Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial

• Status: Recruiting
• Trial end date: 2026-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Rationale: Up to 40% of patients undergoing a coronary angiogram for symptoms/signs of ischemia do not have obstructive coronary artery disease (CAD). In about half of them the mechanism underlying cardiac ischemia is coronary microvascular dysfunction (CMD). In CMD, myocardial ischemia is caused by impaired endothelial and/or non-endothelial coronary vasoreactivity resulting in the coronary microvasculature not dilating properly or becoming vasospastic. Recently published diagnostic criteria state that to confirm the diagnosis, CMD patients should either have an impaired coronary flow reserve (CFR), increased microvascular resistance (IMR) or have evidence of microvascular spasms. Hence, invasive coronary function testing (CFT) is considered the reference standard for a definitive diagnosis of CMD.

Patients with microvascular angina often have continuing episodes of chest pain leading to frequent first aid visits and hospital re-admissions with associated high health care costs. Moreover, CMD is associated with a worsened cardiovascular prognosis. Therefore, adequate treatment is paramount. However, current treatment options are based on a limited number of small studies, most of which were not placebo-controlled. Based on prior studies and our clinical experience we believe diltiazem, a calcium channel blocker (CCB) could improve coronary microvascular function in patients with CMD.

Objective: Our primary objective is to assess the effect of diltiazem on coronary microvascular function as assessed by CFT in symptomatic patients with CMD. Our secondary objective is to assess the effect of diltiazem on the individual coronary function parameters.

Study design: This is a clinical multi-center randomized with 1:1 ratio, double-blind, placebo-controlled study. Patients with chronic angina in the absence of obstructive CAD will be screened for study enrollment. Eligible patients will be asked for informed consent after which the screening visit will take place. Within 8 weeks after screening they will undergo CFT with the assessment of the coronary flow reserve (CFR), index of microcirculatory resistance (IMR) and coronary spasm.

• Intervention arm: if CFT shows either a CFR ≤ 2.0, an IMR ≥ 25 and/or coronary spasm, the patient will continue in the intervention arm of the trial and will be randomized to either diltiazem or placebo treatment for 6 weeks. After 6 weeks, a CFT will be repeated and the diltiazem/placebo treatment will be discontinued. Follow-up will be obtained after 6 weeks of treatment, and 1 year and 5 years after treatment discontinuation.

• Registration arm: If the CFT at baseline shows no signs of vascular dysfunction, patients will enter in the registration arm of the study. These patients will not receive any study medication. Follow-up will be obtained after 1 year and 5 years.

Study population: Adult patients with chronic angina in the absence of obstructive CAD will be screened for participation. They will be recruited from the outpatient clinic of the cardiology department of the participating sites. Patients with contra-indications for coronary function testing (with the use of adenosine and acetylcholine) and/or diltiazem treatment (i.e. severe AV conduction delay, hypersensitivity, reduced left ventricular function) will not be eligible.

Intervention: After establishing an abnormal coronary vascular function, 6 weeks treatment with either diltiazem 120-360 mg or placebo will be initiated in a double-blind fashion. Every two weeks dose titration will be performed if possible, under the guidance of patient tolerance (dizziness, leg oedema, etc.), blood pressure and heart rate.

Main study parameters/endpoints: The proportion of patients having a successful treatment with diltiazem, defined as normalization of at least one abnormal parameter and none of the normal parameters becoming abnormal.. A normal IMR is specified as IMR < 25, a normal CFR being a CFR > 2 and a normal acetylcholine test is specified as one without ECG abnormalities and without signs of spasm at the same acetylcholine dose used at baseline. Main secondary endpoints will be the change in the individual coronary function parameters.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The extensive experience with diltiazem and the favourable safety profile in combination with the short duration of treatment make the treatment risk low for participants. Related to the study procedure several reports show that CFT is a safe procedure with serious complication rates (death, myocardial infaction, etc.) ranging from 0 to 0.7%. The first CFT is clinically indicated by the treating physician. The second CFT will bring additive risk to the participants in the intervention arm. However, we believe it is essential to investigate the effect of diltiazem on coronary function to justify its use in CMD patients.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Radboud University
• Treatments: Diltiazem

Criteria

Inclusion Criteria:

• Patients with chronic angina, defined as symptoms of angina at least 2 times a week despite medical therapy for the last 3 months.

• No signs of obstructive coronary artery disease (CAD), documented within 5 years* before inclusion by one of the following modalities:

• Patients with non-obstructive (< 50% stenosis) coronary arteries, or patients with one or more intermediate stenoses (between 50 and 70%) with documented FFR > 0.80 or iFR > 0.89 on angiogram.

• Coronary computed tomography angiography (CCTA) with finding of non-obstructive coronary arteries

• Baseline coronary function testing with at least one of the following:

1. CFR ≤ 2.0

2. IMR ≥ 25

3. Abnormal acetylcholine test defined as the presence of (recognizable) angina, ischemic ECG abnormalities with or without epicardial spasm.

• Signed written informed consent * Note: in cases of clinically suspected progression of atherosclerosis as per the Investigator, more contemporary (i.e., 6 months) evidence should be provided.

Exclusion Criteria:

• Other cause of angina deemed highly likely by the treating physician.

• Active use of calcium channel blockers or any use of calcium channel blockers in the previous two weeks or known intolerance for non-dihydropyridine calcium channel blockers.

• Left ventricular ejection fraction < 50%.

• Recent PCI within the past 3 months.

• Patients with history of coronary artery bypass grafting (CABG).

• Surgically uncorrected significant congenital or valvular heart disease, cardiomyopathy or myocarditis.

• Significant renal impairment (eGFR < 30).

• Significant hepatic impairment (history or cirrhosis or abnormal serum ALT or AST 3-fold greater than the upper limit of normal).

• Pregnant women or women of child bearing potential who are planning to become pregnant within the next 3 months.

• Prior non-cardiac illness with an estimated life expectancy < 1 year.

• Contra-indication to coronary function testing:

1. Contraindication or known hypersensitivity to adenosine.

2. Contraindication or known hypersensitivity to acetylcholine.

3. Ongoing dipyridamole treatment.

• Contra-indication for treatment with CCB: second or third degree AV block, sinus node dysfunction, bradycardia (heart rate < 50 beats/minute) and/or potentially dangerous interaction due to the use of another CYP3A4 substrate in the opinion of the investigator.

• Symptomatic hypotension or systolic BP < 100 mmHg at screening visit on 2 consecutive measurements.

• History of hospitalization for asthma and/or current use of ≥ 2 types of pulmonary medications for asthma and/or severe COPD with FEV1 < 50% of predicted.

• Participation in another clinical study with an IMP within one month prior to enrolment.

• Inability of the patient, in the opinion of the investigator, to understand and/or comply with study medications, procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study.

• Unable to give informed consent (i.e. due to language barrier).