FAME 2 at 10 Years: Less Urgent Revascularization With FFR-Guided PCI

Long-term follow-up of the FAME 2 trial shows that treating physiologically important coronary lesions with PCI was associated with a significant reduction in the study’s primary endpoint of all-cause mortality, MI, or urgent revascularization—a benefit that was driven by the decrease in revascularization—when compared with medical therapy alone.

There was a suggestion, too, that fractional flow reserve (FFR)-guided PCI was associated with a lower risk of MI, but the benefit was not statistically significant, investigators report in a paper published online recently in Nature Medicine.

“Making decisions based on FFR gives important and useful long-term information” on the benefits of coronary revascularization in this stable population with coronary artery disease, lead author Carlos Collet, MD, PhD (Cardiovascular Center Aalst, Belgium, and Cardiovascular Research Foundation, New York, NY), told TCTMD.

The FAME 2 trial, when published 14 years ago in the New England Journal of Medicine, showed that PCI of functionally significant stenoses determined by FFR decreased the primary endpoint in 1,220 stable patients with coronary artery disease, a benefit resulting from less need for urgent revascularization. Five-year follow-up confirmed the reduction in urgent revascularization but also hinted at a possible reduced risk of MI with FFR-guided PCI over medical therapy.

“We were interested in the long-term evolution of untreated lesions over 10 years, to see if there was a late catch-up phenomenon,” said Collet, noting that FAME 2 was instrumental in shaping the guidelines around the use of FFR. “The 5-year results suggested there was a strong trend toward reduced MI that didn’t reach significance.”

Kevin Bainey, MD (University of Alberta/Mazankowski Alberta Heart Institute, Edmonton, Canada), an interventional cardiologist, said the 10-year follow-up is impressive given that very few studies can follow patients for that long. The results, he said, aren’t surprising since the 1- and 5-year outcomes showed a positive impact of PCI on the primary endpoint that was powered by the reduction in urgent revascularization.

“I think what’s important for people to understand is that there’s no difference in death or MI out to 10 years,” he told TCTMD. “Those are our hard endpoints—urgent revascularization is considered more of a soft endpoint—so I see this the other way. With no difference in death or MI with FFR-guided PCI versus medical therapy, that to me means that medical therapy is doing pretty good after 10 years.”

Long-term Follow-up

FAME 2 included 447 patients randomized to FFR-guided PCI plus medical therapy and 447 to medical therapy alone. At 10 years, follow-up information was available for 329 patients in the revascularization arm and 325 patients in the medical-therapy group.

The biggest limitation of the extended follow-up was that researchers had to reconsent patients to participate in the study, said Collet. Sixteen sites participated while 12 did not, with reconsent being the most challenging in the United Kingdom. Data on all-cause mortality, MI, and urgent revascularization were collected through clinic visits or telephone follow-up. Vital status was additionally ascertained using national death registers, which ensured complete data on all-cause deaths of patients from participating sites.

Outcomes were assessed using the win ratio because the traditional time-to-event analysis would be affected by the missing data, according to the researchers. The win ratio compares a hierarchy of clinical events, with every patient on treatment compared with every patient randomized to the control (in this case, PCI and medical therapy). For each pairing, the hierarchy of outcomes is evaluated in descending order until either shows a better outcome, or win, over the other. A loss occurs if the control fares better.

There’s no need to rush into a revascularization strategy right away. Kevin Bainey

For the primary outcome of death, MI, or urgent revascularization, there were 47.5% ties, meaning patients fared equally well with PCI or medical therapy. PCI won in 29.2% and lost in 23.3% of head-to-head comparisons. This translated into a win ratio of 1.25 in favor of PCI (95% CI 1.01-1.56), with a number needed to treat of 17.

“Roughly half of patients treated with PCI or medical therapy will do equally okay,” said Collet. “I think this is informative for patients.”

Among the patients with ties on all-cause mortality, comparisons between PCI and optimal medical therapy resulted in a conditional win ratio of 1.50 (95% CI 0.98-2.31). For the remaining patients tied on MIs, 47.5% of comparisons resulted in ties for urgent revascularization and 6.8% and 1.5% in wins and losses, respectively, for PCI. That translated into a conditional win ratio of 4.57 (95% CI 2.53-8.24) favoring FFR-guided revascularization.

Shadow of ISCHEMIA

To TCTMD, Collet said the results should be interpreted in light of ISCHEMIA, a landmark trial comparing an invasive strategy plus medical therapy to medications alone. In that study, the invasive strategy provided no benefit beyond medical therapy alone in preventing a range of major cardiovascular events in patients with stable coronary artery disease. While there was no difference in the risk of MI overall, subsequent analyses showed there was a higher number of procedural MIs with the invasive strategy. Type 1 MIs, or spontaneous infarctions, were less frequent with invasive revascularization.

“However, both ISCHEMIA and our trial indicate that an invasive treatment strategy is unlikely to offer a survival benefit compared to an initially conservative strategy with medical therapy alone,” say the researchers.

To TCTMD, Bainey said that he would like to see long-term quality-of-life data but understands the limitations of the analysis. On the backdrop of both ISCHEMIA and the 10-year follow-up from FAME 2, Bainey said it can be worthwhile to send stable CAD patients to have CT angiography to define the anatomy.

“Then once you define the anatomy, I think you can have that conversation with the patient about guideline-directed medical therapy versus PCI, whether angiography- or FFR-guided,” he said. “This happens to us almost on a daily basis in clinic where you can give medical therapy a good try. There’s no need to rush into a revascularization strategy right away.

“I actually saw a patient just yesterday where we decided to continue with medical therapy once I knew his anatomy,” Bainey continued, “because there’s really no difference in death or MI at 4 years in ISCHEMIA and now we’re seeing no difference in death or MI out to 10 years in FAME 2.”

Note: Collet is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.