primary outcome:
Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X‐linked dilated cardiomyopathy
Dystrophinopathies typically cause profound and progressive physical disability, so even in the context of severe dilated cardiomyopathy, patients usually experience few if any cardiac symptoms. Therefore it is rarely possible to differentiate death in the context of a chest infection with associated respiratory failure from death of primary cardiac aetiology. Indeed it is likely that the occurrence of a lower respiratory infection in a patient with advanced cardiomyopathy can precipitate cardiorespiratory deaths. For this reason we have chosen surrogate measures of cardiac function rather than morbidity and mortality as our primary outcome measure.We assessed changes in cardiac function following a six‐month period of intervention using 'equivalent techniques' such as echocardiography (ejection fraction (EF), fractional shortening (FS), ventricular dimensions: left ventricular systolic diameter (LVsd), left ventricular diastolic diameter (LVdd), wall motion), tissue Doppler echocardiography, cardiac magnetic resonance imaging (CMRI), and gated radionuclide imaging (ejection fraction). For each, we divided reported outcomes into those measuring benefit (i.e. stable or improved) and those measuring deterioration. In children, in whom echocardiography is usually the preferred intervention, measuring FS and EF have been shown to correlate well with other modalities such as CMRI (Soslow 2016; Spurney 2015).Duboc 2005 did not provide data on numbers of participants whose cardiac function improved or remained stable versus deteriorated, nor did authors report outcomes for the six‐month time period. The trial authors did report a dichotomous cardiac function outcome: the number of participants with an LVEF of less than 45% at the end of each study phase (36 months and 60 months).At the end of phase 1 (the randomised phase), LVEF remained normal in most participants, and there was no significant difference in mean LVEF of either group (exact P value not given). Baseline LVEF was 65.0% (SD 5.5) in the treated group (N = 28) and 65.5% (SD 5.5) in the placebo group (N = 29). At the end of 36 months, mean LVEF was 60.7% (SD 7.6) in the treated group versus 64.4% (SD 9.8) in group 2. The difference between groups was not statistically significant (exact P value not given). However, one participant in each group had an LVEF of less than 45% (i.e. established cardiomyopathy) at 36 months (RR 1.04, 95% CI 0.07 to 15.77; very low‐certainty evidence; N = 57; Analysis 1.1).We downgraded the certainty of evidence three times, from high to very low, because of serious imprecision (small study size and low event rate), study limitations, and indirectness (a three‐year follow‐up is too short at this stage of DMD to detect effects on cardiac function). See the Discussion for data from the non‐randomised phase 2 of the study and long‐term follow‐up (Duboc 2005; Duboc 2007).In Allen 2013, the authors do not quote the numbers whose LVEF% improved or stabilised versus those in whom it deteriorated, which we specified as our primary outcome; however, the trialists reported the number whose LVEF fell below 45%. The other primary trial outcome was reduction in mean LVEF, which trialists reported after four months, eight months, and one year of therapy.Mean LVEFs were similar at baseline: 47.5% in the lisinopril group (N = 12) and 48.3% in the losartan group (N = 10) (P = 0.93). At eight months, mean LVEF% was similar in the two groups: 52.9% in the lisinopril group (N = 10) and 53.7% in the losartan group (N = 9). Trialists did not report SDs.LVEF improved in each group from baseline to 12 months (lisinopril group, P = 0.02 and losartan group, P = 0.03), but there was no important difference in LVEF between the two groups among participants who provided data at 12 months (lisinopril 54.6% (SD 5.19) versus losartan 55.2% (SD 7.19); MD −0.60%, 95% CI −6.67 to 5.47; 16 participants; very low‐certainty evidence). The study was curtailed early because of funding shortfalls, but the trial authors showed clearly where data were missing.We downgraded the certainty of evidence three times, from high to very low, because of serious imprecision (small study size and CI that included clinically important effects in either direction) and study limitations (multiple but not controlled concomitant medications, and a large number of dropouts in the lisinopril group (due to cessation of funding (n = 5), allergic reaction (n = 1) and poor LVEF at the start of the study or during the study (n = 3)).Buyse 2011 reported outcomes at one year but not at six months. The trial authors did not provide data for our primary outcome (number of participants in whom left ventricular function improved or stabilised versus deteriorated). They reported continuous cardiac function outcomes comparing the difference between idebenone treatment and placebo for global ventricular function and left ventricular peak strain measures.In terms of measures of global ventricular function, the mean change in fractional shortening from baseline to 12 months 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). Corresponding changes in ejection fraction were −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 = 19).We downgraded the certainty of evidence three times for these measures from high to very low because of very serious imprecision (downgraded twice for imprecision because the trial was small and CI included clinically relevant effects in either direction), and once for study limitations (baseline imbalance), and some indirectness (participants appeared to be at a more advanced stage of cardiomyopathy than 'pre‐clinical' but were not receiving ACE inhibitors).Posterolateral left ventricular peak strain measures were lower at baseline in those randomised to idebenone. This was because those randomised to idebenone (N = 13) were significantly older than those randomised to placebo (N = 8). Idebenone showed an improvement in left ventricular peak systolic radial strain measures from baseline compared to placebo. The mean increase was 17.3% (SD 13.1) in the idebenone group versus 7.5% (SD 12) P = 0.067) in the placebo group (MD 9.80%, 95% CI −1.99 to 21.59; Analysis 3.3; low‐certainty evidence). The change in systolic radial strain rate left ventricular inferolateral wall in the idebenone group was 0.5 s‐1 (SD 0.6; N = 10) and in the placebo group 0.0 s‐1 (SD 0.9; N = 7) (MD 0.50 s‐1, 95% CI −0.26 to 1.26; Analysis 3.4; very low‐certainty evidence).We downgraded the certainty of evidence from high to very low because of serious imprecision (the trial was small and CI included clinically relevant effects in either direction), study limitations (baseline imbalance) and indirectness.Due to the significant age‐related baseline difference between the groups, the authors performed a prespecified secondary analysis to determine percentage change from baseline. This showed a 104.4% change from baseline for idebenone compared to 28.9% for placebo (P = 0.030; SD for changes not given).See Analysis 3.5; Analysis 3.6; Analysis 3.7; Analysis 3.8 for other cardiac measures from this study.Raman 2014 does not state the number of participants whose left ventricular function improved or stabilised versus the number who deteriorated. The study reported results as the difference in changes in LVEF% and circumferential strain between patients receiving eplerenone or placebo from baseline to 6 months, 6 to 12 months, and baseline to 12 months. The study randomised 42 participants and gave the total number of participants completing baseline, 6‐month and 12‐month visits, together with total numbers of analysable examinations, but the number of participants providing data for the outcomes at each time point is not clear.There was no significant difference in the median decline of LVEF from baseline to six months between the eplerenone group (0%, IQR −3.8 to 4.0) and the placebo group (1.0%, IQR −5.0 to 2.1) (P = 0.474). From 6 months to 12 months, the decline in LVEF was smaller in the eplerenone group (1.6, IQR −0.8 to 2.9) than in the placebo group (−2.8, IQR −5.7 to −1.8) (P = 0.036). This difference was also present in the change from baseline to 12 months, when the median decline of LVEF in the eplerenone group was −1.8% (IQR −2.9 to 6.0) versus −3.7% (IQR −10.8 to 1.0) in the placebo group (P = 0.032).There were no significant differences in mean decline in left ventricular systolic circumferential strain magnitude between the eplerenone group (0.84% (SD 2.68)) and the placebo group (0.38% (SD 2.56)) from baseline to six months (P = 0.602 or from 6 months to 12 months (P = 0.379). At 12 months, the median decline in left ventricular systolic circumferential strain was less in the eplerenone‐treated group (1.0%, IQR 0.3 to −2.2) than in the placebo group (2.2%, IQR 1.3 to −3.1) (P = 0.020).The trial authors considered an absolute difference of 1% in strain units at 12 months as clinically significant.We downgraded the evidence to very low certainty for study limitations (the study did not control for concomitant medications, which were numerous) and twice for imprecision; as the study was small (N = 42 randomised), and measures of variance allow for the possibility of a clinically important difference in either direction. There was also some indirectness. LVEF% in some participants would constitute 'definite cardiomyopathy'.Cittadini 2003 did not provide data on the numbers of participants whose heart function improved or stabilised versus deteriorated, and authors reported outcomes only at three – not at six – months. The study authors reported continuous cardiac function outcomes comparing LVEF and left ventricular mass index in participants receiving GH or placebo for a three‐month time period. There were no between‐group comparisons of echocardiographic indices for the DMD group (N = 6) due to the small sample size; left ventricular mass index, end‐systolic stress and ejection fraction results were presented graphically. Authors reported results in BMD and DMD participants for active versus placebo therapy separately.We considered the certainty of evidence very low because of study limitations, imprecision (N = 16), and indirectness (three‐month study duration rather than our specified six months).In participants with BMD (N = 10), left ventricular volumes were larger and LVEF lower compared with DMD participants. In the GH‐treated BMD participants, left ventricular mass increased by approximately 42 g (trend towards increased left ventricular posterior and anterior wall thickness) compared with a slight decrease in these measurements in the placebo group. The authors reported a "concentric remodelling of the left ventricular cavity with a significant increase of the relative wall thickness of 12%" in the GH‐treated BMD group, compared to no change in the placebo‐treated group (no measures of variance reported). End diastolic volumes did not change significantly over time.In GH‐treated DMD participants, the study authors report a 29% increase in left ventricular mass compared to the placebo‐treated group. The study authors also report a non‐significant trend for increase in left ventricular fractional shortening (LVFS) in GH‐treated DMD participants.