Planning and Conducting the ISCHEMIA Trial: Setting the Record Straight

David J. Maron, MD; Robert A. Harrington, MD; Judith S. Hochman, MD


Circulation. 2018;138(14):1384-1386. 

In This Article

Eligibility Criteria

During the design phase, ISCHEMIA investigators debated whether the qualifying stress test should reflect clinical practice (eg, read by sites without core laboratories—pragmatic design), include all stress imaging modalities and nonimaging exercise tolerance testing (ETT), or be limited to nuclear myocardial perfusion imaging with core laboratory readings of all studies. The original ISCHEMIA protocol entry criteria allowed only stress imaging tests demonstrating moderate or severe ischemia. After starting the trial, we discovered that the prevalence of at least moderate ischemia on stress tests as interpreted by local laboratories was less than the reported prevalence of ≈15% to 20%.[3,4] This finding had a negative effect on recruitment, and we needed to make an adjustment to meet our projected recruitment milestones without harming the trial's integrity. We reconsidered ETT as a qualifying test. To reduce the risk of false-positive stress tests and less than moderate ischemia, we proposed the requirement of stable angina, an interpretable resting ECG, evidence of core laboratory-confirmed major ischemic ST depression occurring at an early stage, and ≥70% stenosis in a major epicardial coronary artery on coronary computed tomography angiography. This deviation from the original design was hotly debated by the steering committee, with opponents arguing that severity of ischemia cannot be measured without imaging, ETT cannot be equated to stress imaging tests, and we could potentially dilute study power by allowing ETT to qualify. Proponents of the change argued that ETT is the most common form of stress testing globally, is recommended by guidelines for patients with an interpretable ECG,[5] has the potential to improve the trial's relevance to practice, and could improve recruitment. In January 2014, the trial-independent Data and Safety Monitoring Board recommended approval of the protocol amendment to allow ETT as a method to determine participant eligibility, and NHLBI concurred with this recommendation.