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The Puzzle of Noninvasive Testing in Women

Filling in the Pieces With the CRESCENT Trial (Calcium Imaging and Selective CT Angiography in Comparison to Functional Testing for Suspected Coronary Artery Disease)
Originally publishedhttps://doi.org/10.1161/CIRCIMAGING.117.006085Circulation: Cardiovascular Imaging. 2017;10:e006085

    In the past 2 years, a tremendous amount of much-needed data has been generated on the effectiveness of anatomic imaging with computed tomographic angiography (CTA) versus functional stress testing for stable patients with symptoms concerning for coronary artery disease (CAD). Between the recent PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain),1 SCOT-HEART trial (Scottish Computed Tomography of the Heart),2 and CRESCENT3 trial (Calcium Imaging and Selective CT Angiography in Comparison to Functional Testing for Suspected Coronary Artery Disease), an impressively consistent picture of clinical outcome equivalence, if not superiority, has emerged between anatomic and stress testing. These trials demonstrate that CTA is a safe and effective alternative to stress testing in the population of outpatients with stable chest pain.

    See Article by Lubbers et al

    Yet, there has been hope that CTA might be particularly beneficial in women who present with symptoms concerning for coronary ischemia. This group of patients deserves special attention because overwhelming evidence documents that women experience higher rates of false-positive exercise tolerance tests and nuclear stress tests compared with men,4,5 indicating a greater need for improved diagnostic strategies. This need is further reflected in the higher rate of adverse outcomes that women experience compared with their male counterparts6,7 and may, in part, explain the lower rate of obstructive CAD seen on angiography in women.8 With direct visualization of coronary atherosclerosis, it is reasonable to hypothesize that CTA would provide, particularly in women, greater diagnostic efficiency and clinical outcome efficacy than stress testing. Indeed, benefit has already been shown in the more downstream patient population examined in ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography II), which showed that women who present to the emergency department with acute chest pain have a greater reduction in length of stay with CTA than men.9

    In this issue of Circulation: Cardiovascular Imaging, Lubbers et al10 report on an important study that begins to fill in the missing pieces of the puzzle for women and men with stable angina. They detail the findings of a prespecified sex-focused analysis of the CRESCENT trial, which was a multicenter randomized controlled trial of CTA versus functional stress testing (mostly exercise treadmill testing [ETT]) in 350 stable chest pain patients in the Netherlands.3 In the overall trial, fewer patients in the CTA arm reported anginal symptoms, final diagnosis was established sooner, and less downstream testing was required. One-year clinical outcomes were similar in both testing arms, but this was a secondary outcome.

    In the current secondary analysis, the authors examine whether there were sex-based differences in the CTA and stress testing arms with regard to a variety of measures, including quality of life, diagnostic efficiency and cost, safety, and a composite clinical end point of all-cause mortality, nonfatal myocardial infarction or major stroke, unstable angina pectoris with objective ischemia or requiring revascularization, or unplanned cardiac evaluations and late revascularization procedures. They found that compared with women in the stress-testing arm, women who underwent CTA more frequently had chest pain resolution at 1 year (40% CTA versus 22% stress; P=0.026), although there was no difference in change in quality-of-life scores by testing arm. Furthermore, women underwent less additional diagnostic testing with CTA compared with stress testing and had lower downstream diagnostic costs (€326±470 CTA versus €478±493 stress; P<0.001), a benefit not seen in men. Similarly, women in the CTA arm more frequently reached a final diagnosis on the same day of presentation compared with women in the stress-testing arm (86% CTA versus 44% stress; P<0.001), and this difference was greater than that seen in men (interaction P=0.011). Thus, the authors demonstrated substantial improvements in processes of care and diagnostic efficiency with CTA testing in women.

    This study adds information to the previous literature on a direct sex-specific comparison between CTA and ETT because most patients in the stress-testing arm received ETT as their initial test. In addition, it provides important information on patient-centered quality-of-life and processes-of-care outcomes, which have been previously reported for CTA versus stress testing but not for women and men separately.11 Furthermore, this report provides valuable international data on how CTA and stress testing perform in women and men in community practice. Thus, these data from CRESCENT fill in some of the gaps from the sex-specific secondary analysis of the PROMISE trial, which showed that women derived greater prognostic information from a positive CTA than from a positive stress test, whereas men seemed to derive similar prognostic information from both.12 Although the PROMISE study shed light on the potential value of CTA in women with stable angina, it was still unclear whether the results would have differed with a different mix of noninvasive tests (the majority of stress tests performed in PROMISE were nuclear stress tests), what the impact of CTA would be on more subjective, patient-centered outcomes such as quality-of-life measures and resolution of angina, and whether the results would be generalizable to other settings with different patient groups and practice patterns.

    Although the CRESCENT report presented by Lubbers et al addresses many of these questions, the data should be interpreted with some caveats. First, randomization was not stratified by patient sex; therefore, it is important to remember that this is an observational substudy of a trial cohort and is potentially subject to residual confounding and bias. Second, the sample size of this trial was relatively small, which may have limited the power the investigators had to detect differences between the groups, especially with regard to clinical events. Finally, the lower downstream diagnostic testing rates and costs seen in women with CTA may not have been present if the comparison group was comprised of stress imaging testing, such as nuclear stress or stress echocardiography, rather than ETT. The known high rate of indeterminate and false-positive ETTs in women likely contributed to these results,4 and it is unclear whether such differences would be seen in settings where imaging stress testing was used more frequently.

    What this study makes perfectly clear is that we are quickly amassing enough prospective data to warrant a reassessment of the current US guidelines for CAD diagnosis, especially with regard to women. The 2012 stable ischemic heart disease guidelines from the American College of Cardiology/American Heart Association recommend using functional stress testing as the first-line diagnostic strategy and resorting to CTA only if patients have a contraindication to stress testing or if they have a high likelihood of ischemic heart disease and are unable to exercise.13 In contrast, the UK NICE guidelines recommend CTA as the first-line strategy; stress testing should only be used if the CAD seen on CTA is of unknown significance or if the test is nondiagnostic.14 Even these guidelines may need to be further amended as we learn more about fractional flow reserve using CTA (fractional flow reserve-computed tomography), which has the potential to provide both anatomic and functional data about coronary stenosis. In prospective research, fractional flow reserve-computed tomography has been shown to lead to lower downstream costs compared with standard of care in patients with angina and equivalent short-term clinical outcomes.15 Such a diagnostic tool might be particularly useful in women, who are more likely than men to experience symptoms from nonobstructive CAD.8

    As more data emerge on noninvasive testing in patients with stable angina, it is critical to keep in mind that men and women experience CAD differently, with varying symptoms, underlying pathologies, and outcomes.5 As such, it is incumbent on researchers in this field to prespecify and adequately power their studies for sex-specific analyses, just as it is incumbent on all of us, as clinicians and consumers of this research, to be inquisitive about how diagnostic strategies might differ in women and men. Lubbers et al should be commended for conducting a rigorous sex-specific analysis of the CRESCENT trial and for filling in pieces to the puzzle that is CAD diagnosis in women and men. With each incremental piece of data, we are learning that CTA is a viable alternative to functional stress testing and that in women it may even be preferable. We look forward to continued research from these authors and others to further elucidate the role of CTA in the diagnosis of CAD in women and men.

    Footnotes

    The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

    Correspondence to Neha J. Pagidipati, MD, MPH, Duke Clinical Research Institute, Duke University School of Medicine, PO Box 17969, Durham, NC 27715. E-mail

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