76 Chapter 4 the ANOCA patients without epicardial spasm have coronary microvascular dysfunction or microvascular spasm, which is not investigated in all studies. This is supported by Jespersen et al. describing an increased risk of all-cause mortality and MACE in ANOCA patients compared to a population without ischemic heart disease.41 In addition the most important finding is that patients experience a high number of recurrent angina during follow-up, which is in line with previous studies such as the CorMicA-trial. This trial was the first controlled clinical trial that randomized ANOCA patients based on invasive coronary function testing to stratified treatment or to standard care.27 After 6 months patients in the stratified treatment group reported a significant improvement in angina and quality of life.27 The frequently reported recurrent angina in the included studies of our review, might be due to insufficient medical treatment in CAS patients. Three studies reported the use of calcium-channel blockers during follow-up, in which a high variability was seen in the reported use. In two of these studies, less than half of all patients used calciumchannel blockers at follow-up. The reason for this low use of calcium-channel blockers is not reported, however raises two concerns. First, the effect of calcium-channel blockers might not be sufficient in CAS and new treatment options are necessary. Second, these patients are not prescribed to adequate tailored treatment including sometimes much higher doses than usually given in patients with obstructive CAD. Limitations Several limitations of our study should be acknowledged. First, an important limitation is the heterogeneity of the diagnostic criteria and spasm provocation test protocols used, which most likely let to the heterogeneity between studies in the meta-analysis. Also, publication bias could not be excluded (Supplementary Figures S3, S4). However, an additional analysis, including studies within the funnel-plot, showed a similar prevalence as compared to the prevalence using all the included studies (Supplementary Figure S5, S6). Second, the prevalence depends on the patient population selected for the spasm provocation testing. Included studies in this review most often used a selected population of patients. Third, the prognostic data should be interpreted cautious in view of the different follow-up periods and limited insight in medical treatment. Fourth, most included studies compared epicardial spasm in ANOCA patients with ANOCA patients without epicardial spasm. This could have led to distorting evidence considering different diagnostic criteria were used in the included studies. Patients categorized as suffering from epicardial spasm could have been diagnosed as ANOCA without epicardial spasm in studies using stricter criteria. Fifth, limited data were available regarding duration and type of angina complaints of the included ANOCA patients. Conclusion This systematic review provides an overview of ANOCA patients with epicardial and microvascular spasm based on the available data to date and demonstrates a high prevalence of both entities. Men are more likely to have epicardial spasm, while women are more likely to have microvascular spasm and a lower prevalence of epicardial
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