Clinical event adjudication

Editors-in-Chief: C. Michael Gibson, M.S., M.D. [1]

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List of terms related to Clinical event adjudication

This chapter presents definitions used in the Clinical Event Committee adjudication processes. These definitions are current as of 3/26/10.

Death

Definition of Cardiovascular Death

Cardiovascular death includes sudden cardiac death, death due to acute myocardial infarction, death due to heart failure, death due to stroke, and death due to other cardiovascular causes, as follows:

1.Sudden Cardiac Death: refers to death that occurs unexpectedly and includes the following deaths:

a.Death witnessed and instantaneous without new or worsening symptoms

b.Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms

c.Death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-defibrillator review)

d.Death after unsuccessful resuscitation from cardiac arrest

e.Death after successful resuscitation from cardiac arrest and without identification of a non-cardiac etiology (Post-Cardiac Arrest Syndrome)

f.Unwitnessed death without other cause of death (information regarding the patient’s clinical status preceding death should be provided, if available)

General Considerations Regarding The Adjudication of Death in Cardiovascular Trials

1. A subject seen alive and clinically stable 12-24 hours prior to being found dead without any evidence or information of a specific cause of death should be classified as an “Unwitnessed Death.” Typical scenarios include

• Subject well the previous day but found dead in bed the next day
• Subject found dead at home on the couch with the television on

Deaths for which there is no information beyond “Patient found dead at home” may be classified as “Undetermined Cause of Death”.

2. Death due to Acute Myocardial Infarction refers to a death within 30 days after a myocardial infarction (MI) related to consequences seen immediately after the myocardial infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia. If these events occur after a “break” (e.g., a CHF and arrhythmia free period), they should be designated by the immediate cause. The acute myocardial infarction should be verified either by the diagnostic criteria outlined for acute myocardial infarction or by autopsy findings showing recent myocardial infarction or recent coronary thrombus, and there should be no conclusive evidence of another cause of death.

Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood should be considered death due to acute myocardial infarction.

If death occurs before biochemical confirmation of myocardial necrosis can be obtained, adjudication should be based on clinical presentation and ECG evidence.

Death resulting from a procedure to treat myocardial ischemia or to treat a complication resulting from myocardial infarction should also be considered death due to acute MI.

Death due to a myocardial infarction that occurs as a direct consequence of a cardiovascular investigation/procedure/operation should be classified as death due to other cardiovascular cause.

3.Death due to Heart Failure* or Cardiogenic Shock refers to death occurring in the context of clinically worsening symptoms and/or signs of heart failure (see Chapter 7) without evidence of another cause of death.

Death due to Heart Failure or Cardiogenic shock should include sudden death occurring during an admission for worsening heart failure as well as death from progressive heart failure or cardiogenic shock following implantation of a mechanical assist device.

New or worsening signs and/or symptoms of congestive heart failure (CHF) include any of the following:

a. New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an increase in, treatment directed at heart failure or occurring in a patient already receiving maximal therapy for heart failure

b. Heart failure symptoms or signs requiring continuous intravenous therapy or chronic oxygen administration for hypoxia due to pulmonary edema

c. Confinement to bed predominantly due to heart failure symptoms

d. Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context of an acute myocardial infarction, worsening renal function, or as the consequence of an arrhythmia occurring in the absence of worsening heart failure

e. Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the consequence of an arrhythmia occurring in the absence of worsening heart failure.

Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for greater than 1 hour, not responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary to cardiac dysfunction and associated with at least one of the following signs of hypoperfusion:

• Cool, clammy skin or • Oliguria (urine output < 30 mL/hour) or • Altered sensorium or • Cardiac index < 2.2 L/min/m2

Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm Hg in less than 1 hour with positive inotropic or vasopressor agents alone and/or with mechanical support.

Heart failure may have a number of underlying causes, including acute or chronic ischemia, structural heart disease (e.g. hypertrophic cardiomyopathy), and valvular heart disease. Where treatments are likely to have specific effects, and it is likely possible to distinguish between the various causes, then it may be reasonable to separate out the relevant treatment effects. For example, obesity drugs such as fenfluramine (pondimin), phentermine (ionamin), and dexfenfluramine (redux) were found to be associated with the development of valvular heart disease and pulmonary hypertension. In other cases, the aggregation implied by the definition above may be more appropriate.

4. Death due to Stroke: refers to death occurring up to 30 days after a stroke that is either due to the stroke or caused by a complication of the stroke.

5. Death due to Other Cardiovascular Causes: refers to death due to a cardiovascular cause not included in the above categories (e.g. dysrhythmia, pulmonary embolism, cardiovascular intervention, aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of cardiac surgery or non-surgical revascularization, even if “non-cardiovascular” in nature, should be classified as cardiovascular deaths.

Definition of Non-Cardiovascular Death

Non-cardiovascular death is defined as any death not covered by cardiac death or vascular death. Suggested categories* include:

• Pulmonary causes • Renal causes • Gastrointestinal causes • Infection (includes sepsis) • Non-infectious (e.g., systemic inflammatory response syndrome (SIRS)) • Malignancy (i.e., new malignancy, worsening of prior malignancy) • Accidental/Trauma • Hemorrhage, not intracranial • Suicide • Non-cardiovascular system organ failure (e.g., hepatic failure) • Non-cardiovascular surgery • Other non-cardiovascular, specify: ________________

• Categorization may vary between trials, diseases, and interventions, but should be planned so that trials are able to define the effects of drugs on causes of death that are relevant to the disease under study. Death due to a gastrointestinal bleed should not be considered a cardiovascular death.

Definition of Undetermined Cause of Death

Undetermined Cause of Death refers to a death not attributable to one of the above categories of cardiovascular death or to a non-cardiovascular cause.

A common analytic approach for cause of death analyses is to assume that all undetermined cases are included in the cardiovascular category (e.g. presumed cardiovascular death).

Nevertheless, categorization may vary between trials, diseases, and interventions.

Myocardial Infarction

1. Criteria for Acute Myocardial Infarction

The term myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Under these conditions, any one of the following criteria meets the diagnosis for myocardial infarction.

For each MI type, one must consider the totality of clinical, electrocardiographic, and cardiac biomarker information to determine whether or not a MI has occurred. Specifically, timing and trends in cardiac biomarkers and electrocardiographic information require careful analysis.

a. Spontaneous MI

Detection of rise and/or fall of cardiac biomarkers (CK-MB or troponin) with at least one value above the 99th percentile of the upper reference limit (URL)* together with evidence of myocardial ischemia with at least one of the following:

• Symptoms of ischemia
• ECG changes indicative of new ischemia [new ST-T changes or new left bundle branch block (LBBB)]**
• Development of pathological Q waves*** in the ECG
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

*For cardiac biomarkers, laboratories should report an upper reference limit (URL). If the 99th percentile of the upper reference limit (URL) from the respective laboratory performing the assay is not available, then the URL for myocardial necrosis from the laboratory should be used. If the 99th percentile of the URL or the URL for myocardial necrosis is not available, the MI decision limit for the particular laboratory should be used as the URL. Laboratories can also report both the 99th percentile of the upper reference limit and the MI decision limit. Reference limits from the laboratory performing the assay are preferred over the manufacturer’s listed reference limits in an assay’s instructions for use. CK may be used in the absence of CK-MB.

**ECG manifestations of acute myocardial ischemia (in absence of left ventricular hypertrophy (LVH) and left bundle branch block (LBBB)):

• ST elevation
  New ST elevation at the J point in two anatomically contiguous leads with the cut-off points: ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads.
• ST depression and T-wave changes
  New horizontal or down-sloping ST depression ≥ 0.05 mV in two contiguous leads; and/or new T inversion ≥ 0.1 mV in two contiguous leads.

The above ECG criteria illustrate patterns consistent with myocardial ischemia. In patients with abnormal biomarkers, it is recognized that lesser ECG abnormalities may represent an ischemic response and may be accepted under the category of abnormal ECG findings.

***Definition of a pathological Q-wave

• Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3
• Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF)^a

^aThe same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal plane lead grouping.

b. Percutaneous Coronary Intervention-Related Myocardial Infarction

For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL* within 48 hours of the procedure are indicative of peri-procedural myocardial necrosis. By convention, increases of biomarkers greater than 3 x 99th percentile URL* (Troponin or CK-MB > 3 x 99th percentile URL*) are consistent with PCI-related myocardial infarction. MB is the preferred biomarker.

If the cardiac biomarker is elevated prior to PCI, a ≥ 50% increase of the value in the second cardiac biomarker sample within 48 hours of the PCI (and Troponin or CK-MB > 3x 99th percentile URL*) and documentation that cardiac biomarker values were decreasing (two samples 3-6 hours apart) prior to the suspected recurrent MI is also consistent with PCI-related myocardial infarction.

Symptoms of cardiac ischemia are not required.

c. Coronary Artery Bypass Grafting-Related Myocardial Infarction

For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevation of cardiac biomarkers above the 99th percentile URL within 72 hours of the procedure is indicative of peri-procedural myocardial necrosis. By convention, an increase of biomarkers greater than 5 x 99th percentile URL (Troponin or CK-MB > 5 x 99th percentile URL) plus

• either new pathological Q waves in at least 2 contiguous leads that persist through 30 days or new persistent non-rate related LBBB or
• angiographically documented new graft or native coronary artery occlusion or other complication in the operating room resulting in loss of myocardium or
• imaging evidence of new loss of viable myocardium

is consistent with CABG-related myocardial infarction. MB is the preferred biomarker.

If the cardiac biomarker is elevated prior to CABG, a ≥ 50% increase of the value in the second cardiac biomarker sample within 72 hours of CABG (and Troponin or CK-MB > 5 x 99th percentile URL) and documentation that cardiac biomarker values were decreasing (two samples 3-6 hours apart) prior to the suspected recurrent MI plus any of the three bullets above is consistent with a periprocedural myocardial infarction after CABG.

Symptoms of cardiac ischemia are not required.

2. Criteria for Silent Myocardial Infarction or Prior Myocardial Infarction (with or without Symptoms)

No evidence of acute myocardial infarction AND any one of the following criteria:

• Appearance of new persistent pathological Q waves. A confirmatory ECG is recommended if there have been no clinical symptoms or history of myocardial infarction.
• Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause
• Pathological findings of a healed or healing myocardial infarction

ECG Changes associated with prior myocardial infarction:

• Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3
• Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF)^a
• R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a concordant positive T-wave in the absence of a conduction defect

^aThe same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal plane lead grouping.

3. Criteria for Reinfarction

In patients where recurrent myocardial infarction is suspected from clinical signs or symptoms following the initial infarction, recurrent infarction should be diagnosed if there is a ≥ 20% increase of the value between a measurement (cardiac biomarker) made at the time of the initial presentation and a further sample taken 3-6 hours later. This value should also exceed the 99th percentile URL.*). This scenario applies to patients enrolled in a clinical trial with an acute myocardial infarction who experience a recurrent myocardial infarction post-enrollment or in patients enrolled in a clinical trial without an acute myocardial infarction but who subsequently experience a myocardial infarction during the course of the trial and a recurrent myocardial infarction.

If cardiac biomarkers are elevated prior to the suspected new MI, there must be decreasing cardiac biomarker values on two samples at least 3 hours apart prior to the suspected new MI in combination with other criteria for reinfarction (ECG, imaging).

If biomarkers are increasing or peak is not reached, then a definite diagnosis of recurrent MI is generally not possible.

Unstable angina requiring hospitalization

Congestive Heart Failure