The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.

Study Overview
=================
Brief Summary
-----------------
Hypertrophic obstructive cardiomyopathy (HOCM) patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical beneﬁt in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs.

Detailed Description
-----------------
Background Hypertrophic cardiomyopathy (HCM) is characterized by an increase in left-ventricular wall thickness, typically localized at the interventricular septum. The hypertrophy can increase to an extend that causes a dynamic obstruction of the left ventricular outflow tract (LVOTO); these patients have hypertrophic obstructive cardiomyopathy (HOCM). Due to the obstruction, patients develop high interventricular pressure gradients, which may overtime become detrimental to the left ventricular function. HOCM patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical beneﬁt in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs. Objective The investigators wants to quantify the effects of metoprolol on myocardial function and perfusion, hemodynamics and heart failure symptoms in patients with HOCM. Hypotheses Primary • Metoprolol treatment reduces ∆ pulmonary capillary wedge pressure (PCWP) (rest-exercise) Secondary Metoprolol treatment reduces PCWP at rest Metoprolol treatment increases maximal oxygen consumption (VO2-max) . Metoprolol treatment reduces LVOT gradient during exercise Metoprolol treatment increases the coronary flow reserve Metoprolol treatment decrease External Work Metoprolol treatment reduces heart failure symptoms, estimated by the Kansas City Cardiomyopathy Questionnaire Design and methods A randomized, double-blinded, placebo-controlled, crossover study, anticipated to examine 32 patients with HOCM both during treatment with metoprolol and placebo. Patients will be examined in a set-up of simultaneous 1) right heart catheterization 2) cardiopulmonary exercise test and 3) transthoracic echocardiography. The set-up allows the investigators to evaluate the hemodynamic values during rest and maximum exercise.

Official Title
-----------------
The Effect of Metoprolol on Myocardial Function, Perfusion, Hemodynamics and Heart Failure Symptoms in Patients With Hypertrophic Obstructive Cardiomyopathy.

Conditions
-----------------
Hypertrophic Cardiomyopathy

Intervention / Treatment
-----------------
* Drug: Metoprolol Succinate
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Wall thickness ≥ 15 mm in one or more myocardial segments that is not explained by loading conditions. LVOT gradient > 30 mmHg at rest and/or > 50 mmHg at Valsalva's maneuver or exercise New York Heart Association Functional class (NYHA) ≥ II Exclusion Criteria: Age < 18 years Known allergy to trial medicine Contraindications to beta-blocker treatment Contraindications to Magnetic resonans scan, including contraindication to the contrast agent gadolinium. Female patients who are pregnant (positive plasma-HCG), breastfeeding or of child-bearing potential while not practicing effective chemical contraceptive hormones. In case of patients having a pacemaker, they may not be pace-dependent. Treatment with Amiodarone Atrial fibrillation/flutter at the time of examination Bradycardia < 49 beats/min Systolic blood pressure < 100 mmHg Trifascicular block Previous transcoronary ablation of septum hypertrophy (TASH) or myectomy Current abuse of alcohol and/or drugs Significant co-morbidity or issues that makes the patient unsuitable for participation, judged by the investigator Patients who cannot give valid consent (e.g. mental illness or dementia) Patients who do not understand danish

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metoprolol Succinate<br>Metoprololsuccinat | Drug: Metoprolol Succinate<br>* week: uptitration with 50 mg capsules per day, until maximum dosage of 150 mg´s/day. week: steady state treatment with the maximum tolerated dose of the 1.week.<br>|
| Placebo Comparator: Placebo oral capsule<br>Placebo | Drug: Placebo oral capsule<br>* week: uptitration with 1 capsule per day, until maximum tolerated dosage of 3 capsules/day. week: steady state treatment with the maximum tolerated dose of the 1. week<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ∆Pulmonary capillary wedge pressure (rest-exercise) | Changes in pulmonary capillary wedge pressure in mmHg from rest to exercise, measured during right heart catheterization | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary capillary wedge pressure at rest | Changes in pulmonary capillary wedge pressure in mmHg during rest, measured during right heart catheterization | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 
| VO2-max | Changes in maximal oxygen consumption (L/min) measured during cardiopulmonary exercise test | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 
| LVOT gradient during maximum exercise | Changes of the LVOT gradient during maximum exercise, measured in mmHg during 2D echocardiography | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 
| Coronary flow reserve | Changes in the ratio of maximum coronary blood flow (induced by infusion of adenosin) to resting coronary blood flow, estimated by 2D doppler echocardiography | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 
| N-terminal prohormone of brain natriuretic peptide | Changes in level of N-terminal prohormone of brain natriuretic peptide (ng/L) in blood sample | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 
| Changes of symptoms and quality of life with Kansas City Cardiomyopathy Questionnaire | Changes of symptoms and quality of life with Kansas City Cardiomyopathy Questionnaire assessed by clinical evaluation | Changes will be evaluated after an expected average of 2 weeks of treatment in both treatment arms | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metoprolol, heart diseases, cardiovascular diseases, ventricular outflow obstruction, hemodynamics