Sex differences in treatment strategy for coronary artery aneurysms: Insights from the international Coronary Artery Aneurysm Registry

Underlying mechanisms and clinical outcome of coronary artery disease (CAD) are different for men and women. Studies have suggested that women exhibit less extensive CAD and less ischaemia in stable ischaemic heart disease and more frequent plaque erosion in sudden cardiac death than men [1, 2]. Nevertheless, poor clinical outcome and suboptimal management in especially postmenopausal women is of great concern. A rare but not uncommon variant of CAD are coronary artery aneurysms. The prevalence varies according to the clinical setting and geography, ranging from 0.1 to 3.5%, being around 1.4% in post-mortem studies [3, 4]. Current American and European guidelines on CAD do not mention coronary aneurysms, while their impact on clinical outcome is significant and their clinical management is very challenging due to anatomical features and lack of evidence from randomised trials [5‐8].

The international Coronary Artery Aneurysm Registry (CAAR) is the first study assessing contemporary therapeutic management and clinical outcome of coronary aneurysms [9]. Recent analysis showed that the prevalence of coronary aneurysms is 0.35%. Patients with coronary aneurysms represent a very high cardiovascular risk burden with a high proportion of chronic kidney disease and peripheral artery disease. Most patients receive dual antiplatelet therapy (DAPT) or—to a lesser extent—anticoagulation and percutaneous revascularisation appear to be safe [4]. The aim of this study is to explore any differences between male and female patients with coronary aneurysms in presentation, therapeutic management and clinical outcome.

A total of 1565 patients were included in the CAAR for final analysis, as described previously [4]. Compared with the male patients, the female patients (n = 336; 21% of total cohort) were older at presentation (65 ± 12 vs 68 ± 14 years; p < 0.001) and more often hypertensive (70% vs 81%; p < 0.001) (Tab. 1). They less frequently had a smoking habit (47% vs 21%; p < 0.001), less frequently had previous coronary artery disease (40% vs 27%; p < 0.001), less frequently had a history of aortic aneurysms or related pathology (10% vs 3%; p < 0.001) and less frequently had severe coronary stenosis (88% vs 82%; p = 0.001).

Diabetes mellitus, family history of CAD and dyslipidaemia were equally distributed between male and female patients. No differences were found in the clinical presentation, the extent of CAD or type of aneurysm. The size and number of aneurysms per patient did not differ between sexes, nor did the coronary territories supplied by aneurysms (Tab. 1).

Female patients received conservative treatment more frequently than the male patients (37% vs 29%, p = 0.01) (Tab. 2). In invasively treated patients, no differences were found in revascularised aneurysmatic segments. However, nonaneurysmatic lesions were treated more frequently in male patients (59% vs 53%; p = 0.042). The type of revascularisation strategy was not different between male and female patients. No sex differences were found in the choice for bare metal stents, drug-eluting stents or coronary artery bypass grafting (CABG). Female patients received significantly less frequently aspirin or DAPT at discharge. In addition, median DAPT duration was also significantly shorter compared with male patients (3 vs 9 months, p = 0.001). It is unknown to what extent the shorter duration was related to physician’s prescription behaviour or patient compliance. The percentage of patients on anticoagulation was higher in the female group, but this difference was not statistically significant (Tab. 2). Clopidogrel was the most frequently chosen P2Y₁₂ inhibitor in both female and male patients (94% vs 93%) (data not shown).

Kaplan-Meier survival analysis revealed no statistically significant differences in the occurrence of death, MACE or bleeding during a median follow-up duration of 37 months (IQR 15–72) (Fig. 1). Total number of deaths was 240 (18% of females, 15% of males) (Tab. 3). MACE occurred in 485 cases (29% of females, 32% of males) and bleeding in 89 patients (4% of females, 6% of males). During follow-up, male patients were diagnosed more frequently with ACS.

The current analysis showed that coronary aneurysms exist in the context of severe and extensive CAD and that invasive management was chosen equally often in both sexes. Surprisingly, female patients received less frequently aspirin or DAPT—and the duration of DAPT was shorter—without any differences in death, MACE or bleeding during follow-up.

Sex differences exist, and they remain challenging for ischaemic heart disease in terms of clinical presentation and management, as well as outcome. In coronary aneurysms, the challenge is even greater in the absence of guideline-supported recommendations and prospective clinical studies. In that context, the CAAR findings provide a unique insight into both clinical characteristics and therapeutic management along with long-term outcome data representative for a significant part of the world.

In the absence of other causes than atherosclerosis, coronary aneurysms are considered a variant of CAD. This is supported by the high prevalence of multiple risk factors for cardiovascular disease (Tab. 1). The subgroup analysis of the ISCHEMIA trial showed that female patients had less extensive CAD with less severe ischaemia [1]. The CAAR findings suggest that coronary aneurysms are at a different level of the CAD spectrum. The slightly higher age at presentation together with the fact that the number of vessels with severe stenosis is also high may suggest that coronary aneurysms are indeed an advanced stage of CAD.

There are many analyses showing that disparities between the sexes exist in clinical presentation and in management of ischaemic heart disease. Even in the setting of ACS, women are less likely to receive guideline-recommended therapeutics such as aspirin and statins, which may partly explain the difference in clinical outcome [10, 11].

In our study, a significantly higher percentage of female patients were treated conservatively, probably related to the lower number of severe stenotic lesions in women. Approximately 45–50% of the patients did undergo percutaneous coronary intervention and about 15% underwent CABG. Both male and female patients received any type of revascularisation to a similar degree, and both groups received mostly clopidogrel when a P2Y₁₂ receptor inhibitor was prescribed. Given that equal proportions of male and female patients received invasive therapy, the differences in the use of antiplatelet therapy are surprising but are largely in line with the results of previous reports [10, 11]. Besides less frequent prescription of aspirin or DAPT in female patients at discharge, the DAPT duration was significantly shorter in female patients.

Several recent analyses from contemporary trials and registries such as PARIS, CARDIOBASE and GLOBAL LEADERS have clearly demonstrated that women have a higher risk of drug-related bleedings and that this is an important reason for DAPT cessation [12‐14]. Although with the CAAR database, it was not possible to explore the arguments behind the differences in medical treatment between male and female patients, one could argue that the higher risk of bleeding complications in women may have played an important role for physicians to prescribe DAPT less often and with a shorter duration in women in the absence of clear guideline recommendations for coronary artery aneurysms. In patients with ACS, for whom guidelines clearly recommend 12 months of DAPT, the duration of DAPT did not differ between the sexes: the median duration in both sexes was 12 months. This was also the case for patients who received a drug-eluting stent: 92% of the female and 93% of the male patients who received a drug-eluting stent were given DAPT (data not shown). Again, the median DAPT duration in both sexes was 12 months. Nevertheless, the adherence to guideline recommendations for ACS was only observed for the duration of DAPT.

Additional analysis in the same ACS subpopulation revealed that the number of patients who were prescribed aspirin and DAPT at discharge were significantly lower in female than in male patients (89% vs 96%, p < 0.001 and 71% vs 81%, p = 0.032, respectively). The notion that the higher bleeding risk in women made physicians reluctant to prescribe less and shorter-lasting DAPT was also supported by the observation that bleeding events occurred to the same degree in male and female patients. Either reduced prescription of DAPT at discharge or premature cessation of DAPT during follow-up may have been related to unrecorded events of bleeding or other adverse (side) effects in female patients. Altogether, less and shorter-lasting DAPT may have reduced the bleeding rate in female patients to a level that is similar to that in male patients. In addition, the higher rate of female patients treated conservatively could also have resulted in less frequent DAPT and may be related to the lower number of severe stenotic lesions.

The issue of sex disparities is a complex interplay of psychological and biological factors, and of patients’ and healthcare providers’ perceptions on cardiovascular disease in women [15]. An important factor is the perception—of both patients and healthcare providers—that women have a low risk of cardiovascular disease, causing delays in medical contact and differences in clinical management. While the coronary anatomy was known in our study (all patients had to undergo invasive angiography) and delays in medical contact were not recorded, it might have been the perception of physicians that women with coronary aneurysms ought to be treated differently than men. It is possible that the relative rareness of coronary aneurysms caused the differences in (D)APT and its duration since there are no clear guideline recommendations or clinical trial results to guide our decision-making process. However, even in ‘clear-cut’ clinical presentations such as ST-segment elevation myocardial infarction, contemporary studies have demonstrated that women around the globe still experience differences in diagnosis, (invasive) treatment and post-myocardial infarction rehabilitation [16‐18]. This demonstrates once again the importance of continuing education and increasing awareness among patients and healthcare providers.

Despite the differences in especially DAPT, there were no statistical differences in death and MACE observed between the sexes. Subgroup analysis did reveal a significant difference in the number of cardiovascular deaths (more frequently diagnosed in women). The difference in confirmed cardiovascular deaths could be related to chance or factors that are associated with observational studies, such as the impossibility to confirm the cause of death in all included patients. The higher incidence of ACS in male patients during follow-up—despite more frequent DAPT prescription—could be explained by the more than twice as high number of male smokers, more frequent previous CAD and more significant coronary stenosis.

In the light of the current analysis, both male and female patients with coronary aneurysms have a very high-risk atherosclerotic profile, a similar extent of CAD and similar clinical outcome despite differences in antiplatelet and invasive treatment strategies. The question remains whether equality in treatment strategy would have changed the clinical outcome in female patients with coronary aneurysms. The data also suggest that we need to increase awareness regarding women’s risk of cardiovascular disease and disparities in clinical management. Future studies are necessary to clarify the impact of equal antiplatelet/antithrombotic strategy and invasive management in women with coronary aneurysms in terms of net clinical outcome (bleeding vs ischaemic risk).