MUNICH, Germany—In patients with stable coronary artery disease (CAD) and at least 1 proven ischemic stenosis, percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) plus optimal medical therapy markedly reduces the need for urgent revascularization compared with optimal medical therapy alone. The contribution to the vexed issue of when elective PCI is justified was presented August 28, 2012, at the European Society of Cardiology Congress and simultaneously published in the New England Journal of Medicine.

Bernard De Bruyne, MD, of OLV Clinic (Aalst, Belgium), reported full results of the FAME 2 (FFR-Guided Percutaneous Coronary Intervention Plus Optimal Medical Therapy vs. Medical Therapy Alone in Patients with Stable Coronary Artery Disease) trial. Preliminary findings from the study’s randomized cohort were released in May 2012 at EuroPCR in Paris, France.

For FAME 2, investigators at 28 sites in Europe and North America enrolled 1,220 patients with stable CAD who had angiographically assessed stenosis in at least 1 coronary vessel and evaluated those stenoses with FFR. The 888 patients who were determined to have at least 1 flow-limiting lesion (FFR ≤ 0.8) were randomized to optimal medical therapy with (n = 447) or without (n = 441) FFR-guided PCI.

Nonischemic Cohort Serves as Comparator

The remaining 332 patients were enrolled in a registry and treated with optimal medical therapy.  

Importantly, the baseline characteristics of randomized and registry patients were similar, except for more peripheral arterial disease and multivessel disease in the randomized cohort.

Enrollment was halted prematurely after an interim analysis determined that, compared with those on optimal medical therapy alone, FFR-guided patients had substantially fewer events related to the primary composite endpoint of all-cause death, MI, or urgent revascularization (4.3% vs. 12.7%; HR 0.32 95% CI 0.19-0.53; P < 0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group (0.7% vs. 9.5%; HR 0.07; 95% CI 0.02-0.22; P < 0.001), with no differences in rates of death (0.2% vs. 0.7%; P = 0.31) or MI (3.4% vs. 3.2%; P = 0.89). Notably, in the PCI group, fewer urgent revascularizations were triggered by an MI or ECG evidence of ischemia.

By contrast, only 3% of patients in the registry suffered a primary endpoint event, with low rates of mortality, MI, and any revascularization. In 1-year Kaplan-Meier estimates, there was little disparity in the risk of the primary endpoint between the PCI group and the registry cohort but a clear divergence between patients in the optimal medical therapy arm (with proven ischemic lesions) and the registry cohort (with nonischemic CAD). The difference in the primary endpoint was driven by need for urgent revascularization (table 1).  

Table 1. Comparison of 1-Year Outcomes: Randomized Arms and Registry Cohort

Abbreviation: OMT, optimal medical therapy.

A landmark analysis found an interaction between time and treatment, suggesting that the benefit of PCI may become more apparent with time. Within the first 7 days after randomization, there was no difference between the treatment groups for urgent revascularization and a higher rate of the composite of death and MI, whereas after that point PCI showed a clear ongoing advantage for urgent revascularization and a trend toward reduced death or MI (table 2).

Table 2. Landmark Analysis of Key Outcomes

Abbreviation: OMT, optimal medical therapy.

FAME 2 “answers questions raised by the COURAGE trial, which found no difference in outcomes between PCI plus optimal medical therapy and optimal medical therapy alone,” Dr. DeBruyne said in a press statement. “The data show that in patients with stable CAD and functionally significant stenosis, FFR-guided PCI plus optimal medical therapy decreases the need for urgent revascularization compared with optimal medical therapy alone. In contrast, in patients without ischemia-producing lesions, the outcome is favorable with optimal medical therapy alone.”

More Questions than Answers?

But in an editorial accompanying the published paper, William E. Boden, MD, of Albany Medical College (Albany, NY), highlighted issues that may weaken the trial’s conclusion. For example, he observed, in this unblinded trial investigators may have had a lower threshold for recommending PCI for patients in the medical therapy group who had recurrent angina.

“Clearly, FFR holds potential promise for a more targeted approach to PCI, Dr. Boden wrote. “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 [MI], and the lack of a significant, sustained treatment effect on the reduction of angina beyond 6 months leave more questions than answers.”

Dr. Boden concluded that the “only enduring finding of the FAME 2 trial appears to be that of a reduced short-term rate of unplanned revascularization with FFR-guided PCI, with little evidence of long-term, incremental benefit on prognostically important clinical outcomes.”

PCI Now Validated for Ischemic Lesions

Dr. De Bruyne had a different perspective. Asked in a press conference whether these data suggest that PCI in stable patients will in fact have an influence on relevant clinical endpoints, he answered, “Yes, provided patients are properly selected. If patients are selected on the basis of FFR , they will do better with contemporary PCI with second-generation DES. Urgent revascularization with hospitalization can no longer be considered a minor endpoint. We are in a different era.”

The Society for Cardiovascular Angiography and Interventions (SCAI), had a similar response. “The findings from FAME [2] are now the best data currently available to inform treatment decisions for patients with stable coronary artery disease,” SCAI said in a press statement. “These data clearly demonstrate that the benefit of PCI plus medical therapy in stable patients with ischemia-producing lesions extends beyond symptom relief and quality of life. Unlike COURAGE, the study additionally reflects the current use of evidence-based tests (such as FFR) and modern treatment options (including the use of second-generation drug-eluting stents) and their combined roles in improving patient outcomes.”

In an editorial posted on the SCAI Web site in advance of print in Catheterization and Cardiovascular Interventions, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), and J. Jeffrey Marshall, MD, of the Northeast Georgia Heart Center (Gainesville, GA), agreed. They note that "the findings from FAME 2 represent a further critical piece of evidence in favor of the ischemia hypothesis in [stable ischemic heart disease]; namely, that the safe and effective revascularization of ischemia-producing lesions can lead to improved patient outcomes and quality of life metrics above and beyond symptom relief."

Commenting on Dr. De Bruyne’s presentation, Frans Van de Werf, MD, PhD, of Katholieke Universiteit Leuven (Leuven, Belgium), said that the “final answer” to the question of which stable CAD patients warrant PCI may come from the ongoing ISCHEMIA trial. The key difference from previous trials, he noted, is that investigators will be blinded to CT angiographic assessment of participants before randomization. Also, follow-up is planned for at least 4 years.

1. De Bruyne B. Fractional flow reserve—Guided PCI versus medical therapy in stable coronary disease: FAME 2. Presented at: European Society of Cardiology Congress; August 28, 2012; Munich, Germany.

2. De Bruyne B, Pijls NHJ, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;Epub ahead of print.

3. Boden WE. Which is more enduring—FAME or COURAGE? New Engl J Med. 2012;Epub ahead of print.

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