A gender issue in the diagnostic imaging work-up of stable coronary artery disease? Insights from DISCHARGE

Comment on the article ‘Comparative effectiveness of initial computed tomography and invasive coronary angiography in women and men with stable chest pain and suspected coronary artery disease: multicentre randomised trial’ which was published in the BMJ, https://doi.org/10.1136/bmj-2022-071133. This pre-specified gender-specific analysis of the Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE) trial aimed to compare the effectiveness of computed tomography (CT) vs. invasive coronary angiography (ICA) among women and men with stable chest pain and suspected coronary artery disease (CAD).1 In the DISCHARGE trial, a total of 3667 stable patients with intermediate (i.e. 10% to 60%) pre-test probability of obstructive CAD were randomized to CT or ICA as the initial diagnostic imaging strategy, and randomization was stratified by gender and centre.2 In the present study, the effect of gender on primary and secondary endpoints of the DISCHARGE trial as well as interactions between gender and study arms was assessed. The primary endpoint was the incidence of major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary endpoints were an expanded MACE composite (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, transient ischaemic attack, or major procedure-related complication occurring during or within 48 h after CT or ICA) and major procedure-related complications. In the modified intention-to-treat analysis, 3561 patients (mean age, 60 years) were included (2002 women and 1559 men). As compared with men, women were older (62 vs. 58 years) and were more likely to have typical angina (23% vs. 3%). Mean pre-test probability of obstructive CAD was lower (33% vs. 44%). Irrespective of the diagnostic imaging strategy, signs of CAD were less frequent in women than in men (47% vs. 32%) and were less likely to show obstructive CAD (19% vs. 34%) or high-risk coronary anatomy (9% vs. 17%). The incidence of MACE over a median follow-up of 3.5 years was similar in women and men (2.3% vs. 2.8%), without significant interaction between gender and study group [hazard ratio (HR), 1.58; 95% confidence interval (CI), 0.68–3.66, P = 0.29]. The incidence of the expanded MACE composite and major procedure-related complications was also similar in women and men, without significant interaction between gender and study group (expanded MACE composite: HR, 1.31; 95% CI, 0.65–2.67; P = 0.45; major procedure-related complications: HR, 0.28; 95% CI, 0.06–1.33; P = 0.11). In men, CT as the initial diagnostic test instead of initial ICA was associated with a lower risk of the expanded MACE composite (2.8% vs. 5.3%; HR, 0.52; 95% CI, 0.31–0.87). In women, the incidence of major procedure-related complications was lower in the CT group than in the ICA group (0.3% vs. 2.1%; HR 0.14; 95% CI, 0.04–0.46). The diagnostic procedures and management of women with suspected CAD are often challenging as the clinical presentation occurs later in life and is often characterized by atypical and more severe symptoms, in spite of less diffuse myocardial ischaemia and lower incidence of obstructive atherosclerosis.3 Women are less likely to be referred for ICA after a positive functional test, have lower rates of revascularization, and are generally prescribed fewer lifestyle interventions and medical therapies than men.4,5 All these factors deserve to be considered when planning the diagnostic work-up, as a lower level of care may result in a worse clinical outcome. From this perspective, the use of CT angiography might be advantageous in women due to both the high negative predictive value of this technique and the lower incidence of obstructive coronary atherosclerosis as compared with men.4,5 However, there remains uncertainty regarding the most appropriate initial diagnostic test in female patients, as previous trials have often experienced a gender imbalance.6 The DISCHARGE trial showed no difference between CT and ICA as the initial diagnostic imaging strategy with regard to MACE in the overall population.2 Taking advantage of randomization stratified by gender, this pre-specified analysis showed no difference in the primary MACE outcome between women and men with stable chest pain when using CT rather than ICA as the initial diagnostic test.1 However, these results should be interpreted with caution, as the study was not powered for subgroup comparisons, and the observed MACE rate was lower than expected. In addition, these findings cannot be generalized to the whole population of patients with stable chest pain, as the DISCHARGE trial included patients at relatively low clinical risk and without high-risk coronary anatomy. Consistent with the results of other gender-specific analyses in patients with ischaemic heart disease, women had non-obstructive CAD and normal coronary arteries more frequently than men.7 Within the limitations of subgroup analysis, the incidence of major procedure-related complications was lower in the CT group than in the ICA group (0.3% vs. 2.1%) in women. It should be considered, however, that the rate of femoral access use in the trial was relatively high (>10%), particularly in a low-risk population, and that a more systematic use of the radial approach might have further reduced the low complication rate. Indeed, major procedure-related complications substantially contributed to the reported excess of expanded MACE composite observed in the ICA group among men. For these reasons, the conclusions of the paper regarding the differences in secondary endpoints between CT and ICA within gender subgroups should be viewed, in our opinion, with caution. Another important point to consider is that the results of this gender-specific analysis did not include patient-reported outcomes, such as angina at follow-up. This is particularly relevant when considering that approximately one-fourth of women had severe angina inadequately controlled by medical treatment. In this regard, it may be worth mentioning that in patients with angina and non-obstructive CAD, an initial assessment with ICA may have provided other important information such as that related to coronary vasomotor testing, aiding the achievement of a more definite diagnosis, and prognostic implications as well as the optimization of anti-anginal therapy.8 As the DISCHARGE trial did not provide data on the use of novel non-invasive techniques, such as CT angiography-derived fractional flow reserve (CT-FFR) or CT-derived plaque morphology, gender differences in these parameters could not be evaluated.9,10 Interestingly, recent studies showed that the relatively lower myocardial mass to coronary volume ratio in women results in higher CT-FFR values, independent of anatomical diameter stenoses, and these findings may account for the less frequent detection of obstructive CAD and subsequent lower revascularization rate in women with stable angina.9 In conclusion, this analysis confirms the clinical advantages of using CT as an initial diagnostic approach in a relatively low-risk population of patients with stable chest pain regardless of gender and provides further support to the ‘gatekeeper’ role of CT in the diagnostic imaging work-up of chronic ischaemic heart disease. No new data were generated or analysed in support of this research.