Review question
What are the effects of treatments used to prevent or treat heart complications in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM)?
Background
The protein dystrophin is essential for muscles to work normally. DMD, BMD and XLDCM are inherited muscle diseases caused by changes in the gene that controls production of dystrophin. People with these conditions develop muscle wasting and weakness. In the heart, a lack of dystrophin causes muscle damage and scarring, which over time causes the heart to fail. Eventually the heart chambers enlarge, which is known as dilated cardiomyopathy. This serious complication can be a cause of death. There are a number of possible treatments for heart problems in these muscle conditions. One option is to reduce the workload of the heart with drugs that lower blood pressure (angiotensin-converting-enzyme inhibitors, ACE inhibitors) or slow the heart rate (beta blockers or ivabradine). Another approach is to reduce muscle damage with antioxidants (e.g. idebenone) or medicines that target inflammation (e.g. corticosteroids). Recently, drugs that increase dystrophin have been developed, including ataluren and eteplirsen.
Study characteristics
Cochrane Review authors collected all relevant studies to answer their review question. They searched for trials looking to prevent or treat heart complications in people with DMD, BMD or XLDCM. They limited the review to trials that randomly assign participants to one treatment or another, which usually provide the best evidence. They identified five small trials, with a total of 205 participants.
- A three-year study of perindopril versus placebo (an inactive pill) to prevent heart complications in 57 boys with DMD. The randomised trial was followed by two years of open treatment, then a follow-up study of 10 years when all children received perindopril.
- A one-year study of lisinopril versus losartan in 23 patients with DMD and newly diagnosed heart complications.
- A one-year study of idebenone versus placebo in 21 boys with DMD, which the manufacturer funded.
- A one-year study of eplerenone versus placebo in 42 patients with DMD who already had heart complications, which the manufacturer partly funded.
- A three-month study of growth hormone versus placebo in 10 patients with DMD or BMD.
Key results and certainty of the evidence
Based on the available evidence from RCTs, early treatment with ACE inhibitors or angiotensin receptor blockers (ARBs) may help people with DMD. In boys with early heart involvement, the effect of ACE inhibitor and ARB may be equivalent; however, the evidence is very uncertain. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice. Very low-certainty evidence indicates that adding eplerenone might give additional benefit in DMD when early cardiomyopathy is detected. We did not see a clinically meaningful effect for growth hormone or idebenone in the studies examined, although the certainty of the evidence was also very low. The trials provided only low or very low-certainty evidence on side effects.
Overall, the numbers of patients in each of these studies was small, and some studies had limitations that might have affected the results, so we are very uncertain about the results.
The evidence is current to October 2017.
Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.
The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further.
To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months.
On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies.
We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months.
Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria.
We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.
The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).
A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) −0.60% CI −6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).
A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD −0.20%, 95% CI −3.07 to 2.67, N = 21), and for ejection fraction the mean change was −1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD −2.30%, 95% CI −9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).
A multicentre controlled study added eplerenone or placebo to 42 patients with DMD with early cardiomyopathy but preserved left ventricular function already established on ACEI or ARB therapy. Results showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months (eplerenone group median 1.0%, interquartile range (IQR) 0.3 to −2.2; placebo group median 2.2%, IQR 1.3 to −3.1%; P = 0.020). The median decline in LVEF over the same period was also less in the eplerenone group (−1.8%, IQR −2.9 to 6.0) than in the placebo group (−3.7%, IQR −10.8 to 1.0; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision. Serious adverse events were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).
A randomised placebo-controlled study of subcutaneous growth hormone in 16 participants with DMD or BMD showed an increase in left ventricular mass after three months' treatment but no significant improvement in cardiac function. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were no clinically significant adverse events (very low-certainty evidence).
Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the prophylactic use of perindopril for cardioprotection ahead of detectable cardiomyopathy, and for lisinopril or losartan plus eplerenone once cardiomyopathy is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice.