Angiography May Overestimate Disease Severity vs. FFR in Women

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At a given degree of stenosis, women tend to have a higher fractional flow reserve (FFR) than men, according to a study of sex differences in anatomic and functional tests published in the June 2013 issue of JACC: Cardiovascular Interventions. Decisions based on angiography alone, therefore, may lead to overtreatment of female patients, according to the study authors and outside sources interviewed by TCTMD.

Researchers led by Seung-Jung Park, MD, PhD, of Asan Medical Center (Seoul, South Korea), prospectively examined 700 patients (493 men, 207 women) with single LAD lesions. Patients underwent quantitative coronary angiography, IVUS, FFR, and echocardiographic assessment of LV mass.

Mismatch Between Tests More Common in Women

Women in the cohort tended to be older than men (64 ± 10 yrs vs. 60 ± 10 yrs) and to have smaller body surface area (BSA; 57 ± 0.13 m2 vs. 1.79 ± 0.13 m2) and LV mass (151 ± 37 g vs. 171 ± 41 g; P < 0.001 for each). There were no differences in baseline FFR values between female and male patients (0.93 ± 0.05 vs. 0.93 ± 0.06; P= 0.138), though FFR at maximal hyperemia was significantly higher in women (0.83 ± 0.09 vs. 0.79 ± 0.09) and FFR < 0.80 less frequent (27% vs. 43%; P < 0.001 for both).

On QCA, there were no differences in diameter stenosis or lesion length according to sex, though female patients had smaller reference segment lumen diameters. Angiographic diameter stenosis of ≥ 53% best predicted an FFR value < 0.80, with a sensitivity of 64%, specificity of 69%, positive predictive value (PPV) of 56%, negative predictive value (NPV) of 76%, and overall concordance rate of 67% (area under the curve [AUC] 0.733; 95% CI 0.70-0.76; P < 0.001).

IVUS demonstrated that the lumen and external elastic membrane at the proximal and distal reference segments were smaller in women vs. men. In addition, at the site of minimal lumen area, lumen area and percent stenosis area did not differ by sex. A minimal lumen area (MLA) value on IVUS of ≤ 2.51 mm2 was the best cutoff for predicting FFR < 0.080, with a sensitivity of 82%, specificity of 62%, PPV of 56%, NPV of 84%, and an overall concordance rate of 69% (AUC 0.762; 95% CI 0.73-0.79; P < 0.001).

Mismatch between tests was more frequent for women than for men. Using a QCA cutoff of > 50% diameter stenosis, 30% of female patients had FFR values of ≥ 0.80 vs. 22% of men (P = 0.002). The prevalence of mismatch using an MLA cutoff of ≤ 2.5 mm2 followed a similar pattern at 34% for women and 20% for men; P < 0.001). Reverse mismatch—with anatomic tests showing no stenosis but FFR indicating ischemia—was less common on both QCA and IVUS for women vs. men.

Multivariable analysis found that age, BSA, lesion length, angiographic diameter stenosis, MLA on IVUS, and plaque burden all independently affected FFR values. When LV mass was considered as a variable, it replaced BSA as an independent predictor of FFR. Importantly, female sex did not predict FFR in either analysis.

At 1 year, there were no differences in the rate of MACE between patients by sex or by an FFR cutoff of 0.80.

Smaller Myocardial Territory at Work

In an e-mail communication with TCTMD, Dr. Park said that a “smaller myocardial territory in females may [explain] the more frequent visual-functional mismatch.”

William F. Fearon, MD, of Stanford University Medical Center (Stanford, CA), told TCTMD in an e-mail communication that the paper is consistent with a previous subanalysis of the FAME trial, which also demonstrated that women tend to have a higher FFR for a given stenosis compared with men (Kim HS, et al. J Am Coll Cardiol Interv. 2012;5:1037-1042).

“[T]his study extends those findings by incorporating IVUS findings and echocardiography-derived left ventricular mass revealing that women have smaller amounts of myocardium subtended by their coronary arteries,” said Dr. Fearon, who served as principal investigator of FAME. “The smaller mass may explain the lower flow across a stenosis and the higher FFR.  However, one would expect the arteries to be smaller in proportion to the smaller mass, which they were based on IVUS, so I am not sure this is the only explanation.”

In short, he said, “I think women may have more microvascular dysfunction, both due to differences in sex and because they were older, and we know older patients have more microvascular dysfunction.”

FFR the ‘Gold Standard,’ Especially for Women

Together, the results of FAME paired with those of the current analysis “highlight the importance of using FFR to identify ischemia-producing lesions in all patients, but even more so in women. FFR remains the gold standard for invasively identifying lesions responsible for ischemia,” Dr. Fearon concluded.

Dr. Park agreed that FFR is the best guide. “Because most of previous data have shown a high rate of discordances between the morphological parameters and inducible ischemia, functional evaluation is the best in determining to treat or not to treat,” he noted.

“When operator decision-making is based on morphological criteria, the majority of women may undergo unnecessary PCI,” he stressed, adding that overtreatment is particularly risky for women given their increased rates of in-hospital mortality and adverse outcomes after PCI.

In a telephone interview with TCTMD, Massoud Leesar, MD, of the University of Alabama at Birmingham (Birmingham, AL), expressed similar thoughts but went a step further, stressing that “Everything should be based on FFR value. We should not rely on angiography [when deciding] to stent or not stent. That is the bottom line.”

Based on the results of FAME, the same FFR cutoff of 0.80 still holds for both men and women, all 3 physicians confirmed. Dr. Leesar predicted that a prospective study on the impact of sex on interpretation of FFR is unlikely based on funding limitations.

Note: Study coauthor Gary S. Mintz, MD, is editor-in-chief of TCTMD and also a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.


Kang S-J, Ahn J-M, Han S, et al. Sex differences in the visual-functional mismatch between coronary angiography or intravascular ultrasound versus fractional flow reserve. J Am Coll Cardiol Intv. 2013;6:562-568.



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  • Drs. Park and Leesar report no relevant conflicts of interest.
  • Dr. Fearon reports receiving research support from St. Jude Medical.