting for the baseline AT/AF burden. The ANCOVA model
contained effects for treatment group and baseline AT/AF
burden.
[1594] For patient GCI, the Cochran-Mantel-Haenszel test was used
to compare each ATI-2042 dose group to the placebo group. The
Jonckheere-Terpstra test was used to test for a dose response.
[1595] Statistical methods for safety: Adverse events (AEs) were
summarized by system organ class and preferred term. Laboratory
parameters and vital signs were summarized by descriptive
statistics and shift tables were also created for laboratory
parameters. The percent of patients with physical examination
findings that changed over the study, with ECG abnormalities by
visit, and with corneal deposits were summarized. Chest X-rays and
pulmonary function test results were provided in listings.
[1596] The ITT/safety population included 72 treated patients.
Among the treated patients, 18 were randomized to placebo, 21 to
200 mg BID, 18 to 400 mg BID, and 15 to 600 mg BID. The mITT
population was comprised of 60 patients and 45 patients comprised
the EE population. Overall, 84.7% of the treated patients completed
the study. The average age was 69.2 years (range, 51 to 88) and
98.6% of patients were white. Males comprised 56.9% and females
43.1% of the treated patients. Overall medical and cardiovascular
history did not show notable differences among treatment groups.
The mean AT/AF burden at screening was comparable across treatment
groups and ranges from 17.8% to 23.4%.
[1597] ATI-2042 at 400 mg BID and 600 mg BID achieved a significant
reduction in AT/AF burden compared to placebo over Treatment Months
1-3. The median percent reductions from baseline were 54% (p=0.015)
and 75% (p=0.006) for the 400 mg BID and 600 mg BID groups,
respectively, in the mITT population, and 54% (p=0.013) and 74%
(p=0.001) in the ITT population (FIG. 1). A significant dose
response (p<0.0001) was seen for the primary endpoint of the
study for both the mITT and ITT populations. The reduction in AT/AF
burden was statistically significant in each of the 3 months of
treatment in both the 400 mg BID and 600 mg BID groups. As the dose
and treatment duration increased the effect became more pronounced.
The maximal effect was seen at Treatment Month 3 (16 weeks) for the
600 mg BID group, with a median percent reduction of 83% (p=0.010)
in the mITT population and 80% (p=0.002) in the ITT population.
[1598] All secondary endpoints showed statistically significant
improvement over Treatment Months 1-3 with 600 mg BID as shown by
median percent changes from baseline in the number of AT/AF
episodes (-62.1% in the mITT and -52.9% in the ITT population),
duration of AT/AF episodes (-51.3% in the mITT population and
-51.3% in the ITT population) and an increase in the duration of
NSR (241.8% in the mITT population and 208.8% in the ITT
population). See FIG. 3 through FIG. 6.
[1599] These are profound results that demonstrate how budiodarone
can prevent or reverse atrial remodeling and reduce stroke risk. As
mentioned above, AF is progressive, with PAF evolving to persistent
and eventually permanent AF--a progression that occurs and
accelerates with greater time spent in AF. That is, what is
initially electrical and thrombotic remodeling on the hours and
days timescale, eventually leads to structural remodeling on the
months and years timescale, and with greater structural remodeling
and greater electrical remodeling comes greater resistance to
cardioversion. FIG. 3 shows that number and duration of AF episodes
were reduced about 70% below baseline for patients on drug 600 mg
drug. FIG. 4 shows that on 600 mg drug, patients' mean episode
duration was reduced to less than 1 hour (down from nearly 24), and
at month 3, the median AF episode duration was 0. More than half
the patients had their AF eradicated during the study period. FIG.
6 shows that for the 600 mg dose group, no patients experienced an
AF episode lasting 24 or more hours. The 400 mg dose cohort
experienced only a single 24 hour episode. Less time in AF,
particularly zero or only sporadic episodes of less than an hour,
is much less likely to cause electrical, thrombotic and structural
remodeling. Moreover, the concomitant increase in time in NSR
enables the reversal of atrial remodeling. Thus, progression of AF
should be retarded, halted or reversed, and stroke risk reduced.
The concomitant administration of a potent anticoagulant on top of
budiodarone will further reduce stroke risk, and likely below the
age-adjusted overall stroke risk, i.e., lower than the general
population not specifically diagnosed with AF. Since budiodarone is
primarily metabolized by esterases, synergistic lowering of stroke
rate with an effective anticoagulant should not be due to
pharmacokinetic interactions raising the effective dose of
anticoagulant (with coincident increase in bleeding risk and
further drug-drug interactions in this patient group highly
susceptible to polypharmacy), but rather pharmacodynamic
synergy.
[1600] Patient GCI Scale showed significant dose responses, with
60.0% of the patients in the ITT population reporting that they
were a lot or completely satisfied with the test medication and
46.7% of patients in the ITT population reporting a lot of
improvement or complete relief in the mITT population. There were
few significant findings for the AFSS survey. There was a positive
trend in the more common AF symptoms of palpitations and shortness
of breath during physical activity when analysis was restricted to
symptomatic patients only.
[1601] All doses of ATI-2042 in this study were well tolerated with
an acceptable overall TEAE profile. The most frequent TEAEs were
changes in INR values. Increases in INR are expected given that
ATI-2042 is an inhibitor of cytochrome P450 2C9 (CYP2C9), which is
a primary metabolism pathway for warfarin, and decreased INR values
were most likely caused by dose adjustments made to lower increased
INRs. Thyroid function changes related to known effects of the drug
were mild and reversible, and in only one case led to
discontinuation of the study medication. There were no dose-related
changes in hematological tests, testicular function tests and the
great majority of chemistry tests. There was a reversible elevation
in creatinine that is undoubtedly due to inhibition of tubular
secretion and did not result in any reduction in glomerular
filtration as evidenced by unchanged BUN levels. There was a mild,
reversible increase in ALT that appeared to be dose related and was
not associated with signs of cholestasis or other signs of liver
injury. There were no notable changes in vital signs, physical
examinations, ECGs, eye examinations, chest X-rays, and pulmonary
function tests, and no safety concerns were identified with
ATI-2042 treatment. No evidence of amiodarone-like end-organ
toxicity was seen (pulmonary fibrosis, corneal deposits,
neuropathy, photosensitivity). There was no evidence of budiodarone
tissue accumulation based on lack of corneal microdeposits on slit
lamp examination at the end of the treatment period.
[1602] The study achieved its primary objectives and demonstrated
the efficacy of ATI-2042 at 400 mg BID and 600 mg BID in reducing
AT/AF burden in patients with PAF, compared to placebo, for 12
weeks of treatment.
[1603] The primary statistical efficacy analysis in the mITT
population showed significance for ATI-2042 at the 400 mg BID
(p=0.015) and 600 mg BID (p=0.005) doses. The AT/AF burden in these
two treatment groups was reduced from baseline by a median of 54%
and 75%, respectively. Although the 200 mg BID dose decreased AFB
by 10%, that did not reach statistical significance.
[1604] The analysis of primary endpoint adjusted for baseline
burden confirmed that the drug was efficacious independently of the
baseline AF burden.
[1605] The overall dose response effect was both robust and linear
with p=0.0001.
[1606] Randomization was balanced across all four treatment
groups.
[1607] The benefit of ATI-2042 on the larger ITT population in
reducing AFB was also highly significant. The percentage reduction
in AFB for the 400 mg BID group was 54% (p=0.013) and for the 600
mg BID group it was 74% (p=0.001). A similarly marked dose response
effect was seen (p<0.0001).
[1608] The efficacy of 600 mg BID in the ITT population was also
demonstrated for the number and duration of AT/AF episodes, and the
mean duration of NSR. There was a significant reduction in both the
number and duration of AT/AF episodes and a corresponding increase
in mean duration of NSR. These results are supportive of the
primary endpoint.
[1609] The efficacy analysis also included a month-by-month
assessment of the patients' burden. The reduction in AFB was
statistically significant in each of the 3 months of treatment in
both the 400 mg BID group and the 600 mg BID group in the ITT
population. As the dose and duration of treatment of ATI-2042 was
increased, the effect of the drug in reducing AFB became more
pronounced. The maximal effect was seen in the third month on 600
mg BID when the median percentage reduction was 83% (p=0.009).
[1610] In each of the three ATI-2042 dose groups, the AFB returned
to essentially the baseline values within the one-month washout
period. The washout data showed no evidence of accumulation or of a
rebound effect in the AFB (FIG. 2).
[1611] The ITT population achieved statistically significant
satisfaction with test medication for all doses tested and reported
statistically significant control of atrial fibrillation symptoms
in the 400 mg BID and 600 mg BID groups.
[1612] The safety of ATI-2042 was demonstrated in this study by the
mild TEAE profile. Only one SAE was possibly related to ATI-2042
(hematuria and high INR) and the discontinuation rate was low and
balanced across the treatment groups.
[1613] The results on thyroid function were not unexpected since
ATI-2042 shares the same iodinated chemical structure as
amiodarone. Amiodarone inhibits the metabolic conversion of T4 to
T3 and it is presumed that ATI-2042 acts in a similar fashion.
Lowering levels of T3 and TSH elevations that were observed in the
study were consistent with this mechanism and with findings from
the previous studies. With the exception of one patient on 200 mg
BID who discontinued due to hyperthyroidism (limited to changes in
laboratory values only) the effects on thyroid function were
considered mild and did not affect study participation.
[1614] INR was monitored closely in this study to allow adjustment
of the warfarin dose as needed for patients on concomitant therapy.
Time within normal range improved in all active drug groups as the
initial dose adjustments were made during the first month of
treatment. The early increase in INR is expected after start of
dosing based on the ability of ATI-2042 to inhibit CYP2C9.
[1615] Chest X-ray and pulmonary function tests were performed
during the study to monitor for the symptoms of amiodarone
pulmonary toxicity. No safety concern was identified.
[1616] Because amiodarone is known to accumulate in the cornea and
form microcrystalline deposits, slit-lamp examinations were
performed. No patient treated with ATI-2042 developed corneal
deposits during the study. Together with the washout period data,
these findings provide evidence of the lack of tissue accumulation
of ATI-2042 and its metabolites.
[1617] This, budiodarone significantly reduced AFB at doses of 400
mg BID and 600 mg BID, and appeared to be safe and tolerable at
these doses. This was the first controlled study to use permanently
implanted pacemakers to continuously record AFB. Use of AFB as a
continuously recorded variable offers several advantages. It allows
a patient to serve as his or her own control; it accounts for both
symptomatic and asymptomatic episodes, thus providing a more
accurate measure of clinical response than measurements triggered
only by symptoms; and it allows establishment of a dose-response
curve with fewer patients than, for example, traditional time to
first symptomatic recurrence studies.
[1618] The patients recruited for this study had a mean AT/AF
burden at screening that ranged from a 17.8% to 23.4%. This is a
significant amount of time spent in atrial fibrillation as opposed
to normal sinus rhythm. The time spent in atrial fibrillation,
especially long duration episodes, has been correlated with
increased risk of stroke. For a patient who is experiencing
symptoms of atrial fibrillation, this amount of AF also may present
a serious quality of life issue.
[1619] ATI-2042 was well tolerated, including in CHF NYHA Class I
and II patients in this study, and did not exhibit any of the side
effects associated with amiodarone accumulation in peripheral
tissues. There were no corneal deposits, no evidence of pulmonary
toxicity or photosensitivity.
[1620] The significant reduction of AFB, shortening of atrial
fibrillation episodes and increase in duration of normal sinus
rhythm achieved by ATI-2042 in this study thus suggests that
budiodarone can offer a considerable advantage for the patient.
[1621] The ACs and anti-arrhythmic drugs described herein may be
administered together in dosage unit form or as separate,
independent dosages, and each, independently, can be administered
orally or parenterally (and preferably orally or intravenously) in
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles. The term parenteral as
used herein includes percutaneous, subcutaneous, intravascular
(e.g., intravenous), intramuscular, or intrathecal injection or
infusion techniques and the like. In addition, there is provided a
pharmaceutical formulation comprising an AC, an anti-arrhythmic and
a pharmaceutically acceptable carrier. One or more AC and
anti-arrhythmics described herein may be present in association
with one or more non-toxic pharmaceutically acceptable carriers
and/or diluents and/or adjuvants, and if desired other active
ingredients. The pharmaceutical compositions containing compounds
described herein may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[1622] Formulations are described in detail in a number of sources
that are well known and readily available to those skilled in the
art. For example, Remington's Pharmaceutical Science by E. W.
Martin describes formulations that can be used in connection with
the subject invention. In general, the compositions of the subject
invention will be formulated such that an effective amount of the
bioactive compound(s) is combined with at least one suitable
carrier, solvent, excipient, and/or adjuvant in order to facilitate
effective administration of the composition.
[1623] In accordance with the invention, pharmaceutical
compositions comprising, as an active ingredient, an effective
amount of one or more of the compounds described herein and one or
more non-toxic, pharmaceutically acceptable carrier(s) and/or
diluent(s). Examples of such carriers for use in the invention
include ethanol, dimethylsulfoxide, glycerol, silica, alumina,
starch, and equivalent carriers and diluents.
[1624] Further, acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories and dispersible granules. A solid carrier
can be one or more substances that may act as diluents, flavoring
agents, solubilizers, lubricants, suspending agents, binders,
preservatives, tablet disintegrating agents or an encapsulating
material.
[1625] The disclosed pharmaceutical compositions may be subdivided
into unit doses containing appropriate quantities of the active
component. The unit dosage form can be a packaged preparation, such
as packeted tablets, capsules, and powders in paper or plastic
containers or in vials or ampoules.
[1626] The terms "individual(s)" and "patient(s)" are defined as a
mammal to which is administered a compound of the present
invention. The mammal may be, for example, a pig, a horse, a
rabbit, a goat, a cow, a cat, a dog, or can be a human. In a
preferred embodiment, the individual is a human.
[1627] All patents, patent applications, provisional applications,
and publications referred to or cited herein are incorporated by
reference in their entirety, including all figures and tables, to
the extent they are not inconsistent with the explicit teachings of
this specification.
[1628] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application.
[1629] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the invention and that
modifications may be made therein without departing from the spirit
or scope of the invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *