63 Meta-analysis and systematic review of coronary vasospasm in ANOCA patients Patient characteristics The 25 included studies describing patients with CAS had a combined total study population of 15.975 patients, encompassing 14.554 ANOCA patients, since three studies compared patients with obstructive coronary artery disease with ANOCA patients. The total study population had a mean age of 58.2 years of which 44.2% were women (n = 7.064). Twelve studies (n = 4.287) described Western World populations (mean age 57.7; 40.3% women)8–10, 12–14, 20–22, 26–28 and 13 studies (n = 11.688) described Asian populations (mean age 58.4; 42.0% women).11, 15–19, 23, 25, 29–32 Prevalence of CAS In the included studies, different definitions were used for the diagnosis of epicardial and microvascular spasm (Table 1). Concerning epicardial spasm, in 5 of the included studies the diagnostic criteria were in accordance with the COVADIS criteria. Twenty studies applied less strict criteria, i.e., vasoconstriction of <90% to define epicardial spasm or criteria were used that did not include concomitant ischemic ECG changes or recognizable symptoms during provocation testing. For microvascular spasm similarly different definitions were used, 7 of 10 studies used diagnostic criteria in accordance with the COVADIS criteria. A detailed description of the different diagnostic criteria used can be found in Supplementary Appendix 3 of the supplementary files. The prevalence of epicardial spasm in ANOCA patients was reported in 17 studies, including 11.762 ANOCA patients with a mean age of 58.1 years of which 52.2% were women (Supplementary Table S5).8, 9, 11, 12, 14, 17–20, 22–25, 27, 28, 30, 31 Studies reported an incidence of epicardial spasm between 16%–73% and an overall prevalence of epicardial spasm (n = 5.614) of 43% [95% confidence interval (CI), 33%–53%], based on random effects analysis (Figure 2). When studies only using Ach as diagnostic agent and using similar diagnostic criteria (i.e., 75% or 90% epicardial vasoconstriction with ischemic ECG changes and symptoms) were included in a separate random effects analysis, studies reported an overall prevalence of 44% (95% CI, 30%-58%) (Supplementary Figure S1).8, 9, 14, 22, 23, 25, 27 In addition, Supplementary Figure S2 shows the prevalence of epicardial spasm in studies published the past five years, reporting a prevalence of 50% (95% CI, 36%-64%). Furthermore, a separate analysis including studies within the funnel-plot (Supplementary Figure S3) was performed, reporting a prevalence of 42% (95% CI, 36%- 48%) (Supplementary Figure S5). The prevalence of microvascular spasm was reported in 10 studies (n = 4,403 ANOCA patients) with a mean age of 61.9 years of which 51.6% were women.8, 9, 14, 17, 19, 22–24, 27, 30 Based on random effects analysis, studies reported an overall prevalence of 25% (95% CI, 16%–36%) (Figure 3). A separate analysis including studies within the funnel plot (Supplementary Figure S4) reported a prevalence of 24% (95% CI 15%-37%) (Supplementary Figure S6). 4
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