ABSTRACT & COMMENTARY
FFR in Stable Coronary Artery Disease: A Second Chance at FAME?
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: De Bruyne B, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014; Sep 1.
[Epub ahead of print.]
In acute coronary syndromes, percutaneous coronary intervention (PCI) has clear benefits in terms of hard clinical endpoints. In the realm of stable coronary disease, however, optimal medical therapy has for some time now taken center stage, with PCI relegated to a supporting role whose primary purpose is to treat symptoms. This is based on a number of research studies, most prominently the 2007 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, which reported that PCI driven by angiography is no better than medical therapy alone at preventing clinical outcomes including death and myocardial infarction (MI). In addition to using angiography to drive treatment decisions, COURAGE used primarily older, bare-metal stents for treatment. Since the original FAME trial was published in 2009, fractional flow reserve (FFR) has gained significant traction as a more objective means (compared with angiography alone) to determine the ischemic potential of epicardial stenoses. The Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial was designed to compare medical therapy with PCI using modern techniques and second-generation drug-eluting stents in patients with stable CAD and functionally significant coronary lesions as defined by FFR.
Although 2-year outcomes were pre-specified in the trial design, the study was stopped early after an average follow-up of only 7 months due to an excess of urgent revascularization in the medical therapy group. Death and MI were not significantly different between the groups. The problem with the early termination decision and subsequent criticism of the published result seems obvious — physicians as well as patients were aware of the cardiac cath findings and study group assignments, which clearly could have lowered the threshold for urgent revascularization in the medical therapy arm.
De Bruyne and colleagues now present the long-awaited 2-year follow-up data from the FAME 2 trial. In the trial, 888 patients with 1601 PCI-eligible lesions were enrolled. These patients were randomized to undergo FFR-guided PCI plus medical therapy (447 patients) or to receive medical therapy alone. The primary endpoint was a composite of death from any cause, nonfatal MI, or unplanned hospitalization leading to urgent revascularization within 2 years. As with the early data, the most striking difference between groups was a 77% reduction in urgent revascularization in the PCI group, as compared with the medical-therapy group (4.0% vs 16.3%; hazard ratio [HR], 0.23; 95% CI, 0.14-0.38; P < 0.001). While more than half of these urgent revascularization decisions were prompted by clinical presentation alone, there was also a lower incidence of revascularization triggered by MI or ECG changes in the PCI group compared with the medical therapy group (3.4% vs 7.0%; P = 0.01). More importantly, when excluding periprocedural MI, patients in the PCI group had a 44% relative risk reduction for the composite of death or MI (4.6% vs 8.0%; HR, 0.56; 95% CI, 0.32-0.97; P = 0.04). As expected for this stable CAD population, mortality was low (mean of 1.4%) and did not show a significant difference between groups.
How will these results change practice? Will we now concede that PCI in stable coronary disease has the potential to change hard clinical outcomes? While these results are compelling and thought provoking, several points are worth noting. The authors of the study argue quite convincingly that urgent revascularization represents a failure of the assigned treatment, and the accompanying editorial dubs this "a viable hard end point." Nonetheless, the unblinded nature of the study leaves open the probability that awareness of a functionally significant stenosis influenced decision making of the physician or the patient during follow-up. And while just over 40% of patients in the medical-therapy group had crossed over to undergo PCI by 2 years, this also suggests that nearly 60% of these patients with FFR-positive stenoses did fine without revascularization. This would seem to buttress the argument for an initial strategy of medical therapy in stable coronary disease.
It is important to recognize that the between-group difference reported in death or MI was not significant for the data set as a whole. A significant difference was only measured by excluding data from the first 7 days following randomization, which effectively cordoned off periprocedural MI events. While the authors contend that "periprocedural infarctions rarely have an effect on the long-term prognosis for patients undergoing PCI," the relatively stringent definition of MI used in this trial (10× the upper limit of normal in the CK-MB or an increase by a factor of more than 5 when accompanied by objective evidence of tissue loss) supplies a basis for criticism of this premise. In the end, we are left with some very intriguing food for thought, but without a clear answer that is likely to change practice guidelines.