This study has been transitioned to CTIS with ID 2024-512030-15-00 check the CTIS register for the current data. Our primary objective is to assess the effect of diltiazem on coronary microvascular function as assessed by coronary reactivity testing…
ID
Source
Brief title
Condition
- Coronary artery disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients having a successful treatment with diltiazem,
defined as normalization of at least one abnormal parameter 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.
Secondary outcome
Change in the different parameters of the CRT (change in IMR, CFR,
acetylcholine test parameters and absolute coronary blood flow).
Background summary
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 reactivity testing (CRT) 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.
Study objective
This study has been transitioned to CTIS with ID 2024-512030-15-00 check the CTIS register for the current data.
Our primary objective is to assess the effect of diltiazem on coronary
microvascular function as assessed by coronary reactivity testing in
symptomatic patients with CMD.
Study design
This is a clinical multicenter 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 at the screening visit. Within 4 weeks after
screening they will undergo coronary reactivity testing consisting of
assessment of coronary flow reserve (CFR), index of microcirculatory resistance
(IMR) and acetylcholine testing. If this shows either a CFR <= 2.0, an IMR >= 25
and/or abnormal acetylcholine testing indicating coronary spasm, the patient
will continue in the intervention arm and will be randomized to either
diltiazem or placebo treatment for 6 weeks. After 6 weeks, a coronary
reactivity test with the assessment of CFR, IMR and spasm 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.
If the coronary reactivity testing at baseline shows no signs of vascular
dysfunction, patients will enter in the registration arm of the study (after
informed consent). These patients will not receive any intervention. Follow-up
will be obtained after 1 year and 5 years. Written informed consent is also
required for enrollment in the registration arm.
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 edema, etc.), blood pressure
and heart rate.
Study burden and risks
The extensive experience with diltiazem and the favourable safety profile in
combination with the short duration of treatment make the risk low for
participants. While the first coronary angiography with assessment of coronary
function is clinically indicated in these patients, the second CRT is only in
relation with study participation. Several reports show that CRT is a safe
procedure with serious complication rates (death, myocardial infaction, etc.)
ranging from 0 to 0.7%. We believe it is essential to investigate the effect of
diltiazem on coronary function to justify its use in CMD patients.
Geert Groteplein Zuid 10
Nijmegen 6500 HB
NL
Geert Groteplein Zuid 10
Nijmegen 6500 HB
NL
Listed location countries
Age
Inclusion criteria
1. Patients above the age of 18.
2. Patients with chronic angina, defined as symptoms of angina at least 2 times
a week despite medical therapy for the last 3 months.
3. No signs of obstructive coronary artery disease (CAD), documented within 5
years* before inclusion by one of the following modalities:
a. Coronary angiography: patients with non-obstructive (< 50% stenosis)
coronary arteries are eligible, or patients with intermediate stenosis (between
50 and 70%) with documented FFR > 0.80 or iFR > 0.89 on angiogram.
b. Coronary computed tomography angiography (CCTA) with finding of
non-obstructive coronary arteries
4. Baseline coronary reactivity testing with at least one of the following:
a. CFR <= 2.0
b. IMR >= 25
c. Abnormal acetylcholine test defined as the presence of (recognizable)
angina, ischemic ECG abnormalities with or without epicardial spasm.
5. Signed written informed consent
Exclusion criteria
1. Other cause of angina deemed highly likely by the treating physician.
2. 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.
3. Left ventricular ejection fraction < 50%.
4. Recent PCI within the past 3 months.
5. Patients with history of coronary artery bypass grafting (CABG).
6. Surgically uncorrected significant congenital or valvular heart disease,
cardiomyopathy or myocarditis.
7. Significant renal impairment (eGFR < 30).
8. Significant hepatic impairment (history or cirrhosis or abnormal serum ALT
or AST 3-fold greater than the upper limit of normal).
9. Pregnant women or women of child bearing potential who are planning to
become pregnant within the next 3 months.
10. Prior non-cardiac illness with an estimated life expectancy < 1 year.
11. Contra-indication to coronary reactivity testing:
a. Contraindication or known hypersensitivity to adenosine.
b. Contraindication or known hypersensitivity to acetylcholine.
c. Ongoing dipyridamole treatment.
12. Contra-indication for treatment with CCB: second or third degree AV block,
sinus node dysfunction, and/or 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.
13. Symptomatic hypotension or systolic BP < 100 mmHg at screening visit on 2
consecutive measurements.
14. 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.
15. Participation in another clinical study with an IMP during the last month
prior to enrollment.
16. 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.
17. Unable to give informed consent (i.e. due to language barrier).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512030-15-00 |
| EudraCT | EUCTR2018-003518-41-NL |
| CCMO | NL67497.091.19 |