Clinical event adjudication: Death

For the list of clinical event adjudication definitions, click here

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

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Death

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

1. 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:

a. Sudden Cardiac Death

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

• Death witnessed and instantaneous without new or worsening symptoms
• Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms
• 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)
• Death after unsuccessful resuscitation from cardiac arrest
• Death after successful resuscitation from cardiac arrest and without identification of a non-cardiac etiology (Post-Cardiac Arrest Syndrome)
• 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

• 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”.

b. Death due to Acute Myocardial Infarction

Death due to 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.

c. Death due to Heart Failure or Cardiogenic Shock

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:

• 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
• Heart failure symptoms or signs requiring continuous intravenous therapy or chronic oxygen administration for hypoxia due to pulmonary edema
• Confinement to bed predominantly due to heart failure symptoms
• 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
• 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.

General Considerations
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.

d. Death due to Stroke

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.

e. Death due to Other Cardiovascular Causes

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.

2. 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.

3. 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.