U.S. patent application number 17/730501 was filed with the patent office on 2022-08-11 for early administration of low-dose colchicine after myocardial infarction.
The applicant listed for this patent is INSTITUT DE CARDIOLOGIE DE MONTREAL. Invention is credited to Jean-Claude TARDIF.
Application Number | 20220249409 17/730501 |
Document ID | / |
Family ID | 1000006290811 |
Filed Date | 2022-08-11 |
United States Patent
Application |
20220249409 |
Kind Code |
A1 |
TARDIF; Jean-Claude |
August 11, 2022 |
EARLY ADMINISTRATION OF LOW-DOSE COLCHICINE AFTER MYOCARDIAL
INFARCTION
Abstract
The invention relates to colchicine for use in a method of
treating a patient after having a myocardial infarction (MI), the
method including initiating the administration of colchicine at a
daily low dose to the patient within about 3 days of the MI.
Inventors: |
TARDIF; Jean-Claude;
(Montreal, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INSTITUT DE CARDIOLOGIE DE MONTREAL |
Montreal |
|
CA |
|
|
Family ID: |
1000006290811 |
Appl. No.: |
17/730501 |
Filed: |
April 27, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17097285 |
Nov 13, 2020 |
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17730501 |
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63093988 |
Oct 20, 2020 |
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62935865 |
Nov 15, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/10 20180101; A61K
31/165 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61P 9/10 20060101 A61P009/10 |
Claims
1. A method of treating a patient after having a myocardial
infarction (MI), the method comprising initiating the
administration of colchicine at a daily low dose to the patient
within about 3 days of the MI.
2. The method according to claim 1, wherein percutaneous coronary
intervention was performed for treating the patient's MI.
3. The method according to claim 1, wherein the patient was
prescribed a medication.
4. The method according to claim 3, wherein the medication is an
antiplatelet agent.
5. The method according to claim 3, wherein the medication is
aspirin.
6. The method according to claim 3, wherein the medication is a
statin.
7. The method according to claim 1, wherein the patient is at a
lower risk of a cardiovascular event, relative to a patient not
being administered colchicine.
8. The method according to claim 7, wherein the cardiovascular
event is an ischemic cardiovascular event.
9. The method according to claim 7, wherein the cardiovascular
event is resuscitated cardiac arrest.
10. The method according to claim 7, wherein the cardiovascular
event is myocardial infarction.
11. The method according to claim 7, wherein the cardiovascular
event is stroke.
12. The method according to claim 7, wherein the cardiovascular
event is urgent hospitalization for angina requiring coronary
revascularization.
13. The method according to claim 1, wherein the patient has
atherosclerotic coronary artery disease.
14. The method according to claim 1, wherein the administration of
colchicine is initiated upon assessment in (a) an emergency
department (ED), (b) the hospital, or (c) a medical office
setting.
15. The method according to claim 1, wherein the colchicine is in
the form of a tablet.
16. The method of claim 15, wherein the tablet is coated.
17. The method of claim 16, wherein the tablet is film-coated.
18. The method according to claim 1, wherein the colchicine is
administered at 0.3 to 0.7 mg.
19. The method according to claim 18, wherein the colchicine is
administered at 0.4 to 0.6 mg
20. The method according to claim 16, wherein the colchicine is
administered at 0.5 mg.
21. The method according to claim 9, wherein the colchicine is
administered at 0.5 mg.
22. The method according to claim 10, wherein the colchicine is
administered at 0.5 mg.
23. The method according to claim 11, wherein the colchicine is
administered at 0.5 mg.
24. The method according to claim 12, wherein the colchicine is
administered at 0.5 mg.
25. The method according to claim 1, wherein the colchicine is
administered once, twice or three times a day.
26. The method according to claim 25, wherein the colchicine is
administered once per day.
27. The method according to claim 1, wherein the colchicine is
administered without pre-loading the patient with colchicine.
28. The method according to claim 1, wherein the patient is an
adult human.
29. A method of reducing the risk of a stroke in a patient after
having an MI, the method comprising initiating the administration
of colchicine at a daily low dose to the patient within about 30
days of an MI.
30. The method according to claim 29, wherein the method comprises
administering colchicine within 4 to 7 days of the MI.
Description
BACKGROUND OF THE INVENTION
[0001] The invention relates to a treatment regimen for patients
after suffering a myocardial infarction.
[0002] Inflammation appears to play an important role in
atherosclerosis (Hansson G K, Inflammation, atherosclerosis, and
coronary artery disease. N Engl J Med 2005; 352:1685-95).
Inhibition of interleukin-1.beta. by the injectable monoclonal
antibody canakinumab led to a 15% lower risk of cardiovascular
events than was observed with placebo in the Canakinumab
Antiinflammatory Thrombosis Outcomes Study (CANTOS) but also led to
a slightly higher incidence of fatal infections (Ridker P M et al.,
Antiinflammatory therapy with canakinumab for atherosclerotic
disease. N Engl J Med 2017; 377:1119-31). In contrast, methotrexate
did not affect cardiovascular outcomes or plasma markers of
inflammation in the Cardiovascular Inflammation Reduction Trial
(CIRT) (Ridker P M et al., Low-dose methotrexate for the prevention
of atherosclerotic events. N Engl J Med 2019; 380:752-62).
Considering these differing results and given that canakinumab is
not clinically available for cardiovascular prevention, the search
for a widely used alternative antiinflammatory treatment that may
reduce the risk of atherosclerotic events among patients with
coronary artery disease continues.
[0003] Colchicine is an inexpensive, orally administered, potent
anti-inflammatory medication that was initially extracted from the
autumn crocus and has been used for centuries. Its mechanism of
action is through the inhibition of tubulin polymerization and
microtubule generation and, possibly, effects on cellular adhesion
molecules, inflammatory chemokines, and the inflammasome (Ravelli R
B et al., Insight into tubulin regulation from a complex with
colchicine and a stathmin-like domain. Nature 2004; 428:198-202;
Perico N et al., Colchicine interferes with L-selectin and
leukocyte function-associated antigen-1 expression on human T
lymphocytes and inhibits T cell activation. J Am Soc Nephrol 1996;
7:594-601; Pope R M and Tschopp J, The role of interleukin-1 and
the inflammasome in gout: implications for therapy. Arthritis Rheum
2007; 56:3183-8). Colchicine is currently indicated for the
treatment of gout, familial Mediterranean fever, and pericarditis
(Cerquaglia C et al., Pharmacological and clinical basis of
treatment of Familial Mediterranean Fever (FMF) with colchicine or
analogues: an update. Curr Drug Targets Inflamm Allergy 2005;
4:117-24; and Imazio M et al., Colchicine in addition to
conventional therapy for acute pericarditis: results of the
COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;
112:2012-6).
[0004] In the Low-Dose Colchicine (LoDoCo) trial, patients with
stable coronary disease treated with colchicine at a dose of 0.5 mg
once daily had fewer cardiovascular events than those not receiving
colchicine (Nidorf S M et al., Low-dose colchicine for secondary
prevention of cardiovascular disease. J Am Coll Cardiol 2013;
61:404-10). However, that trial enrolled only 532 patients and was
not placebo-controlled.
[0005] Because acute coronary syndromes are associated with higher
risks of recurrent events and exacerbated inflammation a need
exists in the art for new treatment regimens.
SUMMARY OF THE INVENTION
[0006] A clinical trial referred to as the Colchicine
Cardiovascular Outcomes Trial (COLCOT) was conducted to evaluate
the effects of colchicine on cardiovascular outcomes as well as its
long-term safety profile in patients who had recently had a
myocardial infarction.
[0007] The results of the COLCOT trial support that the use of
colchicine in patients who have recently had a myocardial
infarction significantly improved their quality of life in several
ways. Colchicine at a daily low dose of 0.5 mg led to a
statistically significant lower risk of ischemic cardiovascular
events than placebo. Death from cardiovascular causes, resuscitated
cardiac arrest, myocardial infarction, stroke, and urgent
hospitalization for angina leading to coronary revascularization
was also significantly lower among the patients who received 0.5 mg
of colchicine than those who received placebo. Patients receiving
low dose colchicine had reduced morbidity relative to placebo, as
is demonstrated by the rates of the respective primary composite
end points for the two patient populations (P=0.02). This reduction
in morbidity was particularly prominent among colchicine-receiving
patients in the reduction of severe conditions, such as stroke and
urgent hospitalization for angina leading to revascularization:
hazard ratios are 0.26 (95% confidence interval is 0.10-0.70) and
0.50 (95% confidence interval is 0.31-0.81), respectively. Still
further, unlike the use of the anti-inflammatory canakinumab for
atherosclerotic events, colchicine did not increase the incidence
of septic shock. Moreover, no serious adverse event of myopathy
linked to colchicine occurred despite the use of statins in 99% of
trial participants.
[0008] The results of the COLCOT trial have been further analyzed
to determine if time to treatment initiation (TTI) had any effect
on the outcome of the treatment. Three different cutoffs for TTI
were used in order to determine the association between early
initiation of therapy and clinical outcomes. These cutoffs were
determined based on the usual journey of patients with MI. The
first 30-day post-MI timeline was divided into three independent
periods of time, and analyzed as such: from day 0 to 3, referring
to in-hospital management; from day 4 to 7, referring to early
post-discharge period and from day 8 to 30, referring to late
post-discharge period.
[0009] The main COLCOT results revealed that colchicine reduced the
risk of ischemic CV events by 23% in the post-MI setting. Results
from the present TTI analysis support that early suppression of
inflammation after MI provides even greater benefits, with a
reduction of 48% in the risk of the composite primary endpoint when
colchicine was initiated between days 0 and 3. The demonstrated
cost-effectiveness of low-dose colchicine also supports its
large-scale use after MI. Results of the LoDoCo2 study of patients
with stable coronary artery disease complement those of COLCOT in
the post-MI setting.
[0010] In view of the aforementioned, the invention, in one aspect,
relates to colchicine for use in a method of treating a patient
alter having a myocardial infarction (MI), the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 3 days of the MI.
[0011] In another aspect, the invention relates to a colchicine for
use in a method of treating a patient after having a MI; the method
comprising initiating the administration of colchicine at a daily
low dose to the patient within about 4 days of the MI.
[0012] In another aspect, the invention relates to a colchicine for
use in a method of treating a patient after having a MI; the method
comprising initiating the administration of colchicine at a daily
low dose to the patient within about 5 days of the MI.
[0013] In another aspect, the invention relates to a colchicine for
use in a method of treating a patient after having a MI, the method
comprising initiating the administration of colchicine at a daily
low dose to the patient within about 30 days of the MI.
[0014] In another aspect, the invention relates to a method of
treating a patient after having a MI, the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 3 days of the MI.
[0015] In another aspect, the invention relates to a method of
treating a patient after having a MI, the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 4 days of the MI.
[0016] In another aspect, the invention relates to a method of
treating a patient after having a MI, the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 5 days of the MI.
[0017] In another aspect, the invention relates to a method of
treating a patient after having a MI, the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 30 days of the MI.
[0018] In another aspect, the invention relates to the use of a
daily low dose of colchicine for treating a patient after having a
MI, wherein the use is initiated within about 3 days of the MI.
[0019] In another aspect, the invention relates to the use of a
daily low dose of colchicine for treating a patient after having a
MI, wherein the use is initiated within about 4 days of the MI.
[0020] In another aspect, the invention relates to the use of a
daily low dose of colchicine for treating a patient after having a
MI, wherein the use is initiated within about 5 days of the MI.
[0021] In another aspect, the invention relates to the use of a
daily low dose of colchicine for treating a patient after having a
MI, wherein the use is initiated within about 30 days of the
MI.
[0022] In a further aspect, the invention: relates to the use of
colchicine for the manufacture of a medicament for treating a
patient after having a MI, wherein the colchicine is a low dose
colchicine for daily administration initiated within about 3 days
of the MI.
[0023] In a further aspect, the invention relates to the use of
colchicine for the manufacture of a medicament for treating a
patient after having a MI, wherein the colchicine is a low dose
colchicine for daily administration initiated within about 4 days
of the MI.
[0024] In a further aspect, the invention relates to the use of
colchicine for the manufacture of a medicament for treating a
patient after having a MI, wherein the colchicine is a low dose
colchicine for daily administration initiated within about 5 days
of the MI.
[0025] In a further aspect, the invention relates to the use of
colchicine for the manufacture of a medicament for treating a
patient after having a MI, wherein the colchicine is a low dose
colchicine for daily administration initiated within about 30 days
of the MI.
[0026] In another aspect, the present invention relates to low-dose
colchicine for use in treating a patient having a MI, wherein the
colchicine is for daily administration initiated within about 3
days of the MI.
[0027] In another aspect, the present invention relates to low-dose
colchicine for use in treating a patient having a MI, wherein the
colchicine is for daily administration initiated within about 4
days of the MI.
[0028] In another aspect, the present invention relates to low-dose
colchicine for use in treating a patient having a MI, wherein the
colchicine is for daily administration initiated within about 5
days of the MI.
[0029] In another aspect, the present invention relates to low-dose
colchicine for use in treating a patient having a MI, wherein the
colchicine is for daily administration initiated within about 30
days of the MI.
[0030] In some embodiments, the method involves administering
colchicine within 5 days of the MI (for example, at 1 day, 2 days,
3 days, or 4 days). In some embodiments, the method includes
administering colchicine within 4 days of the myocardial infarction
(for example, at 1 day, 2 days, or 3 days), in still other
embodiments, the method includes administering colchicine within 3
days of the myocardial infarction (for example, at 1 day or 2
days).
[0031] In some embodiments, the patient administered colchicine
received percutaneous coronary intervention for treating the
patient's myocardial infarction.
[0032] In some embodiments, the myocardial infarction is acute MI
(AMI). In some embodiments, the MI is not type 2 MI.
[0033] In some embodiments, the patient administered was previously
prescribed a medication (for example, an antiplatelet agent, a
statin, aspirin or a combination thereof).
[0034] In some embodiments, the patient administered is
concurrently being treated with a medication (for example, an
antiplatelet agent, a statin, aspirin, or a combination
thereof).
[0035] In some embodiments, the patient is at a lower risk of a
cardiovascular event, relative to a patient not being administered
colchicine. For example, the cardiovascular event is an ischemic
cardiovascular event. In some embodiments, the cardiovascular event
is cardiovascular death, resuscitated cardiac arrest, myocardial
infarction, stroke, or urgent hospitalization for angina requiring
coronary revascularization.
[0036] In some embodiments, the patient has atherosclerotic
coronary artery disease.
[0037] In some embodiments the patient does not have severe heart
failure, reduced left ventricular fraction, recent stroke, type 2
MI, planned coronary artery bypass by graft (CABG), inflammatory
bowel disease or chronic diarrhea.
[0038] In another aspect, the invention relates to a method of
reducing the risk of or preventing a stroke in a patient after
having an MI, the method comprising initiating the administration
of colchicine at a daily low dose to the patient within about 30
days of an MI.
[0039] In some embodiments, the method involves administering
colchicine within 4-7 days (for example, 5 days, 6 days, or 7 days)
of the MI.
[0040] In some embodiments, the method involves administering
colchicine within 3 days of the MI.
[0041] In another aspect, the invention relates to the use of a
daily low dose of colchicine for reducing the risk of or preventing
a stroke in a patient after having a MI, wherein the use is
initiated within 30 days of the MI.
[0042] In another aspect, the invention relates to the use of a
daily low dose of colchicine for reducing the risk of or preventing
a stroke in a patient after having a MI, wherein the use is
initiated between 4-7 days after the MI.
[0043] In some embodiments, the invention relates to the use of a
daily low does of colchicine for reducing the risk of or preventing
a stroke in a patient after having a MI, wherein the use is
initiated within 3 days of the MI.
[0044] In a further aspect, the invention relates to the use of
colchicine for the manufacture of a medicament for reducing the
risk of or preventing a stroke in a patient after having a MI,
wherein the colchicine is a low dose colchicine for daily
administration initiated within 30 days of the MI.
[0045] In a further aspect, the invention relates to the use of
colchicine for the manufacture of a medicament for reducing the
risk of or preventing a stroke in a patient after having a MI,
wherein the colchicine is a low dose colchicine for daily
administration initiated between 4 and 7 days of the MI.
[0046] In another aspect, the present invention relates to the use
of colchicine for the manufacture of a medicament for reducing the
risk of or preventing stroke in a subject after having a MI,
wherein the colchicine is for daily administration initiated within
about 3 days of the MI.
[0047] In some embodiments, the administration of colchicine is
initiated upon assessment in (a) an emergency department (ED), (b)
the hospital, or (c) a medical office setting.
[0048] In some embodiments, colchicine is administered in the form
of a tablet or a capsule (e.g., a coated tablet or capsule). In
some embodiment, colchicine is administered in the form of a
film-coated tablet.
[0049] In some embodiments, colchicine is administered at 0.3 to
0.7 mg. For example, colchicine is administered at 0.4 to 0.6 mg,
and is preferably administered at about 0.5 mg. In some
embodiments, colchicine is administered in a 0.5 mg tablet or a 0.6
mg tablet. In other embodiments, colchicine is administered in a
0.25 mg tablet.
[0050] In some embodiments, colchicine is administrated once,
twice, or three times daily.
[0051] In some embodiments, colchicine is administered once per
day.
[0052] In some embodiments, the colchicine is administered without
pre-loading the patient with colchicine (e.g., administering a
higher dose, such as 1.0 mg per day or higher (1.5 mg or 2.0 mg) in
a single or multiple doses, at the onset of the treatment for one,
two, or three days before switching to a lower dose of, e.g., 0.5
mg per day, for the remainder of the duration of treatment).
[0053] In some embodiments, the patient is an adult human (i.e.,
the patient is 18 years old or older).
[0054] In another aspect, the invention relates to colchicine for
use in a method of treating a patient after having a myocardial
infarction (MI), the method including the administration of
colchicine at a daily low dose to the patient within about 3 days
(e.g., 1 day, 2 days, and 3 days) of the MI.
[0055] Use of colchicine for treating a patient after having a
myocardial infarction typically continues, as needed, throughout
the life of a patient. For example, in some embodiments, the
duration of treatment is for 6 months, 12 months, 18 months, 24
months, 30 months, 36 months, or even longer as is needed. In some
embodiments, the duration of the treatment is for at least about 23
months.
[0056] Various colchicine formulations, including film-coated
tablets, are readily available and well known in the art.
[0057] Other features and advantages of the invention will be
apparent from the following Detailed Description, the Drawings, and
the Claims.
Definitions
[0058] As used herein, the term "cardiovascular death" refers to
death resulting from a cardiovascular disease, including coronary
heart disease, cerebrovascular disease, peripheral arterial
disease, rheumatic heart disease, congenital heart disease, deep
vein thrombosis, or a pulmonary embolism, or sudden cardiac event,
including cardiac arrest and myocardial infarction.
[0059] As used herein, the term "myocardial infarction" refers to a
cardiovascular disorder characterized by localized necrosis
resulting from obstruction of the blood supply. MI may be
classified as an ST elevation myocardial infarction (STEW) or
Non-ST elevation myocardial infarction (NSTEMI) based on the
results of an ECG. A more explicit classification system, based on
international consensus in 2012, also exists. This classifies
myocardial infarctions into five types including types 1 and 2.
Type-1 AMI is caused by an acute atherothrombotic coronary event;
type-2 AMI is a more heterogeneous entity, where a condition other
than coronary artery disease (CAD) contributes to an acute
imbalance between oxygen supply (e.g., hypoxemia, anemia,
hypotension) and demand (e.g., tachycardia, hypertension).
[0060] As used herein, the term "resuscitated cardiac arrest"
refers an abrupt loss of heart function resulting in a loss of
blood flow to the body which requires the subject be resuscitated
using any method known to one of skill in the art, including
cardiopulmonary resuscitation or a defibrillator.
[0061] As used herein, the term "urgent hospitalization for angina
requiring coronary revascularization" refers to an immediate need
for a patient to be hospitalized due to severe chest discomfort
felt due to ischemic heart disease which requires surgical
intervention grafting and/or stenting approaches to improving blood
flow to the heart and relieve angina.
[0062] As used herein, the term "stroke" refers to a condition
which occurs when the blood supply to a part of the brain is
suddenly interrupted (i.e., ischemic stroke) or when a blood vessel
in the brain bursts and releases blood into the spaces surrounding
the brain cells (i.e., hemorrhagic stroke). The symptoms of a
stroke include numbness or weakness, especially on one side of the
body corresponding to the contralateral side of the stroke,
confusion, trouble understanding or producing speech, impaired
vision in both eyes, impaired mobility, dizziness, or loss of
balance or coordination. Stroke may be diagnosed using several
techniques, such as, e.g., neurological examination, blood testing,
computed tomography (CT) scan, magnetic resonance imaging (MRI)
scan, Doppler ultrasound, and arteriography. Although stroke is a
disease of the brain, it can affect the entire body by causing,
e.g., paralysis, cognitive impairment, speech impairment, emotional
dysregulation, and pain.
BRIEF DESCRIPTION OF THE DRAWINGS
[0063] FIG. 1 is a schematic of a flow chart of the randomization
and subject disposition of the patients in the Time-to-Treatment
study.
[0064] FIG. 2 is a graph of the association between the
time-to-treatment initiation and the adjusted hazard ratio (solid
line) with the 95% confidence intervals of the adjusted hazard
ratio (dashed line) calculated using a quadratic multivariable Cox
regression model.
[0065] FIG. 3A is a graph of the cumulative incidence of
cardiovascular events (time-to-treatment population). Shown are the
Kaplan-Meier event curves for the primary efficacy composite end
point (a composite of cardiovascular death, resuscitated cardiac
arrest, MI, stroke, or urgent hospitalization for angina requiring
coronary revascularization) in the colchicine group and the placebo
group for patients with a time-to-treatment initiation of .ltoreq.3
days. The inset shows the same data on an enlarged y-axis.
[0066] FIG. 3B is a graph of the cumulative incidence of
cardiovascular events (time-to-treatment population). Shown are the
Kaplan-Meier event curves for the secondary efficacy composite end
point (a composite of cardiovascular death, resuscitated cardiac
arrest, myocardial infarction, or stroke) in the colchicine group
and the placebo group for patients with a time-to-treatment
initiation of days. The inset shows the same data on an enlarged
y-axis.
DETAILED DESCRIPTION OF THE INVENTION
[0067] We performed a randomized, double-blind trial involving
patients recruited within 30 days after a myocardial infarction.
The patients were randomly assigned to receive either low-dose
colchicine (0.5 mg once daily) or placebo. A total of 4745 patients
were enrolled; 2366 patients were assigned to the colchicine group,
and 2379 to the placebo group. Patients were followed for a median
of 22.6 months.
[0068] The primary efficacy end point was a composite of death from
cardiovascular causes, resuscitated cardiac arrest, myocardial
infarction (e.g., acute myocardial infraction or type II myocardial
infarction), stroke, or urgent hospitalization for angina leading
to coronary revascularization. The components of the primary end
point and safety were also assessed.
Study Design and Patient Population
[0069] COLCOT was an international multicenter, randomized,
double-blinded trial that randomly assigned patients to receive
either low-dose colchicine (0.5 mg once daily) or placebo. The
study protocol and main results have been published (see, Tardif et
al., N Engl J Med 2019). Patients were considered eligible if they
had a recent MI (<30 days). Main exclusion criteria were severe
heart failure, reduced left ventricular ejection fraction
(<35%), recent stroke (<3 months), type 2 MI, recent (<3
years) or planned coronary artery bypass graft (CABG), history of
cancer (<3 years), and inflammatory bowel disease or chronic
diarrhea. All patients enrolled in the trial benefited from
percutaneous coronary intervention whenever indicated and
guidelines-directed management of CV disease prior to randomization
(see. Tardif et al., N Engl J Med 2019).
[0070] Clinical follow-up consisted of evaluations at 1 and 3
months after randomization and every 3 months thereafter. An
independent clinical endpoint committee, blinded to trial-group
assignment, adjudicated clinical endpoints. The trial was locally
approved by the various institutional review boards, and all
patients signed a written informed consent before enrollment.
Efficacy Endpoints
[0071] The primary efficacy endpoint was a composite of CV death,
resuscitated cardiac arrest, MI, stroke, or urgent hospitalization
for angina requiring coronary revascularization. The secondary
endpoints consisted of the components of the primary efficacy
endpoint, all-cause death, and a composite of CV death,
resuscitated cardiac arrest, MI, or stroke. Exploratory endpoints
included all coronary revascularizations, including both elective
and urgent coronary revascularizations.
Cutoffs for Time-to-Treatment Initiation (TTI) of Colchicine
[0072] Three different cutoffs for TTI were used in order to
determine the association between early initiation of therapy and
clinical outcomes. These cutoffs were determined based on the usual
journey of patients with MI. The first 30-day post-MI timeline was
divided into three independent periods of time, and analyzed as
such: from day 0 to 3, referring to in-hospital management; from
day 4 to 7, referring to early post-discharge period and from day 8
to 30, referring to late post-discharge period.
Results
Baseline Characteristics for Patients in TTI Analysis
[0073] Of the 4745 patients randomized in COLCOT, 4661 were
included in the TTI analysis (colchicine, N=2322; placebo, N=2339)
(FIG. 1). Overall, patients were randomized at 13.5.+-.10.1 days
following the index MI, 25.6% between days 0 and 3, 15.4% between
days 4 and 7 and 59.0% at day 8 or after. Baseline characteristics
were similar between the colchicine and placebo groups (Table 1).
Patients were mostly men (81.0%) with a mean age of 60.5 years,
20.2% had diabetes, 51.0% had a history of hypertension, 29.7% were
active smokers, and 16.8% had had a prior PCI. Background therapy
included aspirin, a second anti-platelet agent and a statin in
98.8%, 98.0% and 99.0% of patients, respectively. The vast majority
of patients (93.0%) underwent percutaneous coronary intervention
(PCI) during the index hospitalization, with no difference in terms
of time to PCI between the two groups.
TABLE-US-00001 TABLE 1 Baseline Characteristics according to
treatment allocation for Time-to-Treatment Initiation (TTI) All
patients Colchicine group Placebo group Characteristics N = 4661 N
= 2322 N = 2339 Age (years) - 60.5 .+-. 10.6 60.6 .+-. 10.6 60.5
.+-. 10.6 mean .+-. SD Male sex - no. (%) 3774 (81.0%) 1861 (80.1%)
1913 (81.8%) BMI (kg/m.sup.2) - 28.3 .+-. 4.7 28.2 .+-. 4.8 28.4
.+-. 4.7 mean .+-. SD Current Smoking - 1382/4659 (29.7) 694/2322
(29.9%) 688/2337 (29.4%) no./total no. (%) History of 2377 (51.0%)
1160 (50.0%) 1217 (52.0%) Hypertension - no. (%) History of 942
(20.2%) 451 (19.4%) 491 (21.0%) Diabetes - no. (%) Prior MI - no.
(%) 751 (16.1%) 360 (15.5%) 391 (16.7%) Prior PCI - no. (%) 783
(16.8%) 382 (16.5%) 401 (17.1%) Prior CABG - 146 (3.1%) 66 (2.8%)
80 (3.4%) no. (%) Prior HF - no. (%) 90 (1.9%) 48 (2.1%) 42 (1.8%)
Prior Stroke or 119 (2.6%) 53 (2.3%) 66 (2.8%) TIA - no. (%) PCI
associated 4336 (93.0%) 2154 (92.8%) 2182 (93.3%) with the index
event - no. (%) Medication use - no. (%): Aspirin 4605 (98.8%) 2291
(98.7%) 2314 (98.9%) Other antiplatelet 4567 (98.0%) 2267 (97.6%)
2300 (98.3%) agent Statin 4615 (99.0%) 2297 (98.9%) 2318 (99.1%)
Beta-blocker 4143 (88.9%) 2077 (89.4%) 2066 (88.3%) TTI 0-3 days -
1193 (25.6%) 604 (26.0%) 589 (25.2%) no. (%) TTI 4-7 days - 720
(15.4%) 364 (15.7%) 356 (15.2%) no. (%) TTT .gtoreq. 8 days - 2748
(59.0%) 1354 (58.3%) 1394 (59.6%) no. (%) Time from 13.5 .+-. 10.1
13.5 .+-. 10.1 13.5 .+-. 10.0 index MI to randomization (days) -
mean .+-. SD Time from Index 1.4 .+-. 2.9 1.4 .+-. 2.9 1.4 .+-. 2.9
MI to PCI (days) - mean .+-. SD Time from PCI to 11.9 .+-. 9.9 11.9
.+-. 9.9 11.9 .+-. 9.9 randomization (days) - mean .+-. SD
Abbreviations: CABG, coronary-artery bypass graft surgery; HF,
heart failure; PCI, percutaneous coronary intervention; TIA,
transient ischemic attack. Data were missing on the following
characteristics: age (assessed according to date of birth; see
below) for 431 patients (213 in the colchicine group and 218 in the
placebo group) and body-mass index (the weight in kilograms divided
by the square of the height in meters) for 5 (1 and 4 patients,
respectively). Date of birth was not required field because it was
considered in some countries to be sensitive data that could allow
for the identification of patients. For statistical reporting,
missing information regarding the day of birth was replaced by 15,
and missing information regarding the month and day of birth was
replaced by July 1.
[0074] Baseline characteristics according to TTI strata are shown
in Table 2. Patients in whom therapy was initiated between days 0
and 3, when compared to those at days 8 to 30, were younger
(59.1.+-.10.8 vs. 61.3.+-.10.4 years) and more often active smokers
(43.8 vs. 20.2%), had less commonly hypertension (41.1 vs. 56.2%)
and diabetes (17.4 vs. 22.0%) but underwent more often PCI
associated with the index MI (95.8 vs. 91.3%), all p<0.05.
TABLE-US-00002 TABLE 2 Baseline characteristics according to TTI
TTI 0-3 days TTI 4-7 days TTI .gtoreq. 8 days Characteristics N =
1193 N = 720 N = 2748 p* p** Age (years) - 59.1 .+-. 10.8 60.1 .+-.
11.0 61.3 .+-. 10.4 <0.0001 <0.0001 mean .+-. SD Male sex -
no. (%) 980 (82.2%) 605 (84.0%) 2189 (80.0%) 0.014 0.071 BMI
(kg/m.sup.2) - 28.1 .+-. 4.6 27.7 .+-. 4.6 28.6 .+-. 4.8 <0.0001
0.004 mean .+-. SD Current Smoking - 522 (43.8%) 306 (42.6%) 554
(20.2%) <0.0001 <0.0001 no. (%) History of 490 (41.1%) 343
(47.6%) 1544 (56.2%) <0.0001 <0.0001 Hypertension - no. (%)
History of 208 (17.4%) 130 (18.1%) 604 (22.0%) 0.001 0.001 Diabetes
no. (%) Prior MI - no. (%) 170 (14.3%) 111 (15.4%) 470 (17.1%)
0.070 -- Prior PCI - no. (%) 182 (15.3%) 107 (14.9%) 494 (18.0%)
0.035 0.037 Prior CABG - no. (%) 34 (2.9%) 30 (4.2%) 82 (3.0%)
0.218 -- Prior HF - no. (%) 14 (1.2%) 12 (1.7%) 64 (2.3%) 0.046
0.017 Prior Stroke 20 (1.7%) 21 (2.9%) 78 (2.8%) 0.084 -- or TIA -
no. (%) PCI associated with 1143 (95.8%) 685 (95.1%) 2508 (91.3%)
<0.0001 <0.0001 the index event - no. (%) Medication use -
no. (%) Aspirin 1181 (99.0%) 715 (99.3%) 2709 (98.6%) 0.219 --
Other antiplatelet 1177 (98.7%) 708 (98.3%) 2682 (97.6%) 0.072 --
agent Statin 1188 (99.6%) 708 (98.3%) 2719 (98.9%) 0.024 0.047
Beta-blocker 1093 (91.6%) 642 (89.2%) 2408 (87.6%) 0.001 0.0003
Time from index MI 2.1 .+-. 0.8 5.1 .+-. 1.1 20.8 .+-. 6.6
<0.0001 <0.0001 to randomization (days) - mean .+-. SD Time
from Index MI 0.4 .+-. 0.7 1.4 .+-. 1.8 1.8 .+-. 3.6 <0.0001
<0.0001 to PCI (days) - mean .+-. SD Time from PCI to 1.6 .+-.
0.9 3.7 .+-. 1.9 18.8 .+-. 7.3 <0.0001 <0.001 randomization
(days) - mean .+-. SD Abbreviations: CABG, coronary-artery bypass
graft surgery; HF, heart failure; PCI, percutaneous coronary
intervention; TIA, transient ischemic attack. Data were missing on
the following characteristics: age (assessed according to date of
birth; see below) for 431 patients (213 in the colchicine group and
218 in the placebo group) and body-mass index (the weight in
kilograms divided by the square of the height in meters) for 5 (1
and 4 patients, respectively). Date of birth was not a required
field because it was considered in some countries to be sensitive
data that could allow for the identification of patients. For
statistical reporting, missing information regarding the day of
birth was replaced by 15, and missing information regarding the
month and day of birth was replaced by July 1. *Group comparison
TTI 0-3 vs. TTI 4-7 vs. TTI .gtoreq. 8 days **Group comparison TTI
< 3 vs. TTI .gtoreq. 8 days
Effects of Time-to-Treatment Initiation on the Primary Efficacy
Endpoint
[0075] The effects of colchicine on the primary endpoint according
to TTI are shown in Table 3 and FIG. 2. A primary endpoint event
occurred in 4.3% of patients in the colchicine group, as compared
to 8.3% of those in the placebo group when TTI was between days 0
and 3 (N=1193, HR=0.52, 95% CI 0.32-0.84, p=0.007, FIG. 3A).
Corresponding rates were 6.0 and 5.9% when TTI was between days 4
and 7 (N=720) and 5.7 and 7.1% when TTI was on day 8 or after
(N=2748), but these differences between groups did not reach
statistical significance. Table 3 also shows the percentages of
patients with events and the hazard ratios for the components of
the primary endpoint, including CV death (HR=1.04, 95% CI
0.15-7.37), resuscitated cardiac arrest (HR=0.33, 95% CI
0.03-3.20), MI (HR=0.58, 95% CI 0.32-1.05), stroke (HR=0.21, 95% CI
0.02-1.81) and urgent hospitalization for angina requiring coronary
revascularization (HR=0.35, 95% CI 0.14-0.88).
TABLE-US-00003 TABLE 3 Efficacy endpoints according to TTI (N =
4661, colchicine vs. placebo) TTI 0-3 days, N = 1193 TTI 4-7 days,
N = 720 TTI .gtoreq. 8 days, N = 2748 Colchicine vs. placebo
Colchicine vs. placebo Colchicine vs. placebo no. (%) no. (%) no.
(%) Endpoints HR (95% CI); p HR (95% CI); p HR (95% CI); p Primary
composite 26 (4.3%) vs. 49 (8.3%) 22 (6.0%) vs. 21 (5.9%) 77 (5.7%)
vs. 99 (7.1%) endpoint 0.52 (0.32-0.84); p = 0.007 0.96
(0.53-1.75); p = 0.896 0.82 (0.61-1.11); p = 0.200 CV death 2
(0.3%) vs. 2 (0.3%) 2 (0.5%) vs. 4 (1.1%) 15 (1.1%) vs. 18 (1.3%)
1.04 (0.15-7.37); p = 0.970 0.45 (0.08-2.46); p = 0.356 0.89
(0.45-1.76); p = 0.734 Resuscitated cardiac 1 (0.2%) vs. 3 (0.5%) 2
(0.5%) vs. 1 (0.3%) 2 (0.1%) vs. 2 (0.1%) arrest 0.33 (0.03-3.20);
p = 0.340 1.90 (0.17-20.95); p = 0.600 1.02 (0.14-7.22); p = 0.986
MI 17 (2.8%) vs. 29 (4.9%) 16 (4.4%) vs. 9 (2.5%) 52 (3.8%) vs. 59
(4.2%) 0.58 (0.32-1.05); p = 0.071 1.67 (0.74-3.78); p = 0.218 0.93
(0.64-1.35); p = 0.710 Stroke 1 (0.2%) vs. 5 (0.8%) 1 (0.3%) vs. 3
(0.8%) 2 (0.1%) vs. 11 (0.8%) 0.21 (0.02-1.81); p = 0.156 0.28
(0.03-2.71); p = 0.272 0.19 (0.04-0.84); p = 0.029 Urgent
hospitalization 6 (1%) vs. 17 (2.9%) 4 (1.1%) vs. 6 (1.7%) 15
(1.1%) vs. 26 (1.9%) for angina requiring 0.35 (0.14-0.88); p =
0.026 0.63 (0.18-2.24); p = 0.476 0.61 (0.32-1.16); p = 0.131
coronary revascularization Secondary Composite 20 (3.3%) vs. 36
(6.1%) 18 (4.9%) vs. 16 (4.5%) 67 (4.9%) vs. 77 (5.5%) Endpoint
0.55 (0.32-0.95); p = 0.031 1.04 (0.53-2.03); p = 0.919 0.92
(0.66-1.28); p = 0.629 All-cause death 6 (1.0%) vs. 6 (1.0%) 8
(2.2%) vs. 7 (2.0%) 26 (1.9%) vs. 31 (2.2%) 1.03 (0.33-3.19); p =
0.962 1.03 (0.37-2.84); p = 0.957 0.90 (0.53-1.51); p = 0.684 All
Coronary 33 (5.5%) vs. 51 (8.7%) 25 (6.9%) vs. 18 (5.1%) 72 (5.3%)
vs. 94 (6.7%) Revascularizations 0.63 (0.40-0.97); p = 0.037 1.41
(0.76-2.61); p = 0.275 0.81 (0.59-1.10); p = 0.172
[0076] The effects of colchicine on the primary endpoint for a TTI
of less than 4 days is shown in Table 4 and Table 5. The effects of
colchicine on the primary endpoint for a TTI of less than 5 days is
shown in Table 6 and Table 7. Both the TTI of less than 4 days and
the TTI of less than 5 days was were calculated using a basic model
(Table 4 and Table 6) as well as an adjusted model (Table 5 and
Table 7) which is described below in the statistical analysis
section. In all cases, the interaction p-value was not significant
(p>0.05), meaning that the conclusion over Placebo vs.
Colchicine group can be obtained directly from the respective
p-values for HR. In other words, relationships within the placebo
and colchicine groups with TTI are both linear/parallel and the
interpretation is straightforward. For a TTI of 4 days or less,
colchicine was shown to offer additional protection over the
placebo in both the basic (Table 4 and Table 6) and the adjusted
models (Table 5 and Table 7). The adjusted models resulted in a
hazard ratio (HR) of 0.58 and a p value of 0.0126.
TABLE-US-00004 TABLE 4 Effect of Colchicine with TTI of <4 days
calculated using basic model POSITIVELY DELAY BETWEEN ADJUDICATED
RANDOMIZATION PRIMARY Placebo Colchicine All AND ENDPOINT (0-4)
days N 0.32 768 1580 Yes 85 (2.63) 34 (4.44) 44 (5.99) No 856
(32.48) 734 (95.88) 1392 (94.14) (5-30) days n 1627 1554 3161 Yes
115 (7.84) 91 (5.99) 244 (4.89) No 1612 (92.99) 1662 (54.19) 7975
(91.53) Interaction Effect p-value Delay between randomization and
index 0.1595 MI .times. Randomized intermittent group Delay between
randomization and index MI Effect p-value (0-4) days Colchicine vs.
placebo 6.39 (0.39, 0.37) 0.698 (5-20) days Colchicine vs. placebo
0.89 (0.63, 1.69) 0.1755 indicates data missing or illegible when
filed
TABLE-US-00005 TABLE 5 Effect of Colchicine with TTI of <4 days
calculated using adjusted model POSITIVELY DELAY BETWEEN
ADJUDICATED RANDOMIZATION PRIMARY Placebo Colchicine All AND
ENDPOINT (0-4) days N 9.50 768 1490 Yes 84 (7.52) 34 (4.49) 84
(5.97) No 853 (42.43) 724 (95.88) 1392 (94.18) (5-30) days n 1617
1884 2141 Yes 224 (7.14) 93 (5.95) 244 (8.34) No 1812 (92.44) 1482
(54.24) 2972 (38.24) Interaction Effect p-value Delay between
randomization and index 0.2533 MI .times. Randomized intermittent
group Delay between randomization and index MI Effect p-value (0-4)
days Colchicine vs. placebo 0.34 (0.58, 0.69) 0.0128 (5-20) days
Colchicine vs. placebo 0.34 (0.54, 3.11) 0.3129 indicates data
missing or illegible when filed
TABLE-US-00006 TABLE 6 Effect of Colchicine with TTI of <5 days
calculated using basic model POSITIVELY DELAY BETWEEN ADJUDICATED
RANDOMIZATION PRIMARY Placebo Colchicine All AND PENDPOINT (0-4)
days N 0.21 0.89 1586 Yes 64 (4.04) 40 (4.79) 98 (8.72) No 748
(93.28) 819 (56.24) 1864 (94.14) (5-30) days n 1518 1461 2681 Yes
112 (7.35) 26 (0.24) 120 (6.58) No 1645 (82.69) 1378 (64.14) 1763
(93.63) Interaction Effect p-value Delay between randomization and
index 0.4861 MI .times. Randomized intermittent group Delay between
randomization and index MI Effect p-value (0-4) days Colchicine vs.
placebo 0.87 (4.45, 1.93) 0.0864 (5-20) days Colchicine vs. placebo
0.76 (0.59, 1.08) 0.744 indicates data missing or illegible when
filed
TABLE-US-00007 TABLE 7 Effect of Colchicine with TTI of <5 days
calculated adjusted basic model POSITIVELY DELAY BETWEEN
ADJUDICATED RANDOMIZATION PRIMARY Placebo Colchicine All AND
ENDPOINT (0-4) days N 816 954 2520 Yes 46 (4.25) 44 (4.25) 86
(8.72) No 753 (32.29) 519 (93.24) 1528 (96.38) (5-30) days n 1818
2542 2543 Yes 183 (9.53) 65 (5.86) 154 (5.52) No 1445 (92.53) 1828
(54.25) 2181 (48.49) Interaction Effect p-value Delay between
randomization and index 4.3815 MI .times. Randomized intermittent
group Delay between randomization and index MI Effect p-value (0-4)
days Colchicine vs. placebo 4.43 (4.45, 1.42) 0.0451 (5-20) days
Colchicine vs. placebo 0.35 (4.45, 1.25) 5.5423 indicates data
missing or illegible when filed
[0077] For a TTI of 5 days or less, colchicine showed borderline
significance with respect to the benefits of administering
colchicine within 5 days of an MI. This data suggests that some
benefit is still possible administering colchicine 5 days after an
MI, having HR 0.68 (0.45-1.02) and p=0.063 using the adjusted
model.
Effects of Time-to-Treatment Initiation on the Secondary and
Exploratory Efficacy Endpoints
[0078] The effects of colchicine on the secondary and exploratory
endpoints are shown in Table 3. The secondary efficacy endpoint
consisting of a composite of CV death, cardiac arrest, myocardial
infarction or stroke occurred in 3.3% of the patients in the
colchicine group and in 6.1% of those in the placebo group when TTI
was between days 0 and 3 (HR=0.55; 95% CI, 0.32-0.95, FIG. 3B). The
exploratory endpoint of all coronary revascularizations, not
coronary revascularizations limited to those observed as the
primary composite endpoint, including urgent revascularization
following unstable angina and hospitalization, occurred in 5.5% of
patients in the colchicine group, as compared to 8.7% of those in
the placebo group when TTI was between days 0 and 3 (HR=0.63, 95%
CI 0.40-0.97). There were 6 deaths in both study groups when TTI
was between days 0 and 3 (HR=1.03, 95% 0.33-3.19).
[0079] This TTI analysis of COLCOT shows that early initiation of
low-dose colchicine within the first 3 days after MI is associated
with a reduction of 48% in the risk of the primary endpoint
consisting of a composite of CV death, resuscitated cardiac arrest,
MI, stroke, or urgent hospitalization for angina requiring coronary
revascularization, in comparison with placebo. This result was due
to a lower incidence of MIs, strokes and urgent hospitalizations
for angina leading to coronary revascularization. The secondary
efficacy endpoint consisting of a composite of CV death,
resuscitated cardiac arrest, MI or stroke was also significantly
reduced by 45% with early initiation of low-dose colchicine. The
benefits were more marked when treatment was initiated within the
first 3 days after MI, as compared to between days 4 and 30,
supporting the strategy of in-hospital initiation of colchicine in
order to improve CV outcomes post-MI.
[0080] The main COLCOT results revealed that colchicine reduced the
risk of ischemic CV events by 23% in the post-MI setting. Results
from the present COLCOT analysis suggest that early suppression of
inflammation after MI provides even greater benefits, with a
reduction of 48% in the risk of the composite primary endpoint when
colchicine was initiated between days 0 and 3. The demonstrated
cost-effectiveness of low-dose colchicine also supports its
large-scale use after MI. Results of the LoDoCo2 study of patients
with stable coronary artery disease complement and further support
those of COLCOT in the post-MI setting (see Nidorf et al. N Engl
Med, 2020. and Tong et al. Circulation, 2020).
[0081] Early initiation of low-dose colchicine after MI greatly
reduced the risk of ischemic CV events compared with placebo. These
results support in-hospital initiation of adjunctive
anti-inflammatory therapy with colchicine for post-MI
prevention.
Statistical Analysis
[0082] For the COLCOT trial, it was estimated that a sample of
approximately 4500 patients undergoing randomization (with 2250
patients in each group) or, in terms of events, a total number of
301 patients with a first positively adjudicated primary end-point
event would yield adequate power. The sample-size calculation was
based on the primary efficacy end point and assumed a 27% lower
risk with colchicine than with placebo, indicated by a hazard ratio
of 0.724. With the use of a two-sided test at the 0.05 significance
level, the trial would have 80% power if it continued until 301
positively adjudicated primary events occurred in the combined
trial groups. The trial design assumed an event rate of 7% in the
placebo group at 24 months, an 18-month recruitment period during
which patients would be uniformly recruited, a 24-month minimum
follow-up period, and a 1% annual rate of loss to follow-up or
withdrawal of consent.
[0083] The efficacy analyses were conducted with the use of
positively adjudicated data and according to the intention-to-treat
principle. The primary end point was compared between the two trial
groups with the use of a log-rank test, and the hazard ratio from a
Cox proportional-hazards model, with a 95% confidence interval, was
calculated. A Cox proportional-hazards model with adjustment for
important baseline characteristics was also used as prespecified in
the protocol.
[0084] For the present TTI analysis, the data were centrally
analyzed by an independent academic biostatistics center at the
Montreal Health Innovations Coordinating Center. The analysis was
conducted amongst patients who received at least one dose of the
study medication (referred to as the safety population in the main
protocol, FIG. 1). TTI was defined as the length of time in days
between the index MI and the initiation of the study medication,
and three specific cutoffs were analyzed day 3, days 4 to 7, and
day 8). Early initiation of therapy was defined as TTI 3 days.
Baseline characteristics were summarized using counts and
percentages for categorical variables and mean.+-.standard
deviation (SD) for continuous variables. For each baseline
characteristic, comparisons were made using ANOVA for continuous
variables and Chi-Square test for categorical variables according
to TTI strata. Analyses of the efficacy endpoints, expressed as
time to event, were conducted according to time to treatment
initiation. Adjusted hazard ratios (HR) along with 95% confidence
intervals (CI) were calculated from stepwise multivariable Cox
regression models adjusted for the same covariates that were used
in the main analysis of the COLCOT trial (FIG. 2). All statistical
tests were two-sided and conducted at the 0.05 significance level.
Statistical analyses were performed with the use of SAS software,
version 9.4 (SAS Institute).
EXAMPLES
[0085] The following examples are provided to further illustrate
some embodiments of the present invention, but are not intended to
limit the scope of the invention; it will be understood by their
exemplary nature that other procedures, methodologies, or
techniques known to those skilled in the art may alternatively be
used.
Example 1: Meta-Analysis of Randomized Controlled Trials (RCTs) of
Colchicine for Secondary Prevention of Cardiovascular Disease
Data Sources
[0086] Medline (PUBMED), EMBASE, and Cochrane central were searched
to identify RCTs comparing colchicine to placebo or no colchicine
for secondary cardiovascular prevention (inception to Sep. 1,
2020). To maximized sensitivity, citation chasing was performed in
Google Scholar, Scopus, and Web of Science. Secondary prevention
was defined as patients with clinically manifest or established
CAD. Query terms included "colchicine", "coronary artery disease",
"acute coronary syndrome", "myocardial infarction", "cardiovascular
disease", "atherosclerosis", and "secondary prevention", either
separately or in combination.
Study Selection, Data Extraction, and Bias Assessment
[0087] RCTs that met the following criteria were included in the
meta-analysis: 1) compared daily use of low-dose (0.5 mg)
colchicine to placebo or no colchicine for secondary cardiovascular
prevention; 2) the study reported at least one of the following
outcomes: cardiovascular death, MI, stroke, cardiac arrest, or
urgent coronary revascularization; 3) other than the trial
medication, patients in both arms were treated in accordance to
guideline directed medical therapy; 4) the minimum follow-up was at
least 1 year; and 5) trials were published in a peer-reviewed
scientific journal. Review articles, editorials, meta-analyses,
observational studies, and published abstracts were excluded from
the present meta-analysis.
[0088] Study selection was performed by two independent reviewers,
using two levels of screening. At the first level, titles and
abstracts of searched studies were screened, followed by review of
full texts. The reviewers were not blinded to the title of the
journals, authors, or affiliated institutions. Reasons for
exclusion were recorded and any discrepancies were discussed until
a consensus was achieved.
[0089] Using standardized forms, data on study characteristics,
patient characteristics, and outcomes were extracted on the
intent-to-treat population independently by two reviewers from each
eligible study. The Cochrane Collaboration risk-of-bias tool for
randomized trials was used to evaluate study quality. The
meta-analysis was conducted in accordance to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines.
Outcomes
[0090] The primary efficacy endpoint was a composite of
cardiovascular death, MI, ischemic stroke, and urgent coronary
revascularization. Secondary efficacy endpoints consisted of the
components of the primary endpoint, composite of cardiovascular
death, MI, and ischemic stroke, as well as deep vein thrombosis or
pulmonary embolus, and atrial fibrillation (AF). To maximize
consistency in pooling efficacy endpoints among trials, the primary
and secondary composite efficacy and stroke endpoints in COLCOT
were modified to meet the definition of primary and stroke
endpoints of the LoDoCo2 trial. Therefore, adjudicated events of
resuscitated cardiac arrest and non-ischemic stroke in COLCOT were
excluded from the pooled primary endpoint. The component endpoint
of stroke was also restricted to include only ischemic strokes.
Incidence rates and hazards ratios (HRs) were calculated for the
new primary composite endpoint and ischemic stroke endpoint using
individual patient data from COLCOT.
[0091] Safety outcomes were limited to serious adverse events
(SAEs) and included all-cause and non-cardiovascular mortality,
hospitalization for gastrointestinal event, infection, and
pneumonia, as well as diagnosis of cancer. Incidence of SAEs were
recalculated for COLCOT using the intent-to-treat population.
Data Synthesis and Statistical Analyses
[0092] The DerSimonian and Laird random-effects model was used to
calculate the pooled HR and corresponding 95% confidence intervals
(CI) for primary and secondary endpoints in the overall trial and
in subgroup analyses of the primary endpoint. For safety outcomes,
the DerSimonian and Laird random-effects model was used to compute
risk ratios (RR) and corresponding 95% CIs. Heterogeneity was
evaluated with the Higgins I.sup.2 statistic. I.sup.2 values of
<25%, 25-75%, and >75% were considered to indicate low,
moderate, and high degrees of heterogeneity, respectively. In
subgroup analyses, the Ob statistic was calculated to determine
inconsistency and variability in the treatment effect between
strata. Publication and small study bias were assessed with the
Egger's regression test and visually by asymmetry in funnel plots.
Sensitivity analyses were performed for the primary composite and
component outcomes for 1) RCTs in patients with acute coronary
syndrome (COLCOT and COPS), and 2) RCTs in patients with stable CAD
(LoDoCo and LoDoCo2); and after exclusion of 3) the LoDoCo trial
[open-label trial and control group was not randomized to placebo]
and 4) the LoDoCo and COPS [increased dose (0.5 mg twice daily) of
colchicine prescribed during first month] trials. Statistical
analyses were performed using SAS software version 9.4 (SAS
Institute, Cary, N.C.) and Stata (Version 16, StataCorp, College
Station, Tex.).
Results
Literature Search Results and Risk of Bias
[0093] The search strategy identified 79 studies. After the first-
and second-level screening processes, four RCTs were retained in
the present meta-analysis. The characteristics of included RCTs are
listed in Table 8. The Low-Dose Colchicine (LoDoCo) and Low-Dose
Colchicine 2 (LoDoCo2) trials assessed the efficacy of colchicine
in patients with stable CAD (defined as clinically stable for
months) (see, Nidorf et al. N Engl Med, 2020. and Tong et al.
Circulation, 2020). In comparison, the Colchicine Cardiovascular
Outcomes Trial (COLCOT) was conducted in patients who had a recent
MI (30 days) and the Colchicine in Patients with acute coronary
Syndrome (COPS) trial enrolled patients with acute coronary
syndromes (ACS) (see, Tardif et al. N Engl J Med.)
[0094] The pooled sample size of enrolled patients was 11,594, of
which 5774 patients were randomized to colchicine and 5820 patients
were randomized to placebo (or no colchicine, in the LoDoCo trial
only). Three trials were designated as "low risk" for overall bias
(see, Tardif et al. N Engl J Med., Nidorf et al., N Engl J Med,
2020, and Tong et al, Circulation, 2020) and 1 trial was marked as
being of "some concern" (see, Nirdorf et al., J Am Coll Cardiol.
2013; 61: 404-10) in the Cochrane Collaboration risk-of-bias
assessment.
TABLE-US-00008 TABLE 8 Study characteristics LoDoCo COLCOT COPS
LoDoCo2 Year 2013 2019 2020 2020 Study design Single-blind RCT
Double-blind, Double-blind, placebo Double-blind, placebo
controlled controlled RCT placebo controlled RCT RCT Study Stable
CAD Recent MI (<30 ACS Stable CAD population days) N 532 4,745
795 5,522 Key inclusion Angiographically MI within 30 days ACS
Evidence of CAD criteria proven CAD; prior; completed
(STEMI/NSTEMI/UA); on invasive clinically stable planned Evidenced
CAD on angiography or for <=6 months percutaneous coronary
angiography, computed revascularization managed with either
tomography procedures; PCI or medical angiography or a treated
according therapy coronary calcium to national score of .gtoreq.400
guidelines that Agaston units on a included intensive
coronary-artery use of statins calcium scan; clinically stable
condition for .gtoreq.6 months Key Bypass surgery Severe heart CAD
requiring surgical Moderate-to- exclusion within 10 years failure;
left revascularization pre- severe renal criteria prior ventricular
ejection existing long-term impairment; fraction <35%;
colchicine use or severe stroke within the immunosuppressant heart
failure; previous 3 therapy; severe severe valvular months; type 2
hepatic or renal disease index MI; insufficiency; known
coronary-bypass active malignancy surgery either within previous 3
years or planned; severe renal or hepatic disease; known cancer
Median 24 months 22.6 months 12 months 28.6 months follow-up
Primary Composite: ACS, Composite: CV Composite: All-cause
Composite: CV endpoint out-of-hospital mortality, mortality, ACS
death, MI, cardiac arrest, or resuscitated (STEMI/NSTEMI/UA),
ischemic stroke, or non-cardioembolic cardiac arrest, MI,
ischemia-driven ischemia-driven ischemic stroke stroke, or urgent
revascularization, or coronary hospitalization for
non-cardioembolic revascularization angina requiring ischemic
stroke revascularization *ACS, acute coronary syndrome; CAD,
coronary artery disease; CV, cardiovascular; MI, myocardial
infarction; RCT, randomized controlled trial; STEM, ST elevation
myocardial infarction; NSTEMI, non-ST elevation myocardial
infarction; UA, unstable angina
Patient Characteristics
[0095] Baseline patient characteristics for each RCT are summarized
in Table 9. The mean age of patients ranged from 60 to 67 years. In
all trials, <20% of enrolled patients were women and more than
90% of patients were on concomitant statin therapy. LoDoCo and
LoDoCo2 trials had a higher proportion of patients who underwent
prior coronary revascularization [percutaneous coronary
intervention (PCI) and coronary artery bypass graft (CABG)
surgery]. The distribution of all other patient characteristics was
relatively similar between trials.
TABLE-US-00009 TABLE 9 Patient characteristics at baseline LoDoCo
COLCOT COPS LoDoCo2 Colchicine Control Colchicine Placebo
Colchicine Placebo Colchicine Placebo N = 250 N = 282 N = 2366 N =
2379 N = 396 N = 399 N = 2762 N = 2760 Age, years 67 .+-. 9.2 66
.+-. 9.6 60.6 .+-. 10.7 60.5 .+-. 10.6 59.7 .+-. 10.2 60.0 .+-.
10.4 65.8 .+-. 8.4 65.9 .+-. 8.7 (mean .+-. SD) Women (%) 11.2%
11.0% 19.9% 18.4% 18.7% 22.3% 16.5% 14.1% Hypertension (%) Not
reported Not reported 50.1% 52.0% 50.8% 49.9% 51.4% 50.3% Diabetes
(%) 27.6% 32.6% 19.5% 20.9% 18.9% 19.0% 17.8% 18.7% History of PCI
(%) 55.2% 59.9% 16.6% 17.1% 12.9% 12.5% 76.0% 75.3% History of CABG
15.6% 22.0% 2.9% 3.4% 3.8% 4.8% 11.5% 14.2% (%) Statin use (%)
94.0%* 96.1%* 98.9% 99.1% 98.2% 99.5% 93.9% 94.0% *The LoDoCo trial
only reported use of high dose statins, not any statin use.
Clinical Efficacy Endpoints
[0096] Clinical efficacy results from each trial are presented in
Table 10. In patients with CAD, the addition of colchicine to
standard medical therapy was associated with a statistically
significant reduction in the primary composite endpoint of
cardiovascular mortality, MI, ischemic stroke, and urgent coronary
revascularization, compared to patients on placebo or no colchicine
[pooled HR 0.68 (95% CI 0.54-0.81); I.sup.2=37.7%]. The reduction
in cardiovascular events in patients randomized to colchicine was
driven by statistically significant reductions in the incidence of
MIs [pooled HR 0.62 (95% CI 0.36-0.88); I.sup.2=68.76%], ischemic
strokes [pooled HR 0.38 (95% CI 0.13-0.63); I.sup.2=0.0%], and
urgent coronary revascularization [pooled HR 0.56 (95% CI
0.30-0.82); I.sup.2=65.1%]. However, there was no statistically
significant difference detected for cardiovascular mortality.
Sensitivity analyses that pooled the results of COLCOT and LoDoCo2
trials demonstrated similar effect estimates for the primary
composite and component outcomes, although magnitude of effect and
heterogeneity (I.sup.2) between studies decreased.
TABLE-US-00010 TABLE 10 Study efficacy outcomes LoDoCo.sup.11
COLCOT.sup.10 COPS.sup.13 LoDoCo2.sup.12 Colchicine Control
Colchicine Placebo Colchicine Placebo Colchicine Placebo N = 250 N
= 282 N = 2366 N = 2379 N = 396 N = 399 N = 2762 N = 2760 Primary
composite outcome: Cardiovascular mortality, myocardial infarction,
ischemic stroke, urgent revascularization Events, NA NA 130 (5.5%)
168 19 (4.8%) 41 187 (6.8%) 264 N (%) (7.1%) (10.3%) (9.6%) HR NA
0.77 (0.61-0.97) 0.47 (0.27-0.82) 0.69 (0.57-0.83) (95% CI)
Cardiovascular mortality Events, NA NA 20 (0.8%) 24 3 (0.8%) 1 20
(0.7%) 25 N (%) (1.0%) (0.3%) (0.9%) HR NA 0.84 (0.46-1.52) 3.09
(0.32-29.71) 0.80 (0.44-1.44) (95% CI) Myocardial infarction
Events, 4 (1.6%) 14 89 (3.8%) 98 11 (3.7%) 22 83 (3.0%) 116 N (%)
(5.6%) (4.1%) (5.5%) (4.2%) HR 0.25 (0.08-0.76) 0.91 (0.68-1.21)
0.52 (0.25-1.07) 0.70 (0.53-0.93) (95% CI) Ischemic stroke Events,
1 (0.4%) 4 4 (0.2%) 16 2 (0.5%) 6 16 (0.6%) 24 N (%) (1.6%) (0.7%)
(1.5%) (0.9%) HR 0.23 (0.03-2.03) 0.25 (0.08-0.75) 0.34 (0.07-1.70)
0.66 (0.35-1.25) (95% CI) Urgent coronary revascularization Events,
NA NA 25 (1.1%) 50 3 (0.8%) 12 135 (4.9%) 177 N (%) (2.1%) (3.0%)
(6.4%) HR NA 0.50 (0.31-0.81) 0.26 (0.07-0.92) 0.75 (0.60-0.94)
(95% CI) *NA = not applicable. A study result was designed NA when
the outcome in the study did not closely match the outcome in the
present meta-analysis.
[0097] In sensitivity analyses of ACS trials (COLCOT and COPS;
N=5540), the primary composite endpoint, MI, and urgent coronary
revascularizations were statistically significantly reduced in
patients randomized to colchicine compared to placebo. Among
patients with stable CAD (LoDoCo and LoDoCo 2; N=6054), the only
comparable outcome between trials was MI which was statistically
significantly decreased with colchicine compared to placebo.
[0098] Although there was no statistically significant difference
in the incidence of key secondary endpoints, there was a trend
towards reduced AF diagnoses and AF episodes among patients
randomized to colchicine [pooled HR 0.86 (95% CI 0.67-1.04);
I.sup.2=0.0%].
[0099] Visual inspection of funnel plots and the results of the
Eggers test indicated there was no significant risk of publication
bias for all outcomes (p>0.05 for all) except urgent coronary
revascularization (p=0.02).
Subgroup Analyses
[0100] The statistically significant reduction in the incidence of
the primary composite cardiovascular endpoint among patients
randomized to colchicine was consistent for most subgroup analyses.
There was no significant heterogeneity of the effect of colchicine
in the different subgroups studied. Overall, the Q.sub.b statistic
suggests that there is minimal variability and inconsistency in the
treatment effect between strata in subgroup analyses (p>0.05 for
all).
Major Adverse Events
[0101] There was no statistically significant difference between
treatment arms for the risk of all-cause [pooled RR 1.04 (95% CI
0.61-1.78); I.sup.2=62.01%] and non-cardiovascular mortality
[pooled RR 1.38 (95% CI 0.99-1.93); I.sup.2=0.0%] (FIG. 3). The
rates of infections, pneumonias, hospitalizations for
gastrointestinal events, and diagnoses of cancer were also not
significantly different. For pneumonia, there was a high degree of
heterogeneity between trials with opposite directions for the
treatment effect (I.sup.2=81.5%0.
[0102] In this contemporary meta-analysis of RCTs comparing
colchicine to placebo (or no colchicine) for secondary
cardiovascular prevention, we found that: 1) treatment with
colchicine was associated with a 32% reduction in the incidence of
major cardiovascular events; 2) significantly fewer MIs, ischemic
strokes, and urgent coronary revascularizations were the primary
drivers for the overall decrease in cardiovascular events; 3) the
protective treatment effect of colchicine was relatively consistent
among most subgroups studied, and 4) colchicine had a favorable
safety profile. This is the first comprehensive meta-analysis of
RCTs evaluating efficacy and safety of colchicine for secondary
cardiovascular prevention in which the endpoints were harmonized
across trials. Overall, the synthesis of current evidence in the
present meta-analysis indicates that treatment with colchicine for
secondary cardiovascular prevention confers beneficial clinical
effects.
Secondary Prevention of Cardiovascular Diseases
[0103] Although the 4 RCTs investigated the efficacy of colchicine
in different segments of the CAD population, including stable CAD,
recent MI, and ACS, the results of all trials consistently
demonstrated that colchicine was protective against a composite
endpoint of cardiovascular mortality, MI, ischemic stroke, and
urgent coronary revascularization. The individual trials were not
powered to detect statistically significant differences in the
components of the primary endpoint. Whereas all trials showed a
decrease in urgent coronary revascularizations among patients
randomized to colchicine, only COLCOT detected a reduction in
ischemic strokes [HR 0.25 (95% CI 0.08-0.75)] and LoDoCo2 a
decrease in MIs [HR 0.70 (95% CI 0.53-0.93)]. Pooling HRs from the
RCTs revealed that the attenuated risk of major cardiovascular
events was attributed to risk reductions of 38%, 62%, and 44% for
MIs, ischemic strokes, and urgent coronary revascularization,
respectively. Although the 2 largest trials, COLCOT and LoDoCo2,
contributed the most weight to analyses, the inclusion of LoDoCo
and COPS tended to increase the magnitude of the risk reduction by
4-5%.
[0104] Individual trials and pooled results suggest that there is
no difference in the incidence of cardiovascular or all-cause
mortality with colchicine. These pooled analyses provide
reassurance about the safety of colchicine for the outcome of
all-cause mortality. Results from both the LoDoCo2 and COPs trials
showed a trend towards increased all-cause mortality with
colchicine, although neither reached statistical significance
[LoDoCo2 HR 1.21 (95% CI 0.86-1.71) and COPS HR 8.20 (95%
1.02-65.61)]. The increased power from pooled analyses demonstrated
that the effect of colchicine on all-cause mortality was closer to
null or no effect than suggested by individual trials [pooled RR
1.04 (95% CI 0.61-1.78)].
[0105] The anti-inflammatory properties of colchicine work through
various mechanisms to inhibit the pathogenesis of CAD, and
subsequently reduce the incidence of ischemic cardiovascular
events. In addition to targeting the NLRP3 inflammasome leading to
the reduction of circulating levels of IL-1.beta. and IL-6,
colchicine also inhibits cholesterol crystals that promote
inflammation and plaque instability in atherosclerosis.
Treatment Effects Across Subgroups
[0106] The treatment effect of colchicine was similar with
overlapping confidence intervals across age categories (.ltoreq.65
or >65 years), presence or absence of diabetes and hypertension,
and among patients with or without prior coronary
revascularization. Although the risk reduction appeared less marked
in women compared to men, less than 20% of trial populations were
women (1977 women compared to 9617 men). It is, therefore, possible
that the lack of a statistically significant reduction in
cardiovascular events with colchicine in the subgroup analysis of
women reflects limited power. There was no significant
heterogeneity between the effects in subgroups and that in the
overall population.
Safety
[0107] Colchicine has an established safety profile from its
centuries of use to treat gout. There was a numerical imbalance in
the number of non-cardiovascular deaths between study arms, which
did not reach statistical significance. Importantly, there was no
effect of colchicine on all-cause mortality. In the COPS study, the
increased dose of colchicine during the first month of follow-up
might have contributed to higher non-cardiovascular deaths. In
addition, 3 of 5 colchicine patients who died from
non-cardiovascular causes in COPS had also discontinued colchicine
prior to date of death, which may suggest that on-treatment
analyses may provide further evidence to the safety of colchicine
for non-cardiovascular mortality. Furthermore, the quality of
follow-up in COPS was poor, with more than twice the number of
patients with incomplete vital status than that of deaths due to
inadequate resources (2 part-time healthcare workers following 795
patients). In contrast, the quality of follow-up and rate of vital
status ascertainment of the 10,267 patients included in COLCOT and
LoDoCo2 were excellent and did not reveal a significant difference
in non-cardiovascular mortality between study arms. Finally, the
meta-analysis showed no difference in all-cause mortality between
groups.
[0108] Only the COLCOT trial detected a difference in the rate of
pneumonia between patients randomized to colchicine (0.9%) or
placebo (0.4%). Pooled analyses of COLCOT and LoDoCo2 did not show
an increased risk of pneumonia with colchicine, suggesting this
result in the former may have been due to chance. The lack of a
difference between groups for infections, hospitalizations, and
diagnoses of cancer further validates that colchicine is safe to
use in patients with CAD.
[0109] As we did not have access to patient-level data from 3 of 4
trials, only modified study-level data was used for the present
meta-analysis. Although meta-analyses based on aggregate patient
data continue to be the mainstay of systematic reviews that inform
clinical practice, meta-analyses based on individual patient data
have several advantages including the ability to verify data,
address new questions, and adjust for the same variables across
studies. Finally, the small number of eligible studies precluded
meta-regression analyses to determine the influence of specific
variables or effect modifiers on the association between colchicine
and cardiovascular events. Nevertheless, the potential for effect
modification was addressed in part by subgroup analyses.
[0110] In patients with CAD, the addition of low-dose colchicine to
standard medical therapy consistently and significantly reduces the
incidence of major cardiovascular events compared to standard
medical therapy alone. With the exception of cardiovascular
mortality, significant reductions were observed for components of
the primary outcome, including MIs, ischemic strokes, and urgent
coronary revascularizations.
Example 2: Administration of Low-Dose Colchicine after Myocardial
Infarction
[0111] The results of the main COLCOT trial support that the use of
colchicine in patients who have had a myocardial infarction in the
past 30 days significantly improved their quality of life in
several ways. The COLCOT trial was performed as follows. A
randomized, double-blind trial involving patients recruited within
30 days after a myocardial infarction was performed. The patients
were randomly assigned to receive either low-dose colchicine (0.5
mg once daily) or placebo. A total of 4745 patients were enrolled;
2366 patients were assigned to the colchicine group, and 2379 to
the placebo group. Patients were followed for a median of 22.6
months to observe the occurrence of the primary efficacy end point
which was a composite of death from cardiovascular causes,
resuscitated cardiac arrest, myocardial infarction, stroke, or
urgent hospitalization for angina leading to coronary
revascularization. The components of the primary end point and
safety were also assessed in this study.
[0112] In this randomized, double-blind, placebo-controlled,
investigator-initiated trial, we assigned patients in a 1:1 ratio
to receive either colchicine (at a dose of 0.5 mg once daily) or
placebo. The trial protocol, available at NEJM.org, was designed by
a trial steering committee.
Trial Population
[0113] Adult patients were eligible if they had had a myocardial
infarction within 30 days before enrollment, had completed any
planned percutaneous revascularization procedures, and were treated
according to national guidelines that included the intensive use of
statins.
[0114] Patients were excluded if they had severe heart failure, a
left ventricular ejection fraction of less than 35%, stroke within
the previous 3 months, a type 2 index myocardial infarction,
coronary-bypass surgery either within the previous 3 years or
planned, a history of noncutaneous cancer within the previous 3
years, inflammatory bowel disease or chronic diarrhea,
neuromuscular disease or a nontransient creatine kinase level that
was greater than three times the upper limit of the normal range
(unless due to infarction), clinically significant nontransient
hematologic abnormalities, severe renal disease with a serum
creatinine level that was greater than two times the upper limit of
the normal range; severe hepatic disease, drug or alcohol abuse,
current or planned long-term systemic glucocorticoid therapy, or a
history of clinically significant sensitivity to colchicine.
[0115] Written informed consent was obtained from all the patients
before enrollment. Clinical evaluations occurred at 1 month and 3
months after randomization and every 3 months thereafter.
End Points
[0116] The primary efficacy end point was a composite of death from
cardiovascular causes, resuscitated cardiac arrest, myocardial
infarction, stroke, or urgent hospitalization for angina leading to
coronary revascularization in a time-to-event analysis.
[0117] The secondary end points consisted of the components of the
primary efficacy end point; a composite of death from
cardiovascular causes, resuscitated cardiac arrest, myocardial
infarction, or stroke; and total mortality in time-to-event
analyses. Coronary revascularization, hospitalization for heart
failure, atrial fibrillation, and deep venous thrombosis or
pulmonary embolus were prespecified as exploratory end points in
the protocol.
[0118] Additional prespecified exploratory end points included the
change from baseline to 6 months in the high-sensitivity C-reactive
protein level and the change from baseline to 12 months in the
white-cell count. The C-reactive protein biomarker substudy was
implemented after a protocol amendment and was optional for sites
and for patients; 34 sites chose to participate in this
substudy.
[0119] All serious adverse events were recorded. The only other
adverse events recorded were those that were considered to be
related to the gastrointestinal system, events that were judged by
the investigator to be related to colchicine or placebo, or
laboratory abnormalities that had been judged by the investigator
to be clinically significant,
Statistical Analysis
[0120] In this event-driven trial, it was estimated that a sample
of approximately 4500 patients undergoing randomization (with 2250
patients in each group) or, in terms of events, a total number of
301 patients with a first positively adjudicated primary end-point
event would yield adequate power. The sample-size calculation was
based on the primary efficacy end point and assumed a 27% lower
risk with colchicine than with placebo, indicated by a hazard ratio
of 0.724. With the use of a two-sided test at the 0.05 significance
level, the trial would have 80% power if it continued until 301
positively adjudicated primary events occurred in the combined
trial groups. The trial design assumed an event rate of 7% in the
placebo group at 24 months, an 18-month recruitment period during
which patients would be uniformly recruited, a 24-month minimum
follow-up period, and a 1% annual rate of loss to follow-up or
withdrawal of consent.
[0121] The efficacy analyses were conducted with the use of
positively adjudicated data and according to the intention-to-treat
principle. The primary end point was compared between the two trial
groups with the use of a log-rank test, and the hazard ratio from a
Cox proportional-hazards model, with a 95% confidence interval, was
calculated. A Cox proportional-hazards model with adjustment for
important baseline characteristics was also used as prespecified in
the protocol.
[0122] The analysis of the primary end point was repeated in the
per-protocol population (i.e., patients without major protocol
deviations). Secondary and exploratory end points expressed as time
to event were analyzed similarly. The changes from baseline to
follow-up were analyzed with the use of an analysis of covariance
model with adjustment for baseline value, and estimates of
treatment effect are presented with 95% confidence intervals.
[0123] The efficacy end points expressed as time to event could be
assessed in all patients because the event dates and censoring
dates were complete, with the exception of one incomplete event
date for atrial fibrillation; therefore, imputation for missing
data was not done.
[0124] In the analysis of time to event, the following censoring
rules were used. For death from any cause and death from
cardiovascular causes, data from event-free patients who completed
the trial were censored at the date of trial completion, and data
from patients who did not complete the trial, such as those who
were lost to follow-up or who withdrew consent, were censored at
the date of last contact or the date of the assessment of survival
status, whichever was later.
[0125] For the analysis of death from cardiovascular causes,
patients who died from a noncardiovascular cause had their data
censored at the time of death.
[0126] For all other end points, including the primary end point,
the same censoring rules applied, but the survival status was not
used because no formal assessment of end points was done at the
assessment of survival status.
[0127] An analysis of the components of the primary end point with
death from noncardiovascular causes as a competing event for death
from cardiovascular causes, and with death from any cause as a
competing event for the other components, was conducted with the
use of the Fine and Gray subdistribution hazard model (Fine J P and
Gray R J, A proportional hazards model for the subdistribution of a
competing risk. J Am Stat Assoc 1999; 94:496-509). No missing data
were imputed except for age
[0128] To account for the occurrence of multiple primary end-point
events within patients, recurrent-event analyses were undertaken
with the use of negative binomial regression, Andersen-Gill, and
Wei-Lin-Weissfeld models (Rogers J K et al., Analysing recurrent
hospitalizations in heart failure: a review of statistical
methodology, with application to CHARM-Preserved. Eur J Heart Fail
2014; 16:33-40; Andersen P K and Gill R D, Cox's regression model
for counting processes: a large sample study. Ann Stat 1982;
10:1100-20; Lin D Y and Wei L J, The robust inference for the
proportional hazards model. J Am Stat Assoc 1989; 84:1074-8; Lin D
Y et al. Semiparametric regression for the mean and rate functions
of recurrent events. J R Stat Soc 2000; 62:711-30; Wei L J and
Glidden D V, An overview of statistical methods for multiple
failure time data in clinical trials. Stat Med 1997; 16:833-9;
Ghosh D, Methods for analysis of multiple events in the presence of
death. Control Clin Trials 2000; 21:115-26; Li Q H and Lagakos S W,
Use of the Wei-Lin-Weissfeld method for the analysis of a recurring
and a terminating event. Stat Med 1997; 16:925-40; Metcalfe C and
Thompson S G, The importance of varying the event generation
process in simulation studies of statistical methods for recurrent
events. Stat Med 2006; 25:165-79; Jahn-Eimermacher A, Comparison of
the Andersen-Gill model with Poisson and negative binomial
regression on recurrent event data. Comput Stat Data Anal 2008;
52:4989-97).
[0129] An interim analysis was performed after 50% of the primary
end-point events had been positively adjudicated. The prespecified
stopping rule for efficacy was based on the Lan-DeMets procedure
with the O'Brien-Fleming alpha-spending function. After review of
the interim results, the data and safety monitoring board
recommended that the trial should continue as planned.
[0130] To account for this interim analysis, the statistical
significance level was set to 0.0490 for the final analysis of the
primary end point. All other statistical tests were two-sided and
conducted at the 0.05 significance level. Statistical analyses were
performed with the use of SAS software, version 9.4 (SAS
Institute). There was no prespecified plan to adjust for multiple
comparisons across the multiple methods that were used to analyze
the primary and secondary end points; results of these analyses are
reported with point estimates and 95% confidence intervals, without
P values. The 95% confidence intervals were not adjusted for
multiple comparisons, and inferences drawn from them may not be
reproducible.
[0131] The final amendment to the statistical analysis plan was
approved on Aug. 28, 2019, before unblinding of the trial-group
assignments occurred.
Results
Patients
[0132] Trial enrollment began in December 2015 and was completed in
August 2018; the last trial visit was in July 2019. A total of 4745
patients underwent randomization (with 2366 being assigned to the
colchicine group and 2379 to the placebo group) and were followed
for a median of 22.6 months. At the time of the database lock on
Aug. 28, 2019, and unblinding on Aug. 29, 2019, vital status was
available for all except 23 patients (99.5%); 89 patients (1.9%)
were lost to follow-up, and 30 patients (0.6%) withdrew
consent.
[0133] The characteristics of the patients at baseline are shown in
Table 10.
TABLE-US-00011 TABLE 10 Characteristics of the Patients Colchicine
Placebo Characteristic (N = 2366) (N = 2379) Age - yr 60.6 .+-.
10.7 60.5 .+-. 10.6 Female sex - no. (%) 472 (19.9) 437 (18.4)
White race - no./total no. (%).dagger. 1350/1850 (73.0) 1329/1844
(72.1) Body-mass index 28.2 .+-. 4.8 28.4 .+-. 4.7 Current smoking
- no./total no. (%) 708/2366 (29.9) 708/2377 (29.8) Hypertension -
no. (%) 1185 (50.1) 1236 (52.0) Diabetes - no. (%) 462 (19.5) 497
(20.9) History of myocardial infarction - no. (%) 370 (15.6) 397
(16.7) History of PCI - no. (%) 392 (16.6) 406 (17.1) History of
CABG - no. (%) 69 (2.9) 81 (3.4) History of heart failure - no. (%)
48 (2.0) 42 (1.8) History of stroke or TIA - no. (%) 55 (2.3) 67
(2.8) Time from index myocardial infarction to 13.4 .+-. 10.2 13.5
.+-. 10.1 randomization - days PCI for index myocardial infarction
- no./total no. 2192/2364 (92.7) 2216/2375 (93.3) (%) Medication
use - no. (%) Aspirin 2334 (98.6) 2352 (98.9) Other antiplatelet
agent 2310 (97.6) 2337 (98.2) Statin 2339 (98.9) 2357 (99.1)
Beta-blocker 2116 (89.4) 2101 (88.3) * Plus-minus values are means
.+-. SD. Data were missing on the following characteristics: age
(assessed according to date of birth; see below), for 435 patients;
body-mass index (the weight in kilograms divided by the square of
the height in meters), for 5; and information about the index
myocardial infarction, for 6. Date of birth and race were not
required fields because both were considered in some countries to
be sensitive data that could allow for the identification of
patients. For statistical reporting, missing information regarding
the day of birth was replaced by 15, and missing information
regarding the month and day of birth was replaced by July 1. CABG
denotes coronary-artery bypass graft surgery, PCI percutaneous
coronary intervention, and TIA transient ischemic attack.
.dagger.Race was reported by the patient.
[0134] Patients were enrolled a mean of 13.5 days after myocardial
infarction. The mean age of the patients was 60.6 years, 19.2% of
the patients were women, and 20.2% had diabetes. Most patients
(93.0%) underwent percutaneous coronary intervention for their
index myocardial infarction. Aspirin, a different antiplatelet
agent, and a statin were taken by 98.8%, 97.9% and 99.0% of the
patients, respectively.
[0135] At the end of the trial, the trial regimen had been
discontinued in 18.4% of the patients in the colchicine group and
in 18.7% of those in the placebo group. Among the patients who
discontinued the trial regimen, the median time of taking the trial
drug was 7.1 months (interquartile range, 1.9 to 14.6) in the
colchicine group, as compared with 6.1 months (interquartile range,
1.6 to 14.4) in the placebo group. Overall, the median duration of
receipt of the trial drug was 19.6 months in the colchicine group
and 19.5 months in the placebo group.
Clinical Efficacy End Points
[0136] A primary end-point event occurred in 5.5% of the patients
in the colchicine group, as compared with 7.1% of those in the
placebo group (hazard ratio, 0.77; 95% confidence interval [CI],
0.61 to 0.96; P=0.02 by the log-rank test). A multivariable Cox
regression model with adjustment for baseline covariates yielded a
similar result (Table 11).
TABLE-US-00012 TABLE 11 Multivariable Cox Regression Model for Time
to First Primary Endpoint. Adjusted Hazard Effect Ratio (95% CI) P
Value Randomized treat- Colchicine vs. 0.78 (0.62-0.98) 0.03 ment
group Placebo Age at randomization 1.02 (1.01-1.03) <0.001
(years) History of diabetes Yes vs. No 1.86 (1.46-2.37) <0.001
Prior coronary Yes vs. No 2.02 (1.58-2.58) <0.001
revascularization (PCI or CABG) Prior heart failure Yes vs. No 1.81
(1.08-3.04) 0.03 CABG denotes coronary artery bypass graft, and PCI
percutaneous coronary intervention. The model was based on 4745
observations. All baseline characteristics that showed an
association (P < 0.20) with the occurrence of a first positively
adjudicated primary endpoint were included in the stepwise
multivariable Cox regression. For age at randomization, the hazard
ratio is for an increase of one year of age.
was based on 4745 observations. All baseline characteristics that
showed an association (P<0.20) with the occurrence of a first
positively adjudicated primary endpoint were included in the
stepwise multivariable Cox regression. For age at randomization,
the hazard ratio is for an increase of one year of age.
[0137] In the prespecified per-protocol analysis involving patients
who adhered to the protocol, the primary end point occurred in 5.1%
of the patients in the colchicine group and in 7.1% of those in the
placebo group (hazard ratio, 0.71; 95% CI, 0.56 to 0.90) (Table
12).
TABLE-US-00013 TABLE 12 Rates and Hazard Ratios for the Primary
Endpoint and its Components in the Per-Protocol Population.dagger..
Clinical Outcome Hazard Per-protocol Colchicine Placebo Ratio
population N = 2260 N = 2270 (95% CI) Primary 115 (5.1%) 162 (7.1%)
0.71 (0.56-0.90) endpoint - no. (%) CV death - no. (%) 19 (0.8%) 23
(1.0%) 0.83 (0.45-1.53) Resuscitated 5 (0.2%) 5 (0.2%) 1.00
(0.29-3.46) cardiac arrest - no. (%) MI - no. (%) 77 (3.4%) 92
(4.1%) 0.84 (0.62-1.14) Stroke - no. (%) 5 (0.2%) 19 (0.8%) 0.26
(0.10-0.71) Urgent 22 (1.0%) 47 (2.1%) 0.47 (0.28-0.78)
hospitalization for angina requiring revascularization - no. (%) CV
denotes cardiovascular, and MI myocardial infarction. .dagger.The
per-protocol population consisted of patients without major
protocol deviations.
[0138] Table 13 shows the percentages of patients with events and
the hazard ratios for the components of the primary end point,
including death from cardiovascular causes (hazard ratio, 0.84; 95%
CI, 0.46 to 1.52), resuscitated cardiac arrest (hazard ratio, 0.83;
95% CI, 0.25 to 2.73), myocardial infarction (hazard ratio, 0.91;
95% CI, 0.68 to 1.21), stroke (hazard ratio, 0.26; 95% CI, 0.10 to
0.70), and urgent hospitalization for angina leading to coronary
revascularization (hazard ratio, 0.50; 95% CI, 0.31 to 0.81). The
hazard ratios remained unchanged in the analysis that took
competing events into account.
TABLE-US-00014 TABLE 13 Major Clinical End-points
(Intention-to-Treat Population) Colchicine Placebo (N = 2366) (N =
2379) Hazard Ratio End Point number (percent) (95% CI) P Value
Primary composite end point 131 (5.5) 170 (7.1) 0.77 (0.61-0.96)
0.02.dagger. Components of primary end point Death from
cardiovascular causes 20 (0.8) 24 (1.0) 0.84 (0.46-1.52)
Resuscitated cardiac arrest 5 (0.2) 6 (0.3) 0.83 (0.25-2.73)
Myocardial infarction 89 (3.8) 98 (4.1) 0.91 (0.68-1.21) Stroke 5
(0.2) 19 (0.8) 0.26 (0.10-0.70) Urgent hospitalization for angina
25 (1.1) 50 (2.1) 0.50 (0.31.-0.81) leading to revascularization
Secondary composite end point.dagger. 111 (4.7) 130 (5.5) 0.85
(0.66-1.10) Death 43 (1.8) 44 (1.8) 0.98 (0.64-1.49) Deep venous
thrombosis 10 (0.4) 7 (0.3) 1.43 (0.54-3.75) or pulmonary embolus
Atrial fibrillation 36 (1.5) 40 (1.7) 0.93 (0.59-1.46) * Only the
initial event was counted in the analyses of time to first event
for the primary composite end point and for the secondary composite
end point. In the component analysis, all events (first and
subsequent) were counted separately. .dagger. The log-rank test and
the multivariable Cox proportional-hazards model (including age,
history of diabetes, previous coronary revascularization, and
previous heart failure yielded similar P values. .dagger-dbl. The
secondary composite end point included death from cardiovascular
causes, resuscitated cardiac arrest, myocardial infarction, and
stroke.
[0139] The secondary efficacy end point consisting of a composite
of death from cardiovascular causes, cardiac arrest, myocardial
infarction, or stroke occurred in 4.7% of the patients in the
colchicine group and in 5.5% of those in the placebo group (hazard
ratio, 0.85; 95% CI, 0.66 to 1.10). Data on the primary, secondary,
and exploratory efficacy end points are provided in Table 13. Two
patients had a first positively adjudicated event of urgent
hospitalization for angina leading to coronary revascularization
within 14 days after randomization. The median time to this
clinical end point was 258 days.
[0140] Efficacy results in prespecified subgroups are shown in
Table 14. The total number of primary end-point events (first and
recurrent) was 154 in the colchicine group and 223 in the placebo
group, over periods of 52,949 and 53,060 patient-months of
follow-up, respectively. Thus, the primary end-point event rates
per 100 patient-months were 0.29 in the colchicine group and 0.42
in the placebo group (rate ratio, 0.66; 95% CI, 0.51 to 0.86)
(Table 15).
TABLE-US-00015 TABLE 14 Primary Efficacy Composite Endpoint in
Prespecified Subgroups.dagger.. Colchicine Placebo Hazard ratio
(95% CI) Subgroup no. of patients with event/total no. of patients
(%) All patients 131/2366 (5.5%) 170/2379 (7.1%) 0.77 (0.61-0.96)
Smoking Non-smoker 47/787 (6.0%) 52/797 (6.5%) 0.90 (0.61; 1.34)
Previous smoker 46/871 (5.3%) 77/872 (8.8%) 0.59 (0.41; 0.85)
Active smoker 38/708 (5.4%) 41/708 (5.8%) 0.93 (0.60; 1.44) History
of diabetes Yes 40/462 (8.7%) 65/497 (13.1%) 0.65 (0.44; 0.96) No
91/1904 (4.8%) 105/1882 (5.6%) 0.85 (0.64; 1.13) History of
hypertension Yes 83/1185 (7.0%) 112/1236 (9.1%) 0.76 (0.57; 1.01)
No 48/1181 (4.1%) 58/1143 (5.1%) 0.80 (0.54; 1.17) Prior MI Yes
46/370 (12.4%) 47/397 (11.8%) 1.05 (0.70; 1.58) No 85/1996 (4.3%)
123/1982 (6.2%) 0.68 (0.51; 0.89) Prior PCI or CABG Yes 48/419
(11.5%) 57/447 (12.8%) 0.91 (0.62; 1.34) No 83/1947 (4.3%) 113/1932
(5.8%) 0.72 (0.54; 0.95) Prior stroke or TIA Yes 8/55 (14.5%) 9/67
(13.4%) 1.09 (0.42; 2.82) No 123/2311 (5.3%) 161/2312 (7.0%) 0.76
(0.60; 0.96) Sex.dagger-dbl. Male 94/1894 (5.0%) 135/1942 (7.0%)
0.70 (0.54; 0.91) Female 37/472 (7.8%) 35/437 (8.0%) 0.99 (0.63;
1.58) White blood cell count Below median 41/660 (6.2%) 46/637
(7.2%) 0.85 (0.56; 1.29) Above median 34/637 (5.3%) 44/664 (6.6%)
0.80 (0.51; 1.25) CABG denotes coronary artery bypass graft, MI
myocardial infarction, PCI percutaneous coronary intervention, and
TIA transient ischemic attack. .dagger.The final amendment to the
statistical analysis plan, which listed the subgroups of interest,
was approved on Aug. 28, 2019 and unblinding occurred on Aug. 29,
2019. .dagger-dbl.The hazard ratio for the primary endpoint was
0.70 (0.52; 0.93) in men and 0.81 (0.47; 1.41) in women in the
per-protocol population.
[0141] The median value for total white blood cell count was
8.64.times.10.sup.3/.mu.L.
TABLE-US-00016 TABLE 15 Total (First and Recurrent) Primary
Endpoint Events. Total Primary Colchicine Placebo Endpoint Events
(N = 2366) (N = 2379) Number of primary 0 2235 2209 endpoint events
per 1 111 132 patient 2 18 26 3 1 9 4 1 3 Total number of primary
154 223 endpoint events Total follow-up months 52949 53060 Rate of
primary endpoint 0.29 0.42 events per 100 patient-months Hazard
Ratio or Rate Ratio (95% CI) Negative binomial model.dagger. 0.66
(0.51; 0.86) Andersen-Gill models.dagger-dbl. 0.69 (0.54; 0.88) WLW
model 1.sup.st Event 0.77 (0.61; 0.96) 2.sup.nd Event 0.73 (0.48;
1.11) 3.sup.rd Event 0.64 (0.37; 1.10) Average 0.77 (0.61; 0.96)
WLW denotes Wei-Lin-Weissfeld method. .dagger.The negative binomial
regression model was used to calculate marginal rate ratio.
.dagger-dbl.The Andersen-Gill model was used with a robust variance
estimator (sandwich estimator) to calculate hazard ratio.
[0142] Regarding Table 15, the Wei-Lin-Weissfeld marginal model was
used to calculate hazard ratios for the time to the first, second
and third event as well as the weighted average of these hazard
ratios.
[0143] To account for the occurrence of multiple primary endpoint
events within patients, recurrent event analyses were undertaken
using three statistical approaches as there is no strong consensus
as to which method is preferable. First, a negative binomial
regression model was used with the number of events as the outcome
and the length of follow-up time in months as an offset term
(Hansson G K. Inflammation, atherosclerosis, and coronary artery
disease. N Engl J Med 2005; 352:1685-95). Marginal rate ratio was
provided, along with 95% confidence interval. The Andersen and Gill
model (Ridker P M, et al., Antiinflammatory therapy with
canakinumab for atherosclerotic disease. N Engl J Med 2017;
377:1119-31) with a robust variance estimator (Ridker P M et al.,
Low-dose methotrexate for the prevention of atherosclerotic events.
N Engl J Med 2019; 380:752-62; and Ravelli R B et al., Insight into
tubulin regulation from a complex with colchicine and a
stathmin-like domain. Nature 2004; 428:198-202) was utilized to
account for the dependency of within-patient events based on a
gap-time approach considering the time since a previous event. The
Andersen-Gill model is a simple extension of the Cox model based on
all events of all patients and estimates a hazard ratio assuming
that the instantaneous risk of experiencing an event is the same
irrespective of whether previous events occurred. Results from
these two models are often similar (Perico N et al., Colchicine
interferes with L-selectin and leukocyte function-associated
antigen-1 expression on human T lymphocytes and inhibits T cell
activation. J Am Soc Nephrol 1996; 7:594-601; and Pope R M and
Tschopp J, The role of interleukin-1 and the inflammasome in gout:
implications for therapy. Arthritis Rheum 2007; 56:3183-8).
Finally, an approach based on the Wei, Lin and Weissfeld marginal
model was conducted whereby times from randomization to first,
second and subsequent event were modeled with a Cox proportional
hazards model that used a covariance matrix estimate for the
regression coefficients that accounted for the possible
intra-patient correlation (Cerquaglia C et al., Pharmacological and
clinical basis of treatment of Familial Mediterranean Fever (FMF)
with colchicine or analogues: an update. Curr Drug Targets Inflamm
Allergy 2005; 4:117-24; Imazio M et al., Colchicine in addition to
conventional therapy for acute pericarditis: results of the
COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;
112:2012-6; and Nidorf S M et al., Low-dose colchicine for
secondary prevention of cardiovascular disease. J Am Coll Cardiol
2013; 61:404-10). This approach assumes that all patients are at
risk for any event since randomization. Marginal hazard ratios for
a k.sup.th event (i.e. based on time from randomization to k.sup.th
event), as well as a weighted average of these hazard ratios, were
provided along with 95% confidence intervals. It has been argued
that this approach preserves the randomization and permits valid
treatment effect estimation (Fine J P and Gray R J, A proportional
hazards model for the subdistribution of a competing risk. J Am
Stat Assoc 1999; 94:496-509).
Biomarkers of Inflammation
[0144] High-sensitivity C-reactive protein was measured in a
subgroup of only 207 patients at the time of randomization and 6
months later, and the median concentration at trial entry was 4.28
mg per liter. The baseline characteristics of these patients were
similar to those of the overall population (Table 16), but the
small and selected subgroup with these data limits the
interpretation of these analyses. The adjusted geometric mean
percent changes in the high-sensitivity C-reactive protein level at
6 months after myocardial infarction were -70.0% in the colchicine
group and -66.6% in the placebo group, and the placebo-adjusted
geometric mean percent change was -10.1% percentage points in the
colchicine group (95% CI, -28.6 to 13.4) (Table 17).
TABLE-US-00017 TABLE 16 Characteristics of the Trial Patients with
hs-CRP data values. Characteristic Colchicine (N = 99) Placebo (N =
108) Age - years 62.1 .+-. 9.7 61.2 .+-. 10.2 Female sex - no. (%)
18 (18.2%) 14 (13.0%) Caucasian - no. (%) 91 (93.8%) 89 (89.0%)
Body-mass index 28.8 .+-. 4.5 29.1 .+-. 4.2 (kg/m.sup.2) Smoking -
no. (%) 20 (20.2%) 20 (18.5%) Hypertension - no. (%) 44 (44.4%) 62
(57.4%) Diabetes - no. (%) 12 (12.1%) 15 (13.9%) Prior MI - no. (%)
14 (14.1%) 16 (14.8%) Prior PCI - no. (%) 24 (24.2%) 21 (19.4%)
Prior CABG - no. (%) 4 (4.0%) 6 (5.6%) Prior heart failure - no.
(%) 4 (4.0%) 1 (0.9%) Prior stroke/TIA - no. (%) 1 (1.0%) 2 (1.9%)
Index MI to 17.0 .+-. 9.2 15.8 .+-. 9.8 randomization - days PCI
for index MI - no. (%) 93 (93.9%) 104 (96.3%) Aspirin use - no. (%)
98 (99.0%) 106 (98.1%) Other anti-platelet 98 (99.0%) 108 (100%)
agent - no. (%) Statin use - no. (%) 99 (100%) 107 (99.1%)
Beta-blocker - no. (%) 83 (83.8%) 86 (79.6%) CABG denotes coronary
artery bypass graft surgery, MI myocardial infarction, PCI
percutaneous coronary intervention, and TIA transient ischemic
attack.
TABLE-US-00018 TABLE 17 Biomarkers of Inflammation. Biomarker
Colchicine Placebo Hs-C reactive protein (mg/L) N = 99 N = 108
Randomization, geometric mean (IQR).dagger. 4.27 (2.12, 7.22) 5.09
(2.45, 11.96) 6 months, geometric mean (IQR) 1.37 (0.75, 2.13) 1.60
(0.90, 2.65) Adjusted GM percent change (95% CI).dagger-dbl. -70.0
(-74.6, -64.5) -66.6 (-71.5, -60.8) Placebo-adjusted GM percent
change (95% CI) -10.1 (-28.6, 13.4) -- N = 992 N = 980 Total white
blood cell count (10.sup.3/.mu.L) Randomization, geometric mean
(IQR).dagger. 8.54 (7.10, 10.40) 8.63 (7.20, 10.70) 12 months,
geometric mean (IQR) 6.95 (5.99, 8.30) 7.03 (5.96, 8.48) Adjusted
GM percent change (95% CI).dagger-dbl. -18.81 (-20.12, -17.47)
-19.02 (-20.46, -17.55) Placebo-adjusted GM percent change (95% CI)
0.26 (-2.15, 2.72) -- Circulating lymphocytes (10.sup.3/.mu.L)
Randomization, geometric mean (IQR).dagger. 1.79 (1.40, 2.40) 1.79
(1.42, 2.46) 12 months, geometric mean (IQR) 1.83 (1.50, 2.44) 1.82
(1.50, 2.44) Adjusted GM percent change (95% CI).dagger-dbl. 1.80
(-0.46, 4.11) 0.69 (-1.54, 2.98) Placebo-adjusted GM percent change
(95% CI) 1.10 (-2.06, 4.36) -- Circulating neutrophils
(10.sup.3/.mu.L) Randomization, geometric mean (IQR).dagger. 5.45
(4.36, 7.15) 5.47 (4.30, 7.46) 12 months, geometric mean (IQR) 3.95
(3.27, 5.08) 3.99 (3.34, 5.20) Adjusted GM percent change (95%
CI).dagger-dbl. -27.63 (-29.48, -25.73) -27.95 (-29.91, -25.93)
Placebo-adjusted GM percent change (95% CI) 0.45 (-3.28, 4.32) --
GM denotes geometric mean, HS high-sensitivity, and IQR
inter-quartile range. .dagger.The geometric mean was obtained by
exponentiating the mean of log-transformed data. .dagger-dbl.The
adjusted geometric mean percent change was obtained by
exponentiating the adjusted mean from the analysis of covariance
model (based on log-transformed data), then subtracting 1 and
multiplying by 100. The bounds of the 95% confidence intervals were
obtained similarly.
[0145] In Table 17, the placebo-adjusted geometric mean percent
change was obtained by exponentiating the adjusted mean difference
between groups from the analysis of covariance model (based on
log-transformed data), then subtracting 1 and multiplying by
100.
[0146] In addition, the C-reactive protein biomarker sub-study was
implemented following a protocol amendment and was optional for
sites and for patients; 34 sites accepted to participate in this
substudy. There were 213 and 208 patients who provided blood
samples at baseline and 6 months, respectively. Paired baseline and
6-month hs-CRP values were available in 207 patients. Clinically
available white blood cell counts were obtained from 2598 patients
at baseline and 1998 patients at 12 months, and paired baseline and
12-month values were available in 1972 patients. Statistical
analysis was conducted on the patients who provided both baseline
and follow-up data and as these were exploratory analyses, no
missing data was imputed.
[0147] Information about white-cell counts at baseline and at the
12-month follow-up were also available for a relatively small
subgroup of 1972 patients. The adjusted geometric mean percent
changes from baseline to 1 year in the total white-cell count were
-18.8% in the colchicine group and -19.0% in the placebo group,
with no significant difference between groups (0.3% percentage
points; 95% CI, -2.2 to 2.7).
Safety and Adverse Events
[0148] The incidence of adverse events that were considered to be
related to trial drug was 16.0% in the colchicine group and 15.8%
in the placebo group, and the overall incidence of serious adverse
events was 16.4% and 17.2%, respectively (Table 18).
TABLE-US-00019 TABLE 18 Adverse Events (Safety Population)
Colchicine Placebo (N = 2330) (N = 2346) Event number of patients
(percent) P Value Any related adverse event.dagger. 372 (16.0) 371
(15.8) 0.89 Any serious adverse event.dagger-dbl. 383 (16.4) 404
(17.2) 0.47 Gastrointestinal 408 (17.5) 414 (17.6) 0.90 adverse
event Gastrointestinal serious 46 (2.0 ) 36 (1.5) 0.25 adverse
event Diarrhea adverse event 225 (9.7) 208 (8.9) 0.35 Nausea
adverse event 43 (1.8) 24 (1.0) 0.02 Flatulence adverse event 15
(0.6) 5 (0.2) 0.02 Gastrointestinal hemorrhage 7 (0.3) 5 (0.2) 0.56
Infection serious 51 (2.2) 38 (1.6) 0.15 adverse event Pneumonia
serious 21 (0.9) 9 (0.4) 0.03 adverse event Septic shock serious 2
(0.1) 2 (0.1) 0.99 adverse event Hospitalization for 25 (1.1) 17
(0.7) 0.21 heart failure Cancer.sctn. 43 (1.8) 46 (2.0) 0.77 Anemia
14 (0.6) 10 (0.4) 0.40 Leukopenia 2 (0.1) 3 (0.1) 0.66
Thrombocytopenia 3 (0.1) 7 (0.3) 0.21 * The safety population was
defined as patients who took at least one dose of colchicine or
placebo. All serious adverse events were recorded, and the only
other adverse events recorded were those that were related to the
gastrointestinal system, events that were judged by the
investigator to be related to colchicine or placebo, or laboratory
abnormalities that were judged by the investigator to be clinically
significant. This table lists serious adverse events that were
present in more than 2% of the patients in either trial group,
adverse events that were considered to be related to colchicine or
placebo in more than 5% of the patients in either trial group, and
any other safely events of special interest. Chi-square tests were
conducted to compare the incidence of adverse events between the
trial groups. .dagger.These adverse events were considered to be
related to colchicine or placebo by the physician in charge of the
participant. .dagger-dbl.There was one serious adverse event of
myopathy, which was attributed to high-dose statin therapy
(rosuvastatin at a dose of 40 mg daily) by the local investigator
and academic sponsor, in a man of short stature (165 cm, 68 kg)
with normal renal function in the colchicine group who had received
colchicine for 8 days 3 months before the adverse event.
.sctn.Cancers, excluding nonmelanoma skin cancers, occurred in 42
patients (1.8%) in the colchicine group and in 44 (1.9%) in the
placebo group.
[0149] At least one gastrointestinal adverse event during the
double-blind period occurred in 17.5% of the patients in the
colchicine group, as compared with 17.6% of those in the placebo
group. Diarrhea was reported in 9.7% of the patients in the
colchicine group and in 8.9% of those in the placebo group
(P=0.35), and nausea was more common in the colchicine group than
in the placebo group (1.8% vs. 1.0%, P=0.02). Pneumonia was
reported as a serious adverse event in 0.9% of the patients in the
colchicine group, as compared with 0.4% of those in the placebo
group (P=0.03).
[0150] In COLCOT, the risk of the primary composite efficacy end
point of death from cardiovascular causes, resuscitated cardiac
arrest, myocardial infarction, stroke, or urgent hospitalization
for angina leading to coronary revascularization, as assessed in a
time-to-event analysis, was significantly lower among the patients
who were randomly assigned to receive 0.5 mg of colchicine once
daily than among those who received placebo. This result was due
predominantly to a lower incidence of strokes and urgent
hospitalizations for angina leading to coronary
revascularization.
[0151] These results were observed against a background of
appropriate medications, which included aspirin, a different
antiplatelet agent, and a statin in 98 to 99% of the patients. In
addition, percutaneous coronary intervention was performed in 93%
of the patients for their index myocardial infarction. The benefits
of colchicine with regard to cardiovascular end points in COLCOT
were at least as large as those of canakinumab in CANTOS (Ridker P
M et al., Antiinflammatory therapy with canakinumab for
atherosclerotic disease. N Engl J Med 2017; 377:1119-31). In the
small subgroup of patients with available data, a large (>65%)
reduction in the C-reactive protein level occurred over the first 6
months after myocardial infarction in both trial groups in COLCOT,
but the difference between the changes in the groups was not
significant. These findings must be interpreted cautiously given
that this was a small subgroup that was not randomly selected from
the full trial sample. A similar observation was made with
white-cell counts. The different patient populations involved in
the two trials--early after myocardial infarction in COLCOT and
stable coronary disease in CANTOS--may also have affected the
relationship between biomarkers of inflammation and the effects of
treatments on ischemic end points.
[0152] The known benefits of colchicine in the treatment of
pericarditis were not at play in COLCOT.
[0153] Postinfarction pericarditis typically occurs within the
first few days after the injury, whereas the mean time from the
index myocardial infarction to randomization was 13.5 days. There
were only two patients with a first positively adjudicated event of
urgent hospitalization for angina leading to coronary
revascularization within 14 days after randomization, and the
median time to this clinical end point was 258 days.
[0154] The most common adverse events observed were
gastrointestinal. Diarrhea was reported in 9.7% of the patients in
the colchicine group and in 8.9% of those in the placebo group, and
nausea occurred in 1.8% and 1.0%, respectively. Infection as a
serious adverse event was more frequent in the colchicine group
than in the placebo group (in 2.2% vs. 1.6% of the patients), and
pneumonia as a serious adverse event was also more frequent in the
colchicine group (0.9% vs. 0.4%). These differences in the
incidence of infections could be due to the play of chance or could
reflect altered immunologic responses.
[0155] In contrast to canakinumab (Ridker P M et al.,
Antiinflammatory therapy with canakinumab for atherosclerotic
disease. N Engl J Med 2017; 377:1119-31), colchicine did not
increase the incidence of septic shock in our trial. Infections
have previously been described in patients who have attempted
suicide by taking an overdose of colchicine (Kocak Z et al.,
Colchicine intoxication and infection risk: a case report. J Clin
Pharm Ther 2008; 33:451-2). There was no serious adverse event of
myopathy linked to colchicine despite the use of statins in 99% of
the patients in the trial.
[0156] In conclusion, among patients with a recent myocardial
infarction, colchicine at a dose of 0.5 mg daily led to a
significantly lower percentage of patients with ischemic
cardiovascular events than placebo.
Other Embodiments
[0157] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features
hereinbefore set forth, and follows in the scope of the claims.
[0158] Some embodiments of the invention are within the following
numbered paragraphs.
1. A method of treating a patient after having a myocardial
infarction (MI), the method comprising initiating the
administration of colchicine at a daily low dose to the patent
within about 3 days of the MI. 2. A method of treating a patient
after having a myocardial infarction (MI), the method comprising
initiating the administration of colchicine at a daily low dose to
the patient within about 4 days of the MI. 3. The method paragraph
1 or 2, wherein percutaneous coronary intervention was performed
for treating the patient's MI. 4. The method of any one of
paragraphs 1-3, wherein the patient was prescribed a medication. 5.
The method according to paragraph 4, wherein the medication is an
antiplatelet agent. 6. The method according to paragraph 4, wherein
the medication is aspirin. 7. The method according to paragraph 4,
wherein the medication is a statin. 8. The method according to any
one of paragraphs 1-7, wherein the patient is at a lower risk of a
cardiovascular event, relative to a patient not being administered
colchicine. 9. The method according to paragraph 8, wherein the
cardiovascular event is an ischemic cardiovascular event. 10. The
method according to paragraph 8, wherein the cardiovascular event
is cardiovascular death, resuscitated cardiac arrest, myocardial
infarction, stroke, or urgent hospitalization for angina requiring
coronary revascularization. 11. The method according to any one of
paragraphs 1-10, wherein the patient has atherosclerotic coronary
artery disease. 12. A method of reducing the risk of a stroke in a
patient after having an MI, the method comprising initiating the
administration of colchicine at a daily low dose to the patient
within about 30 days of the MI. 13. The method according to
paragraph 12, wherein the method comprises administering colchicine
within 4-7 days of the MI. 14. The method according to paragraph
12, wherein the method comprises administering colchicine within 3
days of the MI. 16. The method according to any one of paragraphs
1-15, wherein the administration of colchicine is initiated upon
assessment in (a) an emergency department (ED), (b) the hospital,
or (c) a medical office setting. 17. The method according to any
one of paragraphs 1-16, wherein the colchicine is in the form of a
tablet. 18. The method of paragraph 17, wherein the tablet is
coated. 19. The method of paragraph 18, wherein the tablet is
film-coated. 20. The method according to any one of paragraphs
1-19, wherein the colchicine is administered at 0.3 to 0.7 mg. 21.
The method according to any one of paragraphs 1-20, wherein the
colchicine is administered at 0.4 to 0.6 mg 22. The method
according to paragraph 21, wherein the colchicine is administered
at about 0.5 mg.
[0159] The method according to any one of paragraph 1-22, wherein
the colchicine is administered once, twice or three times a
day.
24. The method according to paragraph 23, wherein the colchicine is
administered once per day. 25. The method of any one of paragraphs
1-24, wherein the colchicine is administered without pre-loading
the patient with colchicine. 26. The method of any one of
paragraphs 1-25, wherein the patient is an adult human.
[0160] Other embodiments are within the claims.
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