U.S. patent application number 11/317831 was filed with the patent office on 2006-06-22 for apparatus and methods for risk stratification of patients with chest pain of suspected cardiac origin.
This patent application is currently assigned to ISCHEMIA TECHNOLOGIES, INC.. Invention is credited to Peter A. Crosby, Deborah L. Morris, Mark M. Soane.
Application Number | 20060135875 11/317831 |
Document ID | / |
Family ID | 33476600 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060135875 |
Kind Code |
A1 |
Crosby; Peter A. ; et
al. |
June 22, 2006 |
Apparatus and methods for risk stratification of patients with
chest pain of suspected cardiac origin
Abstract
The subject invention relates to the detection, diagnosis and
risk stratification of clinical events such as acute coronary
syndrome, in patients with signs and symptoms of suspected cardiac
origin. In one embodiment, a clinical event in a patient is
diagnosed by obtaining the patient's ECG, and at least one in vitro
diagnostic assay, preferably an assay for a marker of ischemia, and
optionally in vitro diagnostic assays for necrotic markers or other
cardiac indicators, and combining the foregoing results in an
algorithm to provide a diagnosis or a risk stratification of the
clinical condition.
Inventors: |
Crosby; Peter A.; (Denver,
CO) ; Morris; Deborah L.; (Redondo Beach, CA)
; Soane; Mark M.; (Denver, CO) |
Correspondence
Address: |
SWANSON & BRATSCHUN L.L.C.
1745 SHEA CENTER DRIVE
SUITE 330
HIGHLANDS RANCH
CO
80129
US
|
Assignee: |
ISCHEMIA TECHNOLOGIES, INC.
Waltham
MA
|
Family ID: |
33476600 |
Appl. No.: |
11/317831 |
Filed: |
December 22, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10441155 |
May 19, 2003 |
|
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11317831 |
Dec 22, 2005 |
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Current U.S.
Class: |
600/509 |
Current CPC
Class: |
G16H 50/30 20180101;
G16H 50/20 20180101; A61B 5/318 20210101; A61B 5/14546 20130101;
G01N 33/6893 20130101; G01N 2800/324 20130101; G01N 2800/56
20130101; A61B 5/7275 20130101; G16H 10/40 20180101; G01N 33/5302
20130101; G01N 2800/50 20130101 |
Class at
Publication: |
600/509 |
International
Class: |
A61B 5/04 20060101
A61B005/04 |
Claims
1. A method, comprising: receiving at least one assay value
indicative of a result of an in vitro assay for albumin that has
been modified by exposure to ischemic tissue, the assay having been
performed on a sample that includes material derived from a human;
receiving at least one electrocardiogram value indicative of an
electrocardiogram obtained from the human; and determining, based
at least in part on the assay and electrocardiogram values, at
least one diagnostic value indicative of a diagnosis or risk
stratification of acute cardiac ischemia, acute coronary syndrome,
or unstable angina of the human.
2. The method of claim 1, comprising determining, based at least in
part on the at least one diagnostic value, a diagnosis or risk
stratification of acute cardiac ischemia, acute coronary syndrome,
or unstable angina of the human.
3. A method, comprising: receiving at least one albumin assay value
indicative of a result of a first in vitro assay for albumin that
has been modified by exposure to ischemic tissue, the first assay
having been performed on a sample that includes material derived
from blood of a human; receiving at least one necrosis assay value
indicative of a result of a second in vitro assay for a marker of
necrosis, the second assay having been performed on a sample that
includes material derived from blood of the human; receiving at
least one electrocardiogram value indicative of an
electrocardiogram obtained from the human; and determining, based
at least in part on the albumin assay, necrosis assay, and
electrocardiogram values, at least one diagnostic value indicative
of a diagnosis or risk stratification of acute coronary syndrome of
the human.
4. The method of claim 3, comprising determining, based at least in
part on the albumin assay, necrosis assay, and electrocardiogram
values, a diagnosis or risk stratification of acute coronary
syndrome of the human.
5. An apparatus, comprising: an electrocardiogram device configured
to obtain an electrocardiogram from a human and provide at least
one electrocardiogram value indicative of the electrocardiogram; an
analysis device configured to receive a sample analysis strip and
determine at least one assay value indicative of a result of an in
vitro assay performed using the sample analysis strip; and at least
one of (a) a processor configured to receive the electrocardiogram
and assay values and determine the presence of or probability that
the human has a condition based at least in part on the
electrocardiogram and assay values or (b) an output device
configured to output at least one indication of the
electrocardiogram and assay values.
6. The apparatus of claim 5, wherein the condition is selected from
the group consisting of acute cardiac ischemia, acute coronary
syndrome, or unstable angina of the human.
Description
FIELD OF THE INVENTION
[0001] The subject invention relates to the detection, diagnosis
and risk stratification of clinical events, such as acute coronary
syndrome, in patients with signs and symptoms of suspected cardiac
origin.
BACKGROUND OF THE INVENTION AND PRIOR ART
[0002] Each year in the United States, approximately eight million
people present to a hospital emergency room (ER) with chest pain
suggestive of cardiac origin (Storrow et al. (2000) Ann. Emerg.
Med. 35:449), and even more present to their primary care
physician. Acute Coronary Syndrome (ACS) presents as a
constellation of symptoms such as chest pain, shortness of breath,
inability to maintain physical exertion, sense of dread, pain or
tingling on the left arm, and may also be accompanied by clinical
signs such as altered electrocardiogram and elevation in
biochemical markers of necrosis such as cardiac troponin. Chest
pain of suspected cardiac origin is often referred to by its
clinical description of angina pectoris. Chest pain is the number
two reason for emergency room presentation, accounting for about
eight percent of all patients.
[0003] The chest pain patient presents a diagnostic nightmare for
the emergency room physician. On one hand, if the patient really is
having a heart attack, early and rapid therapy is crucial to
prevent more damage to the heart muscle, and missed diagnosis may
result in poor consequences for the patient including death. On the
other hand, if the patient is not having a heart attack and the
physician keeps the patient in the hospital for a long time
performing many diagnostic tests, the patients will consume
precious health care resources that could be better spent on
others. In fact, it is estimated that diagnosis of chest pain
patients represents about $6 billion of wasted resources in the US
alone.
[0004] The term "infarct" or "infarction" means a region of tissue
which is dead and non-functional. For example, it is possible to
have a brain infarct as a result of a stroke, or a bowel infarct as
a result of severe bowel ischemia. A myocardial infarction (MI) is
a region of dead heart muscle which is therefore unable to
contribute to the pumping function of the heart. The term "heart
attack" usually refers to an acute myocardial infarction or AMI,
which is the emerging or developing MI, and is the end stage of
ACS.
[0005] As a person ages, there is often a buildup of fatty plaque
in the coronary arteries. The plaque is usually due to deposition
of cholesterol from the blood, and consists of a soft core, with a
harder membrane overlying it. At some time, a plaque may become
unstable and rupture. A ruptured plaque will trigger a cascade of
reactions in the blood, leading to formation of a clot or thrombus.
The thrombus may be carried downstream in the coronary artery
circulation, which becomes progressively narrower. Eventually, the
thrombus will occlude a coronary artery, disrupting circulation and
preventing blood supply to the cardiac muscle or myocardium.
[0006] Ischemia is the condition of imbalance between oxygen supply
and demand. Ischemia can be transitory or continuous. In the case
of myocardial ischemia, the oxygen supply is provided by the blood
flow in the coronary arteries. The demand may depend on the
physical exertion of the person. Thus, ischemia can result from
increased demand with a limited supply (e.g.: as a result of
increased stress with occluded coronary arteries), or from suddenly
restricted supply, as may occur with plaque disruption and thrombus
formation in a coronary artery. The first case is often referred to
as stable angina. This word "stable" refers to the fact that the
angina is reproducible because the restriction in supply is stable
(and usually due to stable plaque), and the ischemia can be
reversed by simply ceasing the activity. Unstable angina is chest
pain which occurs when coronary artery flow is rapidly compromised
due to disruption of a plaque (so called unstable plaque) and is
inadequate to supply the oxygen demands of the heart during minimal
activity. In this case, the ischemia cannot be stopped by ceasing
activity, and it may deteriorate to something worse, such as acute
myocardial infarction.
[0007] Once the blood supply to the myocardium is restricted, the
myocardium becomes starved of oxygen, leading to ischemia. In the
early stages, the tissue is reversibly ischemic, meaning that with
resumption of blood supply the tissue will recover and return to
normal function. After a while, the tissue becomes irreversibly
ischemic, meaning that although the cells are still alive, if the
blood supply is restored, the tissue is beyond salvation, and will
inevitably die. Finally, the tissue dies (i.e., becomes necrosed),
and forms part of the myocardial infarct. In fact, myocardial
infarction is defined as "myocardial cell death due to prolonged
ischemia."
[0008] The events which occur in an AMI are illustrated
diagramatically in FIG. 1. An occlusion of a coronary artery (1)
results in reduced blood flow. Tissue becomes first reversibly
ischemic, then irreversibly ischemic, and finally necrosed (dead).
The tissue which has been ischemic for the longest time is that
which dies first. Because much of the myocardial tissue is supplied
via capillaries, regions furthest from the site of occlusion are
the last to receive oxygenated blood, and therefore are ischemic
for shorter time than the areas closer to the site of occlusion.
Thus, there are several zones of conditions proceeding in the
tissue downstream from the coronary artery occlusion. The zone
furthest away is reversibly ischemic (2), progressing to
irreversibly ischemic (3), then finally necrosed (4). Eventually
the entire region of tissue becomes necrosed with no remaining
ischemic tissue, and there is a complete infarct.
[0009] Patients presenting with chest pain may be having stable
angina, unstable angina, AMI, non-ischemic cardiac problems such as
congestive heart failure, or non-cardiac problems such a gastro
esophageal reflux disease (GERD). The optimal therapy for each of
these patient types and the urgency for therapy is quite different,
hence rapid diagnosis and risk stratification has enormous clinical
importance.
[0010] Until recently, the diagnosis of an MI was done
retrospectively. The criteria established by the World Health
Organization (WHO) defined MI as any two of the three
characteristics of (a) typical symptoms (i.e., chest discomfort),
(b) enzyme rise, and (c) typical ECG pattern involving the
development of Q-waves (an indication of necrosed myocardium). With
these criteria, which were established some years ago, the "enzyme
rise" refers to the rise of serum levels of creatine kinase (CK) or
its more cardiac specific isoform CK-MB. CK-MB is one of the
molecules released from dead cardiac muscle cells and therefore is
a serum marker of necrosis. As a heart muscle cell dies as a result
of prolonged ischemia, the cell membrane ruptures, releasing the
cytosolic contents into the extracellular fluid space, then into
the lymphatic system, and from there it enters the bloodstream.
[0011] Since the WHO criteria were first promulgated, new
biochemical markers of cardiac necrosis have been discovered and
commercialized. (For a complete description of many of these
markers, see Wu, A. H. B. (ed.) Cardiac Markers, Humana Press ISBN
0-89603-434-8, 1998). The most specific markers of cardiac necrosis
so far developed are the cardiac troponins. These are proteins
which are part of the contractile apparatus of myocardial cells.
Two versions, cTnI and cTnT have been commercialized, and shown to
be very specific for detection of even small amounts of myocardial
damage. The cardiac troponins, similar to CK-MB, are released from
dead cardiac muscle cells when the cell membrane ruptures, and are
eventually detectable in the blood. Necrosis can certainly occur as
a result of a prolonged myocardial ischemia, but can also result
from myocardial cell damage from other causes such as infection,
trauma, or congestive heart failure. Thus, the observation of an
increase in cardiac markers of necrosis alone does not lead to a
definitive diagnosis of myocardial infarction.
[0012] The cardiac markers described above are excellent markers of
necrosis, but are not markers of ischemia. However, there is much
confusion in the medical community and in the literature on this
point, and it is not uncommon to see references to troponin, CK-MB
and myoglobin (another marker of cardiac necrosis) being described
as markers of cardiac ischemia. Although it is true that necrosis
is always preceded by and is a consequence of ischemia, it is not
true that ischemia always leads to necrosis. Therefore these
necrosis markers are not necessarily markers of ischemia. For
example, stable angina is cardiac ischemia as a result of exercise
which will not necessarily lead to necrosis. If the person stops
exertion, the demand will fall to the level which can be adequately
supplied by the circulation, and the ischemia dissipates, and there
is thus no elevation of markers of cardiac necrosis.
[0013] The American College of Cardiology (ACC) and the European
Society of Cardiology (ESC) published a consensus document (Alpert,
J. S. et al. (2000) J. Am. Coll. Card. 36:3) with a proposed
redefinition of myocardial infarction. Part of the consensus
document is a new definition of acute, evolving or emerging MI. The
new definition is that either one of the following criteria
satisfies the diagnosis for an acute, evolving or recent MI: [0014]
1. typical rise and gradual fall (troponin) or more rapid rise and
fall (CK-MB) of biochemical markers of myocardial necrosis with at
least one of the following: [0015] a. ischemic symptoms; [0016] b.
development of pathologic Q-waves on the ECG; [0017] c. ECG changes
indicative of ischemia (ST segment elevation or depression); or
[0018] 2. coronary artery intervention (e.g., coronary
angioplasty); or [0019] 3. pathologic findings of acute MI.
[0020] Implicit in this definition is the idea that an AMI includes
both an ischemic component and a necrosis component. The problem is
that although there are excellent biochemical markers of necrosis
(i.e., troponin), there are no accepted biochemical markers of
ischemia, and therefore reliance is made on clinical impressions
combined with symptoms and changes in the ECG. The fact that
troponin is not a marker of ischemia is highlighted in the
consensus document which states "these biomarkers reflect
myocardial damage but do not indicate its mechanism. Thus an
elevated value in the absence of clinical evidence of ischemia
should prompt a search for other causes of cardiac damage, such as
myocarditis."
[0021] The problem is that cardiac ischemia is extremely difficult
to diagnose. The National Heart Lung and Blood Institute (NHLBI) of
the US National Institutes of Health (NIH) created a National Heart
Attack Alert Program (NHAAP) in the early 1990s. In 1997, a working
group of the NHAAP published an evaluation of all technologies
available at the time for identifying acute cardiac ischemia in the
emergency department (Selker, H. P. et al. (1997) A Report from the
National Heart Attack Alert Program (NHAAP) Coordinating Committee
Blackwell Science ISBN 0-632-04304-0). The key reason for this
report was that new technologies for reperfusion (in particular
percutaneous transluminal coronary angioplasty or PTCA, and a whole
class of thrombolytic drug therapies such as TPA (tissue
plasminogen activator) and streptokinase) had shown that dramatic
improvements in mortality and morbidity were related to the
interval between the onset of chest pain and the start of therapy.
This is clearly because the earlier therapy can be applied, the
more of the myocardial tissue is still reversibly ischemic instead
of necrosed, and therefore there is higher likelihood that it will
recover if blood supply is restored. Obviously, the key to reducing
the time to therapy is to improve the performance of diagnostic
tests in the emergency department (ED) such that the diagnosis can
be made earlier while reversible ischemia is still present. In
fact, the introduction of the NHAAP book states that "identifying
only AMI would miss a large number of ED patients at significant
and immediate cardiac risk."
[0022] The standard of care and the most widely accepted tool for
diagnosis of ACS in the ED is the standard twelve lead
electrocardiogram (ECG or EKG). Changes such as ST Segment
Elevation are indicative of injury to the myocardium, and lead to a
diagnosis of MI. Changes such as ST Segment depression are
indicative of ischemia. The ECG is also used to diagnose and
classify arrhythmias such as atrial fibrillation and ventricular
tachycardia. A patient with an arrhythmia such as Left Bundle
Branch Block (LBBB) obscured features on the ECG and makes the ECG
uninterpretable for ACS.
[0023] The ECG suffers from imperfect sensitivity and specificity
for acute cardiac ischemia, and when interpreted using stringent
criteria for AMI, sensitivity drops to 50% or below. Other tools
which have been investigated but not yet well accepted include
variations on the ECG or algorithms involving the ECG, cardiac
markers such as CK-MB and TnI, radionuclide myocardial perfusion
imaging (MPI) using .sup.99Tc sestamibi and thallium, ECG exercise
stress test, and ultrasound echocardiography. None of these has
been shown to have consistently reliable sensitivity and
specificity to the point where it has been accepted as standard of
care. Furthermore, some technologies such as MPI, while offering
relatively good accuracy, are expensive and have limited
availability.
[0024] There have been several attempts to develop a device and/or
algorithms for diagnosing AMI in chest pain patients using
biochemical markers (see, for example, Jackowski, G., U.S. Pat. No.
5,710,008 (1998)). The '008 patent describes a method and a device
for using a combination of at least three biochemical markers in
conjunction with an algorithm for diagnosis of AMI. Cardiac
Troponin has been accepted as the "gold standard" biochemical
marker for diagnosis of acute myocardial infarction. The clinical
performance of Troponin I has been reported by many publications,
and by many manufacturers of troponin assays.
[0025] Although troponin is a very specific marker for cardiac
necrosis, its clinical utility, especially in the early period
following onset of chest pain (i.e., immediately after the coronary
artery occlusion leading to ischemia) is limited by the slow
kinetics of the marker itself, and the fact that it is a marker for
necrosis, not ischemia, and therefore released late in the clinical
sequence. In other words, the clinical sensitivity of troponin for
detection of AMI approaches 100% provided sufficient time has
elapsed. However, the clinical sensitivity of troponin for
detection of AMI (or ACS) is less than 20% at presentation of a
patient within 2 hours of the onset of chest pain (Mair et al.
(1995) Clin. Chem. 41:1266; Antman et al. (1995) JAMA 273:1279).
This is important because the median time for presentation to a
hospital emergency room after onset of chest pain is about two
hours in patients who will be subsequently diagnosed as having AMI
(Goff et al. (1999) Am. Heart J. 138:1046).
[0026] Attempts to obtain better diagnosis of AMI using
combinations of results from biochemical markers of necrosis have
been described. For example, Shah et al., U.S. Pat. No. 5,382,515
(1995), describe an algorithm using sequential closely spaced
measurements of different isoforms of creatine kinase to determine
both the presence and the time of an AMI. The concept was expanded
by Groth, T. et al., U.S. Pat. No. 5,690,103 (1997), who describe
the use of an algorithm implemented by a neural network whose
inputs are several closely spaced measurements of several markers
released from necrotic tissue (CK-MB and troponin). Although this
method may be beneficial in that it is still better than
measurement of a single necrosis marker, or multiple necrosis
markers at a single time, it is still not possible to make the
determination until at least three hours have passed, and does not
work for detection of ischemia since only necrosis markers are
used.
[0027] A similar approach (although without a neural network) was
proposed by Armstrong et al. (U.S. Pat. No. 6,099,469 (2000)),
although in this case the algorithm is designed to run on the
computer embedded in an automated laboratory analyzer, and suggests
which test should be performed next. Again, the Armstrong invention
suffers from the limitation that it uses only markers of necrosis,
and requires multiple sequential measurements to achieve adequate
performance.
[0028] Ohman et al. (U.S. Pat. No. 6,033,364 (2000)) described
algorithms using combinations of existing markers of necrosis which
have also been used to assess reperfusion after thrombolytic
therapy. In this invention, an algorithm using sequential
measurements of a necrosis marker (CK-MB) and a model based on the
rise and fall kinetics of CK-MB can determine when therapy has
allowed restoration of coronary artery flow and therefore arrested
the growth of infarcted tissue and hence release of further markers
of necrosis.
[0029] Partly as a result of the difficulty of obtaining a firm
diagnosis in chest pain patients, there has been a growing emphasis
in clinical medicine in recent years to focus more on risk
stratification than a hard diagnostic endpoint. To meet these
clinical practice guidelines, emergency physicians need diagnostic
tools and procedures that can help identify high risk ACS patients
in less than 30 minutes. The concept of a "Chest Pain Evaluation
Unit" (CPEU) has gained rapid acceptance in the emergency medicine
field. The basic concept is rapid risk stratification based on ECG,
clinical presentation, and often troponin, in a hierarchy. High
risk patients may receive more aggressive diagnostic testing (e.g.:
cardiac catheterization) and therapy (e.g.; anti-coagulant drugs),
whereas low risk patients may be relegated to watchful waiting and
eventual discharge. Patients who can not be adequately risk
stratified at presentation are subjected to serial testing, and
often provocative testing such as stress ECG. With currently
available tools combining ECG and troponin, only about 25% of
patients can be reliably risk stratified at presentation, and the
remainder will spend many hours with serial testing and watchful
waiting before receiving therapy or being discharged.
[0030] One of the problems with early risk stratification of chest
pain patients has been the problem of obtaining rapid assessment of
biochemical markers such as troponin when the instruments are in a
central laboratory, and may not be configured for "stat"
utilization. As a result, there has been a growing interest in
Point of Care (POC) Testing, often with dedicated instruments
placed in the emergency room or near the patient to perform a
limited number of diagnostic tests, but to give the results in a
short period of time. For example, Anderson et al in U.S. Pat. No.
6,394,952 and U.S. Pat. No. 6,267,722 "Point of Care Diagnostic
Systems" describe an apparatus for performing rapid testing and
turning the results into diagnostic or risk assessment
information.
[0031] Interpretation of an electrocardiogram is fraught with
error, particularly by physicians who do not perform this task
often and routinely. To help solve this problem,
electrocardiographic machines have been developed which perform
automatic analysis on the ECG, for example to look at deviations of
the ECG ST segment to determine if ischemia is present or absent.
See U.S. Pat. No. 4,546,776 "Portable EKG Monitoring Device for ST
Deviation" for an early example of this technology. Many algorithms
have been invented for improving the performance of equipment to
detect ST segment changes indicative of cardiac ischemia--see for
example U.S. Pat. No. 6,507,753 (2003) "Method and Apparatus to
Detect Acute Cardiac Syndromes in Specified Groups of Patients
using ECG", and U.S. Pat. No. 4,930,075 (1990) "Technique to
Evaluate Myocardial Ischemia from ECG Parameters". Alternative
parameters in the ECG have been evaluated as a detector for
ischemia, including interval data--see for example U.S. Pat. No.
6,361,503 (2002) "Method and System for Evaluating Cardiac
Ischemia". Because of the relatively poor performance of ECG as a
signal source for diagnosis of ischemia, there have been attempts
to allow the user to "trade off" sensitivity and specificity in the
way the algorithms are performed, see for example U.S. Pat. No.
6,171,256 B1 (2001) "Method and Apparatus for Detecting a Condition
Associated with Acute Cardiac Ischemia".
[0032] This shift in emphasis from hard diagnosis to risk
stratification which has been seen in the recent use of biochemical
markers has also had an impact on the world of electrocardiography.
Inventions have been directed towards estimating the probability
that a patient has cardiac ischemia as opposed to merely providing
a "yes" or "no" diagnostic answer. For example, in US Patent
Application US2002/0133087A1 (2002), "Patient Monitor for
Determining a Probability that a Patient has Acute Cardiac
Ischemia", the inventors use continuously monitored and analyzed
ECG signals to provide a numerical probability of acute cardiac
ischemia for a patient in an emergency department. A similar
objective is targeted in the invention described in European Patent
Application EP.1.179.319.A1 (2001) "Method and Apparatus to Detect
Acute Cardiac Syndromes in Specified Groups of Patients using
ECG".
[0033] There would be an advantage to providing diagnosis of ACS
before a patient presents to an emergency room, for example in an
ambulance or in the physician's office. Some inventions have been
directed towards improving the performance of ECG analysis in a
telemedicine environment--see for example U.S. Pat. No. 6,424,860
"Myocardial Ischemia and Infarction Analysis and Monitoring Method
and Apparatus." There have also been attempts to detect ischemia
using an implantable device (see U.S. Pat. No. 6,128,526 "Method
for Ischemia Detection and Apparatus Using Same").
[0034] However, the object of the inventions described above is to
improve the analytical performance of equipment where the
fundamental signal source--ECG--is flawed or inadequate. Thus there
is a need to provide more and better tools for emergency medicine
physicians, and others, to make more reliable assessment of a
patient's risk of cardiac ischemia at presentation, both using
existing sources of diagnostic information and, more importantly,
combinations of new and existing sources of information.
SUMMARY OF THE INVENTION
[0035] It is an objective of the present invention to use one or
more biochemical markers in conjunction with the electrocardiogram
to perform a diagnosis of clinical conditions such as ACS, or risk
stratification of patients presenting with suspected ACS.
Furthermore, it is an objective of the present invention to use a
biochemical marker of ischemia in conjunction with the ECG to
perform the diagnosis or risk stratification of patients presenting
with chest pain suspected to be cardiac ischemia. It is a further
object of the present invention to use a biochemical marker of
ischemia, in conjunction with a biochemical marker of myocardial
necrosis, to perform the diagnosis or risk stratification of
patients presenting with chest pain suspected to be cardiac
ischemia. Finally, it is an object of the present invention to
provide for a method whereby the algorithm by which the results of
the ECG tests and the in vitro diagnostic assays are combined is
continuously improved as a result of learning from prior
experience, by accessing the results of previous tests and
comparing the results with the clinical diagnosis or outcome of the
patient.
[0036] In its broadest aspect, the subject invention comprises a
method for diagnosing a clinical event occurring in a patient by
obtaining from the patient at least one sample of a substance
stream from the patient (e.g.: from the bloodstream); conducting a
first in vitro diagnostic assay and optionally additional in vitro
diagnostic assays on the sample; performing an electrocardiographic
test on the patient; and combining the results of the foregoing
tests using an algorithm to provide, for example, a positive or
negative diagnosis of the clinical event, or a risk stratification
or assessment of the risk of a clinical condition. Note that the
sequence of events of performing the ECG and in vitro diagnostic
tests is unimportant, and they can be performed in the order
described above or any other order, or simultaneously. An
"algorithm" as used herein refers to the steps involved in making a
diagnosis or assessment of the risk (or probability) of the
occurrence of a clinical condition utilizing the results of one or
more of the ECG and the diagnostic tests. As used herein, "risk
stratification" refers to an estimation of the probability (risk)
that the patient has the clinical condition at the time the sample
is taken; for purposes of the subject application, this term does
not refer to predictions of the risk of future episodes of the
clinical condition for the patient. The invention also includes an
apparatus to achieve the described method, which in simple terms
consists of a housing containing an electrocardiograph means and an
apparatus for performing an in vitro diagnostic test on a patient
sample, and may also include computing and processing means within
the machine for performing the calculations of the algorithm.
[0037] The substance stream refers to any flowing body tissue or
fluid including but not limited to urine, saliva, tears, semen,
mucus, feces, blood, lymph, serum, plasma and expired breath.
[0038] The clinical condition can be, for example, an acute
myocardial infarction (AMI), acute cardiac ischemia (ACI), Acute
Coronary Syndrome (ACS), or unstable angina (UA). If the clinical
condition is ACS, UA or ACI, the assay for a molecule that is
present in the stream and which is modified by the clinical event,
can be an assay for ischemia modified albumin (IMA). The patient
sample can be blood, serum or plasma and the assay for ischemia
modified albumin can be, for example, the Albumin Cobalt Binding
(ACB.RTM.) Test or an immunoassay specific for ischemia modified
albumin, i.e., using antibodies directed to the altered N-terminus
of albumin, a metal affinity assay for IMA, or an electrochemical
or optical test for IMA. Some of these methods are described in
U.S. Pat. Nos. 5,290,519, 5,227,307, 6,492,179, and 6,461,875, and
co-pending patent applications which are hereby incorporated by
reference: U.S. Ser. No. 10/304,610, U.S. Ser. No. 09/849,956, U.S.
Ser. No. 10/319,263, U.S. Ser. No. 09/846,411 and
PCT/US02/16860.
[0039] The subject invention also includes a method for ruling out
a diagnosis of a clinical condition such as ACS, ACI or UA by
obtaining a sample of a patient's blood, serum or plasma,
conducting at least one in vitro assay for a marker of cardiac
ischemia and/or a marker of cardiac necrosis, and combining the
results of the assay(s) with the results of the ECG analysis using
an algorithm to provide a negative diagnosis or assessment of low
risk. A negative diagnosis may be made where all ischemia marker
tests and all necrosis marker tests are negative, or where the
majority of both the ischemic marker tests and necrosis marker
tests are negative, when the ECG is either "normal" or
"non-diagnostic". As is discussed herein, the subject method can
have the advantage of a high negative predictive value (NPV),
making it useful in ruling-out the occurrence of a ACS or AMI.
Ruling-out AMI or ACS relatively early after patient presentation
at an emergency room can lead to early patient release and
conservation of medical resources.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 is a diagrammatic illustration of the zones of
reversibly ischemic, irreversibly ischemic, and necrotic tissue a
short time after a coronary artery occlusion.
[0041] FIG. 2 is a diagrammatic illustration of a device which
includes apparatus for ECG analysis in conjunction with apparatus
for performing one or more in vitro diagnostic tests.
[0042] FIG. 3 is a block diagram of the interaction between the ECG
machine and the device for performing one or more in vitro
diagnostic tests.
[0043] FIG. 4 is a diagrammatic illustration showing the sequence
of rise and fall of ischemia modified albumin and troponin after a
coronary artery occlusion.
[0044] FIG. 5 is a graph of sensitivity for detection of ACS for
ECG, cardiac troponin T, and IMA.
[0045] FIG. 6 is a graph of the Receiver Operating Characteristics
(ROC) curve for IMA for detection of ACS from Study 1.
[0046] FIG. 7 is a graph of the probability of ACS vs value of IMA
alone.
[0047] FIG. 8 is a graph of the probability of ACS vs value of
troponin T alone.
[0048] FIG. 9 is a graph of the probability of ACS using troponin
and IMA combined.
[0049] FIG. 10 is a graph of the ROC curve for IMA for detection of
ACS from Study 2.
DETAILED DESCRIPTION OF THE INVENTION
[0050] It has been found that the N-terminus of human serum albumin
can be modified by exposure to ischemic tissue in such a way that
it is less capable of binding certain metals, in particular cobalt.
The detection of such ischemia modified albumin (IMA.TM.) is
embodied in the Albumin Cobalt Binding Test (ACB.RTM. Test)
developed by Ischemia Technologies, Inc., Denver, Colo. The
measurement of modified metal binding ability of serum proteins
(including albumin) for detection of ischemia was first described
in BarOr, D. et al. (see (1993) U.S. Pat. No. 5,227,307, Test for
the Rapid Evaluation of Ischemic State, and BarOr, D. et al. and
(1994) U.S. Pat. No. 5,290,519, Test for the Rapid Evaluation of
Ischemic States and Kit). Further developments relating to
diagnosis of ischemia have been described in U.S. Pat. Nos.
6,492,179, and 6,461,875, all of which are hereby incorporated in
their entireties by reference. Preliminary results of experiments
to confirm the mechanism of IMA have also been published (BarOr D,
Curtis G, Rao N, Bampos N, Lau E. Characterization of the Co2+ and
Ni2+ Binding Amino-Acid Residues of the N-terminus of Human
Albumin. Eur. J. Biochem. 200; 268, 42-47).
[0051] There is a fundamental difference between conventional
markers of necrosis such as troponin, myoglobin and CK-MB (for
example, as described by Jackowski, et al., supra) and the use of
ischemia modified albumin. In the former case, biochemical markers
of necrosis are molecules available in the bloodstream some time
after the cytosolic contents of a cell are released as a result of
rupture of the cell membrane from necrosis. The molecules are
released first into the extracellular space, from there to the
lymphatic system, and thence drain into the bloodstream. In the
case of IMA, albumin is circulating in blood, and is rapidly
modified as a result of exposure to ischemic tissue. Therefore,
there is no requirement for the cell membranes to rupture, nor is
there a long time delay between the event leading to ischemia and
the time the biochemical marker can be detected in the bloodstream.
The ACB Test has been demonstrated to detect the rapid rise in IMA
following a transient ischemic event, caused by percutaneous
transluminal coronary angioplasty (PTCA) (BarOr D, Winkler J,
VanBenthuysen K, Harris L, Lau E, Hetzel F. "Reduced albumin-cobalt
binding with transient myocardial ischemia after elective
percutaneous transluminal coronary angioplasty: A preliminary
comparison to creatine kinase-MB, myoglobin and troponin I" Am
Heart J, 2001;141:985-991). PTCA is a procedure during which a
catheter is threaded into a coronary artery via radiographic
guidance to the location of a coronary artery occlusion. The
catheter has a long thin balloon at its tip. When in position, the
balloon is inflated, pushing the plaque up against the wall of the
artery, thereby increasing the size of the lumen, and restoring
flow upon balloon deflation. The PTCA procedure is well accepted in
clinical practice.
[0052] At the time of balloon inflation (typically 30 seconds to
two or three minutes), there is no coronary artery flow. The
absence of flow therefore induces temporary ischemia downstream
from the site of balloon inflation. However, this short duration of
ischemia does not induce the changes seen as a result of long
duration ischemia, such as cell necrosis.
[0053] Further studies showing the utility of the ACB Test as a
diagnostic tool are described in BarOr D, Lau E, Winkler J. "A
Novel Assay for Cobalt-Albumin Binding and its Potential as a
Marker for Myocardial Ischemia-a Preliminary Report" J Emerg Med
2000;19:4.; Wu A H B, Morris D L, Fletcher D R, Apple F S,
Christenson R H, Painter P C. "Analysis of the Albumin Cobalt
Binding (ACB.TM.) Test as an Adjunct to Cardiac Troponin for the
Early Detection of Acute Myocardial Infarction" Cardiovascular
Toxicology, 2001;1:2,147-152.; and Christenson R L, Duh S H, Sanhai
W R, Wu A H B, Holtman V, Painter P, Branham E, Apple F S, Murakami
M A, Morris D L. "Characteristics of an Albumin Cobalt Binding Test
for Assessment of Acute Coronary Syndrome Patients: A Multicenter
Study" Clinical Chemistry 2001;47:3, 464-470.
[0054] As discussed above, one embodiment of the subject invention
includes an improved method for risk stratification of the
suspected ACS patient by conducting at least one test for a marker
of ischemia and optionally another in vitro diagnostic test, in
conjunction with measuring the ECG, and combining all the results
in an algorithm. Preferably, the in vitro diagnostic test should be
for a necrosis marker. Preferably, the test for the ischemic marker
is a test for IMA such as the ACB Test, and the necrosis marker
test is a troponin assay. Alternatively, the necrosis markers can
be CK-MB or myoglobin or other necrotic markers known in the art,
such as those described in Wu, A. H. B. (1998), supra.
[0055] A further embodiment of the present invention is where the
ECG is combined with more than one test for the ischemia marker,
such that each test provides additional information about the
ischemia. Another possible marker of ischemia is Free Fatty Acids
or FFA (see Kleinfeld A M, Prothro D, Brown D L, Davis R C,
Richieri G V, DeMaria A Increases in Serum Unbound Free Fatty Acid
Levels Following Coronary Angioplasty. Am. J. Cardiol. 1996 Dec.
15;78(12):1350-4), and thus the ECG can be combined with FFA, with
IMA, or with both.
[0056] A further embodiment of the present invention is where the
ECG is combined with the ischemic marker result and additionally
with more than one test for myocardial necrosis marker, including
troponin, CK-MB, or myoglobin.
[0057] A further embodiment of the present invention is where the
ECG is combined with the ischemic marker assay result, plus other
markers useful in cardiology (i.e.: not markers of ischemia and not
markers of necrosis) such as a marker of inflammation like
C-Reactive Protein (CRP), or a marker of myocardial muscle load
such a B type natriuretic peptide (BNP) or associated molecules
such as N-terminal pro-BNP.
[0058] The relationship between the ECG and troponin for diagnosis
has been defined in guidelines published by the American Heart
Association and the American College of Cardiology (Braunwald et
al., "Management Of Patients With Unstable Angina And
Non-St-Segment Elevation Myocardial Infarction Update" ACC/AHA 2002
Guideline Update for the Management of Patients With Unstable
Angina and Non-ST-Segment Elevation Myocardial Infarction, A Report
of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on the Management of
Patients With Unstable Angina) Circulation, October
2002;106:1893-1900)). The guidelines state that after clinical
signs and symptoms, the ECG is used as the first diagnostic tool.
If the ECG is normal or not helpful, then markers of necrosis such
as troponin are the next diagnostic tool. However, it is believed
that there are no prior art publications on the use of the
combination of ECG and a biochemical marker of ischemia, since
prior to the advent of Ischemia Modified Albumin there has not been
a biochemical marker of ischemia available.
[0059] Furthermore, the published guidelines refer to the use of
ECG and troponin for ruling in a patient with suspected ACS (i.e.:
making a positive diagnosis). The ECG and troponin can not be used
for early rule out (i.e.: making a negative diagnosis) because the
sensitivity of ECG and troponin alone or in combination is too low
to yield a clinically acceptable negative predictive value. The
primary reason for this is that troponin is a slow rising marker
(first detectable within 6 hours of the onset of chest pain, and
peaks within 24 hours) such that the guidelines indicate that there
is no point in taking a troponin measurement earlier than 6 hours
from the onset of chest pain. On the other hand, IMA is a rapidly
rising marker with high sensitivity, so therefore it can be used
for both rule in and rule out--not possible with the present
technology.
[0060] In the present invention, the risk of the patient is
computed according to an algorithm and indicated by considering the
ECG and the results from a test for at least one marker of ischemia
and optionally at least one marker of necrosis (e.g.:
troponin).
[0061] For example, the algorithm may comprise making a positive
diagnosis for ACS if the ECG is diagnostic for ACS (e.g.: ST
segment elevation). If the ECG is normal or non diagnostic (e.g.:
there is an arrhythmia), then the patient is at highest risk if at
least one of the tests for necrosis is positive (regardless of the
value of the test for the marker(s) of ischemia), and is at higher
(but not highest) risk if all marker(s) of necrosis are normal and
at least one of the tests for ischemia is positive, and is at
lowest risk when all of the tests for necrosis and all of the tests
for ischemia are negative. The algorithm may also take into account
the quantitative value of the ischemia marker or other in vitro
diagnostic test to provide an estimate of the patient's probability
of having the clinical condition. FIG. 6 (from Example 1, described
below), shows the probability of a patient having ACS as a function
of the values of the cardiac Troponin T test and the ACB Test to
measure IMA. Therefore, one embodiment of the present invention is
an algorithm which takes the output of the ECG analysis and if it
is either normal or non-diagnostic for ischemia, then the values of
IMA and troponin together are used to compute a probability of the
patient having ACS.
[0062] The algorithm may also take into account the probability
that a patient has the clinical condition as determined by the
analysis of the ECG alone (e.g.: using the invention of
US2002/0133087A1 supra), and combining this probability with the
probabilities determined by the results of the in vitro diagnostic
tests, for example by utilizing Bayes' theorem.
[0063] An example of an algorithm is shown in Table 1, where binary
(i.e.: positive or negative) results of the tests are used
(although of course a similar algorithm which uses quantitative
results of each of the tests is also applicable). This algorithm is
hierarchical, and ordered in that the highest risk conditions are
at the top of the table, and risk decreases going down tha table.
That is, if the ECG provides definite diagnostic information (e.g.:
ST Segment Elevation), then the diagnosis is clear and no other
tests are necessary. If the ECG is non-diagnostic or normal, and
troponin is elevated, then the diagnosis is by definition Non-ST
Elevation Myocardial Infarction (NSTEMI), and no other tests are
required to make the diagnosis. If the ECG is non-diagnostic or
normal, and troponin is negative (i.e.: below the diagnostic
cutoff), and IMA is elevated, then the patient probably has ACS. If
the ECG is non-diagnostic or normal, and troponin and IMA are not
elevated, then the diagnosis is probably non ischemic chest pain.
TABLE-US-00001 TABLE 1 ECG IMA Troponin Diagnosis ST Segment +/-
+/- ST Segment Elevation elevation Myocardial Infarction ST Segment
+/- +/- ST Segment depression ACS depression Normal or +/- + Non-ST
Elevation non-diagnostic Myocardial Infarction Normal or + - ACS
(probable ACI or UA) non-diagnostic Normal or - - Non-ischemic
chest pain non-diagnostic
[0064] The algorithm to be used can incorporate additional
parameters such as the patient's physical characteristics, family
history, or nature and duration of chest pain. The algorithm can be
extended to incorporate other markers of ischemia, necrosis, or
others (e.g.: BNP or CRP).
[0065] The relationship between IMA and troponin during ACS leading
to AMI is illustrated diagrammatically in FIG. 4. The bottom
section of the graph represents the volume of tissue which is
ischemic or necrosed. The top section of the graph represents the
values of the two markers. At the time of a coronary artery
occlusion (shown as the vertical arrow at the left of the
horizontal time axis), some tissue immediately becomes reversibly
ischemic. With the passage of a small amount of time, the tissue
which has been reversibly ischemic for the longest time starts to
become irreversibly ischemic and will eventually die. As more time
passes, more and more of the tissue becomes ischemic, and more of
the ischemic tissue becomes necrotic. Eventually, the volume of
ischemic tissue starts to decrease, as the ischemic tissue is
converted to necrotic tissue. Eventually, all the tissue affected
by the coronary artery occlusion is necrotic, and there is a full
blown infarct, with no ischemic tissue remaining.
[0066] A short time after the coronary artery occlusion, IMA is
produced and the ACB Test value rises above the cutoff (i.e.: the
upper limit of the normal range), indicating rapidly the presence
of ischemic tissue. As time goes on, the ACB Test remains elevated
while there is still ischemic tissue, and once all the affected
tissue has converted from ischemia to necrosis, the ACB Test starts
to fall. As soon as some of the ischemic tissue becomes necrotic,
troponin is released and makes its way into the bloodstream. Once
there is a sufficient volume of necrotic tissue, and a sufficient
time has passed, the serum troponin level rises above the cutoff
level.
[0067] One of the major limitations of the use of troponin is that
because troponin falls slowly after infarct (usually over several
days), it is extremely difficult to diagnose re-infarct or
subsequent ischemic events. As an example, consider a patient who
presents with chest pain, is diagnosed as having an AMI and is
treated with reperfusion therapy (e.g., thrombolytics, PTCA, stent
or surgery). If this patient presents with another episode of chest
pain two or three days after the initial event, with present
biochemical markers of necrosis it is extremely difficult to
determine if this is another event, because troponin (and possibly
CK-MB) will still be elevated due to cardiac damage from the
initial AMI. However, since the IMA marker falls so rapidly after
an episode, a patient's discharge value of the IMA marker is likely
to be within normal range. Thus, if the patient presents with
another episode, if the IMA marker is elevated upon presentation
the second time, then it is likely to be a second event.
[0068] To take advantage of this unique benefit of IMA, a further
embodiment of the algorithm includes memory about the patient's
previous history. That is, if a patient presents on one date and
the diagnosis is STEMI, and then presents a few days later with
normal ECG, but elevated troponin, then the addition of IMA can
help determine if this presentation is non-ischemic chest pain
(i.e.: IMA normal) or another ischemic event (i.e.: IMA
elevated).
[0069] Since the algorithms described above require evaluation of
whether the tests results are above or below a predetermined
cutoff, it is not strictly necessary for the test method to produce
a quantitative result, although of course a quantitative result
gives additional information about timing of the event,
particularly if sequential measurements are taken. A quantitative
result can also give an indication of the severity of the episode,
i.e., the extent of ischemic tissue.
[0070] In a further embodiment, serial determinations of an assay
for an IMA marker in conjunction with serial testing of ECG and/or
serial testing of a marker of necrosis can yield information about
the time course of a cardiac ischemic event. Reference to FIG. 4
shows diagramatically the rise and fall of the IMA marker and
Troponin for a single event of coronary artery occlusion. Serial
determinations of ischemia marker(s) (and optionally other in vitro
markers) and serial ECG readings from patient populations
presenting with cardiac or suspected cardiac issues, can be
combined to create a model or algorithm similar or analogous to
that of FIG. 4, which maps the time course of ischemic/necrotic/ECG
events for patients undergoing cardiac distress. Physicians may
then correlate a particular patient's (serial) readings to the
model or algorithm to determine the patient's status or position
within the ischemialnecrosis progression and/or determine the time
of onset of the acute myocardial infarction, unstable angina,
etc.
[0071] Although the method has been described in terms of using the
ECG in conjunction with biochemical markers which are detected in
blood (with serum or plasma), the invention is not restricted to
this type of sample. Other substance streams (body fluids or tissue
samples) such as urine, saliva, tears, semen, mucus, feces, expired
breath and the like could be used. For example, Paz, F. (U.S. Pat.
No. 5,515,859 (1996)) disclosed the use of detection of adenosine
in an expired breath sample as a possible marker of cardiovascular
distress. Adenosine is a potent vasodilator and is produced by
tissue in response to stress in an attempt to increase blood flow.
Although it is not released from the interior of cells as a result
of necrosis, it is released by normal physiological mechanisms by
cells. Thus the combination of a measurement of adenosine from
expired breath with a measurement of ECG would satisfy one of the
objects of the present invention.
[0072] In one specific embodiment of the present invention, an
electronic module housing is provided which comprises an ECG means
and an apparatus for reading or conducting a biochemical test using
a test strip. There are many methods of implementing a test strip
for an assay as will be known to those familiar with the art. For
example, Biosite Inc. (San Diego, Calif.) sells a Triage.RTM.
Cardiac Reader for quantitative determination of troponin, CK-MB
and myoglobin.
[0073] FIG. 2 is an illustration of such a device. In FIG. 2, the
electronic module housing (10) comprises an ECG function means
including a means for displaying and/or printing ECG results (11),
and a means such as a keyboard by which an operator controls the
operation of the machine and enters parameters into the machine
(9), and a means by which the operation of the machine is displayed
to the operator such as a display panel (12). The machine is
connected to the patient (16) via a cable (15). The cable has
connected to it a plurality of wires (one is shown as (17))
connected to ECG electrodes (18) placed on the patient's body. The
module housing has an aperture or slot into which a test strip is
inserted (19), and associated means for reading the results of a
test strip for one or more biochemical markers. In the
illustration, the reader means is included in the body of the
housing module (but it could be separate and connected, for
example, via a wire). A test strip (13) has a location (14) such as
a well for application of a patient sample. The test strip is
inserted into the reader means via an aperture or slot (19).
[0074] The term "test strip" refers to assay devices such as those
described in U.S. Ser. No. 09/849,956, filed May 4, 2001, which is
incorporated herein in its entirety by reference, which typically
comprise a carrier media with flow path(s), an application zone for
sample deposition, and a test zone for detection and/or measurement
of target compounds (ischemic and/or necrotic markers). Although
the term "test strip" is used herein, it is intended that
configurations other than an elongated assay strip are included
within the scope of the subject invention. It is also contemplated
that the test strip or like device may be a bar code readable
device such as that described in U.S. Ser. No. 09/846,411, filed
May 1, 2001, incorporated herein in its entirety by reference. The
reader for the test strip will, according to the state of the art,
include means for reading the strip's calibration and other
parameters, such as a bar code reader.
[0075] FIG. 3 is a block diagram of the interaction between the ECG
function of the apparatus and the in vitro diagnostic
testing/reading means. A cable (15) connects the patient and the
plurality of electrodes to the ECG means (31). The IVD test strip
(13) is inserted into the ischemia and/or in vitro diagnostic
testing/reader means (33). The ECG means and the testing/reader
means include means for analyzing the results, and communicating
those results via a signal to an analysis means (32) such as a
microprocessor. The analysis means performs the calculations for an
algorithm to combine the results of the ECG test and the ischemia
and optionally the other in vitro diagnostic tests. The results of
the ECG, the ischemia and other measurements, and the analysis of
the combined results are displayed and/or printed via a Display
and/or print means (11), which is shown as one means for all types
of display or print, but could, in fact, be separate means for each
type of information to be displayed or printed. A control panel and
data entry means (9) is used to control the operation of the
machine, and also to enter data (e.g.: patient parameters such as
nature of chest pain) which may be used as part of the algorithm in
the analysis means.
[0076] The clinical performance of any set of diagnostic tools
depends on the statistical power of the clinical studies which were
employed to determine the statistics of the tool. Such clinical
studies are performed on a population with limited numbers, and
often of very precise composition. Each clinical setting in which
the tools are to be used is likely to have a different patient
population with variations in variables such as age, gender,
ethnicity, diet, and average body weight. All of these factors may
contribute to a modification of the assessment of the risk that a
patient presenting with chest pain has ACS.
[0077] In a further embodiment of the present invention, the
apparatus includes a memory means (item (37) in FIG. 3) used for
storing information. As a patient's data is analyzed by the
apparatus, the input and output parameters are stored in the memory
means. At some later time, the operator can enter via the control
panel (9) the clinical outcome of the patient (or the outcome can
be made available automatically, e.g.: via a communication means
(34) connected with the hospital's internal information system). In
this way, the data in the memory is updated and compared with the
clinical outcome, and the algorithm embodied in the analysis means
(32) can be modified appropriately in response to the new
comparisons from this and other patients to provide improved
performance on next use.
[0078] There are many methods well known in the art for
implementing such a heuristic process, including a neural network.
The heuristic algorithm can be implemented entirely in the
apparatus itself, or could reside on a central computer system with
which the combined ECG machine and test strip apparatus
communicates via a communication means (34), which can be a
physical connection or a virtual one, such as via the internet. In
this latter example, the algorithm of each machine so connected to
the central computer system can be updated and improved every time
additional comparison information is available from any machine
connected to the network.
EXAMPLES
Example 1
The ACB Test used for Diagnosis of Acute Coronary Syndromes
[0079] A study was performed to investigate the performance of IMA
for early risk stratification of patients presenting with chest
pain (or equivalent) of suspected cardiac origin. The performance
of IMA was compared with troponin T and the presentation 12 lead
ECG. The end point was discharge diagnosis of ACS (STEMI, NSTEMI or
UA) or Non Ischemic Chest Pain (NICP), as a measure of short term
risk at presentation.
[0080] Patients who arrived at the Emergency Department (ED) with
clinical signs and symptoms of possible ACS within 3 hours from
symptom onset were enrolled. All patients had a 12 lead ECG and a
blood sample collected within 1-2 hours of arrival to the ED. IMA
and cTnT (Roche Diagnostics) testing was performed on each
presentation sample.
Data Analysis
[0081] ECGs with no ST segment shift or T wave changes (apart from
lead III or V1) were considered "negative". "Positive" ECGs were
those with ST segment depression or elevation.gtoreq.1 mV, or T
wave inversion.gtoreq.2 mV (in .gtoreq.2 consecutive leads).
Equivocal or uninterpretable ECGs (e.g.: left bundle branch block,
paced rhythm, extensive pathological Q waves, and/or persistent
ST-segment elevation following previous AMI) were considered to be
"negative" in this study.
[0082] ACB Test results>85 U/mL were considered positive based
on a previously performed Normal Range Study.
[0083] Cardiac troponin T was measured by electrochemiluminescence
assay with an Elecsys 2010 analyzer (Roche Diagnostics). cTnT
concentrations>0.05 ng/mL were considered positive.
[0084] Institutional discharge diagnosis of ST-elevation AMI
(STEMI), non ST-elevation AMI (NSTEMI), unstable angina (UA), and
non-ischemic chest pain (NICP) were determined according to
institutional guidelines based upon the ESC/ACC criteria for
diagnosis of AMI and the ACC/AHA guidelines for diagnosis of
unstable angina. STEMI, NSTEMI, and UA were considered diagnoses of
high risk. A diagnosis of NICP was considered low risk.
[0085] Diagnosis of acute myocardial infarction (AMI) was confirmed
if ESC/ACC criteria were fulfilled, using a cTnT cutoff of 0.05
ng/mL. AMI was labeled as ST elevation myocardial infarction
(STEMI) or non-ST segment elevation myocardial infarction (NSTEMI)
based on ECG and biochemical criteria, i.e., cTnT>0.05
ng/ml.
[0086] Unstable angina (UA) was diagnosed when there was acute
chest pain without myocardial necrosis (i.e.: no elevation of
cTnT), but with clinical evidence of reduced myocardial perfusion,
positive ECG/echocardiographic stress testing or significant
lesions on coronary angiography.
[0087] Discharge diagnosis of ACS includes AMI and UA.
[0088] Patients with documented non-cardiac causes of chest pain
and/or normal coronary angiography were classified as non-ischemic
chest pain (NICP).
Results
[0089] The total study population included 140 men and 68 women.
Mean age was 61.3 years (range 21-85); 49 (23.5%) were smokers; 31
(15%) were diabetic; 93 (44%) were hypertensive; 65 (31%) had
family history of coronary artery disease; and 73 (35%) were
treated for hypercholesterolemia.
[0090] The data were analyzed for seven cases: [0091] 1. IMA alone
[0092] 2. Troponin T alone [0093] 3. ECG alone [0094] 4.
Combination of troponin T and IMA (denoted as TnT & IMA in the
following tables) [0095] 5. Combination of ECG and IMA (denoted as
ECG & IMA in the following tables) [0096] 6. Combination of ECG
and troponin T (denoted as ECG & TnT in the following tables)
[0097] 7. Combination of ECG and troponin T and IMA (denoted as ECG
& TnT & IMA in the following tables)
[0098] Results of IMA, ECG, and cTnT were analyzed for clinical
sensitivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV), alone and in combination. The 2
and 3 test combinations of IMA, ECG, and cTnT were considered
positive if any one of the tests was positive, and negative if all
were negative. Performance estimates were compared using McNemar's
test for correlated proportions and confidence intervals were
calculated using the exact binomial method. A two tailed p-value of
<0.05 was considered significant. The data are presented below
in contingency tables.
[0099] Sensitivity of each diagnostic test is shown for the total
population of 131 acute coronary syndrome (ACS) patients and also
for the 20 ST elevation MI (STEMI) patients, the 26 non-ST
Elevation MI (NSTEMI) patients, and the 85 unstable angina
patients. Specificity estimates are based upon 77 patients
diagnosed with non-ischemic chest pain (NICP). In the tables below
"+ve" is an abbreviation for "positive" and "-ve" is an
abbreviation for "negative". TABLE-US-00002 IMA Alone Total +ve
Total -ve Grand % 95% STEMI NSTEMI UA ACS ACS Totals CI IMA +ve 12
18 77 107 42 149 PPV 71.8% 63.9-78.9 IMA -ve 8 8 8 24 35 59 NPV
59.3% 45.7-71.9 Total 20 26 85 131 77 208 95% CI Sensitivity
Sensitivity Sensitivity Sensitivity Specificity 60.0% 69.2% 90.6%
81.7% 45.5% 36.1-80.9 48.2-85.7 82.3-95.8 74.0-87.9 34.1-57.2
[0100] TABLE-US-00003 ECG Alone Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI ECG +ve 19 13 27 59 7 66 PPV 89.4%
79.4-95.6 ECG -ve 1 13 58 72 70 42 NPV 49.3% 40.8-57.8 Total 20 26
85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 95.0% 50.0% 31.8% 45.0% 90.0% 75.1-99.9
29.9-70.1 22.1-42.8 36.3-54.0 82.2-96.3
[0101] TABLE-US-00004 TnT Alone Total +ve Total -ve Grand % STEM I
NSTEMI UA ACS ACS Totals 95% CI TnT +ve 6 17 3 26 1 27 PPV 96.3%
81.0-99.9 TnT -ve 14 9 82 105 76 181 NPV 42.0% 34.7-49.5 Total 20
26 85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 30.0% 65.4% 3.5% 19.8% 98.7% 11.9-54.3
44.3-82.8 0.7-10.0 13.4-27.7 93.0-100.0
[0102] TABLE-US-00005 TnT and IMA in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 15 25 78 118 43 161 PPV
73.3% 65.8-79.9 Both -ve 5 1 7 13 34 47 NPV 72.3% 57.4-84.4 Total
20 26 85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 75.0% 96.2% 91.8% 90.1% 44.2% 50.9-91.3
80.4-99.9 83.8-96.6 83.6-94.6 32.8-55.9
[0103] TABLE-US-00006 ECG and IMA in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 20 21 80 121 44 165 PPV
73.3% 65.9-79.9 Both -ve 0 5 5 10 33 43 NPV 76.7% 61.4-88.2 Total
20 26 85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 100% 80.8% 94.1% 92.4% 42.9% 83.2-100.0
60.6-93.4 86.8-98.1 86.4-96.3 31.6-54.6
[0104] TABLE-US-00007 ECG and TnT in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 19 21 29 69 8 77 PPV
89.6% 80.6-95.4 Both -ve 1 5 56 62 69 131 NPV 52.7% 43.8-61.5 Total
20 26 85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 95.0% 80.8% 34.1% 52.7% 89.6% 75.1-99.9
60.6-93.4 24.2-45.2 43.8-61.5 80.6-95.4
[0105] TABLE-US-00008 ECG and TnT and IMA in Combination (any
positive is +ve, all negative is -ve) Total +ve Total -ve Grand %
STEMI NSTEMI UA ACS ACS Totals 95% CI Any +ve 20 25 80 125 45 170
PPV 73.5% 66.2-80.0 All -ve 0 1 5 6 32 38 NPV 84.2% 68.7-94.0 Total
20 26 85 131 77 208 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 100% 96.2% 94.1% 95.4% 41.6% 83.2-100.0
80.4-99.9 86.8-98.1 90.3-98.3 30.4-53.4
[0106] The sensitivities of presentation IMA, cTnT, ECG and
combinations of these tests were compared for statistically
significant differences. FIG. 5 illustrates the sensitivity of IMA
alone and in conjunction with ECG and cTnT. IMA at presentation
identified 107 of 131 ACS patients (82%, 95% Confidence Interval
(CI) 74-88, compared to 59 of 131 (45%, CI 36-54) by admission ECG
and 26 of 131 (20%, CI 13-28) by admission cTnT. When IMA was used
with ECG, the sensitivity increased to 92% (CI 86-96) and this was
similar to that of IMA used with cTnT, 90% (CI 84-95). Sensitivity
of the three tests combined was 95% (CI 90-98), which was
significantly greater than that of IMA and cTnT combined (p=0.02)
and statistically equivalent to the sensitivity of IMA and ECG
combined (p=0.13). When ECG and cTnT were used, as per standard
practice, 53% (CI 44%-62%) of patients with chest pain of ischemic
origin were identified.
[0107] Logistic regression was used to construct predictive models
for final diagnosis. IMA and cTnT were treated as quantitative and
ECG as qualitative. The area under the Receiver Operator
Characteristic (ROC) curve was evaluated for each model's ability
to discriminate ACS from NICP. A p value<0.05 was considered
significant. The ROC curve for IMA alone is shown in FIG. 6, and
the area under the curve is 0.68 (95% CI 0.61-0.76). The results of
this analysis are shown in Table 2. In this table, it can be seen
that the addition of IMA to ECG provides more diagnostic power than
either parameter alone, and the combination of IMA, ECG, and
troponin T provides more diagnostic power in combination than any
single alone, or any pair together. TABLE-US-00009 TABLE 2 Logistic
Area under regression Chi Square p value Significant ROC curve
model for model for model variables (95% CI) IMA alone 23.13
<0.0001 IMA 0.68 (0.61-0.76) ECG alone 32.70 <0.0001 ECG 0.68
(0.61-0.75) cTnT alone 20.73 <0.0001 cTnT 0.64 (0.56-0.72) ECG +
cTnT 47.30 <0.0001 ECG 0.74 (0.68-0.81) IMA + ECG 55.38
<0.0001 IMA and ECG 0.80 (0.74-0.86) IMA + cTnT 49.15 <0.0001
IMA and cTnT 0.77 (0.70-0.83) IMA + ECG + 74.10 <0.0001 IMA and
ECG 0.83 cTnT (0.78-0.89)
[0108] The parameters from the logistic regression analysis were
used to construct curves of the probability of ACS, p[ACS], vs IMA
value, cTnT value, and the two combined.
[0109] FIG. 7 shows p[ACS] vs IMA, with the 95.sup.th percentile
upper limit of normal cutoff shown as a vertical line. This
indicates that IMA values higher than 100 are strongly suggestive
of ACS (for example, p[ACS]>80% for [IMA]>110 U/mL), and IMA
values less than 70 are strongly suggestive of no ACS (e.g.:
p[ACS]<35% for [IMA]<70 U/mL).
[0110] FIG. 8 shows the probability of ACS with different values of
cTnT. This demonstrates that any elevation of cTnT above the cutoff
of 0.05 ng/mL is highly significant for ACS (e.g.: p[ACS]>86%
for [cTnT]>0.1 ng/mL). However, consistent with the published
literature, the data also show that a negative cTnT has no value
for rule out, since the p[ACS] is still >0.5 for [cTnT]=0.
[0111] FIG. 9 shows a family of curves of p[ACS] vs [IA] for
different values of [cTnT], with a vertical line at the ACB Test
value of 85--the 95.sup.th percentile of the upper limit of normal.
These curves demonstrate that the major clinical value of IMA is in
patients where c[TnT] is zero--which, of course, is the majority of
patients at presentation. However, IMA may be helpful in resolving
cases with low values of [cTnT] near the cutoff of 0.05 ng/mL. For
example, if [cTnT]=0.5 ng/mL, and [IMA]>100, then p[ACS]>90%.
On the other hand, if [cTnT]=0.05 ng/mL, and [IMA]<60 U/mL, then
p[ACS]<25%.
Example 2
IMA for Risk Stratification of Chest Pain Patients
[0112] This study was designed to investigate the performance of
IMA, ECG, and troponin T at acute presentation for early risk
stratification of patients with chest pain suggestive of cardiac
origin. The study was performed in a low to medium risk patient
population referred for rest myocardial perfusion imaging (MPI) on
presentation.
[0113] The institutional discharge diagnosis of ACS (i.e.: a
measure of short term risk) was used for data analysis presented in
this section. Serum specimens were drawn prospectively and assayed
at one of two core laboratories with the ACB Test and cardiac
troponin T assays. One blood specimen was drawn prior to injection
of the perfusion agent (the presentation draw or an additional
baseline draw was taken if the MPI study was scheduled >1 hr
from presentation). Another blood draw was taken one hour post
injection of the myocardial perfusion agent. All of these blood
draws were consistent with the timing of blood taken in Study #1
which was while the patient was still in pain or within 3 hours of
feeling pain. IMA was measured by the Albumin Cobalt Binding Test
(ACB.RTM. Test) on the Roche Cobas MIRA.RTM. PLUS.
Data Analysis
[0114] ECGs with no ST segment shift or T wave changes (apart from
lead III or V1) were considered "negative". "Positive" ECGs were
those with ST segment depression or elevation.gtoreq.1 mV, or T
wave inversion.gtoreq.2 mV (in .gtoreq.2 consecutive leads).
Equivocal or uninterpretable ECGs (i.e. left bundle branch block,
paced rhythm, extensive pathological Q waves, and/or persistent
ST-segment elevation following previous AMI) were considered to be
"negative" in this study. Institutional discharge diagnosis of
ST-elevation AMI (STEMI), non ST-elevation AMI (NSTEMI), unstable
angina (UA), and non-ischemic chest pain (NICP) were determined
according to institutional guidelines based upon the ESC/ACC
criteria for diagnosis of AMI and the ACC/AHA guidelines for
diagnosis of unstable angina. STEMI, NSTEMI, and UA were considered
diagnoses of high risk. A diagnosis of NICP was considered low
risk.
[0115] Diagnosis of acute myocardial infarction (AMI) was confirmed
if ESC/ACC criteria were fulfilled, using a cTnT cutoff of 0.05
ng/mL. AMI was labeled as ST elevation myocardial infarction
(STEMI) or non-ST segment elevation myocardial infarction (NSTEMI)
based on ECG and biochemical criteria i.e. cTnT>0.05 ng/ml.
[0116] Unstable angina (UA) was diagnosed when there was acute
chest pain without myocardial necrosis (i.e.: no elevation of
cTnT), but with clinical evidence of reduced myocardial perfusion,
positive ECG/echocardiographic stress testing or significant
lesions on coronary angiography.
[0117] Discharge diagnosis of ACS includes AMI and UA.
[0118] Patients with documented non-cardiac causes of chest pain
and/or normal coronary angiography were classified as non-ischemic
chest pain (NICP).
[0119] ACB Test values>85 U/mL were considered positive based on
a previously performed Normal Range Study. An ACB Test result>85
U/mL in any blood draw taken within 3 hours of presentation was
taken as a positive ACB Test.
[0120] Cardiac troponin T concentrations were measured according to
the package insert by electrochemiluminescence assay with an
Elecsys 2010 analyzer (Roche Diagnostics). cTnT
concentrations>0.05 ng/mL were considered positive. A
troponin>0.05 ng/mL in any blood draw taken within 3 hours of
presentation was taken as a positive troponin for the data
analysis.
Results
[0121] Data were analyzed from patients recruited at 8 clinical
trial sites. Samples were analyzed at one of two core laboratories.
Clinical data and assay results were analyzed for a total of 199
patients. Results of IMA, ECG, and cTnT were analyzed for clinical
sensitivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV), alone and in combination. The 2
and 3 test combinations of IMA, ECG, and cTnT were considered
positive if any one of the tests was positive, and negative if all
were negative.
[0122] The "gold standard" was the discharge diagnosis of ACS.
[0123] The data were analyzed (in the same manner as in Study #1
described above for seven cases as listed below and illustrated in
the tables on the following pages: [0124] 1. IMA alone [0125] 2.
Troponin T alone [0126] 3. ECG alone [0127] 4. Combination of
troponin T and IMA (denoted as TnT & IMA in the following
tables) [0128] 5. Combination of ECG and IMA (denoted as ECG &
IMA in the following tables) [0129] 6. Combination of ECG and
troponin T (denoted as ECG & TnT in the following tables)
[0130] 7. Combination of ECG and troponin T and IMA (denoted as ECG
& TnT & IMA in the following tables) TABLE-US-00010 IMA
Alone Total +ve Total -ve Grand % STEMI NSTEMI UA ACS ACS Totals
95% CI IMA +ve 0 4 8 12 119 131 PPV 9.2% 4.8-15.5 IMA -ve 1 1 0 2
66 68 NPV 97.1% 89.8-99.6 Total 0 5 8 14 185 199 95% CI Sensitivity
Sensitivity Sensitivity Sensitivity Specificity 0.0% 80.0% 100.0%
85.7% 35.7% 0.0-97.5 28.4-99.5 63.1-100.0 57.2-98.2 28.8-43.0
[0131] TABLE-US-00011 ECG Alone Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI ECG +ve 1 2 0 3 13 16 PPV 18.8%
4.0-45.6 ECG -ve 0 3 8 11 172 183 NPV 94.0% 89.5-97.0 Total 1 5 8
14 185 199 95% CI Sensitivity Sensitivity Sensitivity Sensitivity
Specificity 100.0% 40.0% 0.0% 21.4% 93.0% 2.5-100.0 5.3-85.3
0.0-36.9 4.7-50.8 88.3-96.2
[0132] TABLE-US-00012 TnT Alone Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI TnT +ve 1 5 1 7 2 9 PPV 77.8%
40.0-97.2 TnT -ve 0 0 7 7 183 190 NPV 96.3% 92.6-98.5 Total 1 5 8
14 185 199 95% CI Sensitivity Sensitivity Sensitivity Sensitivity
Specificity 100.0% 100.0% 12.5% 50.0% 98.9% 2.5-100.0 47.8-100
0.3-52.7 23.0-77.0 96.1-99.9
[0133] TABLE-US-00013 TnT and IMA in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 1 5 8 14 121 135 PPV
10.4% 5.8-16.8 Both -ve 0 0 0 0 64 64 NPV 100.0% 94.4-100.0 Total 1
5 8 14 185 199 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 100.0% 100.0% 100.0% 100.0% 34.6% 2.5-100.0
47.8-100.0 63.1-100.0 76.8-100.0 27.8-41.9
[0134] TABLE-US-00014 ECG and IMA in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 1 5 8 14 122 136 PPV
10.3% 5.7-16.7 Both -ve 0 0 0 0 63 63 NPV 100% 94.3-100.0 Total 1 5
8 14 185 199 95% CI Sensitivity Sensitivity Sensitivity Sensitivity
Specificity 100% 100.0% 100.0% 100.0% 34.1% 2.5-100 28.4-99.5
63.1-100 76.8-100.0 27.3-41.4
[0135] TABLE-US-00015 ECG and TnT in Combination (either positive
is +ve, both negative is -ve) Total +ve Total -ve Grand % STEMI
NSTEMI UA ACS ACS Totals 95% CI Either +ve 1 5 1 7 15 22 PPV 31.8%
13.9-54.9 Both -ve 0 0 7 7 170 177 NPV 96.0% 92.0-98.4 Total 1 5 8
14 185 199 95% CI Sensitivity Sensitivity Sensitivity Sensitivity
Specificity 100.0% 100.0% 12.5% 50.0% 91.9% 2.5-100 47.8-100.0
0.3-52.7 23.0-77.0 87.0-95.4
[0136] TABLE-US-00016 ECG and TnT and IMA in Combination (any
positive is +ve, all negative is -ve) Total +ve Total -ve Grand %
STEMI NSTEMI UA ACS ACS Totals 95% CI Any +ve 1 5 8 14 124 138 PPV
10.1% 5.7-16.4 All -ve 0 0 0 0 61 61 NPV 100.0% 94.1-100.0 Total 1
5 8 14 185 199 95% CI Sensitivity Sensitivity Sensitivity
Sensitivity Specificity 100% 100.0% 100.0% 100.0% 33.0% 2.5-100.0
47.8-100.0 63.1-100.0 76.8-100.0 26.3-40.3
[0137] Logistic regression was used to construct a predictive model
for final diagnosis using IMA as a quantitative variable. The ROC
curve is shown in FIG. 10, and the area under the ROC curve is 0.68
(95% CI 0.53-0.84), which is equivalent to that found in the
previous study, above.
[0138] This study showed that in a population of patients with
chest pain suggestive of cardiac origin with low prevalence of ACS,
IMA showed equivalent sensitivity, and specificity, but higher
negative predictive value, to that shown in the previous study.
[0139] The sensitivity of presentation IMA for ACS (85.7%) is much
greater than that of TnT (50%). The combination of IMA and TnT
results in no false negatives and 100% negative predictive
value.
[0140] The use of IMA and cTnT in combination shows 100%
sensitivity and identifies more patients with ACS, which will drive
earlier therapy.
[0141] Based on the examples described above, it is clear that the
combination of ECG with a marker of ischemia such as IMA, and
optionally another in vitro diagnostic test such as a marker of
cell death such as troponin, can be used to give higher confidence
in a diagnosis or risk stratification for a patient presenting to a
hospital emergency room with chest pain suggestive of cardiac
origin, or can be used in an algorithm to determine a probability
of ACS.
[0142] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and the scope of the
appended claims.
* * * * *