Author + information
- Published online August 6, 2018.
- J. Dawn Abbott, MD∗ ()
- ↵∗Address for correspondence:
Dr. J. Dawn Abbott, Department of Medicine, Division of Cardiology, Warren Alpert Medical School of Brown University, 593 Eddy Street, RIH APC814, Providence, Rhode Island 02903.
In patients with angina pectoris, diagnostic testing and medical therapy for symptoms and prognosis focus on epicardial atherosclerotic coronary artery disease (CAD). This is justified in that obstructive CAD is the primary cause of ischemic heart disease, and robust research exists on the efficacy of therapeutic measures. The likelihood that chest pain is ischemic in nature, and that the mechanism of ischemia is epicardial disease, however, varies according to several factors, including age, sex, and traditional risk factors. Women with ischemic heart disease have a distinct “phenotype” or makeup from that of men. Pathological and imaging studies show that women have smaller diameter coronary arteries, a more diffuse pattern of atherosclerosis with fewer obstructive lesions, and a higher incidence of plaque erosion as the substrate for acute thrombosis (1). In addition, women have a higher prevalence of microvascular dysfunction contributing to or solely responsible for angina. These underlying differences in ischemic heart disease pathophysiology in women and men explain the finding of significantly lower rates of obstructive CAD (stenosis >50%) in women referred for invasive coronary angiography for angina, termed ischemia and no obstructive CAD (2).
The decision to pursue invasive evaluation is dictated by the severity of anginal symptoms on medical therapy and the cardiovascular risk associated with abnormal findings on a range of noninvasive tests and is ultimately based on clinical judgement. For patients with stable symptoms, the appropriate use criteria suggest that only patients with high pre-test probability of CAD should undergo diagnostic catheterization without prior noninvasive stress testing. This may lead to lower rates of referral to invasive coronary angiography in women, because the pre-test probability of CAD is highly associated with sex. Younger women, <60 years of age, even with typical angina, have an only intermediate likelihood of CAD. When women make it to coronary angiography, consideration of the correct diagnosis of obstructive CAD, ischemia and no obstructive CAD, or noncardiac pain is required. To avoid undertreatment, even minor degrees of plaque should be documented and secondary prevention recommended. In women with severe coronary stenosis, >70%, with typical symptoms or supporting objective evidence of ischemia, revascularization is indicated. In many cases, however, the functional significance of CAD is uncertain. In these cases, the use of invasive physiological testing, such as fractional flow reserve (FFR), is the mainstay of guiding revascularization decisions.
The use of FFR-guided revascularization, compared with angiographic guidance, significantly reduces the risk for major adverse events. Clinical studies have used a dichotomous cutoff of FFR >0.8 to defer percutaneous coronary intervention (PCI) on the basis of high predictive accuracy of 95% for negative ischemia on noninvasive testing. Visual functional mismatch between lesion severity and functional significance is greater in women than men, suggesting a greater role for hemodynamic assessment in women. The sex differences in FFR are postulated to be due to several factors, including smaller vessel size, ventricular mass, and myocardial territory at risk (3). Nonetheless, an FFR-guided strategy, using the same FFR cutoff in women and men, yields reductions in the risk for death, myocardial infarction, and repeat revascularization that are independent of sex (4). More recently, several coronary pressure wire indexes that do not require maximal hyperemia with adenosine have been developed. The main benefit of these techniques is the avoidance of side effects, as well as lower time and cost. Among them, instantaneous wave-free ratio (iFR) was found to be noninferior to FFR in clinical trials (5). Whether this holds true for subgroups including women is not yet clear. Hypothetically, the female ischemic heart disease phenotype may result in differential accuracy of resting and hyperemia wire-based assessment of lesion significance.
In this issue of JACC: Cardiovascular Interventions, Shah et al. (6) report a comprehensive comparison of the adenosine-free coronary pressure wire indexes iFR, distal/proximal coronary pressure ratio, and contrast FFR (cFFR) with the gold standard, FFR, according to sex. The study provides the answer to the important question of whether the accuracy of these measures is similar in women and men. The study design was a post hoc analysis of the multicenter CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?) study in which protocol-acquired physiological measures were analyzed by a core laboratory blinded to subject characteristics including sex. Overall, 28.3% of the subjects (n = 216) were women. As expected, women were older and had a higher prevalence of comorbidities including diabetes mellitus, hypertension, and kidney disease. Angiographically, mean and categorical stenosis severity was similar in women and men. As observed in prior studies, despite similar mean FFR values, fewer women had abnormal FFR using the cutoff of ≤0.8 (42.5% vs. 51.5%; p = 0.04). Using binary thresholds (iFR of <0.9, distal/proximal coronary pressure ratio <0.91, and cFFR ≤0.83) for the adenosine-free measures, no sex difference was observed. Compared with FFR, the accuracy of iFR and distal/proximal coronary pressure ratio was 79% and that of cFFR 86%, without a significant interaction with sex. In every detailed comparison, such as rate of mismatch between FFR and each adenosine-free measure, no statistically significant difference between women and men was observed. One can conclude from this analysis that the diagnostic accuracy of the adenosine-free indexes has more to do with the technique chosen than the sex of the patient.
This study provides reassurance that the same diagnostic algorithm can be used for women and men with intermediate stenosis, with the limitation that the study was not intended to assess clinical outcomes. But the question remains, how do we manage patients with lesions that do not meet the ischemic threshold by one measure? Although there is not an absolute correlation between the indexes, data support the safety of deferring PCI in favor of optimal medical therapy independent of the index used. Using iFR as an example, which was less accurate than cFFR in the present study, the DEFINE-FLAIR trial showed that despite significantly fewer PCIs in the iFR compared with FFR group, there was no difference in clinical event rates during the period of follow-up (5). Physicians, in addition to being reassured that prognosis is independent of performing PCI, want to understand the etiology of patients’ symptoms. In this regard, the subtle differences in the hemodynamic indexes may matter. Although there were no statistically significant differences in all the adenosine-free indexes according to sex, there was a numerically higher accuracy and false-positive rate in women. In addition, the diagnostic accuracy of the adenosine-free indexes is slightly, but nonsignificantly, higher in patients with diabetes mellitus. Women and patients with diabetes may be similar in that resting coronary blood flow is higher in the setting of microvascular dysfunction. Independent of sex and diabetes, patients with a nonischemic but moderately abnormal adenosine-free index can be subject to FFR to assess for a false-negative finding, which would increase the rate of PCI, or be given a trial of intensified antianginal control on the basis of a single adenosine-free index.
Women who have persistent angina on guideline-optimized medical therapy post-deferral or performance of functionally guided PCI require further delineation of the ischemic heart disease makeup. Identified causes of ischemia and no obstructive CAD, including vasospasm and valvular and hypertensive heart disease should be aggressively treated. In the remaining women, concomitant coronary microvascular dysfunction should be evaluated as the mechanism of angina, as the presence portends a poor prognosis (2). Because invasive determination of microvascular dysfunction is rarely performed, positron emission tomography or cardiovascular magnetic resonance imaging, depending on local expertise, can quantify microvascular function with high accuracy (7). Management of angina in patients with confirmed microvascular dysfunction can be challenging and often requires pharmacological and nonpharmacological therapies. Although the study of Shah et al. (6) highlights similarities among women and men with CAD, we also need to acknowledge the differences to improve the care of women with all forms of ischemic heart disease.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Abbott has reported that she has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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