FFR-Guided PCI Reduces Urgent Reinterventions, But Not Change Mortality, MI: FAME II

Reed Miller

August 28, 2012

August 28, 2012 (Munich, Germany) — In the FAME II trial, stable patients who got a stent to treat a functionally significant coronary lesion were less likely to need an urgent reintervention than those treated with medical therapy alone. However, all the other outcomes, including mortality, were the same with either therapy, so the significance of the trial's findings remains controversial [1].

As reported by heartwire , the St Jude–sponsored FAME II trial enrolled 1220 stable patients with suspected coronary disease and examined their coronaries with fractional flow reserve (FFR) to determine whether they had any significant flow-limiting lesions, defined as an FFR <0.80. Patients with at least one such lesion (n=888) were randomized to either PCI or optimal medical therapy. Patients with no flow-limiting lesions shown by FFR were put into a registry and treated with medical therapy (n=332). The primary end point of the study was a composite of death, MI, or urgent revascularization.

The trial was stopped last winter--over the objections of some outside observers--after an interim analysis clearly showed that patients randomized to PCI were much less likely to need an urgent revascularization than patients randomized to optimal medical therapy.

Preliminary results based on 822 patients were presented at the EuroPCR conference in May. Those data showed that the rate of urgent revascularization among patients with no hemodynamically significant disease in the registry was about the same as that for patients with hemodynamically relevant disease randomized to PCI--around 0.6%. But the patients with significant disease shown by FFR who were randomized to medical therapy alone had an urgent revascularization rate of 6% (p<0.0001). The rates for all revascularization were 12.1% vs 1.7% for the medical-therapy and PCI groups, respectively (p<0.0001).

The need for urgent revascularization was the only significant difference in outcomes between the patients randomized to optimal medical therapy only and those randomized to PCI.

But the full results, including the figures for death and MI, were not released until today at the European Society of Cardiology (ESC) 2012 Congress and published online in the New England Journal of Medicine. These complete results reveal that, among the patients with flow-limiting coronary disease, the need for urgent revascularization was the only significant outcome difference between the patients randomized to optimal medical therapy only and those randomized to PCI (9.5% vs 0.7%, HR 0.7, p<0.001). Death and MI rates were similarly low for both groups. So overall, 12.7% of the medical-therapy-only group had had a primary end-point event compared with 4.3% of the PCI group.

How Much Does "Urgent Revascularization" Matter

Dr Bernard De Bruyne

Here at the ESC congress, lead investigator Dr Bernard De Bruyne (OLV Clinic, Aalst, Belgium) reiterated his opinion that the FAME II results complement the lessons of the COURAGE trial. COURAGE showed no benefit of PCI over medical therapy in stable coronary disease patients, but FAME II shows that PCI does yield a benefit over medical therapy among patients with lesions shown to be flow-limiting. In contrast, only about a third of the lesions in COURAGE were truly ischemic, De Bruyne said. Therefore, these results suggest FFR will have an increasingly important role in identifying patients who will benefit from PCI, he said.

Although FAME II did not show any mortality or MI benefit for PCI among stable coronary disease patients, the difference in the need for urgent revascularizations is an important benefit, de Bruyne insists. All of the urgent revascularizations were performed in patients fulfilling the criteria for acute coronary syndrome, either with acute MI, ECG evidence of ischemia, or clear unstable angina. He also pointed out that a landmark analysis showed that PCI patients were more likely to die or have an MI than the medical-therapy only patients within the first week after randomization, but this trend reversed after eight days, "suggesting that over time, we might witness the emergence of a significant difference."

Commenting on the study, interventionalist Dr Ajay Kirtane (Columbia University, New York) told heartwire that doctors should not underestimate importance of an urgent revascularization and the unplanned hospitalizations that result, and therefore, the FAME II results turn COURAGE "on its head" by showing that PCI yields more than just quality-of-life improvements among stable coronary disease patients. This could lead to a "philosophical change" in how interventionalists approach these patients. He also pointed out that FAME II showed no safety cost to choosing PCI over medical therapy alone in patients with flow-limiting lesions.

However, Dr Spencer King (St Joseph's Hospital, Atlanta, GA) told heartwire that "[the FAME II investigators] are making a federal case out of these [urgent revascularizations], that this is 'real acute coronary syndrome,' which is somewhat compelling, but the thing that's weird about that is that, at a year, the mortality is extremely low--less than 2% in the medical group and less than 1% in the PCI group--"which is a little at odds with the idea that these are really worse-off patients."

But, he highlighted that the patients whose FFR scans showed no significantly obstructive disease in the registry part of FAME II did "quite well." So the trial affirms that FFR can accurately identify people who do not need PCI. Without FFR, many of the patients in the registry probably would have received a stent for nonobstructive lesions based on traditional angiography or intravascular ultrasound alone, he said.

Will ISCHEMIA Provide More Answers?

King is concerned that FAME II's demonstration of better outcomes with PCI could make many physicians reluctant to allow their stable coronary disease patients to be randomized to optimal medical therapy in future trials comparing revascularization and medical therapy alone. Perhaps the most important upcoming study like that is the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), a major National Institutes of Health–sponsored trial planned for 8000 patients with stable ischemic heart disease at over 150 sites in more than 30 countries.

ISCHEMIA will compare angiography and revascularization--surgery or PCI--plus optimal medical therapy with optimal medical therapy only. Importantly, ISCHEMIA will randomize patients after they undergo a stress test but before angiography, and those shown to have moderate to severe ischemia on the stress test will also undergo a blinded coronary computed tomography (CT) angiography to exclude left main disease and to confirm they have obstructive coronary disease. Randomizing patients prior to angiography will address the widespread concern that previous trials were biased against PCI because many doctors may have refused to randomize patients whose angiograms appeared to show tight coronary blockage.

Should FAME II Have Ended Early?

In an editorial accompanying the published paper, one of the ISCHEMIA investigators, Dr William Boden (Albany Medical Center, NY), laments that the study was terminated early, because a longer study with more patients may have shown a difference in mortality or MI [2]. "Clearly FFR 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 writes. "Unfortunately, the early termination of the FAME II 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 six months leave more questions than answers."

Despite the difference in unplanned urgent revascularizations, FAME II leaves interventionalists with "little evidence of long-term incremental benefit on prognostically important clinical outcomes," Boden argues.

FAME II is sponsored by St Jude Medical. De Bruyne disclosed receiving research-contract and consulting payments from St Jude Medical. Disclosures for the coauthors are listed at www.nejm.org . Boden previously disclosed that he has served as an advisor or consultant for Gilead Sciences, Sanofi, and CardioDx. He has served as a speaker or a member of a speaker's bureau for Gilead, Sanofi, and Abbott and has received grants for clinical research from Abbott. Kirtane has no relevant disclosures. King previously disclosed serving as an advisor or consultant for CeloNova BioSciences. He has served as a speaker or a member of a speaker's bureau for the Network for Continuing Medical Education and has participated in data safety monitoring boards for Merck, nContact, and Wyeth.

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