74 Chapter 4 Prevalence of CAS and differences in protocols and definitions A wide variation in prevalence was seen in our review, which could be related to differences in used protocols and inclusion criteria as demonstrated in Table 1. First, the wide variety of spasm provocation test protocols could have led to differences in prevalence. It is well known that the occurrence of CAS is dependent on Ach concentrations, which increase with higher dosages of Ach and higher injection speed.32 Second, numerous CAS definitions were applied, which influence the diagnosis and thus prevalence of CAS. For example, Sueda et al. in 2015 used very strict diagnostic criteria, i.e., spasm was defined as coronary vasoconstriction of more than 99%, resulting in a low prevalence of 17%.31 However, we found that, in studies using similar diagnostic criteria the prevalence of epicardial spasm was comparable with the prevalence using all the included studies (Supplementary Figure S2 and S2). To overcome this problem, the COVADIS working group published diagnostic criteria for epicardial and microvascular spasm in 2015.5 As numerous articles were published before this publication it can partly explain the differences we found in definitions and protocols. However, since the COVADIS criteria are the strictest criteria used worldwide, they are not always applied in daily practice, possibly because clinicians are divided how to treat the large group of patients only partly meeting the diagnostic criteria,34 while studies using milder criteria still report high incidences of recurrent angina and MACE.1, 11 Nonetheless, the risk of implementing too lenient criteria is over diagnosis. Third, differences in patient selection could have led to the variety of prevalence. Unfortunately, additional information regarding patient selection, for example the duration and nature of angina symptoms, was rarely reported. In line with our findings, a recently published review by Mileva et al. reported a similar but slightly lower prevalence of spasm of 40% and of microvascular spasm of 24%.35 This difference could be explained by the fact that MINOCA patients were also included in the review of Mileva et al., suggesting a slightly higher prevalence of CAS in ANOCA patients compared to MINOCA patients. In addition to the study of Mileva et al., our study includes additional information as we performed a subgroup analysis of studies using similar Ach testing protocols and diagnostic criteria. Also, this review provides an overview of clinical features and prognosis and investigated differences between continents and sexes. In addition to the above mentioned explanations for the differences in prevalence, it is also important to realize that in the majority of studies only epicardial spasm was reported, while our review reported a prevalence of microvascular spasm of 25%. It is reasonable to assume that the prevalence of microvascular spasm is underestimated since the coexistence of epicardial and microvascular spasm is difficult to diagnose. When after Ach provocation and additional nitroglycerin an Ach re-challenge is performed microvascular
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