A fractional flow reserve (FFR)-guided strategy for percutaneous coronary intervention (PCI) is equally beneficial in women compared with men, according to a substudy of the FAME trial. The post-hoc analysis, published in the October 2012 issue of JACC: Interventions, also found that angiographic lesions of similar severity are less likely to be ischemia-producing in women, suggesting FFR may be even more relevant in this population.

In the main trial, 1,005 patients with multivessel disease were randomized to angiographic assessment with or without FFR measurement to determine who would receive PCI with DES. In the FFR arm, only lesions with an FFR value of 0.80 or less were stented. At 2 years, FFR-guided patients had lower rates of death or MI than their angiography-guided counterparts (8.4% vs. 12.9%; P = 0.02).

For the subanalysis, investigators led by William F. Fearon, MD, of Stanford University Medical Center (Stanford, CA), compared 2-year outcomes for the 744 men (74%) and 261 women (26%) in the trial cohort.

No Difference in Outcomes

At 2 years, women and men had similar rates of MACE (death, MI or repeat revascularization) as well as the component endpoints, and the composite of death or MI regardless of the PCI-guidance strategy (table 1).

Table 1. Two-Year Outcomes by Sex

Relative to the angiography-guided approach, the FFR strategy reduced the risk of death by 37% in men and 18% in women, of MI by 42% in men and 27% in women, and of repeat revascularization by 17% in men and 15% in women. No interaction was seen between sex and treatment approach for any of the outcomes (all P > 0.05).

Women Less Likely to Make the FFR Cut

Overall, FFR values were higher in women than men (0.75 ± 0.18 vs. 0.71 ± 0.17; P = 0.001). When lesions were categorized into 3 ranges of stenosis by visual estimation—50% to 70%, 71% to 90%, and 91% to 99%—the proportion of functionally significant lesions by FFR was lower in women than men at the first 2 levels (21.1% vs. 39.5%; P < 0.001 and 71.9% vs. 82.0%; P = 0.019, respectively), though not at the highest level (97.5% vs. 96.2%; P = 0.682). The same pattern held true when stenoses were measured by quantitative coronary angiography.

In a telephone interview with TCTMD, Massoud Leesar, MD, of the University of Alabama at Birmingham (Birmingham, AL), echoed the authors in emphasizing that because the study results are based on a nonrandomized, ad-hoc analysis involving a relatively small number of women, they should be considered only hypothesis-generating.

Nonetheless, he called the finding that women had fewer functionally significant lesions than men at the same level of stenosis interesting and worth exploring. If confirmed, a possible explanation, he said, is that the women in the study, who were older than the men, had more vascular dysfunction. It is well known that conditions that increase microvascular resistance affect FFR values, he added.

Does One Cutpoint Fit All?

“If microvascular resistance is different in women, then their FFR cutpoint [for determining ischemia] should be higher—perhaps 8.5,” Dr. Leesar said. “If a woman comes in with angina and the FFR is 8.2, that might be significant for her.”

However, a woman’s age may need to be factored in, Dr. Leesar cautioned. Pre-menopausal women whose vessels are still benefitting from estrogen may not have the same resistance and skewed FFR values as older women. A larger, prospective trial is needed to sort out the question, he said. If FFR scores differ consistently among subgroups by sex or age, then appropriate cutpoints need to be determined by comparing FFR results with those from a noninvasive measure such as a nuclear stress test, he added.

However, in a telephone interview with TCTMD, Morton J. Kern, MD, of the University of California, Irvine (Irvine, CA), was skeptical that the FFR cutpoint might need tinkering.

“Let’s say theoretically that women have a lower maximal flow than men,” he said. “They still have whatever the maximal flow is for their heart, and you can determine the resistance of an epicardial lesion based on whatever maximal flow they generate,” he said. “So even though [a woman’s FFR] may be absolutely lower [than a man’s], it doesn’t have any impact on whether or not the lesion in the artery would benefit from a stent.”

Dr. Kern stressed that angiography has limitations in assessing whether or not a stenosis limits flow. “Lesions may look more severe in women, but when you measure them [with FFR] they are not more severe,” he said. “But you don’t alter the gold standard FFR for the angiogram.”

The bottom line is that outcomes were the same for women and men, Dr. Kern observed, and this suggests that “the ischemic lesions were treated correctly and the nonischemic lesions were not treated.”

Gender Equality Confirmed

In fact, there was no previous suggestion that women might not benefit as much as men from an FFR strategy, Dr. Kern said, adding that the substudy was likely prompted by a general concern for determining whether or not women are being shortchanged in terms of diagnosis and treatment.

“In fact, it might be expected that women would benefit more [from FFR] because the smaller size of their vessels and the severity of the lesions may suggest disease beyond what they have,” he said.

In an e-mail communication with TCTMD, Dr. Fearon made a similar point. The fact that moderate lesions were less likely to be ischemia-producing in women than in men is simply “an interesting second finding that . . .  needs to be confirmed in a prospective study,” he wrote. [If anything], it suggests that, particularly in women, our threshold for measuring FFR should be even lower.”

Study Details

Overall, women were older and had higher rates of hypertension and unstable angina than men. In addition, their vessel diameters were smaller. Although women had fewer lesions identified for stenting and lower Syntax scores, the total number and length of stents implanted per patient were similar between the sexes.

FFR was measured with a coronary pressure guidewire (St. Jude Medical Systems; Uppsala, Sweden) at maximum hyperemia induced by intravenous adenosine. All patients received clopidogrel and aspirin for at least 1 year after PCI.

Source:

Kim H-S, Tonino PAL, De Bruyne B, et al. The impact of sex differences on fractional flow reserve-guided percutaneous coronary intervention: A FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) substudy. J Am Coll Cardiol Intv. 2012:5:1037-1042.

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