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Orphanet J Rare Dis. 2019 May 10;14(1):105. doi: 10.1186/s13023-019-1066-9.

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial.

Author information

1
Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Loschgestraße 15, 91054, Erlangen, Germany. sven.dittrich@uk-erlangen.de.
2
German Competence Network for Congenital Heart Defects partner site, Berlin, Germany. sven.dittrich@uk-erlangen.de.
3
Institute of Medical Biometry and Statistics, Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
4
Department of Pediatrics, Division of Pediatric Neurology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
5
Clinic for Pediatrics III, University Hospital Essen, Essen, Germany.
6
Department of Neuropediatrics, University Hospital Essen, Essen, Germany.
7
Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
8
Department of Neurological Surgery, University Hospital Carl-Gustav-Carus, Technical University of Dresden, Dresden, Germany.
9
Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg, Bad Krozingen, Freiburg, Germany.
10
Department of Neuropediatrics and Muscle Disorders, University Medical Center, Freiburg, Germany.
11
Department of Pediatric Cardiology, Ludwig Maximilians-University of Munich, Munich, Germany.
12
Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians- University of Munich, Munich, Germany.
13
Pediatric Cardiology and Congenital Heart Disease, University Hospital Charité, Berlin, Germany.
14
Department of Pediatrics, Division of Neurology, University Hospital Charité, Berlin, Germany.
15
Division of Pediatric Heart Surgery, Pediatric Heart Center, University Hospital UKGM, Justus-Liebig University, Giessen, Germany.
16
Department of Pediatric Cardiology, Elisabeth Children's Hospital, Oldenburg, Germany.
17
Department of Pediatric Neurology, Oldenburg, Germany.
18
Department of Pediatric Cardiology and Intensive Care Medicine, Heart Center, University Medical Center Göttingen, Göttingen, Germany.
19
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Göttingen, Germany.
20
Department of Pediatric Cardiology, University of Heidelberg, Heidelberg, Germany.
21
Pediatric Neurology, University of Heidelberg, Heidelberg, Germany.
22
Clinical Trials Unit of the Medical Center, University of Freiburg, Freiburg, Germany.
23
Institute of Neuropathology, Erlangen University Hospital, Erlangen, Germany.

Abstract

BACKGROUND:

X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function.

METHODS TRIAL DESIGN:

Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting.

INCLUSION CRITERIA:

DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events.

RESULTS:

From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed.

CONCLUSIONS:

Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size.

CLINICAL TRIAL REGISTRATION:

DRKS-number 00000115, EudraCT-number 2009-009871-36.

KEYWORDS:

ACE-inhibitors; Cardiomyopathy; Duchenne muscular dystrophy; ß-blockers

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