In ANOCA, Diltiazem Fails to Improve Vasomotor Function: EDIT-CMD

WASHINGTON, DC—Patients with angina but no obstructive coronary artery disease (ANOCA) see no reduction in coronary vasomotor dysfunction when taking the calcium channel blocker diltiazem, data from the EDIT-CMD trial show. Nor did they see any improvement in symptoms or quality of life.

However, there were some differences related to endotype, researchers found.

Up to 40% of patients undergoing angiography for stable chest pain have ANOCA, and within this subgroup, coronary vasomotor dysfunction is the underlying pathology for 60% to 90%. “ANOCA patients have a worse prognosis, and adequate therapy is paramount,” investigator Tijn P.J. Jansen, MD (Radboud University Medical Center, Nijmegen, the Netherlands), told attendees at today’s American College of Cardiology 2022 Scientific Session. The results were simultaneously published in JACC: Cardiovascular Imaging.

Diltiazem is guideline-recommended and often prescribed in ANOCA with suspected coronary vasomotor dysfunction, Jansen and colleagues note in the paper. “However, studies substantiating its effect is this patient group are lacking.”

Coronary function testing is the “gold standard” for diagnosing such dysfunction in ANOCA, they point out. Also relevant to the questions explored in EDIT-CMD is the CorMicA trial, which showed that using these tests to identify endotype—microvascular disease or vasospasm—“allows for tailored medication that decreases angina and improves quality of life.” This is the first sizeable trial, the researchers say, to look specifically at diltiazem in this context.

Y.S. Chandrashekhar, MD (University of Minnesota, Duluth), editor-in-chief of JACC: Cardiovascular Imaging, told TCTMD that the question when treating patients with ANOCA is: “What’s causing the pain?” Diltiazem would seem to address both possible endotypes. “Most of the spasm is mediated through a mechanism which is responsive to calcium channel blockers. . . . And so, that’s why for decades, we have been using that without any evidence that it works, just based on the biologic plausibility,” he said, adding that diltiazem also probably makes sense in microvascular disease, as a way to improve blood flow.

EDIT-CMD’s neutral findings, then, came as a surprise, Chandrashekhar said, “though if you look into the nuances, there was some effect on the spasm. . . . But that doesn’t translate, at least in this small study, into symptom relief or quality of life or things like that.”

With such a long experience using this drug, however, some clinicians will continue to do so, he predicted. “It’s relatively safe, doesn’t have lot of side effects,” and some patients may indeed feel better as a result of taking it. “So it’s worth it,” he added, “because the risk of the drug is not [high].”

What EDIT-CMD does is make the case for building the evidence base, rather than just saying “we hold these truths to be self-evident,” Chandrashekhar noted. “This is more like: let’s test it, and we may be wrong.” He predicted that increasing attention will be paid to ANOCA thanks to the availability of imaging technologies to dig deeper into what is causing patients’ angina.

“There’s always a danger saying, ‘It’s all in their mind, and it’s not real,’” he cautioned. “This is a real condition.” And now it’s time to rigorously test the various treatment options, which are often tried in a “shotgun approach,” Chandrashekhar said.

Does Endotype Matter?

The double-blind, placebo-controlled EDIT-CMD trial enrolled 125 patients with ANOCA, defined as chronic angina at least twice weekly and no obstructive CAD based on invasive or CT angiography within the past 5 years. Among them, 85 eligible patients with coronary vasomotor dysfunction were randomized to diltiazem or placebo for 6 weeks. Their mean age was 58, around one-third were male, and about one-fifth of patients had a history of PCI. Slightly more than half had severe angina (Canadian Cardiovascular Society [CCS] III/IV), and most had angina at rest and during exercise.

Coronary function testing at baseline and 6 weeks looked at the two main endotypes of vasomotor dysfunction. Coronary artery spasm (epicardial and microvascular) was assessed using the acetylcholine spasm provocation test, and microvascular dysfunction (coronary flow reserve [CFR] and index of microvascular resistance [IMR]) was assessed using the bolus thermodilution method with adenosine.

Within the placebo group, 55% had epicardial spasm and 25% had microvascular spasm at baseline, as compared with 48% and 25% in the diltiazem group. Microvascular dysfunction was seen in 73% of the placebo patients and 54% of the diltiazem patients.

Let’s test it, and we may be wrong. Y.S. Chandrashekhar The primary endpoint of treatment success, defined as normalization of an abnormal endotype with no normal endotype becoming abnormal, was 21% with diltiazem and 29% with placebo. For coronary artery spasm in particular, treatment success rates were 10% and 8%. Rates were 24% and 29% for microvascular disfunction. None of these differences reached statistical significance.

However, there were some hints of benefit with regard to CFR at baseline versus follow-up, which increased with placebo and decreased with diltiazem, while IMR held steady. Also, in patients who had epicardial spasm at baseline, 47% of those on diltiazem changed to microvascular or no spasm, as compared with just 6% of those given placebo (P = 0.006).

While the overall results were discouraging, there’s still room for further research, and their experience with repeat coronary function testing provides insight for future study designs, Tjin noted. “Large trials on the effect of medical therapy on the individual endotypes are needed.”