FFR has been validated against several non-invasive ischemia tests to determine its optimal cutoff value for inducible myocardial ischemia in patients with stable CAD [
25]. The first cutoff value for FFR was determined at 0.66 for inducible myocardial ischemia determined with exercise stress testing [
26], which later was increased to a FFR of 0.75, based on a combination of exercise stress tests, dobutamine stress echo, and myocardial perfusion imaging. In this study by Pijls et al., the FFR cutoff value of 0.75 was associated with 97% diagnostic accuracy for non-invasively determined ischemia-inducing stenoses [
2]. Following these relatively small studies, a multitude of ischemia validation studies have been performed, where there overall optimal cutoff value of FFR was 0.75, with a diagnostic accuracy of 81% for non-invasively assessed myocardial ischemia. Diagnostic accuracy of FFR was highest in single-vessel disease, and, more importantly, validated solely in patients with stable CAD [
27]. Following the initial documentation of a 0.75 FFR cutoff value for myocardial ischemia, this cutoff value was used in the first clinical validation study for FFR, the DEFER trial [
7], which concluded that deferral of revascularization for FFR value ≥ 0.75 in patients with stable CAD is not associated with an increased risk of MACE [
28]. The subsequent randomized FAME trials, however, used a higher FFR cutoff value of 0.80, so called clinical threshold, in order to minimize the number of hemodynamically significant stenoses deferred from revascularization. The first of these large clinical trials, FAME I, evaluated the clinical performance of FFR-guided PCI versus angiography-guided PCI using this 0.80 FFR cutoff value. The long-term results of the FAME trial have documented that FFR-guided PCI leads to equivalent long-term clinical outcomes compared with angiographic guidance, albeit with more swift alleviation of angina complaints while reducing the number of revascularization procedures required [
25,
29]. The DEFER and FAME I and II trial findings have culminated in a class I level of evidence: A recommendation in the European Society of Cardiology (ESC) guidelines [
30] and the ACC/AHA guidelines [
31], where revascularization is advocated in all coronary stenoses with FFR ≤ 0.80. Nonetheless, expert opinion manuscripts from the founders of FFR support revascularization of stenoses with FFR < 0.75, and deferral of revascularization in stenoses with FFR > 0.80. Stenoses with FFR from 0.75 ranging to 0.80 pertain to the clinical FFR “gray zone,” where decision-making should be based on the results of other ischemic tests, as well as the individual risk-benefit profile of the patient. The latter results in both a clinical decision-making tool as well as a limitation of FFR, since individual variance in coronary physiology indices frequently occurs and thus impedes decision-making, especially in FFR values in or around the gray zone [
32,
33].
Meanwhile, the results of the FAME II trial have shed new light on the clinical performance of FFR. FAME II randomized patients with at least one coronary artery with FFR ≤ 0.80 to optimal medical therapy alone or optimal medical therapy plus PCI. It was documented that PCI in addition to optimal medical therapy reduced the number of major adverse cardiac events through the first 2 years of follow-up. However, it is important to realize that the FAME II trial was prematurely halted because of a clear difference in the primary composite endpoint in favor of the PCI arm, thereby limiting the trial’s statistical power, and inducing a potential overestimation of effect size. Moreover, although significantly lower rates of adverse cardiac events were documented for PCI in addition to optimal medical therapy, it is important to realize that 60% of all patients with abnormal FFR values did not require revascularization, and 80% of patients with abnormal FFR values did not suffer from MACE throughout a 2-year follow-up period. Moreover, > 10% of vessels from patients in the reference group with normal FFR values, which were treated by optimal medical therapy alone, suffered MACE within the first 2 years of follow-up. Thus, the majority of FFR-positive vessels actually do not seem to be at risk for revascularization or hard clinical events, and a substantial proportion of FFR-negative vessels are adversely at risk for MACE within the first 2 years of follow-up. These results contradict the extremely high accuracy of FFR for inducible myocardial ischemia documented in the original multitest ischemic study. Subsequently, these results give rise to concerns regarding contemporary revascularization guidelines in which all FFR-positive stenoses are considered alike and eligible for coronary revascularization [
34].