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

Sven DittrichEmail author View ORCID ID profile,
Erika Graf,
Regina Trollmann,
Ulrich Neudorf,
Ulrike Schara,
Antje Heilmann,
Maja von der Hagen,
Brigitte Stiller,
Janbernd Kirschner,
Robert Dalla Pozza,
Wolfgang Müller-Felber,
Katja Weiss,
Katja von Au,
Markus Khalil,
Reinald Motz,
Christoph Korenke,
Martina Lange,
Ekkehard Wilichowski,
Joseph Pattathu,
Friedrich Ebinger,
Nicola Wiechmann,
Rolf Schröder and
on behalf of the German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network Investigators list of additional local Investigators and co-workers of the German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network

Orphanet Journal of Rare Diseases201914:105

https://doi.org/10.1186/s13023-019-1066-9

Received: 2 July 2018
Accepted: 17 April 2019
Published: 10 May 2019

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.