Sex-Based Nuances Seen in iFR and FFR Testing: DEFINE-FLAIR

Patient sex appears to affect the results of physiological assessment with fractional flow reserve (FFR) but not with instantaneous wave-free ratio (iFR), according to a new post hoc analysis of the DEFINE-FLAIR trial. The findings, say investigators, may have implications for subsequent steps in patient care.

Importantly, though, researchers also found that clinical outcomes are similar with both technologies. “This result implies that both iFR and FFR can be effectively used to guide revascularization, regardless of sex, despite the physiologic backgrounds for the difference between women and men,” Chee Hae Kim, MD (VHS Medical Center, Seoul, South Korea), and colleagues note in their paper published online earlier this week in JACC: Cardiovascular Interventions.

Bina Ahmed, MD (Dartmouth-Hitchcock Medical Center, Lebanon, NH), commenting for TCTMD, pointed out that there’s much to be learned about the physiological assessment of coronary lesions in women versus men.

Although similar disparities in FFR have been suggested in the past, “I’m not sure we fully understand why that is the case,” she observed. “I think we know that there are differences in terms of the interaction between epicardial blood flow and the microcirculation between men and women. But what those differences are I think still are a little bit of a mystery.”

Sex-related variations in iFR, on the other hand, haven’t been as well studied, the investigators observe. The two tests work via different mechanisms: FFR involves using adenosine and measuring the pressure gradient across a lesion during hyperemia, whereas iFR is calculated during the resting period and does not require use of hyperemic agents. Both “resting coronary flow and response to hyperemic agents can differ according to sex, and sex [has been] reported as an independent factor for discordance between iFR and FFR,” they note.

Ahmed said the current study’s exploration of these issues raises more questions than it provides answers. Even so, she agreed, “the takeaway here was that, regardless of which strategy was used, the clinical outcomes were the same.”

A Closer Look at DEFINE-FLAIR

DEFINE-FLAIR, originally published in the New England Journal of Medicine, included 2,492 patients (601 women and 1,891 men) with lesions of 40-70% stenosis on visual assessment who were randomized to iFR or FFR guidance. At 1 year, the combined MACE rate of death, nonfatal MI, and unplanned revascularization was similar in the iFR and FFR groups (6.8% vs. 7.0%; P for noninferiority < 0.001), as were the rates of the individual MACE components.

For the current analysis, Kim and colleagues focused on sex-based differences. Overall, women had fewer functionally significant lesions than men (mean 0.31 vs 0.43) and were less apt to undergo revascularization (42.1% vs 53.1%; P < 0.001 for both).

Mean iFR values were 0.91 for both sexes. Mean FFR, though, was higher in women than in men (0.85 vs 0.83; P = 0.001). Among men, the revascularization rate was higher with FFR compared with iFR guidance (57.1% vs 49.3%; P = 0.001). Among women, revascularization was equally common following either test (41.4% vs 42.6%; P = 0.757).

One-year MACE rates were similar with iFR and FFR in women (5.4% vs 5.6%) and in men (6.6% vs 7.0%). This similarity remained after adjustment for age, clinical presentation, Canadian Cardiovascular Society angina class, hypertension, diabetes mellitus, hyperlipidemia, previous MI, and previous PCI.

As the investigators note, “differences in microvascular function, myocardial mass, coronary height, vessel size, plaque characteristics, and diastolic function have been suggested as potential mechanisms for [sex-based variations in FFR]. Those factors can cause higher hyperemic coronary flow and lower FFR in men than in women for the same epicardial stenosis.”

The DEFINE-FLAIR data showing no iFR difference might “be due to relatively higher resting flow in women,” they suggest. “In our study, women were older and showed higher prevalence of hypertension, higher systolic blood pressure, and higher heart rate than men, and these factors can cause higher resting coronary flow in women than in men.”

No Effect on Practice . . . Yet

Asked whether, in practice, it would make sense to adjust the cutoff or interpretation of FFR for women, Ahmed noted that the DEFINE-FLAIR investigators did not allude to this implication in their paper. “I think that’s appropriate,” she said. Not only was the analysis post hoc, but also the number of women in each group was small.

Ahmed raised the possibility that men might be getting more unnecessary PCI, though she noted it’s impossible to answer that question with these data. Moreover, the study didn’t address symptom relief, which could be relevant given that women tend to experience more angina. As Ahmed noted: “How does their chest pain relate to their physiological assessment?”

Even so, “it’s helpful to know that the outcomes here, despite the differences we don’t fully understand, are similar,” she said. What’s needed now, according to Ahmed, is a randomized trial that prospectively pays attention to sex in relation to coronary physiology.

Kim et al agree that “further studies on how sex difference in microvascular function and physiologic response to epicardial stenosis affects iFR and FFR values are needed, as this study does not have data on coronary flow, microvascular dysfunction, and quantitative assessment for epicardial disease severity.”