71 Meta-analysis and systematic review of coronary vasospasm in ANOCA patients Prognosis of epicardial CAS Eleven studies reported long-term outcomes of CAS patients, describing 12.058 patients (mean age 57.4; 47.4% women). Due to heterogeneity combining study results was not feasible, however an overview is presented in Table 4. Eight studies described the incidence of cardiac death (n = 5.968), with a follow-up ranging from 2.4 to 11.7 years. Three studies analyzed the occurrence of cardiac death in ANOCA patients with and without epicardial spasm, with a follow-up period of 7.2, 11.3 and 11.7 years (1, 13, 20). None of the aforementioned found a significant difference in the occurrence of cardiac death between both groups. Eight studies (n = 4.737) reported the incidence of myocardial infarction (MI) in patients with epicardial spasm, with a follow-up ranging from 1 to 11.7 years. Three studies analyzed the occurrence of MI between ANOCA patients with and without epicardial spasm, with a follow-up period of 7.2, 11.3 and 11.7 years. Figueras et al. and Schoenenberger et al. did not report a significant difference between both groups, while Seitz et al. reported that MI occurred more often in epicardial spasm patients compared to patients with microvascular spasm and to ANOCA patients without CAS.1, 13, 20 MACE was reported in 5 studies (n = 3.512), with a follow-up ranging from 1 to 4.4 years. Three studies defined MACE as cardiac death, nonfatal MI and unstable angina, the other two used the same definition as the aforementioned, but added hospitalization for heart failure or stroke and transient ischemic attacks. MACE was reported in 268 patients (12%) with epicardial spasm, more than half of all MACE was caused by hospitalization for unstable angina ranging from 52% to 90% of MACE. In addition, Nishimiya et al. and Sato et al. reported a better prognosis in patients with diffuse spasm compared to focal spasm.29, 30 Recurrent angina was reported in various ways and the key findings are summarized in Table 4. However, overall, recurrent angina occurred frequently during follow up, ranging from 10%–53%. The prognosis of microvascular spasm was rarely reported, however Seitz et al., reported that microvascular spasm is an independent predictor of recurrent angina after a median follow-up period of 7.2 years.1 A causal relationship between medical treatment and prognosis was not reported in the included studies. DISCUSSION This systematic review provides an overview of the prevalence, clinical features and prognosis of CAS in ANOCA patients worldwide. Our data demonstrate that: 1) The prevalence of epicardial spasm in ANOCA patients is 43% (ranging from 16%–73%) and 25% for microvascular spasm (ranging from 7%–39%); 2) A significantly higher prevalence of epicardial spasm is reported in Asian populations compared to Western World populations (52% vs. 33%) while a comparable prevalence is reported for microvascular spasm (20% vs. 33%); 3) While men were more likely to have epicardial spasm (61%), women were more likely to have microvascular spasm (64%); 4) The incidence of cardiac mortality and MI was low and comparable in ANOCA patients with and without epicardial spasm, MACE was dominated by recurrent angina (Central illustration). 4
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