The clinical manifestations of myocardial ischemia are protean in nature and include a variable combination of typical or atypical angina symptoms, electrocardiographic changes, noninvasive findings of regional
wall motion abnormalities, and reversible scintigraphic perfusion defects—the changes of which, importantly, may
or may not be of epicardial coronary origin. Thus, mounting evidence indicates that the presence or absence of
atherosclerotic coronary artery disease (CAD) should no longer be considered a surrogate marker for myocardial
ischemia, as suggested by the high prevalence of minor or absent coronary obstruction among patients with
proven myocardial ischemia. Whereas the management of CAD has been largely predicated on the plausible
assumption that flow-limiting obstructions of the epicardial coronary arteries are the proximate cause of both
angina and myocardial ischemia, there is scant evidence from many randomized trials and several meta-analyses
that treating epicardial coronary obstructions in patients with stable CAD, particularly with percutaneous coronary
intervention (PCI), reduces mortality and morbidity, as compared with optimal medical therapy (OMT). A crucial
scientific question for which evidence has been lacking is whether more severe and extensive myocardial ischemia
is the driver of adverse cardiovascular outcomes and whether an invasive strategy with myocardial revascularization would be superior to OMT alone in such patients. The results of the recent ISCHEMIA trial (International Study
of Comparative Health Effectiveness with Medical and Invasive Approaches), however, have failed to show—even
in this higher-risk CAD subset—any incremental clinical benefit of revascularization as compared with OMT alone
on cardiac event reduction.