Treatment Effects of Bisoprolol and Verapamil in Symptomatic Patients With Non-obstructive Hypertrophic Cardiomyopathy

Summary

Aim: to compare the treatment effects of Bisoprolol (beta 1 receptor specific beta blocker (BB)) and Verapamil (cardio-specific calcium channel blockers (CCB)) in patients with non-obstructive hypertrophic cardiomyopathy (HCM).

Background: Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricular wall and a hypercontracted state of the sarcomeres. This narrows the left ventricular cavity, but though the left ejection fraction is increased the stroke volume and the cardiac output cannot be fully compensated. The disease manifestations can be mild or develop into severe functional limitations and devastating complications at early age. Dyspnea, chest pain, palpitations and syncope are the most common symptoms, and patients are at risk of supraventricular and ventricular arrhythmias. Arrhythmias and sudden cardiac deaths may precede heart failure symptoms. Patients with symptomatic HCM are treated initially with beta blockers and calcium channel blockers. However, there is limited evidence supporting the effectiveness of this guideline-recommended treatment in HCM.

Methods: The study is a multicenter, double-blinded, randomized, placebo-controlled cross-over trial. Patients are randomized in to three 35-days treatment periods with Bisoprolol, Verapamil and Placebo. Each treatment period includes a 7-days up titration period, a 21-days target dose period and a 7-days down titration period. Between treatment periods 45 days treatment pause is allowed. End point will be evaluated at day 21 (- 4 days). Patients will be evaluated by cardiopulmonary exercise test, echocardiography, 7 day Holter-monitoring, biomarkers and the Kansas City Cardiomyopathy Questionnaire (KCCQ). A subgroup of patients will also be evaluated with cardiac magnetic resonance imaging.

Hypotheses: Three separate phases each with one primary effect parameters will be analyzed between treatment with Bisoprolol and Verapamil:

Phase 1: The maximal oxygen consumption (VO2 max) is different (ΔVO2 max ≥1 ml/kg/min) between treatments in non-obstructive HCM patients Phase 2: The left ventricular enddiastolic volume (LVvol) is different (ΔLVvol ≥3 ml) between treatments in non-obstructive HCM patients.

Phase 3: The incidence of non-sustained ventricular tachycardia (NSVT) is different (Hazard ratio ≥ 0.5) between treatments in non-obstructive HCM patients.

The trial will be performed and analyzed in three phases, and each phase may be unblinded and analyzed separately.

Conditions

• Non-obstructive Hypertrophic Cardiomyopathy

Interventions

DRUG

Verapamil

1\. week: uptitration with 120 mg capsules per day, until maximum dosage of 360 mg´s/day. 2-4. week: steady state treatment with the maximum tolerated dose. 5\. week: downtitration

DRUG

Bisoprolol

1\. week: uptitration with 2.5 mg capsules per day, until maximum dosage of 7.5 mg´s/day. 2-4. week: steady state treatment with the maximum tolerated dose. 5\. week: downtitration

DRUG

Placebo

1\. week: uptitration with one capsules per day, until maximum dosage of three capsules/day. 2-4. week: steady state treatment with the maximum tolerated dose. 5\. week: downtitration

Sponsors & Collaborators

• Viborg Regional Hospital

  collaborator OTHER

• Zealand University Hospital

  collaborator OTHER

• Odense University Hospital

  collaborator OTHER

• Morten Steen Kvistholm Jensen

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-08-10

Primary Completion

2027-04-01

Completion

2027-12-31

Countries

• Denmark

Study Locations