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.
SYNOPSIS: The 5-year results of the FAME study did not show any late catch up in major adverse cardiac events in the fractional flow reserve-guided (FFR) group, supporting the long-term safety of the FFR-guided approach to percutaneous coronary interventions.
SOURCE: van Nunen LX, et al, Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5-year follow-up of a randomised controlled trial. Lancet 2015;386:1853-1860.
Although coronary angiography is the gold standard for the diagnosis of coronary atherosclerotic disease, it presents difficulties in identifying targets for percutaneous coronary interventional (PCI) therapies. The visual estimation of coronary stenosis severity by coronary angiography, besides being relatively subjective, in many cases is not the optimal means of determining the presence or absence of myocardial ischemia. In the cardiac catheterization laboratory, that title goes to the measurement of fractional flow reserve (FFR), which allows the quantitative assessment of ischemic capacity in a lesion or series of lesions in a single artery.
The Fractional Flow Reserve Versus Angiography for Guidance of PCI in Patients with Multivessel Coronary Artery Disease (FAME) trial, first published in 2009, was a multicenter trial in which more than 1000 patients with multivessel coronary disease were randomized to having their PCI guided either by angiography or by FFR. In the angiography group, stenting was performed in all angiographically identified lesions. The FFR group had physiologic assessment of all lesions, with PCI performed only if the FFR value was ≤ 0.80. The results are well-known. Patients in the FFR group, on average, had fewer stents placed, as some of the lesions identified by angiography were not significant by FFR. After 1 year, patients in the FFR had fewer major adverse cardiac events and greater freedom from angina. At 2 years, the FFR group had significantly lower rates of death and nonfatal myocardial infarction. The long-term safety of this strategy has not been reported. Specifically, some have expressed concern that medical rather than interventional treatment of less-severe lesions might be susceptible to a catch-up phenomenon.
In August 2015, FAME investigators reported the 5-year results of their study. Major adverse cardiac events (MACE) at 2 and 5 years, defined as a composite of death, myocardial infarction, and any repeat revascularization, were prespecified endpoints of the study. Notably, although events up to the 2-year mark were adjudicated by an independent clinical events committee, the 5-year events were reported by individual sites and were verified by available source documentation. Regardless, completeness of follow-up data was excellent. At 5 years, only 67 of the original angiography-guided patients and 73 of the 509 FFR patients had been lost to follow-up. MACE occurred in 154 of 496 patients in the angiography-guided group vs 143 of 509 patients in the FFR-guided group (relative risk [RR], 0.91; 95% confidence interval [CI] 0.75-1.10; P = 0.31). All-cause mortality was also not significantly different between groups, with 10% mortality (49 of 496 patients) in the angiography-guided group, and 9% (44 of 509 patients) in the FFR-guided group (RR, 0.88; 95% CI, 0.59-1.29; P = 0.50).
Interestingly, there was a positive interaction between patient sex and treatment strategy, with FFR-guided PCI favoring men (P = 0.027). Male patients had a persistently significant difference in MACE at 5 years that was not seen in the female patients, who represented 26% of the total.
The investigators noted that while the absolute difference in MACE between angiography and FFR-guided groups persisted at 5 years, this difference was no longer significant as compared with the 1- and 2-year data. The authors said this result is due to the smaller number of patients at risk and the similar incidence of events in both groups beyond 2 years. Their interpretation is that the benefits of using FFR guidance occur mainly in the first 2 years, with subsequent similar risk increases in both groups. The authors concluded that these results confirm the long-term safety of FFR-guided PCI in multi-vessel disease.
The results of the FAME trial have already substantially changed the practice of clinical cardiology. Patients in the FFR-guidance group, on average, had fewer lesions treated and received fewer stents than those in the angiography group. Despite this less aggressive treatment, these patients actually showed superior hard outcomes in the first 2 years, with lower resource use. Although guidelines reflect the findings, multiple studies have shown that FFR remains relatively underutilized. Some have expressed a concern that the 1- and 2-year benefits of FFR-guided PCI might be undermined by a late catch-up phenomenon, with an excess of events in patients provided FFR-guided therapy. These 5-year results, although imperfect, should do much to allay these fears and pave the way for more consistent use of this technology in clinical decision making.