Design and rationale of the efficacy of endothelin receptor antagonism in treatment of coronary artery spasm: a randomized controlled trial (EDIT-CAS)

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Abstract Introduction Patients with angina and no obstructive coronary artery disease frequently have coronary vasomotor dysfunction as the underlying mechanism for anginal symptoms. They experience a high angina burden and their treatment frequently fails to reduce complaints sufficiently. Targeted therapies are currently unavailable due to heterogeneity in the patient population and incomplete understanding of the underlying pathophysiological mechanisms. Consequently, randomized controlled therapeutical trials are scarce and recommended therapies are largely based on expert opinion. Epicardial spasm, one of the vasomotor dysfunction endotypes, is hypothesized to be a possible target for endothelin receptor antagonism treatment as dysfunctional endothelium causes reduced nitric oxide availability and increased production of endothelin, a potent vasoconstrictor. Purpose The EDIT-CAS trial is a registry based, double blind, randomised, placebo-controlled clinical trial comparing the efficacy of 10 weeks of add-on endothelin receptor antagonist treatment (bosentan) versus placebo in patients with previously confirmed epicardial spasm by invasive coronary function test. The primary outcome is successful treatment, defined as the absence of epicardial spasm at repeat acetylcholine spasm provocation test. Methods From the Netherlands registry of invasive coronary function testing (NL-CFT), a total of 100 patients with a previously confirmed diagnosis of epicardial spasm after acetylcholine testing, with ongoing anginal complaints despite medical therapy, will be included. They will be 1:1 randomized to bosentan vs placebo. Secondary outcome is angina relief as measured by change in Seattle Angina Questionnaire summary score. Exploratory outcomes are quality of life, safety of bosentan treatment measured by rate of (serious) adverse events and discontinuation of study drug, changes in coronary reactivity by means of comparing provocative acetylcholine dosage during spasm provocation testing at baseline versus follow-up and lastly the relationship between baseline endothelin levels and treatment success. At time of submission, 9 patients were included in the first participating centre. Three other hospitals have been initiated and will start enrolling prior to ESC. Conclusion Bosentan is an endothelin receptor antagonist with uncertain effects on vasoconstriction in patients with epicardial vasospasm. The EDIT-CAS trial will assess the efficacy of add-on bosentan therapy compared to placebo on successful prevention of epicardial spasm during repeat spasm provocation test and anginal complaints after 10 weeks.

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