Patient Selection for Elective Revascularization to Reduce Myocardial Infarction and Mortality

Heart Association Guidelines, randomized trials have not demonstrated that elective percutaneous coronary intervention (PCI) reduces myocardial infarction (MI) or mortality over medical treatment.Even the Fractional Flow Reserve Guided PCI Versus Medical Therapy in Stable Coronary Disease (FAME 2) trial showed no statistically significant benefit of PCI over the deferred group by traditional intention-to-treat, nonbenchmark analysis starting at randomization that includes procedure-related events.Benchmark analysis in FAME 2 beginning 1 week after PCI removed procedure-related events that counterbalanced subsequent reduced MI and mortality compared with the deferred group.Meta-analysis of the literature on risk of events related to fractional flow reserve (FFR), including FFR Versus Angiography in Multivessel Evaluation (FAME), and other physiological measures of severity reveal an underappreciated, powerful interdependence among physiological severity of stenosis, diffuse coronary artery disease (CAD), event rates, sample size, and statistical certainty of differences.This analytic review synthesizes an evidenced-based, quantitative hypothesis and potential solution to this issue based on hard data from the literature by coauthors of diverse cardiovascular disciplines in trial design, biostatistics, invasive procedures, coronary physiology, fluid dynamics, coronary pathology, and quantitative imaging.Our synthesis elucidates a dual hypothesis for failure of elective PCI in stable CAD to reduce MI or mortality and novel trial design for selecting patients for whom PCI will likely reduce these events.First, a large burden of global diffuse CAD carries a high risk of coronary events unmitigated by PCI of a focal stenosis.Second, focal stenosis severity in previous randomized revascularization trials has been too modest without objectively quantified sufficient severity to observe benefit of PCI.In previous trials, mixture of diffuse coronary disease and intermediate stenosis may not incur high enough risk for potential benefit by PCI for sample size of reported trials.Greater quantitative severity with higher event rates may overcome this limitation.Because it powerfully alters sample size, event rates, and statistical certainty in randomized trials, quantitative physiological severity of not only focal but also diffuse CAD must inform patient selection in future revascularization trials if reduction in MI and mortality is to be a scientific basis for revascularization and evidenced-based, objectively informed patients. Overview: A Central Issue in Cardiology: Who Benefits From Revascularization toReduce MI or Mortality?Forty-one years ago the senior author reported the concept of coronary flow reserve (CFR) as a physiological measure of stenosis severity. 1Nineteen years later Pijls et al 2 with the senior author proved experimentally the concept of FFR as a practical relative CFR.Twenty-one years after that saw publication of the primary, 2-year FAME 2 follow-up. 3While gratifying, this evolution provides a unique longitudinal view for addressing critically but constructively the issue of FFRguided revascularization for reducing MI and mortality.CFR (also called absolute CFR) is the ratio of peak coronary flow in mL/min or myocardial perfusion in mL/min per gram during vasodilator stress to resting flow or perfusion as a quantitative measure of increasing capacity.It is blunted by stenosis, diffuse, or small-vessel disease.Relative CFR is the ratio of peak flow or perfusion in an abnormal region of a relative perfusion image to the most normal appearing region that, however, may have reduced absolute CFR.Therefore, it reflects relative severity of focal disease but fails to identify superimposed or associated diffuse disease.FFR is a measure of relative flow reserve derived from the stenosis pressure