The recommendation to terminate FAME 2 by the independent data and safety monitoring board at 7 months’ follow-up was based solely on one highly significant treatment difference. That difference was in the end point of urgent revascularization, which was performed in 49 patients in the group that received the best available medical therapy alone vs. 7 patients in the group that underwent percutaneous coronary intervention and also received the best available medical therapy, Dr. William E. Boden wrote in an editorial accompanying the FAME 2 report (N. Engl. J. Med. 2012 Aug. 28 [doi:10.1056/NEJMe1208620]).
"There were very few ‘hard’ events overall, with only four deaths (three in the medical-therapy group and one in the PCI group) and 29 myocardial infarctions (14 in the medical-therapy group and 15 in the PCI group). Of note, the definition of urgent revascularization was largely a clinical one and did not require evidence of ischemia or positive cardiac biomarkers in all patients; 29 of the 56 unplanned revascularizations (52%) were classified solely on the basis of clinical features, whereas in an exploratory subgroup analysis of the remaining 27 patients, there were fewer revascularizations triggered by a myocardial infarction or electrocardiographic evidence of ischemia in the PCI group than in the medical-therapy group," wrote Dr. Boden.
"Clearly, FFR [fractional flow reserve] holds potential promise for a more targeted approach to PCI that might be more clinically effective and cost effective than visually directed PCI for all angiographically significant stenoses," he continued. "Unfortunately, the early termination of the FAME 2 trial before full enrollment and follow-up were achieved, the neutral effects on the rate of death or myocardial infarction, and the lack of a significant, sustained treatment effect on the reduction of angina beyond 6 months leave more questions than answers."
The FAME 2 and COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation] trials are remarkably similar and showed that PCI reduced only the need for revascularization; in the COURAGE trial, there was a significant 40% reduction, whereas "neither the FAME 2 trial (with a mean 7 months of follow-up) nor the COURAGE trial (with a mean 55 months of follow-up) showed a benefit from PCI with respect to a reduction in the rate of death or myocardial infarction. The FAME 2 trial sought to establish the scientific basis for an FFR-guided PCI strategy for all functionally significant stenoses, but the results make this prospect somewhat unappealing," he wrote. Dr. Boden was the lead author of the COURAGE trial.
Current practice guidelines advocate the selective use of FFR to guide PCI decision making regarding borderline visual lesions (approximately 50%-70% stenosis). "It seems likely that the more routine use of FFR for all angiographically-significant stenoses would add considerable time, cost, and complexity to each PCI procedure and might also increase the risk of catheter-related complications such as coronary dissection and perforation," Dr. Boden pointed out.
Some of the uncertainty arising from FAME 2 may be resolved with the results of the ongoing ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The study is designed and powered to evaluate the long-term superiority of revascularization plus the best available medical therapy as compared with the best available medical therapy alone with respect to cardiovascular death or MI in patients with stable coronary artery disease and moderate-to-severe myocardial ischemia documented by means of noninvasive measures. "Until the results of ISCHEMIA are available, the case for a more durable clinical benefit of PCI beyond relief of angina or a reduction in the rate of subsequent revascularization is likely to remain both elusive and illusory," concluded Dr. Boden, who is a coprincipal investigator of ISCHEMIA.
Dr. Boden is the chief of medicine at the Albany Stratton Veterans Affairs Medical Center and vice chair of the department of medicine at Albany (N.Y.) Medical Center. He reported that he is a paid consultant for Arbor Pharmaceuticals and is a speaker for Abbott Laboratories and Gilead Sciences.
