Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial

Abstract

BackgroundDuchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low‐dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate‐dose spironolactone versus eplerenone would provide similar cardioprotection in this first head‐to‐head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial.Methods and ResultsThis was a multicenter, double‐blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12–18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, −0.4 to 0.6] versus 0.2 [interquartile range, −0.2 to 0.7]; P=0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm.ConclusionsIn boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.

Duchenne Dilated Cardiomyopathy: Cardiac Management from Prevention to Advanced Cardiovascular Therapies

“…Raman et al showed that also spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk [ 52 ].…”

“…Although in adult HF, the use of betablockers is mandatory when ventricular function declines, the same evidence in children is lacking. In recent years, some retrospective and non-randomized prospective studies have demonstrated the beneficial effect of BB therapy in patients with DMD/DCM [ 52 , 55 , 56 , 57 , 58 ], while in some others this positive effect was not observed [ 59 , 60 ]. Although most of the studies are retrospective including various ages, BB in adjunct to ACEi showed to improve 5-year and 7-year survival rates [ 58 ], and also improving ventricular function [ 56 ].…”

Mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

“…In cardiac clinical trials in DMD patients, spironolactone nor eplerenone added to ACEi or ARB reduced blood pressure nor changed salt balance from baseline over 3 years compared to standard therapy alone. [21][22][23] Typical measurements of renal function by urine or serum creatine are not used in DMD because of the large amount of muscle breakdown, but cystatin C has been used to demonstrate normal renal function in DMD patients. 45,46 Therefore, although finerenone results in less worsening of renal function in chronic kidney disease, 31 specific investigations of renal function were not included in the present study.…”

<p>Left Ventricular End-Diastolic Diameter and Cardiac Mortality in Duchenne Muscular Dystrophy</p>

“…While the optimal timing for initiation of treatment with aldosterone antagonists remains unknown, early initiation has been shown to offer effective and safe cardioprotection in mice 29 and DMD patients. [30][31][32] However, it is unclear whether the attenuation of cardiac systolic dysfunction by aldosterone antagonists reduces mortality from heart failure, and there are no specific treatment policies for DMD patients with advanced heart failure. Thus, mortality from heart failure is still a major problem despite the availability of contemporary cardio-protective therapies.…”