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FAME 2 Favorable PCI Results Driven by Revascularization

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Is FAME 2 the Final Word on PCI vs. Best Medical Management?

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.



The use of fractional flow reserve to guide percutaneous coronary intervention, along with best medical management, sharply reduced the need for urgent revascularization in patients with stable coronary artery disease and at least one physiologically significant lesion.

However, FFR-guided percutaneous coronary intervention (PCI) had little effect on deaths or myocardial infarctions, when compared with best medical management alone, according to the results of the FAME 2 (Fractional Flow Reserve vs. Angiography for Multivessel Evaluation 2) trial, which was conducted at 28 sites in Europe and North America and halted early.

The percentage of patients who had an MI, death, or urgent revascularization (the combined primary end point) was significantly lower in the PCI group than in the medical therapy group (4.3% vs.12.7%; hazard ratio with PCI, 0.32). This difference was driven by a 13-fold increase in the need for urgent revascularization in the medical-therapy group. Notably, the rate of death from any cause and the rate of MI did not differ significantly between the PCI group and the medical therapy group.

Importantly, patient recruitment was stopped on Jan. 15, 2012, at the recommendation of an independent data and safety monitoring board because of the highly significant difference in the incidence rates of the primary end point between the PCI and medical-therapy groups.

The results of the study were released in the New England Journal of Medicine on Aug. 28 to coincide with the presentation of the study at the annual congress of the European Society of Cardiology (N. Engl. J. Med. 2012 Aug. 28 [doi:10.1056/NEJMoa1205361]).

A total of 1,220 patients out a planned 1,832 were enrolled. Of those, 888 patients had at least one stenosis with an FFR of 0.80 or less: 447 patients were randomly assigned to FFR-guided PCI plus the best available medical therapy, and 441 patients to the best available medical therapy alone. The 332 patients with angiographically significant stenoses, but none with an FFR of 0.80 or less were enrolled in the registry and received the best available medical therapy alone. The mean duration of follow-up was 212 days.

Patients in stable condition who were appropriate candidates for PCI and who had angiographically assessed one-, two-, or three-vessel coronary artery disease suitable for PCI were included in the trial.

All patients were prescribed aspirin at a dose of 80-325 mg daily, metoprolol at a dose of 50 mg-200 mg daily (or any other beta-blocker), lisinopril (at least 5 mg daily, or another ACE inhibitor or an angiotensin receptor blocker)and atorvastatin (20-80 mg daily, or another statin).

All PCI patients were treated with second-generation drug-eluting stents.

Among the 56 patients who underwent urgent revascularization, the procedure was triggered by a MI in 12 patients (21%), by unstable angina accompanied by evidence of ischemia on ECG in 15 patients (27%), and by unstable angina diagnosed on the basis of clinical features in 29 patients (52%).

Patients in the PCI group were 86% less likely to undergo any revascularization and 83% less likely to undergo or nonurgent revascularization than were those in the medical therapy group.

The researchers identified several factors that may explain the differences between results in the present study and those in previous trials involving patients with stable coronary disease. "First, in previous trials in which various revascularization methods were compared with the best available medical therapy, patient enrollment was based primarily on angiographic findings, with or without noninvasive documentation of ischemia. It is likely that a sizable proportion of the patients had only limited ischemia," wrote lead investigator Dr. Bernard B. De Bruyne and his coinvestigators. Dr. De Bruyne is the codirector of the Cardiovascular Center at OLV Hospital in Aalst, Belgium.

"Even in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, in which noninvasive testing was performed in 85% of the patients, less than one-third of the patients had more than 10% ischemia on myocardial perfusion imaging. In daily clinical practice, less than half of patients undergo noninvasive stress testing before elective PCI. In the current trial, all the patients who underwent randomization had at least one functionally significant stenosis," they observed (N. Engl. J. Med. 2007;356:1503-16).

Second, PCI was performed only in lesions with an FFR of 0.80 or less. "This FFR-guided approach is associated with a better clinical outcome than that with PCI performed on the basis of angiographic results alone. These features probably explain the similarity of event rates between patients who were treated with PCI plus the best available medical therapy and patients with equivalent baseline characteristics but no functionally significant lesions who were enrolled in the registry and treated with the best available medical therapy alone," according to the investigators.


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