March 24, 2017

Preliminary results from a study of spironolactone in Duchenne muscular dystrophy (DMD) suggest that the drug is safe in this patient group and may preserve left ventricular function.

Presenting data from the study at the recent American College of Cardiology (ACC) 2017 Scientific Sessions, John Lynn Jefferies, MD, Cincinnati Children's Hospital Medical Center, said the results were "very promising."

"If we can preserve ventricular function with medication in these patients, that would be a huge achievement," he told Medscape Medical News. "Heart failure is the number one killer in Duchenne, and if we could mitigate that then we could significantly expand the lifespan of these young people, reduce heart failure complications and hospitalizations and the need for left ventricular assist devices.  The goal would be to keep patients out of hospital with compensated cardiac function."

He explained that the earliest cardiac involvement in Duchenne appears to be fibrosis, which is linked to a drop in systolic function. "If we can mitigate the scar burden we could preserve ventricular function indefinitely."

Dr Jefferies noted that left ventricular remodelling, hypertrophy, and fibrosis have been associated with elevated aldosterone, and a previous study (published in Lancet Neurology in 2015) showed that addition of the aldosterone antagonist, eplerenone, to background angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy attenuates the progressive decline in left ventricular systolic function over 12 months.

"We wanted to confirm this benefit in another study of longer-term use. This time we used the related drug spironolactone instead of eplerenone as it is cheaper and more extensively available."

The study involved 99 boys (mean age, 14 years) with Duchenne muscular dystrophy who had evidence of myocardial fibrosis on cardiac MRI. Most patients were receiving ACE inhibitor or ARB (90%), b-blockers (79%), and steroids (96%). 

Spironolactone was added at a dose of 25 mg daily. Patients weighing less than 25 kg started on a dose of 12.5 mg, which was uptitrated to 25 mg after 4 weeks.

Coinvestigator Michelle Ploutz, MD, Cincinnati Children's Hospital Medical Center, Ohio, reported that the current study's main focus was safety, with particular interest in potassium levels, as hyperkalemia can be an issue with spironolactone. Results showed that potassium levels remained normal in all but 2 patients, but in both cases it was thought this was due to disease progression rather than the drug therapy, she said. 

Cystatin C, a maker of kidney function, remained normal in all but 11 patients. Three of these patients stopped taking spironolactone therapy, but again it was thought that disease progression contributed to the renal effects, Dr Ploutz noted.

"Overall the study shows reassuring safety results — we don't think the changes in potassium or cystatin were directly related to the drug," she added.

The mean left ventricular ejection fraction was 54.6% at the start of the study and 52.2% after a mean follow-up of 23 months.

"This is not a significant change and is less than what we would expect in these patients," he said. "Ejection fraction often drops by 1.5% to 2% per year in these patients.  So these results suggest that spironolactone may be stabilizing ventricular function. We will know more when we look at the cardiac MRI data on fibrosis. We haven't presented those results yet." 

The researchers plan to keep on following these patients and enroll more patients to obtain longer-term results.

Dr Jefferies noted that in an ideal world it would be best to do a placebo-controlled study, but this is not always possible in orphan diseases such as Duchenne. 

"If there is a suggestion of benefit, many families are averse to enrolling their children into a placebo-controlled trial, and the evidence needed for approval is less stringent in such conditions," he added.

American College of Cardiology (ACC) 2017 Scientific Sessions. Abstract 1248-256. Presented March 18, 2017.

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