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

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. Electronic supplementary material The online version of this article (10.1186/s13023-019-1066-9) contains supplementary material, which is available to authorized users.

A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy

“…In the first of those trials, Duboc et al 9 found no difference in LVEF in the subjects treated with perindopril for 3 years when compared with subjects receiving placebo. In the second trial, 20 19 months of combination therapy with enalapril and metoprolol did not alter the time it took for LV FS to fall to a level below 28% when compared with controls. In the third study, 16 2 years of treatment with enalapril appeared to reduce the progression of fibrosis as assessed by CMR and late gadolinium enhancement when compared with a placebo group; however, there was no significant difference in LVEF between the two groups.…”

“…Randomized trials ( n = 10) studied the effects of ACEI or ACEI plus BB ( n = 4), 8,9,16,20 aldosterone inhibitors ( n = 2), 29‐31 and four other novel therapies 26‐28,32 …”

“…Three trials of ACEI focused on younger patients (mean ages 10.7–13.1 years) with initially normal LV function 9,16,20 . In the first of those trials, Duboc et al 9 found no difference in LVEF in the subjects treated with perindopril for 3 years when compared with subjects receiving placebo.…”

Recurrent hypotension induced by sacubitril/valsartan in cardiomyopathy secondary to Duchenne muscular dystrophy: A case report

“…Thirty-eight patients from 10 sites were centrally randomized into the intervention group (combined treatment with enalapril and metoprolol) and a placebo control group. The results showed that the administration of ACEI and β-blocker delayed the progression of intrinsic cardiomyopathy to left ventricular failure in DMD patients with preserved left ventricular function, although this did not reach statistical significance[25]. Further studies should be conducted to determine the effect of ARNIs in DMD patients with preserved left ventricular function.…”

Cardiac medication management in Duchenne muscular dystrophy

“…While there was no difference in left ventricular ejection fraction between groups, this may have been a function of the duration and size of the study. Longer term and larger studies will be needed to answer this question more definitively given the relatively slow progression of dysfunction noted in the current era 34,35 . Based on the current data, the Care Considerations have recommended initiating therapy at age 10, 1 while the AHA has suggested this approach may be considered before the onset of reduced systolic function 18 .…”