REPORTING FROM TCT 2017
DENVER (FRONTLINE MEDICAL NEWS) – Percutaneous coronary intervention plus optimal medical therapy in stable coronary artery disease (CAD) patients with at least one coronary lesion having an abnormal fractional flow reserve measurement resulted in superior clinical outcomes, better quality of life, and virtually identical cost, compared with optimal medical management alone over 3 years of follow-up in the FAME 2 trial.
“These results reinforce the point that the greater the burden of ischemia, the greater the benefit of revascularization with PCI [percutaneous coronary intervention],” William F. Fearon, MD , said while presenting the FAME 2 findings at the Transcatheter Cardiovascular Therapeutics annual meeting.
FAME 2 was a randomized, multicenter trial designed to help bring clarity regarding the optimal treatment strategy for patients with stable angina and CAD. This is an issue surrounded by considerable controversy. The fog descended a decade ago, when the COURAGE trial created a stir with its conclusion that optimal medical therapy (OMT) alone was as good as PCI plus OMT in terms of clinical outcome and quality of life – and was considerably less expensive as well. And the British ORBITA trial, presented earlier in the same session at TCT 2017 as Dr. Fearon’s report on FAME 2, caused an uproar with its finding that PCI plus OMT was no more effective than sham PCI plus OMT in the setting of stable CAD.
However, FAME 2 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) differed from those studies in a crucial aspect: randomization in FAME 2 was restricted to patients with physiologically significant cardiac ischemia as evidenced by a fractional flow reserve (FFR) measurement of 0.80 or less.
In contrast, COURAGE and ORBITA randomized patients without FFR guidance. As a result, in those trials PCI was performed in a substantial proportion of patients who actually should not have undergone the intervention because they didn’t have physiologic evidence of clinically important ischemia. The non–physiologically based approach to PCI utilized in COURAGE and ORBITA – disappointingly commonplace in daily clinical practice – diluted any true benefit of the procedure when applied appropriately, explained Dr. Fearon, professor of medicine and director of interventional cardiology at Stanford (Calif.) University.
FAME 2 randomized 888 patients with stable single- or multivessel CAD and an FFR of 0.80 or less to PCI plus OMT or an initial strategy of OMT alone at 28 European and North American sites. The primary outcome was the rate of major adverse cardiac events – death, MI, and urgent revascularization – at 3 years. The rate was 10.1% in the PCI group, compared with 22% in the medically managed cohort, Dr. Fearon reported at the meeting sponsored by the Cardiovascular Research Foundation.
Death or MI occurred in 8.3% of the PCI group versus 10.4% in the OMT group, a trend that didn’t reach significance. Of note, however, fully 44% of patients in the OMT group crossed over to PCI during the 3-year study. In the prespecified intent-to-treat analysis they were counted in the OMT group, whereas an as-treated analysis might well have shown statistically significant reductions in death and MI in the PCI group.
The proportion of patients with class II-IV angina was significantly lower in the PCI plus medical therapy group at every time point, including 5.9% versus 15.2% for OMT alone at 1 year, 5.9% versus 12% at 2 years, and 5.2% versus 9.7% at 3 years. This was the case even though the OMT group received significantly more antianginal therapy in an effort to control symptoms.
FAME 2 featured a first-of-its-kind comprehensive cost-effectiveness analysis of OMT vs. PCI over a 3-year period. It showed that, while mean initial costs were as expected higher in the PCI group ($9,944 versus $4,440), by 3 years the cumulative costs were near identical at $16,792 in the PCI group and $16,737 in the initial OMT group. The incremental cost-effectiveness ratio for PCI, compared with OMT at 3 years was attractive at $1,600 per quality-adjusted life-year gained.
The question on TCT attendees’ minds following presentation of the bombshell ORBITA findings was, what would have happened had FAME 2 featured a sham PCI arm? Could the advantageous outcomes for the initial PCI strategy seen in FAME 2 possibly have been due to a placebo effect?
Extremely unlikely, according to Dr. Fearon. For one thing, when he and his coinvestigators broke down the FFR values in the OMT group into quintiles, they saw a clear dose-response effect: The clinical event rate rose further with worsening quintile of FFR. Also, the study endpoints were death, MI, and urgent revascularization – triggered by ACS in half of cases – which are less susceptible to a placebo effect than, say, treadmill exercise time, the primary endpoint in ORBITA.
Moreover, as noted by Gary S. Mintz, MD , who moderated a press conference highlighting the ORBITA and FAME 2 results, placebo effects don’t last for years.
“Most people would say the placebo effect wanes over time. That’s why these 3-year data, analyzed by intent-to-treat, which allow for crossovers to still be analyzed in the medical therapy arm, are pretty compelling to me,” commented Dr. Mintz, chief medical officer for the Cardiovascular Research Foundation in New York.
FAME 2 was supported by St. Jude Medical. Dr. Fearon reported receiving institutional research support from Medtronic, Abbott Vascular, ACIST Medical, CathWorks, and Edwards LifeSciences.