Diltiazem not effective in patients with angina, nonobstructive CAD

WASHINGTON — In the first randomized trial of a therapy for treatment of patients with angina and nonobstructive CAD, diltiazem did not improve coronary vasomotor dysfunction compared with placebo.

For the EDIT-CMD trial, researchers randomly assigned 85 patients with angina and nonobstructive CAD (ANOCA) who underwent coronary function testing to receive up to 360 mg diltiazem or placebo per day.

“ANOCA patients have worse prognosis compared with asymptomatic patients,” Tijn P.J. Jansen, MD, PhD candidate in the department of cardiology at Radboud University Medical Center, Nijmegen, the Netherlands, said during a presentation at the American College of Cardiology Scientific Session. “Guidelines recommend the use of calcium channel blockers in coronary vasomotor dysfunction, and diltiazem is one of the most frequently prescribed medications in these patients. However, these recommendations are based on dated nonrandomized trials. The effect of diltiazem had never been studied in ANOCA patients in a blinded, randomized, placebo-controlled trial.”

All patients had chronic angina occurring at least twice per week and coronary vasomotor dysfunction confirmed by presence of vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction, defined as coronary flow reserve < 2 or index of microcirculatory resistance 25. The mean age of patients was 58 years and about two-thirds were women.

The primary endpoint was a successful treatment at 6 weeks, defined as normalization of one of the abnormal parameters of coronary vasomotor dysfunction and no normal parameter becoming abnormal.

Among the 73 patients who underwent coronary function testing for a second time, there was no difference between the groups in improvement in coronary function test score (diltiazem, 21%; placebo, 29%; P = .46), Jansen said, noting there were also no differences in the cohort with coronary artery spasm or in the cohort with coronary microvascular dysfunction.

However, he said, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular spasm or no spasm (47% vs. 6%; P = .006).

The Seattle Angina Questionnaire Summary Score did not differ between the groups (P = .54), nor did the RAND-36 quality of life score (P for physical = .58; P for mental = .87), nor did any metric of microvascular dysfunction, according to the researchers.

“Six weeks’ treatment with diltiazem was not effective in improving coronary vasomotor dysfunction, symptoms or quality of life as compared to placebo,” Jansen said. “Diltiazem seems to reduce epicardial spasm. However, large trials on the effect of medical therapy on the individual endotypes are needed. We believe that this first study using repeated coronary function testing provides a platform for future research.”

The data were simultaneously published in JACC: Cardiovascular Imaging.

C. Noel Bairey Merz

In a discussion after the presentation, Cardiology Today Editorial Board Member C. Noel Bairey Merz, MD, FACC, FAHA, professor of cardiology and director of the Barbra Streisand Women’s Heart Center at the Smidt Heart Institute at Cedars-Sinai, said the study “is a nice example of a pragmatic trial … but we know as treating physicians, not everything works for everyone. This study is an example of how for every complex problem, there is a simple answer that’s wrong. I think probably the reason that this trial was negative was that it was too heterogenous.”

In contrast, she said, the CorMicA trial showed calcium channel blockers could be effective in this population, but only when physicians could titrate the medication and offer it in conjunction with other therapies if necessary.

Reference:

Perspective

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Janet Wei, MD, FACC

This is the first randomized clinical trial of diltiazem to improve coronary vasomotor dysfunction as defined by invasive coronary function testing. The landmark CorMicA trial tested overall stratified medical therapy based on invasive coronary function testing, but calcium channel blockers were recommended for both the vasospasm endotype and coronary microvascular dysfunction endotype. While we routinely treat vasospasm with calcium channel blockers, evidence for treating coronary microvascular dysfunction with calcium channel blockade is lacking.

Diltiazem did not significantly improve coronary vasomotor dysfunction (including thermodilution CFR < 2 or IMR 25 or more or microvascular spasm) but did reduce the prevalence of epicardial vasospasm after 6 weeks of therapy. Despite lowering BP, diltiazem also did not significantly improve angina and quality of life scores.

For patients with suspected or proven coronary vasospasm, calcium channel blockers and nitrates remain first line therapies. However, for coronary microvascular dysfunction as defined by CFR < 2 or IMR 25 or microvascular spasm, clinicians may consider a beta-blocker first, as recommended by the CorMicA stratified therapy algorithm.

The EDIT-CMD team should be congratulated for adding to the evidence base for therapy of coronary vasomotor dysfunction. Given this condition is so heterogenous with multiple endotypes, we should note that this trial was not powered on the effect of diltiazem on the individual endotypes. Furthermore, this trial did not evaluate the endotype of coronary endothelial dysfunction. Larger trials are needed to investigate response to specific therapy by endotypes as well as long-term CV outcomes.

Janet Wei, MD, FACC

Assistant Professor of Cardiology

Barbra Streisand Womens Heart Center

Smidt Heart Institute at Cedars-Sinai

Cardiology Today Editorial Board Member

Disclosures: Wei reports consulting and serving on an advisory board for Abbott Vascular, for which fees are paid to her institution.

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