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.

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 pecto...

AI Technical Summary

Benefits of technology

[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.

[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.

Problems solved by technology

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.

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.

Ischemia is the condition of imbalance between oxygen supply and demand.

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.

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.

Once the blood supply to the myocardium is restricted, the myocardium becomes starved of oxygen, leading to ischemia.

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.

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.

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.

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 problem is that cardiac ischemia is extremely difficult to diagnose.

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.

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.

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.

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.

Interpretation of an electrocardiogram is fraught with error, particularly by physicians who do not perform this task often and routinely.

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