FAME 2 Results

Lori Alexander

doi:10.1177/155989771213008

Summary

Percutaneous coronary intervention guided by fractional flow reserve plus the best available medical therapy (MT) improves outcomes in patients with stable coronary artery disease compared with optimal MT alone. The benefit is primarily due to a lower rate of rehospitalization for urgent revascularization. These findings, from the Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Therapy versus Optimal Medical Therapy Alone in Patients with Stable Coronary Artery Disease [FAME 2; NCT01132495] trial.

Interventional Techniques & Devices
Cardiology Clinical Trials
Coronary Artery Disease

Percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) plus the best available medical therapy (MT) improves outcomes in patients with stable coronary artery disease (CAD) compared with optimal MT alone. The benefit is primarily due to a lower rate of rehospitalization for urgent revascularization (UR). These findings, from the Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Therapy versus Optimal Medical Therapy Alone in Patients with Stable Coronary Artery Disease [FAME 2; NCT01132495] trial, were reported by Bernard De Bruyne, MD, PhD, Onze-Lieve-Vrouw Clinic, Aalst, Belgium.

In prior studies, PCI has failed to to improve the prognosis for patients with stable CAD. However, Prof. De Bruyne and the FAME 2 investigators hypothesized that PCI plus MT would improve outcomes for patients with stable CAD if the presence of lesions that produced ischemia were confirmed by measurement of FFR. FFR-guided PCI was superior to angiography-guided PCI in the initial FAME trial [Tonino PA et al. N Engl J Med 2009]. The results of FAME 2 were simultaneously published to coincide with the presentation of the study [De Bruyne B et al. N Engl J Med 2012].

The researchers measured FFR in patients with stable CAD for whom PCI was being considered. Patients who had at least 1 functionally significant stenosis (FFR ≤0.80) were randomly assigned to FFR-guided PCI plus the best available MT or the best available MT alone. Patients who had no evidence of ischemia (FFR >0.80) were treated with MT alone and were followed in a registry. The primary endpoint was a composite of death, myocardial infarction (MI), or UR. The trial was designed as a superiority study in 1632 patients and powered to test whether FFR-guided PCI resulted in a 30% relative risk reduction of the primary endpoint over an intended average follow-up of 2 years.

An important first finding was that 27% (n=322) of the patients evaluated for the study had no hemodynamically significant stenosis, and were thus followed in the trial registry. The remaining 73% (n=888) had an FFR ≤0.80 in at least 1 large epicardial artery and were randomly assigned to FFR-guided PCI plus MT (n=447) or MT alone (n=441). The trial was stopped prematurely in January 2012 after 1220 patients were randomized with an average follow-up of 7 months, when the independent Data Safety Monitoring Board judged highly significant differences in the primary endpoint rates between patients randomized to MT alone compared with those who recieved FFR-guided PCI plus MT (4.3% vs 12.7%; HR with PCI, 0.32; 95% CI, 0.19 to 0.53; p<0.001). A large difference in the rate of UR (1.6% vs 11.1%; HR, 0.13; 95% CI, 0.06 to 0.30; p<0.001) was the major factor responsible for the difference in the composite endpoint between the groups. Rates of mortality or MI were infrequent and did not differ significantly between the 2 randomized groups. In the registry, MT alone led to an excellent outcome for patients without FFR-determined ischemia, regardless of the angiographic appearance of the stenoses; the primary endpoint occurred in only 5/166 (3.0%) patients with FFR >0.80.

Science Advisors' Note

Although the reduction in the composite primary endpoint with PCI is provocative, it is worth noting that this observation was predominantly dependent on a difference in the “softer” endpoint of UR, and that the premature termination of this randomized study resulted in the enrollment of only 75% of the patients planned with less than a third of the intended average follow-up. Two additional limitations warrant mention. First, an early signal towards a potential harm as a result of definite or probable stent thrombosis in patients randomized to FFR-guided PCI plus MT (all of whom received a second-generation drug-eluting stent) compared with MT alone (1.1% vs. 0.2% by 12 months; HR with PCI, 4.98; 95% CI, 0.59 to 42.25) could have been better defined with further follow-up and greater event accrual. Second, the non-blinded nature of this study (the patients managed with MT alone did not undergo sham PCI) could have led to a selection bias in referral for “urgent” revascularization, with a lower threshold to refer patients to PCI if they had been randomized to optimal MT without PCI. As Dr. William Boden, one of the lead investigators of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] trial, concluded in his editorial to FAME-2, neither FAME-2 with 7 months of mean follow-up or the COURAGE trial with 55 months of mean follow-up showed a reduction with PCI in “hard” clinical endpoints, such as death or MI [Boden WE. N Engl J Med 2012]. Further insight regarding the comparison of PCI with best available MT in patients with stable CAD and moderate-to-severe ischemia may come from the results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial [ISCHEMIA; NCT01471522].

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