Key Points:
- In the EDIT-CMD study, patients with coronary vasomotor dysfunction (encompassing both coronary vasospasm and microvascular dysfunction, as defined by coronary function testing) were treated with either diltiazem or placebo. The primary outcome was resolution of either vasospasm or microvascular dysfunction on repeat coronary function testing after 6 weeks of treatment. Secondary outcomes included reduction in coronary flow reserve, index of microvascular resistance, flow at rest and hyperemia, and symptoms of angina/quality of life.
- Treatment with diltiazem resulted in reduced epicardial spasm (on an underpowered secondary analysis) but had no effect on the primary outcome (resolution of either spasm or microvascular dysfunction), anginal symptoms, or quality of life. There was a small significant reduction in coronary flow reserve with diltiazem as well.
Coronary vasomotor dysfunction, which encompasses both coronary vasospasm and microvascular dysfunction, is an underdiagnosed etiology of stable angina as well as MI without obstructive coronary disease (MINOCA). While calcium-channel blockers are frequently prescribed for those with definitively diagnosed or presumed coronary vasomotor dysfunction, the efficacy of these agents has not been formally assessed by randomized trial. In a breaking presentation at the 2022 American College of Cardiology Conference today, Tijn Jansen (MD, PhD Candidate, Radboudumc, Netherlands) and his team presented the results of the “Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial” (EDIT-CMD).
The EDIT-CMD study (NCT04777045) was a randomized, double-blind, placebo-controlled, multi-center study conducted across 3 centers in the Netherlands. Patients with stable angina without obstructive coronary disease (ANOCA) were treated with either diltiazem or placebo for a total of 6 weeks. All recruited patients were adults with chronic angina (occurring at least twice a week) with no obstructive coronary disease identified on invasive or CT coronary angiography within the last 5 years. Some relevant exclusion criteria included use of any calcium-channel blocker within 2 weeks, contraindication to coronary function testing with provocative agents, reduced EF<50%, or symptomatic hypotension.
A total of 126 patients were randomized; 41 received diltiazem and 44 received placebo. All patients received baseline coronary function testing to confirm a diagnosis of coronary vasomotor dysfunction (acetylcholine provocation for vasospasm detection and bolus thermodilution with adenosine for detection of microvascular dysfunction). Coronary function testing was then repeated after 6 weeks of treatment. The average age was 58. In the placebo arm, 80% of patients had epicardial or microvascular spasm and 73% had identified microvascular dysfunction; similarly, in the placebo arm, 73% had vasospasm and 54% had microvascular dysfunction. Patients in the diltiazem arm were initiated on 120mg daily, and the doses were titrated up to a maximum of 360mg. The primary outcome was successful treatment (meaning resolution of either vasospasm or microvascular dysfunction on coronary function testing), which was not significantly different between the placebo and diltiazem arms. The primary endpoint was similarly nonsignificant when assessing coronary microvascular dysfunction and coronary vasospasm separately. Other CFT-related secondary outcomes included change in CFR (coronary flow reserve), IMR (index of microvascular resistance), and flow at both rest and hyperemia; CFR was significantly reduced in the diltiazem group (difference in change 1.35, p=0.012), but the other secondary outcomes were not significantly different between groups. Other secondary outcomes included improvement in angina and quality of life, which were not significantly different between groups. In an underpowered secondary analysis, diltiazem appeared to reduce the degree of epicardial spasm (47% vs 6%, p=0.006).
When discussing the implications of the study at the ACC, Tijn Jansen stated: “6 weeks treatment with diltiazem was not effective in improving coronary vasomotor dysfunction symptoms or quality of life as compared with placebo; diltiazem seems to reduce epicardial spasm. However, large trials examining the effect of diltiazem on individual endotypes [ie, vasospasm vs microvascular dysfunction] are needed.”