Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: a Randomized Clinical Trial
Status:
Recruiting
Trial end date:
2026-12-01
Target enrollment:
Participant gender:
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.