Potential Sex Differences Seen for FFR-Guided PCI vs CABG in FAME 3

Among patients with three-vessel coronary disease, the outcomes of PCI guided by fractional flow reserve versus CABG may differ between men and women, a prespecified subanalysis of FAME 3 indicates.

Through 3 years, women did just as well with either FFR-guided PCI or CABG in the trial, whereas men had significantly lower rates of MACCE (all-cause death, MI, stroke, or repeat revascularization) when they underwent surgery, researchers led by Kuniaki Takahashi, MD, PhD, and Hisao Otsuki, MD, PhD (both from Stanford University, CA), report.

“These sorts of studies are really important, because women and men behave differently with respect to their response to our therapies. It’s critical to look at sex differences in cardiovascular medicine trials,” senior author William Fearon, MD (Stanford University and VA Palo Alto Health Care, Palo Alto, CA).

He acknowledged, however, that FAME 3 had a low proportion of women, who made up just 17.7% of the trial population. “Clearly, we need more data. This is just a start,” said Fearon. “But I do believe it provides important, clinically useful information.”

The findings were published online recently in JACC: Cardiovascular Interventions.

Revascularization Outcomes by Sex

Prior research has shown that cardiovascular outcomes often differ between women and men, but there is limited contemporary evidence in the area of coronary revascularization, Fearon said, noting that much of the existing data come from older studies like the SYNTAX trial. In SYNTAX, women had lower 5-year mortality after CABG versus PCI, a difference that was not seen in men and disappeared by 10 years.

To get a more up-to-date look at potential sex differences in an era with improved revascularization techniques and medical therapy, he and his colleagues performed a prespecified subgroup analysis of FAME 3, which compared fractional flow reserve (FFR)-guided PCI using current-generation DES and CABG in patients with three-vessel CAD who were eligible for either procedure. PCI was not shown to be noninferior to CABG at 1 year, with no significant difference between procedures in terms of death, MI, or stroke at 3 years.

Of the 1,500 patients in the trial, only 265 were women, who were older (mean age 67.4 vs 64.6 years), more frequently had hypertension and a family history of CAD, and were less likely to be smokers compared with men. The complexity of CAD was less in women versus men.

During PCI, female patients received fewer stents and had a shorter total stent length per patient. For CABG, women received fewer arterial grafts and were less likely to receive a left internal mammary artery (LIMA) graft and multiple arterial grafts.

MACCE incidence through 3 years of follow-up was higher in women versus men irrespective of revascularization type (18.1% vs 15.4%; adjusted HR 1.43; 95% CI 1.01-2.03). This was driven by women having a greater risk compared with men in the CABG arm (18.1% vs 11.7%; adjusted HR 2.07; 95% CI 1.19-3.60), with no difference between the sexes in the PCI arm (18.2% vs 19.1%; adjusted HR 1.27; 95% CI 0.79-2.03).

Because women tend to be at higher risk due to their older age and greater comorbidity burden, “it may not be that surprising that the outcomes after bypass surgery in women were worse than they were compared with men,” Fearon said.

The impact of the two revascularization strategies appeared to differ between women and men, although none of the P values for the interactions were statistically significant. Among female patients, MACCE risk was similar when comparing FFR-guided PCI to CABG (adjusted HR 1.15; 95% CI 0.62-2.11). But for men, PCI was associated with a greater 3-year risk of MACCE versus CABG (adjusted HR 1.68; 95% CI 1.25-2.25), attributed mostly to higher risks of MI and repeat revascularization.

The lack of a difference between revascularization strategies in women is “partly because women are at higher risk for CABG because of their age and comorbidities, their smaller arteries, things like that,” Fearon proposed. “But also, they may gain more benefit from FFR guidance because they have more negative lesions that don’t need PCI, so their PCIs were less complex. They had shorter stents and fewer stents. So I think it’s a combination of things that led to the similar outcomes.”

These results may differ from what was seen in the SYNTAX trial “because FAME 3 mandated FFR-guided PCI, which may be even more beneficial in women compared with men,” Fearon speculated.

As for the better outcomes with CABG for men, he said, “the sort of simplistic way of looking at it is men are able to tolerate CABG better and they don’t incur the early risk, but they do gain the long-term benefit.”

A Call for More Research in Women

Commenting for TCTMD, cardiothoracic surgeon Jennifer Lawton, MD (Johns Hopkins Medicine, Baltimore, MD), said she wasn’t surprised by the findings since the subgroup analysis in the paper reporting the 1-year results indicated that men did better with CABG, with no difference between strategies in women.

She added, however, that it’s difficult to draw any firm conclusions due to the low number of women in the trial, which points to a larger issue.

“Women are not enrolled in clinical trials as much and in many of the original trials, the data are based on results in men,” Lawton said. She noted that “we’re all looking forward to the [ROMA:Women] trial,” which is enrolling only female patients, and said it’s important to have more women serve as principal investigators for trials. That has been shown to lead to better representation of female participants.

When it comes to personalizing revascularization choices by sex, “I don’t think we’re quite there yet,” Lawton said. “I have an algorithm that I use when I go and see any patient, and no matter what the patient looks like or the sex of the patient, I try to do all arterial grafting in all patients. I try not to be biased from the beginning walking into the room.”

While awaiting much-needed additional data in women, this analysis of FAME 3 does not support a change in practice, she said. “But it does tell us that in terms of FFR-guided decisions, at least in the short term, which is 1- and now 3-year data, CABG is better for men for three-vessel disease.”

In an accompanying editorial, Enrico Fabris, MD, PhD (University of Trieste, Italy), and Roxana Mehran, MD (Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY), note that “there are still many unknowns regarding potential differences in outcomes between men and women that may translate in personalized approaches for coronary revascularization. Therefore, it is crucial to reassess strategies for treating women and address the significant gap in understanding whether sex should influence the choice between PCI and CABG. These knowledge gaps must be addressed.”