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) performed poorly in the trial, compared with surgery, seemingly 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 Therapeutics (TCT) 2021, held virtually and live in Orlando, Florida.
“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 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,” Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, observed for theheart.org | Medscape Cardiology. Such a positive subgroup finding “would be, at best, deemed hypothesis-generating and not hypothesis-validating.”
Overall, “the quality and quantity of evidence is insufficient to support FFR-guided PCI for complex CAD [coronary artery disease]. I would also argue that the evidence for FFR-guided PCI for simple CAD is also not high quality,” Kaul said. “Clearly, a case of enthusiasm exceeding the evidence!”
The FAME 3 trial’s 1500 patients at 48 centers were randomly assigned 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, and 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.
The rate of death, MI, or stroke was 7.3% with FFR-PCI and 5.2% for CABG, for an HR of 1.4 (95% CI 0.9 – 2.1).
FFR-guided PCI fared significantly better than CABG for some safety endpoints, such as 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).
The trial’s definition of procedural MI, a component of the primary endpoint, might potentially be seen as controversial, Fearon said in an interview. Procedural MIs in both the PCI and CABG groups had to meet the standards of CABG-related type-5 MI, in accordance with the 3rd and 4th Universal Definitions. To indicate MI, biomarker elevations 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 one and a half percent in both arms.”
theheart.org | Medscape Cardiology will update this story with further commentary after the FAME 3 presentation at TCT 2021.
FAME 3 was funded by Medtronic and Abbott Vascular. Disclosures for the individual authors can be found at NEJM.com.
N Engl J Med. Published online November 4, 2021. Abstract
Transcatheter 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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