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

Phase 4RecruitingNCT05569382

Morten Steen Kvistholm Jensen100 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Interventions

VerapamilDRUG

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

BisoprololDRUG

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

PlaceboDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥ 18 years * Maximal wall thickness ≥ 15 mm unrelated to hypertension, valve diseases or storage diseases. And one of the following: 1. New York Heart Association - functional class (NYHA) ≥ II 2. A history of NYHA class ≥ II before treatment with BB or CCB 3. Pro-BNP\>300 ng/l/35\>nmol/l or BNP \>100ng/l/\>29nmol/l 4. 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 * 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 \< 40 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.

Locations (4)

Department of Cardiology, Aarhus University Hospital

Aarhus N, Denmark

RECRUITING

Department of Cardiology, Odense University Hospital

Odense, Denmark

RECRUITING

Department of Cardiology, Zealand University Hospital

Roskilde, Denmark

NOT_YET_RECRUITING

Department of Cardiology, Regional Hospital Viborg

Viborg, Denmark

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

Maximal oxygen consumption (VO2 max)

Changes in VO2 max estimated during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

Left ventricular enddiastolic volume (LVvol)

Changes in enddiastolic volume (LVvol) estimated during cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Incidence of non-sustained ventricular tachycardia (NSVT

Changes in NSVT estimated during ECG monitoring

Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

Secondary Outcomes

Kansas City Cardiomyopathy Questionnaire (KCCQ) score

Changes in KCCQ assessed by clinical evaluation

Time frame: Changes will be evaluated at day 21 in each treatment arm

New York Heart Association (NYHA) functional classification

Changes in NYHA class assessed by clinical evaluation

Time frame: Changes will be evaluated at day 21 in each treatment arm

Canadian Cardiovascular Society (CCS) class

Changes in CCS class assessed by clinical evaluation

Time frame: Changes will be evaluated at day 21 in each treatment arm

Pro-BNP/BNP

Changes in level of Pro-BNP/BNP in blood sample

Time frame: 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

Time frame: Changes will be evaluated at day 21 in each treatment arm

Metabolic equivalent of task (METs)

Changes in METs measured during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

Recovery time

Changes in recovery time measured during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

VO2 max Anaerobic threshold

Changes in VO2 max at anaerobic threshold measured during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

Percent predicted VO2 max

Changes in percent predicted VO2 max measured during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

Ventilatory equivalent for carbon dioxide VE/VCO2

Changes in VE/VCO2 measured during cardiopulmonary exercise test

Time frame: Changes will be evaluated at day 21 in each treatment arm

Echocardiographic left ventricular end-diastolic dimension

Changes in left ventricular end-diastolic dimension measured during echocardiography

Time frame: Changes will be evaluated at day 21 in each treatment arm

Echocardiographic global longitudinal strain (GLS) for LV function

Changes in GLS measured during echocardiography

Time frame: Changes will be evaluated at day 21 in each treatment arm

Echocardiographic left ventricular outflow tract time velocity intergral (LVOT VTI) for LV function

Changes in LVOT VTI measured during echocardiography

Time frame: Changes will be evaluated at day 21 in each treatment arm

Echocardiographic dimension of left atrial

Changes in left atrial dimension measured during echocardiography

Time frame: Changes will be evaluated at day 21 in each treatment arm

Episodes of atrial fibrillation (AFIB) on Holter monitoring

Changes in episodes of AFIB measured during Holter monitoring

Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

Number of ventricular ectopic beats on Holter monitoring

Changes in number of ventricular ectopic beats measured during Holter monitoring

Time frame: Changes will be evaluated at day 21 +7 days in each treatment arm

Left ventricular systolic function on Cardiac MRI

Changes in left ventricular systolic function on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Right ventricular dimensions on Cardiac MRI

Changes in right ventricular dimensions on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Right ventricular systolic function on Cardiac MRI

Changes in right ventricular systolic function on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Stroke volume (Aortic flow) on Cardiac MRI

Changes in stroke volume (Aortic flow) on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Coronary sinus flow on Cardiac MRI

Changes in coronary sinus flow on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Dimension of inferior and superior caval vein on Cardiac MRI

Changes in dimension of inferior and superior caval vein on Cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Dimension of left atrium on cardiac MRI

Changes in dimension of left atrium on cardiac MRI

Time frame: Changes will be evaluated at day 21 in each treatment arm

Sex specific analyses of outcome measures

Changes in outcome measures between male and female

Time frame: Changes will be evaluated at day 21 in each treatment arm

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

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts