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

Study Overview
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Brief Summary
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Aim: To compare treatment effects of Bisoprolol and Verapamil in 140 patients with non-obstructive hypertrophic cardiomyopathy. The overall clinical purpose is to reduce the symptomatic burden and arrhythmic complications. 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 1-30 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 equal independent primary effect parameters will be analyzed between treatment with Bisoprolol and Verapamil: The incidence of non-sustained ventricular tachycardia (NSVT) is different between treatment in non-obstructive HCM patients. The left ventricular outflow tract (LVOT) time velocity integral (VTI) is different between treatment in non-obstructive HCM patients. The maximal oxygen consumption (VO2 max) is different between treatments in non-obstructive HCM patients.

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

Conditions
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Non-obstructive Hypertrophic Cardiomyopathy

Intervention / Treatment
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* Drug: Verapamil
* Drug: Bisoprolol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Maximal wall thickness ≥ 15 mm unrelated to hypertension, valve diseases or storage diseases. And one of the following: New York Heart Association - functional class (NYHA) ≥ II A history of NYHA class ≥ II before treatment with BB or CCB Pro-BNP>300 ng/l/35>nmol/l or BNP >100ng/l/>29nmol/l Non-sustained VT (>120 min-1, ≥3 cycles) documented within the last 2 years of screening Exclusion Criteria: Left ventricular ejection fraction < 50% LVOT gradient >30 mmHg at rest or during Valsalva maneuver after discontinuation of BB or CCB respectively Previous history of LVOT gradient >30 mmHg at rest, during exercise or during Valsalva maneuver. Permanent atrial fibrillation Permanent right ventricular pacing Previous intolerance for Bisoprolol (BB) or Verapamil (CCB) Known present obstructive coronary disease (previous percutaneous coronary intervention is accepted) eGFR < 60 ml/min Fertile women (<50 years) who are pregnant (Positive Plasma-HCG), breastfeeding or not using anticonception. Significant liver failure Severe valvular disease Bradycardia (40bpm) Hypotension (systolic <100mmHg) Other significant comorbidity or risks associated with discontinuation of BB or CCB after individual judgement by the investigators. Unable to understand patient information intellectually or linguistically Unable to perform exercise test. Unable to speak and/or understand Danish. Additional exclusion criteria for CMR sub study: Implantable cardioverter defibrillator (any kind) Pacemaker (any kind) Metal implants like to affect image quality Metal implants that poses a risk during CMR Inability to cope with being in the scanner.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Verapamil<br> | Drug: Verapamil<br>* 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<br>* Other names: Verapamil Hydrochloride 240 MG;|
| Active Comparator: Bisoprolol<br> | Drug: Bisoprolol<br>* 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<br>* Other names: Bisoprolol Fumarate 2.5 MG;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 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<br>* Other names: Placebo oral capsule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-sustained ventricular tachycardia (NSVT) in 7-Day Holter Monitoring | Changes in the incidence of non-sustained ventricular tachycardia (NSVT) in 7-Day Holter Monitoring | 7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed. | 
| Left ventricular outflow tract (LVOT) time velocity integral (VTI) | Changes in LVOT VTI estimated during echocardiography | Changes will be evaluated at day 21 in each treatment arm | 
| Maximal oxygen consumption (VO2 max) | Changes in VO2 max estimated during cardiopulmonary exercise test | Changes will be evaluated at day 21 in each treatment arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) score | Changes in KCCQ assessed by clinical evaluation | Changes will be evaluated at day 21 in each treatment arm | 
| New York Heart Association (NYHA) class | Changes in NYHA class assessed by clinical evaluation | Changes will be evaluated at day 21 in each treatment arm | 
| Canadian Cardiovascular Society (CCS) class | Changes in CCS class assessed by clinical evaluation | Changes will be evaluated at day 21 in each treatment arm | 
| Pro-BNP/BNP | Changes in level of Pro-BNP/BNP in blood sample | Changes will be evaluated at day 21 in each treatment arm | 
| High sensitive Troponin I/Troponin T | Changes in level of high sensitive Troponin I/Troponin T in blood sample | Changes will be evaluated at day 21 in each treatment arm | 
| Metabolic equivalent of task (METs) | Changes in METs measured during cardiopulmonary exercise test | Changes will be evaluated at day 21 in each treatment arm | 
| Recovery time | Changes in recovery time measured during cardiopulmonary exercise test | Changes will be evaluated at day 21 in each treatment arm | 
| Anaerobe threshold | Changes in anaerobe threshold measured during cardiopulmonary exercise test | Changes will be evaluated at day 21 in each treatment arm | 
| Left ventricular end-diastolic dimension | Changes in left ventricular end-diastolic dimension measured during echocardiography | Changes will be evaluated at day 21 in each treatment arm | 
| Strain in hypertrophied segment | Changes in strain in hypertrophied segment calculated during echocardiography | Changes will be evaluated at day 21 in each treatment arm | 
| Strain in non-hypertrophied segment | Changes in strain in non-hypertrophied segment calculated during echocardiography | Changes will be evaluated at day 21 in each treatment arm | 
| Left atrial dimension | Left atrial dimension measured during echocardiography | Day 21 in each treatment arm | 
| Atrial fibrillation in 7-Day Holter Monitoring | Changes in the incidence of atrial fibrillation in 7-Day Holter Monitoring | 7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed. | 
| Ventricular ectopic beats in 7-Day Holter Monitoring | Changes in the incidence of ventricular ectopic beats in 7-Day Holter Monitoring | 7-Day Holter-monitoring starts at day 21 in each treatment arm. Subsequently, the Holter report will be analyzed. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Diseases, Cardiovascular diseases, Hypertrophic cardiomyopathy, Bisoprolol, Verapamil, Hemodynamics, Arrhythmia, Beta Blocker, Calcium-channel Blocker, Anti-Arrhythmia Agents, Antihypertensive Agents