Clinical event adjudication: Myocardial infarction

For the list of clinical event adjudication definitions, click here Editors-in-Chief: C. Michael Gibson, M.S., M.D. [mailto:mgibson@perfuse.org]

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

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.

d. Pathological findings of an acute myocardial infarction
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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.

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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.

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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
 * {| border="1px"


 * - style="height:50px" align="center"
 * Types of MI
 * Treatment A Number of patients (N = )
 * Treatment B Number of patients (N = )
 * - align="center"
 * MI Type 1
 * n, %
 * n, %
 * - align="center"
 * MI Type 2
 * n, %
 * n, %
 * - align="center"
 * MI Type 3
 * n, %
 * n, %
 * - align="center"
 * MI Type 4
 * n, %
 * n, %
 * - align="center"
 * MI Type 5
 * n, %
 * n, %
 * - align="center"
 * Total number
 * n, %
 * n, %
 * colspan="3" | 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:
 * 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'''
 * * 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.

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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.