Five-Year FAME 2 Data in Stable CAD Reassuring and Surprising

Patrice Wendling

May 25, 2018

PARIS — The final 5-year FAME 2 analysis shows continued benefit for percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) over medical therapy in stable coronary artery disease (CAD) but also a new signal for fewer myocardial infarctions (MIs) among those treated with stents.

The primary composite endpoint of death, MI, or urgent revascularization occurred in 13.9% of patients randomly assigned to PCI plus medical therapy and 27% of those assigned to optimal medical therapy alone (hazard ratio [HR], 0.46; P < .001).

To put the event rate for PCI in perspective, the primary outcome occurred in 15.7% of patients screened for the trial who had no signs of myocardial ischemia on FFR and were managed in a separate registry with medical therapy alone (PCI vs registry; P = .57).

The primary outcome was driven by a more than threefold higher need for urgent revascularization among randomly assigned patients treated with medical therapy vs PCI (21.1% vs 6.3%; P < .001). Rates of death were similar (5.2% vs 5.1%; P = .95).

The 5-year results were published online May 22 in the New England Journal of Medicine to coincide with their presentation here at the Congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2018.

The 3-year analysis of FAME 2 showed similar advantages for PCI; however, "What is new this time is a very strong signal towards lower myocardial infarctions in the PCI group," study author Panagiotis Xaplanteris, MD, PhD, Cardiovascular Center Aalst, Belgium, said in a hotline session at the meeting.

MI rates were 8.1% with PCI and 12.0% with medical therapy (HR, 0.66; P = .049).

Landmark analyses showed that the benefit for PCI was driven by significant reductions in spontaneous MI (6.5% vs 10.2%; P = .04) but not in periprocedural MI (1.6% vs 2.0%; P = .60).

Further lesion-level analyses are needed to determine whether the spontaneous MIs were within the zone of the artery of interest or occurred elsewhere, he said.

Invited discussant Philip Urban, MD, Center for European Research in Cardiovascular Medicine, Massy, France, said, "It shows that we need patients 5 years to have a really good hard end point, something we don't really have a lot of in interventional cardiology, so thank you for waiting."

"Secondly, if it ain't broke, don't fix it, but if it is, don't procrastinate, I guess, would be a take-home," he said.

The value of PCI for stable CAD has come under fire in the wake of the COURAGE trial and the more recent, sham-controlled ORBITA trial, suggesting PCI offers no additional benefits over optimal medical therapy in terms of angina relief or outcomes.

In FAME 2, all 1220 patients had angiographically significant stenosis and were scheduled for one-, two-, or three-vessel PCI. Based on FFR assessment in all target lesions, 888 patients who had at least one lesion with an FFR of 0.80 or less were randomly assigned to PCI or medical therapy and 332 who had FFR greater than 0.80 across all lesions were assigned to a registry for clinical follow-up with medical therapy.

Longer follow-up revealed PCI lost ground to medical therapy in terms of angina relief, but Xaplanteris told the audience to bear in mind that more than half of patients randomly assigned to medical therapy (51%) had crossed over and received a stent by the end of the 5 years.

At 3 years, the number of patients who had Canadian Cardiovascular Society angina grade II to IV was significantly lower in the PCI group than the medical therapy group (22/420 vs 40/413 patients; P = .014), but the difference was no longer significant at 5 years (26/352 vs 35/343; P = .19).

Urban questioned whether there may be something of a "reverse optimal effect" at play among registry patients that could explain the improved angina, whereby once the physician knows the FFR exceeds 0.80 and the patient knows nothing further needs to be done, "their symptoms improve dramatically" and changes are made to their drug regimen.

"Indeed this was the case that anginal symptoms were decreased over time in the registry patients once these patients were assured they had no significant lesions on the basis of FFR," Xaplanteris replied. All patients received standardized therapy but adherence at 5 years was about 80%, "which honestly is not something we see in everyday clinical practice," he said.

Fellow discussant Michael Haude, MD, Städtische Kliniken Neuss, Germany, said the "registry patients are likely reflecting the natural course of the disease" and questioned their need for revascularization and rates of spontaneous MI.

"The event rates were very similar to the PCI patients, namely total revascs were close to 16% for the registry patients, while the myocardial infarction rate as close to 8%, and there was no statistical difference when comparing the registry group to the PCI plus medical therapy group," Xaplanteris said.

Commenting on the results for theheart.org | Medscape Cardiology, Patrick Serruys, MD, PhD, Imperial College London, United Kingdom, said the availability of newer, albeit more expensive, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors will likely influence the treatment strategy for stable angina.

"I'm sure that people will be treated earlier and earlier and I'm sure that some individual will say, 'I will be patient and go with the pharma for a long period time,'" he said.

Also going forward, Serruys said lesion assessment using FFR with a pressure sensor guidewire will be replaced by quantitative flow ratio  systems that allow operators to obtain an FFR just by looking at the angiography with computational free dynamics.

"We will not have to put a guidewire in the lesion, so that's going to become much more popular," he said. "Even if we lose a little bit more precision, the general population of cardiologists will use this instrument. That's something which is quite positive."

FAME 2 is supported by St Jude Medical, now Abbott. Xaplanteris reported no potential conflicts of interest. Serruys reported serving as a consultant to and/or receiving fees or other honoraria from Abbott, Biosensors, Medtronic, and others.

Congress of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) 2018.

N Engl J Med. Published May 22, 2018. Full text

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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