The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy. (TEMPO)

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertrophic Cardiomyopathy
• Intervention / Treatment: Drug: Metoprolol Succinate; Drug: Placebo oral capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Danmark
    • Aarhus N, Danmark, Denmark, 8200
      • Aarhus University Hospital, Department of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metoprolol Succinate; Metoprololsuccinat	Drug: Metoprolol Succinate; 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.
Placebo Comparator: Placebo oral capsule; Placebo	Drug: Placebo oral capsule; 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

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

Collaborators and Investigators

• Sponsor: Steen Hvitfeldt Poulsen
• Investigators: Study Director: Steen Hvitfeldt Poulsen, MD, Aa; Study Director: Morten Kvistholm Jensen, MD, PhD, Aarhus University Hospital, Department of Cardiology; Study Director: Torsten Bloch Rasmussen, MD, PhD, Aarhus University Hospital, Department of Cardiology

Publications and helpful links

General Publications

• Dybro AM, Rasmussen TB, Nielsen RR, Ladefoged BT, Andersen MJ, Jensen MK, Poulsen SH. Effects of Metoprolol on Exercise Hemodynamics in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2022 Apr 26;79(16):1565-1575. doi: 10.1016/j.jacc.2022.02.024.
• Dybro AM, Rasmussen TB, Nielsen RR, Andersen MJ, Jensen MK, Poulsen SH. Randomized Trial of Metoprolol in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2021 Dec 21;78(25):2505-2517. doi: 10.1016/j.jacc.2021.07.065.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): September 1, 2020
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: April 19, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): March 29, 2021
• Last Update Submitted That Met QC Criteria: March 24, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: cardiovascular diseases; hemodynamics; metoprolol; heart diseases; ventricular outflow obstruction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: 1-10-72-441-17

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No