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

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.

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.

4. Clinical Classification of Different Types of Myocardial Infarction

a. For certain types of trials, it may be helpful to distinguish between particular categories of myocardial infarction (MI) using the following guidelines:

• Type 1
  Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection
• Type 2
  Myocardial infarction secondary to ischemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension, or hypotension
• Type 3
  Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia, accompanied by presumably new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by 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
• Type 4a
  Myocardial infarction associated with PCI
• Type 4b
  Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy
• Type 5
  Myocardial infarction associated with CABG

b. For each myocardial infarction (MI) identified by the CEC, the type of MI may also be described as:

• ST-Elevation MI (STEMI)
  • Also categorize as:
    • Q-wave
    • Non-Q-wave
    • Unknown (no ECG or ECG not interpretable)
• Non-ST-Elevation MI (NSTEMI)
  • Also categorize as:
    • Q-wave
    • Non-Q-wave
    • Unknown (no ECG or ECG not interpretable)
• Unknown (no ECG or ECG not interpretable)

c. For trials in which it would be helpful to distinguish between particular categories of myocardial infarction, consider

• Reporting MI type by treatment group as follows:
  Table 1. Sample Clinical Trial Tabulation of Randomized Patients by
  

Types of Myocardial Infarction

Types of MI	Treatment A Number of patients (N = )	Treatment B Number of patients (N = )
MI Type 1	n, %	n, %
MI Type 2	n, %	n, %
MI Type 3	n, %	n, %
MI Type 4	n, %	n, %
MI Type 5	n, %	n, %
Total number	n, %	n, %
N = total number of patients; n = number of patients with a particular MI.

• Reporting data as multiples of the 99th percentile URL of the applied biomarker as follows:

Table 2. Classification of the Different Types of Myocardial Infarction According to Multiples of the 99th Percentile URL of the Applied Cardiac Biomarker

Multiples X 99 %	MI Type 1 (spontaneous)	MI Type 2 (secondary)	MI Type 3* (sudden death)	MI Type 4** (PCI)	MI Type 5** (CABG)	Total Number
1-2 X
2-3 X
3-5 X
5-10 X
>10 X
Total number

*Biomarkers are not available for this type of myocardial infarction since the patients expired
before biomarker determination could be performed.

**For the sake of completeness, the total distribution of biomarker values should be reported.The
hatched areas represent biomarker elevations below the decision limit used for these types of
myocardial infarction.

General Considerations

• For a diagnosis of acute myocardial infarction, elevation of cardiac biomarkers should be present. However, myocardial infarction may be adjudicated for an event that has characteristics (i.e., ischemic symptoms) of a myocardial infarction but which does not meet the strict definition because biomarker or electrocardiographic results are not available (e.g. not measured) or are non-contributory (e.g. may have normalized).
• Whenever possible, all investigators within a clinical trial should employ the same cardiac troponin assay in order to reduce the inter-assay variability. If reasonable, using a core laboratory with the same assay for all measurements would be optimal.
• Entry criteria for the diagnosis of myocardial infarction in clinical trials may be different than endpoint criteria. For example, use of prior myocardial infarction as an entry criterion may require documentation in the record of “prior MI” and clinical details; however, cardiac enzymes, 12-lead ECG evidence, and cardiac catheterization/percutaneous coronary intervention results may not be required.
• For procedure-related myocardial infarction, all available biomarker information will be taken into account. Furthermore, in cases where the cardiac biomarker is elevated prior to PCI or CABG, the ≥ 20% increase of the value in the secondary cardiac biomarker sample within 48 hours of PCI and within 72 hours of CABG, per the Universal MI definition, is somewhat arbitrary. Some studies may want to use a different percentage, such as ≥ 50% increase. Data should be collected in such a way that analyses using ≥ 20% or ≥ 50% could both be performed.
• There is considerable discussion that in the setting of PCI or CABG, a three-fold increase in CK-MB may not be equivalent to a three-fold increase in troponin and that a five-fold increase in CK-MB may not be equivalent to a five-fold increase in troponin, respectively. Furthermore, it is unclear if this biomarker elevation by itself requires additional confirmation with new ECG changes, procedural complications, or new imaging evidence similar to that required for spontaneous myocardial infarctions or myocardial infarctions occurring in the setting of CABG.
• The prognostic significance of different types of myocardial infarctions (e.g., periprocedural myocardial infarction versus spontaneous myocardial infarction) may be different, and outcomes should be evaluated separately for these two subsets of patients.
• Not infrequently, patients with renal disease or congestive heart failure may have elevated cardiac biomarkers. In these circumstances, the Clinical Endpoints Committee must use the totality of the evidence to determine whether the cardiac biomarker elevation or underlying condition represents the primary process or endpoint event.

Stroke

Stroke is an acute symptomatic episode of neurological dysfunction attributed to a vascular cause.

Classification

A. Ischemic Stroke

Ischemic stroke is defined as an acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction caused by an infarction of central nervous system tissue.

B. Hemorrhagic Stroke

Hemorrhagic stroke is defined as an acute symptomatic episode of focal or global cerebral or spinal dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage.

C. Undetermined Stroke

Undetermined stroke is defined as a stroke with insufficient information to allow categorization as A or B.

Stroke Disability

Stroke disability should be measured by a reliable and valid scale in all cases. For example, the modified Rankin Scale may be used to address this requirement:

Scale	Disability
0	No symptoms at all
1	No significant disability despite symptoms; able to carry out all usual duties and activities
2	Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance
3	Moderate disability; requiring some help, but able to walk without assistance
4	Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance
5	Severe disability; bedridden, incontinent and requiring constant nursing care and attention
6	Dead

Unstable angina requiring hospitalization

Unstable angina requiring hospitalization is defined as

1. Symptoms of myocardial ischemia at rest (chest pain or equivalent) or an accelerating pattern of angina with frequent episodes associated with progressively decreased exercise capacity
   AND
   
2. Prompting an unscheduled visit to a healthcare facility and hospitalization (including chest pain observation units) within 24 hours of the most recent symptoms
   AND
   
3. At least one of the following:

a. New or worsening ST or T wave changes on resting ECG

• 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. It is recognized that lesser ECG abnormalities may represent an ischemic response and may be accepted under the category of abnormal ECG findings.

b. Definite evidence of myocardial ischemia on myocardial scintigraphy (clear reversible perfusion defect), stress echocardiography (reversible wall motion abnormality), or MRI (myocardial perfusion deficit under pharmacologic stress) that is believed to be responsible for the myocardial ischemic symptoms/signs

c. Angiographic evidence of ≥ 70% lesion and/or thrombus in an epicardial coronary artery that is believed to be responsible for the myocardial ischemic symptoms/signs

d. Need for coronary revascularization procedure (PCI or CABG) during the same hospital stay. This criterion would be fulfilled if the admission for myocardial ischemia led to transfer to another institution for the revascularization procedure without interceding home discharge

AND

4. No evidence of acute myocardial infarction

General Considerations

1. Escalation of pharmacotherapy for ischemia, such as intravenous nitrates or increasing dosages of β-blockers, should be considered supportive of the diagnosis of unstable angina. However, a typical presentation and admission to the hospital with escalation of pharmacotherapy, without any of the additional findings listed under category 3, would be insufficient alone to support classification as hospitalization for unstable angina.
   
2. If subjects are admitted with suspected unstable angina, and subsequent testing reveals a non-cardiac or non-ischemic etiology, this event should not be recorded as hospitalization for unstable angina. Potential ischemic events meeting the criteria for myocardial infarction should not be adjudicated as unstable angina.
   
3. Planned rehospitalization for performance of an elective revascularization in the absence of symptoms at rest prompting admission should not be considered a hospitalization for unstable angina. For example, a patient with stable exertional angina whose admission for coronary angiography and PCI is prompted by a positive outpatient stress test should not be considered a hospitalization for unstable angina.
   
4. A patient who undergoes an elective catheterization where incidental coronary artery disease is found and who subsequently undergoes coronary revascularization will not be considered as meeting the hospitalization for unstable angina endpoint.

Heart failure requiring hospitalization

Heart failure (HF) requiring hospitalization is defined as an event that meets the following criteria:

1. Requires hospitalization defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 24* hour stay (or a date change if the time of
   admission/discharge is not available).
   *For this endpoint in any given clinical trial, there should be some flexibility in the required duration of stay, depending on the population and the adverse event profile of the drug to be studied. For example, a clinical trial studying patients with NYHA Class III/IV heart failure may not wish to capture hospitalizations less than 24 hours in duration, because this population may have frequent hospital visits requiring short-term therapy. On the contrary, clinical trials in patients with NYHA Class I/II heart failure may wish to capture shorter hospitalizations that may be predictive of subsequent decompensation.
   AND
   
2. Clinical symptoms of heart failure, including at least one of the following:
   New or worsening
   
   • dyspnea
   • orthopnea
   • paroxysmal nocturnal dyspnea
   • increasing fatigue/worsening exercise tolerance
     AND
     
3. Physical signs of heart failure, including at least two of the following:
   • edema (greater than 2+ lower extremity)
   • pulmonary crackles greater than basilar (pulmonary edema must be sufficient to cause tachypnea and distress 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)
   • jugular venous distension
   • tachypnea (respiratory rate > 20 breaths/minute)
   • rapid weight gain
   • S3 gallop
   • increasing abdominal distension or ascites
   • hepatojugular reflux
   • radiological evidence of worsening heart failure
   • A right heart catheterization within 24 hours of admission showing a pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) ≥ 18 mm Hg or a cardiac output < 2.2 L/min/m²
     
     NOTE: Biomarker results (e.g., brain natriuretic peptide (BNP)) consistent with congestive heart failure will be supportive of this diagnosis, but the elevation in BNP cannot be due to other conditions such as cor pulmonale, pulmonary embolus, primary pulmonary hypertension, or congenital heart disease. Increasing levels of BNP, although not exceeding the ULN, may also be supportive of the diagnosis of congestive heart failure in selected cases (e.g. morbid obesity).
     
     AND
     
     
4. Need for additional/increased therapy
   • Initiation of, or an increase in, treatment directed at heart failure or occurring in a patient already receiving maximal therapy for heart failure and including at least one of the following:
     • Initiation of or a significant augmentation in oral therapy for the treatment of congestive heart failure
     • Initiation of intravenous diuretic, inotrope, or vasodilator therapy
     • Uptitration of intravenous therapy, if already on therapy
     • Initiation of mechanical or surgical intervention (mechanical circulatory support, heart transplantation or ventricular pacing to improve cardiac function), or the use of ultrafiltration, hemofiltration, or dialysis that is specifically directed at treatment of heart failure.
       AND
       

5. No other non-cardiac etiology (such as chronic obstructive pulmonary disease, hepatic cirrhosis, acute renal failure, or venous insufficiency) and no other cardiac etiology (such as pulmonary embolus, cor pulmonale, primary pulmonary hypertension, or congenital heart disease) for signs or symptoms is identified.

NOTE: It is recognized that some patients may have multiple simultaneous disease processes. Nevertheless, for the endpoint event of heart failure requiring hospitalization, the diagnosis of congestive heart failure would need to be the primary disease process accounting for the above signs and symptoms.

Interventional Cardiology Definitions

1. Coronary Revascularization Procedure

A coronary revascularization procedure is a catheter-based or open surgical procedure designed to improve myocardial blood flow. Catheter-based tools (e.g., balloon catheters, cutting balloons, atherectomy devices, lasers, bare metal stents, and drug-eluting stents) improve myocardial blood flow by increasing the luminal area at a site of an obstructive coronary lesion. Aortocoronary bypass grafts (arterial, venous, or synthetic) improve myocardial blood flow by providing a conduit for blood flow distal to an obstructive coronary lesion. Insertion of a guidewire through a coronary guide catheter into a coronary vessel or aortocoronary bypass graft for the purpose of percutaneous coronary intervention (PCI) is considered intention for PCI. However, in the assessment of the severity of intermediate lesions with the use of intravascular ultrasound, Doppler flow velocity, or fractional flow reserve, insertion of a guidewire will NOT be considered PCI.

2. Procedural Success

Achievement of <30 % residual diameter stenosis of the target lesion assessed by visual inspection or quantitative coronary angiography (QCA) and no in-hospital major adverse cardiac events (MACE, a composite of death, MI, or repeat coronary revascularization of the target lesion). Ideally, the assessment of the residual stenosis at the end of the procedure should be performed by an angiographic core laboratory.

3. Elective and Non-elective Procedures

Elective: An elective procedure is one performed on a patient with stable cardiac function in the days or weeks prior to the procedure. Elective cases are usually scheduled at least 1 day prior to the procedure.
Non-elective: A non-elective procedure is one performed on a patient who has been stabilized following initial treatment of acute coronary ischemia, and there is clinical consensus that the procedure should occur within the next 24 hours.
OR
A procedure that is performed without delay on a patient with evidence of ongoing refractory ischemia with or without hemodynamic instability.

4. Target Lesion

A target lesion is any lesion treated or attempted to be treated during the trial procedure with the study device. The target lesion is the treated segment starting 5 mm proximal and ending 5 mm distal to the study device (stent, in most cases).

5. Target Vessel

A target vessel is any native coronary vessel (e.g., left main coronary artery (LMCA), left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX), or right coronary artery (RCA)) or aortocoronary bypass graft to the LAD, LCX, or RCA containing the target lesion. The target vessel includes the target lesion as well as segments of the vessel that are upstream and downstream to the target lesion, including side branches (native vessel).

6. Non-target Lesion

A non-target lesion is one for which revascularization is not attempted or one in which revascularization is performed using a non-study device.

7. Non-target Vessel

A non-target vessel is one for which revascularization is not attempted or one in which revascularization is performed using a non-study device.

8. Target Vessel, Non-Target Lesion

Any lesion or revascularization of a lesion in the target vessel other than the target lesion.

9. Target Lesion Revascularization (TLR)

Target lesion revascularization is any repeat percutaneous intervention of the target lesion (including 5 mm proximal and distal to the target lesion) or surgical bypass of the target vessel performed for restenosis or other complication involving the target lesion. In the assessment of TLR, angiograms should be assessed by an angiographic core laboratory (if designated) and made available to the Clinical Events Committee (CEC) for review.

10. Target Vessel Revascularization (TVR)

Target vessel revascularization is any repeat percutaneous intervention or surgical bypass of any segment of the target vessel. In the assessment of TVR, angiograms should be assessed by an angiographic core laboratory (if designated) and made available to the CEC for review.

11. Clinically-Driven Target Lesion Revascularization

Revascularization is clinically-driven if the subject has a target lesion diameter stenosis ≥ 50% by QCA and clinical or functional ischemia which cannot be explained by another native coronary or bypass graft lesion. Clinical or functional ischemia includes any of the following:

• a. A history of angina pectoris, presumably related to the target vessel
• b. Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), presumably related to the target vessel
• c. Abnormal results of any invasive functional diagnostic test (e.g., Doppler flow velocity reserve or fractional flow reserve (FFR))
• d. A diameter stenosis ≥70% by QCA even in the absence of the above signs or symptoms.
  
  Comment: In the absence of QCA data or if a <50% stenosis is present, TLR may be considered clinically-driven by the CEC if severe ischemic signs and symptoms attributed to the target lesion are present.

Peripheral Arterial Revascularization Procedure

1. Definition of Peripheral Arterial Revascularization Procedure

A peripheral arterial revascularization procedure is a catheter-based or open surgical procedure designed to improve peripheral arterial blood flow. This procedure may include thrombectomy, embolectomy, aneurysm/dissection repair, angioplasty, and stent placement.
The intention to perform percutaneous peripheral arterial intervention is denoted by the insertion of a guidewire through a guide catheter into a peripheral artery.
The target vessel(s) should be specified (e.g., carotid, vertebral, aorta, renal, iliac, femoral) and recorded as well as the type of revascularization procedure (e.g., surgical, angioplasty, stent placement, thromboembolectomy, aneurysm repair).

2. Procedural Success

In the case of percutaneous intervention for obstructive lesions, procedural success is defined as the achievement of a final residual diameter stenosis < 30% by angiography at the end of the procedure without any in-hospital major adverse events (death, acute onset of limb ischemia, need for urgent/emergent vascular surgery). The balloon inflation and/or stent placement may be preceded by device activation (e.g., angiojet, directional or rotational atherectomy, lasers).

3. Elective and Non-elective Procedures

Elective: An elective procedure is one that is scheduled and is performed on a patient with stable peripheral arterial disease.

Non-elective: A non-elective procedure is one that is performed immediately upon diagnosis because of urgency of the medical condition (e.g., acute limb ischemia, acute stroke, acute aortic dissection, acute aneurysm rupture).

4. Traget Vessel

A target vessel is any vessel (e.g., carotid, peripheral artery, mesenteric/renal artery) that contains the target lesion treated with the study device. The target vessel includes the target lesion as well as segments of the vessel that are upstream and downstream to the target lesion, including side branches (native vessel).

5. Non-target Vessel

A non-target vessel is one for which revascularization is not attempted or one is which revascularization is performed using a non-study device.

Stent Thrombosis

Stent Thrombosis: Timing

Stent thrombosis should be reported as a cumulative value over time and at the various individual time points as specified below. Time 0 is defined as the time point after the guiding catheter has been removed and the subject has left the cardiac catheterization laboratory.

Timing

• Acute stent thrombosis¹: 0-24 hours post stent implantation
• Subacute stent thrombosis¹: > 24 hours – 30 days post stent implantation
• Late stent thrombosis²: > 30 days – 1 year post stent implantation
• Very late stent thrombosis²: > 1 year post stent implantation

¹Acute or subacute can also be replaced by the term early stent thrombosis. Early stent thrombosis (0-30 days) will be used herein.
²Includes “primary” as well as “secondary” late stent thrombosis; “secondary” late stent thrombosis is a stent thrombosis after a target lesion revascularization.

Stent Thrombosis: Categories

We propose three categories of evidence to define stent thrombosis, as follows:

1. Definite Stent Thrombosis

Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation:

a. Angiographic confirmation of stent thrombosis^a

• Thrombolysis in Myocardial Infarction (TIMI) flow is:
  • TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus^b,c OR
  • TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus^b,c

AND at least one of the following criteria has been fulfilled within a 48 our time window:

• New acute onset of ischemic symptoms at rest (typical chest pain with duration > 20 minutes)
• New ischemic ECG changes suggestive of acute ischemia
• Typical rise and fall in cardiac biomarkers (See definition of non-procedural-related MI (i.e. spontaneous MI) in Chapter 4.

^a The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion).
^b Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream
^c Occlusive thrombus: TIMI 0 or TIMI 1 flow intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch)

b. Pathologic Confirmation of Stent Thrombosis

Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy.

2. Definite Stent Thrombosis

Probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:

• Any unexplained death within the first 30 days§
  
• Irrespective of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
  

§ In patients undergoing PCI for STEMI, one may consider excluding unexplained death within 30 days of the procedure as evidence of probable stent thrombosis.

3. Possible Stent Thrombosis

Possible stent thrombosis is considered to have occurred with any unexplained death from 30 days following intracoronary stenting until end of trial follow-up.

Bleeding

1. GUSTO

• Severe or Life Threatening
  Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention
• Moderate
  Bleeding that requires blood transfusion but does not result in hemodynamic compromise
• Mild
  Bleeding that does not meet the criteria for severe or moderate

2. TIMI

a. Types of TIMI Bleeding

1. Major

• Any intracranial bleeding
  OR
  
• Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 g/dL.

2. Minor

Any clinically overt signs of hemorrhage (including imaging) that is associated with a fall in Hgb of 3 to < 5 g/dL

3. Medical Attention

Any overt sign of hemorrhage that requires medical evaluation, medical treatment (including discontinuation of medications), or surgical treatment, and that does not meet criteria for a major or minor bleeding event, as defined above.

4. Minimal

Any overt bleeding event that does not meet the criteria above

NOTE: To account for transfusions, Hgb measurements will be adjusted for any packed red blood cells (PRBCs) or whole blood given between baseline and post-transfusion measurements. A transfusion of one unit of blood will be assumed to result in an increase by 1 gm/dL in Hgb. Thus, to calculate the true change in hemoglobin, if there has been an intervening transfusion between two blood measurements, the following calculations should be performed: ∆ Hgb = [Baseline Hgb – Post transfusion Hgb] + [# transfused units].

b. Relationship of Bleeding to Death

1. Fatal Bleeding

Death in which a bleeding event directly led to death within 7 days. Examples of fatal bleeding events are an intracranial hemorrhage that led to herniation of the brain and death within 24 hours, and a massive gastrointestinal hemorrhage that results in shock, hemodynamic collapse, and death. If a bleeding event is considered fatal, then the cause of death must be either intracranial or non-intracranial bleeding.

2. Bleeding Contributed to Death

Death in which a bleeding event was part of a causal chain of medical events that ultimately led to death within 30 days of the bleed, but bleeding was not directly and/or immediately related to the subject’s death. An example of bleeding contributing to death is a large retroperitoneal bleed that leads to surgical evacuation, development of a subsequent abscess in the area of bleeding that leads to sepsis, multiorgan failure, and death 10 days after the onset of bleeding. If bleeding has contributed to death (but the bleeding was not categorized as “fatal”), then the cause of death must be recorded as something other than intracranial / non-intracranial bleeding.

c. Bleeding in the Setting of Coronary Artery Bypass Graft Surgery (CABG)

Minor and minimal bleeding are not adjudicated in the setting of CABG.

As a drop in hemoglobin and transfusions are commonplace in routine CABG cases, one of the following criteria must be met to qualify for major bleeding in any of the preceding definitions:

1. Fatal bleeding (i.e., bleeding that directly results in death)
2. Perioperative intracranial bleeding
3. Reoperation following closure of the sternotomy incision for the purpose of controlling bleeding
4. Transfusion of ≥ 5 units of packed red blood cells (PRBCs) or whole blood within a 48 hour period. Cell saver transfusion will not be counted in calculations of blood products
5. Chest tube output > 2 L within a 24 hour period