Post-Hoc Analysis of ISCHEMIA Trial: The Choice of Myocardial Infarction Definition Influences Clinical Interpretation of Results

Sahar Memar Montazerin, MD
By Sahar Memar Montazerin, MD on

A recent study by Dr. Bernard R. Chaitman, published in Circulation investigated the impact on clinical interpretation of using different definitions for myocardial infarctions in the ISCHEMIA trial.

The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) randomized 5,179 patients with stable ischemic heart disease and moderate or severe myocardial ischemia on noninvasive testing to an initial invasive (angiography and revascularization when feasible) and medical therapy or a conservative strategy of medical therapy alone and angiography if medical therapy failed. The previously published study results failed to provide any evidence that an initial invasive strategy, as compared with an initial conservative strategy, decreases the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years follow-up.

MI events were the predominant component of the composite cardiovascular endpoints in the ISCHEMIA trial, and interpretation of the overall trial was sensitive to the definition of procedural MI. Given recent studies have indicated that a relationship exists between post-procedural CK-MB elevations or cardiac troponin (cTn) elevation and mortality outcomes, this post-hoc analysis investigated whether there is a difference in cardiovascular endpoints when using a definition that includes CK-MB (primary) or cTn (secondary) as the preferred biomarker. Procedural thresholds were >5 times URL for PCI and >10 times for CABG. In addition, procedural MI included 1) a category of elevated biomarker only events with higher biomarker thresholds than the level required when ancillary evidence of myocardial ischemia was present 2) new ST-segment depression of > 1 mm for the primary and > 0.5 mm for the secondary definition and 3) new coronary dissections > NHLBI grade 3. The frequency and prognosis of each type of MI were compared between the two treatment strategies.

A total of 443 (8.6%) and 593 (11.5%) of the 5,179 patients were identified to have had a MI with the primary and secondary definition, respectively. Increased procedural MI event rates using the secondary MI definition explained the difference in total MI rates between the primary and secondary MI definitions. Procedural MI composed 20.1% of all MIs using the primary definition and 40.6% using the secondary definition. With regard to treatment strategy, the rate of type 1 MI was less frequent among those who underwent PCI or CABG compared to those who underwent conservative treatment regardless of the definition applied. Type 1 MI was associated with a higher rate of cardiovascular death regardless of MI definition.

In conclusion, this post-hoc analysis demonstrated that using the primary and secondary definitions of MI, type I MI events were more frequent with an initial conservative strategy and associated with higher rates of cardiovascular death over a 5-year follow-up. As well, when using the secondary MI definition, the rates of procedural MI were higher among those patients who received the invasive strategy compared to those who received the conservative approach. These findings warrant further approval in large-population studies with a longer follow-up period.

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