FFR-Guided PCI Falls Short vs CABG in Multivessel CAD: FAME 3

November 04, 2021

Updated November 4, 2021, 8:40 PM // Editor's Note: This story has been updated with additional commentary from various experts.

Coronary stenting guided by fractional flow reserve (FFR) readings, considered to reflect the targeted lesion's functional impact, was no match for coronary bypass surgery (CABG) in patients with multivessel disease (MVD) in a major international randomized trial.

Indeed, FFR-guided percutaneous coronary intervention (PCI) using one of the latest drug-eluting stents (DES) seemed to perform poorly in the trial, compared with surgery, apparently upping the risk for clinical events by 50% over 1 year.

Designed statistically for noninferiority, the third Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME 3) trial, with 1500 randomized patients, showed that FFR-guided PCI was "not noninferior" to CABG. Of those randomized to PCI, 10.6% met the 1-year primary endpoint of major adverse cardiac or cerebrovascular events (MACCE), compared with only 6.9% of patients assigned to CABG.

The trial enrolled only patients with three-vessel coronary disease with no left-main coronary artery involvement, who were declared by their institution's multidisciplinary heart team to be appropriate for either form of revascularization.

One of the roles of FFR for PCI guidance is to identify significant lesions "that are under-recognized by the angiogram," which is less likely to happen in patients with very complex coronary anatomy, study chair William F. Fearon, MD, Stanford University School of Medicine, California, told theheart.org | Medscape Cardiology.

"That's what we saw in a subgroup analysis based on SYNTAX score," an index of lesion complexity. "In patients with very high SYNTAX scores, CABG outperformed FFR-guided PCI. But if you look at patients with low SYNTAX scores, actually, FFR-guided PCI outperformed CABG for 1-year MACCE."

Fearon is lead author on the study's November 4 publication in the New England Journal of Medicine, its release timed to coincide with his presentation of the trial at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held virtually and live in Orlando, Florida.

He noted that FAME-3 "wasn't designed or powered to test for superiority," so its results do not imply CABG is superior to FFR-PCI in patients with MVD, and remains "inconclusive" on that question.

"I think what this study does is provide both the physician and patients more contemporary data and information on options and expected outcomes in multivessel disease. So if you are a patient who has less complex disease, I think you can feel comfortable that you will get an equivalent result with FFR-guided PCI." But, at least based on FAME-3, Fearon said, CABG provides better outcomes in patients with more complex disease.

"I think there are still patients that look at trade-offs. Some patients will accept a higher event rate in order to avoid a long recovery, and vice versa." So the trial may allow patients and physicians to make more informed decisions, he said.

A main message of FAME-3 "is that we're getting very good results with three-vessel PCI, but better results with surgery," Ran Kornowski, MD, Rabin Medical Center and Tel Aviv University, Israel, said as a discussant following Fearon's presentation of the trial. The subanalysis by SYNTAX score, he agreed, probably could be used as part of shared decision-making with patients.

Not All That Surprising

"It's a well-designed study, with a lot of patients," said surgeon Frank W. Sellke, MD, Rhode Island Hospital and The Miriam Hospital, The Warren Alpert Medical School of Brown University, Providence.

"I don't think it's all that surprising," he told theheart.org | Medscape Cardiology. "It's very consistent with what other studies have shown, that for three-vessel disease, surgery tends to have the edge," even when pitted against FFR-guided PCI.

Indeed, pressure-wire FFR-PCI has a spotty history, even as an alternative to standard angiography-based PCI. For example, it has performed well in registry and other cohort studies but showed no advantage in the all-comers RIPCORD-2 trial or in the setting of complete revascularization PCI for acute myocardial infarction (MI) in FLOWER-MI. And it emitted an increased-mortality signal in the prematurely halted FUTURE trial.

In FAME-3, "the 1-year follow-up was the best chance for FFR-PCI to be noninferior to CABG. The CABG advantage is only going to get better with time if prior experience and pathobiology is true," Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, California, observed for theheart.org | Medscape Cardiology.

Overall, "the quality and quantity of evidence is insufficient to support FFR-guided PCI" in patients with complex coronary artery disease (CAD), he said. "I would also argue that the evidence for FFR-guided PCI for simple CAD is also not high quality."

Kaul also blasted the claim that FFR-PCI was seen to perform better against CABG in patients with low SYNTAX scores. "In general, one cannot use a positive subgroup in a null or negative trial, as is the case with FAME-3, to 'rescue' the treatment intervention." Such a positive subgroup finding, he said, "would at best be deemed hypothesis-generating and not hypothesis-validating."

Fearon agreed that the subgroup analysis by SYNTAX score, though prespecified, was only hypothesis-generating. "But I think that other studies have shown the same thing —that in less complex disease, the two strategies appear to perform in a similar fashion."

Table. 1-year MACCE rates by SYNTAX score, FFR-PCI vs CABG groups

Endpoint FFR-PCI, n=757 (%) CABG, n=743 (%)
Low SYNTAX score (<23) 5.5 8.6
Intermediate SYNTAX score (23-32) 13.7 6.1
High SYNTAX score (≥32) 12.1 6.6


The FAME-3 trial's 1500 patients were randomly assigned at 48 centers to undergo standard CABG or FFR-guided PCI with Resolute Integrity (Medtronic) zotarolimus-eluting DES. Lesions with a pressure-wire FFR of 0.80 or less were stented and those with higher FFR readings were deferred.

The 1-year hazard ratio (HR) for the primary endpoint—a composite of death from any cause, myocardial infarction (MI), stroke, or repeat revascularization—was 1.5 (95% CI, 1.1 - 2.2) with a noninferiority P value of .35 for the comparison of FFR-PCI vs CABG.

FFR-guided PCI fared significantly better than CABG for some safety endpoints, including major bleeding (1.6% vs 3.8%, P < .01), arrhythmia including atrial fibrillation (2.4% vs 14.1%, P < .001), acute kidney injury (0.1% vs 0.9%, P < .04), and 30-day rehospitalization (5.5% vs 10.2%, P < .001).

Did the Primary Endpoint Favor CABG?

At a media briefing prior to Fearon's TCT 2021 presentation, Roxana Mehran, MD, Mount Sinai School of Medicine, New York City, proposed that the inclusion of repeat revascularization in the trial's composite primary endpoint tilted the outcome in favor of CABG. "To me, the FAME-3 results are predictable because repeat revascularization is in the equation."

It's well recognized that the endpoint is less likely after CABG than PCI. The latter treats focal lesions that are a limited part of a coronary artery in which CAD is still likely progressing. CABG, on the other hand, can bypass longer segments of diseased artery.   

Indeed, as Fearon reported, the rates of death, MI, or stroke excluding repeat revascularization were 7.3% with FFR-PCI and 5.2% for CABG, for an HR of 1.4 (95% CI, 0.9 - 2.1).

Mehran also proposed that intravascular-ultrasound (IVUS) guidance, had it been part of the trial, could potentially have boosted the performance of FFR-PCI.

Repeat revascularization, Kaul agreed, "should not have been included" in the trial's primary endpoint. It had been added "to amplify events and to minimize sample size. Not including revascularization would render the sample size prohibitive. There is always give and take in designing clinical trials."

And he agreed that "IVUS-based PCI optimization would have further improved PCI outcomes." However, "IVUS plus FFR adds to the procedural burden and limited resources available."

Fearon said when interviewed that the trial's definition of procedural MI, a component of the primary endpoint, might potentially be seen as controversial. Procedural MIs in both the PCI and CABG groups were required to meet the standards of CABG-related type-5 MI according to the 3rd and 4th Universal Definitions. They also had to be accompanied by "a significant finding like new Q waves or a new wall-motion abnormality on echocardiography," he said.

"That's fairly strict. Because of that, we had a low rate of periprocedural MI and it was similar between the two groups, around 1.5% percent in both arms."

FAME-3 was funded by Medtronic and Abbott Vascular. Disclosures for Fearon and the other authors can be found at NEJM.com. Kaul has disclosed no relevant financial relationships.  Kornowsky receives royalties from or holds intellectual property rights with CathWorks.

Mehran discloses receiving fees or honoraria from Medscape/WebMD, Janssen, and Cine Med Research; that she, her spouse, or her institution have received grants or have other relationships with Abbott Vascular, AstraZenca, Bayer AG, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/Elil Lilly and Company, Medtronic, Novartis Pharmaceuticals, OrbusNeich, CERC, Chiesi, Concept Medical, Applied Therapeutics, Beth Israel Deaconess, Zoll, Arena, Biosensors, Boston Scientific, CellAegis, Insel Gruppe AG, Philips, and Transverse Medical; and that she, her spouse, or her institution hold equity in Elixir Medical, Applied Therapeutics, and ControlRad.

N Engl J Med. Published online November 4, 2021. Abstract

Transcatheter Cardiovascular Therapeutics (TCT) 2021. Late-Breaking Clinical Science Session I: FAME 3: A Randomized Trial of FFR-Guided Stenting Compared With CABG. Presented November 4, 2021.

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