ISCHEMIA Trial: Are We Still Fighting the Last War?

Abstract

While the assessment of stress-induced ischemia has long been used to guide the clinical management of stable ischemic heart disease (SIHD), the value of this approach in the identification of therapeutic selection is an unproven hypothesis. After decades of randomized clinical trials (RCT)—including recent trials comparing revascularization and optimal medical therapy (OMT) to OMT alone—the identification of the patient with SIHD who is an optimal revascularization candidate remains uncertain.1–5 The current issue of Circulation: Cardiovascular Imaging contains a historic overview of investigations examining the role of myocardial ischemia in clinical management as a prelude to a discussion of the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches).6 This outstanding review touches upon many of the underlying issues and challenges faced when examining these questions. Despite the use of ischemia ascertainment in the inclusion criteria of both the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) and the BARI 2D trial (Bypass Angioplasty Revascularization Investigation 2 Diabetes), both failed to demonstrate any survival benefit with the addition of revascularization to OMT.1,7 The failure to define a therapeutic role for ischemia assessment to select revascularization candidates in both the overall study and the relevant nuclear substudies suggested that angiographic characterization of coronary anatomy and, in turn, stress imaging to identify angiography candidates, may not be routinely necessary. On the contrary, the FAME 2 trial (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2),4 using physiological metrics to guide patient management, claimed improved outcomes for a physiology-base strategy compared with an anatomy-based strategy. Similarly, large, single center observational series of patients referred for clinically ordered cardiac single photon emission-computed tomography (SPECT) MPI suggested that revascularization was associated with improved survival compared with medical therapy alone when an ischemia threshold was exceeded (≈>15% of the myocardium ischemic).8,9 It should be noted that medical therapy in these observational studies was undefined and, as shown in large, prospective, multicenter observational studies, likely suboptimal.10 These observational studies also introduced the paradigm that post-CV imaging patient risk is distinct from improving outcomes with a specific treatment strategy. Those patients who accrued a survival benefit were not those at greatest clinical risk (reduced left ventricular function, myocardial scar) but those with the greatest amount of inducible ischemia.8,11,12 Although prior guidelines included a class I recommendation for revascularization in the setting of anatomic CAD with jeopardized myocardium, this use © 2021 American Heart Association, Inc. Circulation: Cardiovascular Imaging