Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

Abstract

Summary Background Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. Methods In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Findings Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. Interpretation In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. Funding BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

“…253 A subsequent randomized, placebocontrolled trial of boys and young men with DMD treated with background ACEI or ARB found that the addition of eplerenone resulted in better preservation of LV circumferential strain measured by CMR. 254 Although it is well known that hyperkalemia is a side effect of aldosterone blockade, and potassium levels must be monitored in patients taking aldosterone antagonists, no hyperkalemia was noted in this trial. 248,249,254 A noninferiority trial is ongoing to compare spironolactone and eplerenone in boys and young men with DMD.…”

“…254 Although it is well known that hyperkalemia is a side effect of aldosterone blockade, and potassium levels must be monitored in patients taking aldosterone antagonists, no hyperkalemia was noted in this trial. 248,249,254 A noninferiority trial is ongoing to compare spironolactone and eplerenone in boys and young men with DMD. Although these early results are promising, the relatively short duration of follow-up and the lack of confirmatory studies make their long-term benefit unknown.…”

Drugs in development and dietary approach for Duchenne muscular dystrophy

“…In this context, Raman et al 48 presented a positive placebo-controlled randomized trial in 42 DMD boys from three US centers treated with eplerenone (Pfizer Inc.) or placebo in association with steroids and on a background of ACE inhibitors or angiotensin receptor blockers. Eplerenone works by blocking the hormone aldosterone (and the aldosterone receptor), and, because it lowers the amount of sodium and water retained in the body, it is used as a diuretic in many cardiac conditions.…”

“…Significantly decreased left ventricular circumferential strain as a primary outcome was found on cardiac magnetic resonance imaging. 48 A longer follow-up would be necessary to determine if the combination of eplerenone and other cardioprotective treatments results in prolonged survival. Another potential limitation of this trial is the relative small cohort of patients, but in a disorder like DMD it is difficult to recruit adequate numbers of patients and perform blinded cardiac magnetic resonance imaging studies.…”

“…49 Two patterns of cardiac involvement are recognized: left ventricular wall motion abnormality, which is frequent in the early stage of the disease; and dilated cardiomyopathy, 4 which is more frequent in the second decade of life, such as in the patients recruited for the study reported by Raman et al 48 In a retrospective analysis, Markham et al 50 demonstrated that steroid-naïve patients (aged 10 years or younger) were four times more likely to have decreased cardiac function than patients in the same age group who had received steroids, while patients older than 10 years who had not received steroids were 15 times more likely to have decreased cardiac function than patients in the same age group who had taken steroids. Prophylactic use of cardioprotective drugs is also worth pursuing.…”