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

NCT04777045 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: NL67497.091.192018-003518-41
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Microvascular Angina; Coronary Vasospasm; Microvascular Ischemia of Myocardium

Keywords

Coronary vasospasm; IMR; CFR; Diltiazem; Coronary function testing

Outcome Measures

Primary Outcomes (1)

• 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 spasm, without ischemic ECG abnormalities and without (recognizable) angina at the same acetylcholine dose used at baseline.

  6 weeks

Secondary Outcomes (5)

• Change in index of microvascular resistance (IMR)

  6 weeks

• Change in Coronary Flow Reserve (CFR)

  6 weeks

• Change in Acetylcholine test parameters

  6 weeks

• Change in Absolute flow parameters - flow (Q) (ml/min)

  6 weeks

• Change in Absolute flow parameters - Resistance (R)

  6 weeks

Other Outcomes (6)

• Safety endpoints

  6 weeks

• Follow-up (MACE)

  5 years

• Change in angina frequency reporting in the patient diary

  5 years

Study Arms (2)

Diltiazem

EXPERIMENTAL

When signs of vascular dysfunction with the coronary function test.

Drug: Diltiazem Hydrochloride

Placebo

PLACEBO COMPARATOR

When signs of vascular dysfunction with the coronary function test.

Drug: Placebo

Interventions

Diltiazem Hydrochloride DRUG

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). It is a white to off-white crystalline powder with a bitter taste. It is freely soluble in water, methanol and chloroform. It has a molecular weight of 450.98. It provides its therapeutic effects by blocking the influx of calcium ions into vascular smooth and cardiac muscle cells during membrane depolarization. The decrease in intracellular calcium causes relaxation of smooth muscle cells and cardiac myocytes by inhibiting actin-myosin interactions. Vasodilation subsequently results in decreased peripheral vascular resistance. The antihypertensive effect of diltiazem in hypertensives is greater than in normotensives. Diltiazem is registered for the treatment of hypertension, heart rate control in supraventricular tachycardia, chronic stable angina pectoris and angina pectoris resulting from coronary artery spasm.

Also known as: Molecular Formula: C22H26N2S.HCl, Diltiazem HCl Retard 120 mg, Prolonged-Release Tablets, CAS 33286-22-5, Chemically diltiazem hydrochloride is the hydrochloride salt of (2S, 3S)-5-(2- Dimethylaminoethyl)- 2, 3, 4, 5-tetrahydro-2-(4-methoxyphenyl)-4-oxo-1, 5-benzothiazepin-3- yl-acetate

Diltiazem

Placebo DRUG

Matching placebo capsules, given QD per oral use. Placebo capsules will be used in the same manner with the same dose titration.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with chronic angina, defined as symptoms of angina at least 2 times a week despite medical therapy for the last 3 months.
• 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:
• CFR ≤ 2.0
• IMR ≥ 25
• 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.

You may not qualify if:

• 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:
• Contraindication or known hypersensitivity to adenosine.
• Contraindication or known hypersensitivity to acetylcholine.
• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (3)

Radboud University Medical Center

Nijmegen, Gelderland, 6525 GA, Netherlands

Location

Catharina Hospital

Eindhoven, Netherlands

Location

Maasstad Hospital

Rotterdam, Netherlands

Location

Related Publications (7)

• Li L, Gu Y, Liu T, Bai Y, Hou L, Cheng Z, Hu L, Gao B. A randomized, single-center double-blinded trial on the effects of diltiazem sustained-release capsules in patients with coronary slow flow phenomenon at 6-month follow-up. PLoS One. 2012;7(6):e38851. doi: 10.1371/journal.pone.0038851. Epub 2012 Jun 27.

  PMID: 22761709 BACKGROUND

• Zhang X, Li Q, Zhao J, Li X, Sun X, Yang H, Wu Z, Yang J. Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X. Coron Artery Dis. 2014 Jan;25(1):40-4. doi: 10.1097/MCA.0000000000000054.

  PMID: 24256699 BACKGROUND

• Kurabayashi M, Asano M, Shimura T, Suzuki H, Aoyagi H, Yamauchi Y, Okishige K, Ashikaga T, Isobe M. Ultra-long acting calcium channel blockers may decrease accuracy of the acetylcholine provocation test. Int J Cardiol. 2017 Jun 1;236:71-75. doi: 10.1016/j.ijcard.2017.02.123. Epub 2017 Feb 28.

  PMID: 28268085 BACKGROUND

• Yeatts SD, Martin RH, Coffey CS, Lyden PD, Foster LD, Woolson RF, Broderick JP, Di Tullio MR, Jungreis CA, Palesch YY; IMS III Investigators. Challenges of decision making regarding futility in a randomized trial: the Interventional Management of Stroke III experience. Stroke. 2014 May;45(5):1408-14. doi: 10.1161/STROKEAHA.113.003925. Epub 2014 Apr 3.

  PMID: 24699059 BACKGROUND

• Lachin JM. A review of methods for futility stopping based on conditional power. Stat Med. 2005 Sep 30;24(18):2747-64. doi: 10.1002/sim.2151.

  PMID: 16134130 BACKGROUND

• Jansen TPJ, de Vos A, Elias-Smale SE, Paradies V, Konst RE, Crooijmans C, Dimitriu-Leen AC, Rodwell L, Maas AHEM, Smits PC, van Royen N, Damman P. Effect of Diltiazem Versus Placebo on Microvascular Dysfunction Assessed By Repeated Continuous Thermodilution Measurements: Results of the EDIT-CMD Trial. J Am Heart Assoc. 2023 Nov 7;12(21):e030188. doi: 10.1161/JAHA.123.030188. Epub 2023 Oct 27. No abstract available.

  PMID: 37889203 DERIVED

• Jansen TPJ, Konst RE, de Vos A, Paradies V, Teerenstra S, van den Oord SCH, Dimitriu-Leen A, Maas AHEM, Smits PC, Damman P, van Royen N, Elias-Smale SE. Efficacy of Diltiazem to Improve Coronary Vasomotor Dysfunction in ANOCA: The EDIT-CMD Randomized Clinical Trial. JACC Cardiovasc Imaging. 2022 Aug;15(8):1473-1484. doi: 10.1016/j.jcmg.2022.03.012. Epub 2022 Apr 2.

  PMID: 35466050 DERIVED

MeSH Terms

Conditions

Microvascular Angina; Coronary Vasospasm

Interventions

Diltiazem

Condition Hierarchy (Ancestors)

Angina Pectoris; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Suzette Elias-Smale, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The blinding of treatment is ensured by using a double-blind technique. The diltiazem capsules and the respective placebo capsules will have the same look and feel. The bottles with the IMP will be labelled with unique identification numbers. No member of the study team, or anyone handling study data will have access to the randomization scheme during the study. In case of an adverse event (AE), the code should only be broken in circumstances when knowledge of the IMP is required for treating the patient. If possible, contact should be initiated with the principal investigator before breaking the code. Code breaking can be performed at any time by the investigator. A sealed emergency envelope per patient randomization number will be present per patient at the research department. If the blind is broken, the Investigator should document the date, time of the day and the reason for code breaking. If the code is broken, patient must discontinue IMP administration but continues the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A clinical multi-center randomized with 1:1 ratio, double-blind, placebo-controlled study. Patients with chronic angina in the absence of CAD will be screened for study enrolment. Eligible patients will be asked for informed consent at the screening visit. Within 8 weeks after screening, participants undergo coronary function testing. If this shows either a CFR ≤ 2.0, an IMR ≥ 25 and/or abnormal acetylcholine testing the patient will continue in the intervention arm and will be randomized to either diltiazem or placebo treatment for 6 weeks. After 6 weeks, coronary function testing will be repeated and the diltiazem/placebo treatment will be discontinued. Follow-up will be obtained 1 month, 1 year and 5 years after treatment discontinuation. If coronary function testing 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 Record Dates

• First Submitted: February 18, 2021
• First Posted: March 2, 2021
• Study Start: October 25, 2019
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 30, 2023

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)