Pharmacological therapy for the prevention and management of cardiomyopathy in Duchenne muscular dystrophy: A systematic review

Accepted Manuscript Title: Pharmacological therapy for the prevention and management of cardiomyopathy in duchenne muscular dystrophy: a systematic review Author: Basmah El-Aloul, Luis Altamirano-Diaz, Eugenio Zapata-Aldana, Rebecca Rodrigues, Monali S. Malvankar-Mehta, Cam-Tu Nguyen, Craig Campbell PII: DOI: Reference:

S0960-8966(16)30811-2 http://dx.doi.org/doi: 10.1016/j.nmd.2016.09.019 NMD 3263

To appear in:

Neuromuscular Disorders

Received date: Revised date: Accepted date:

11-7-2016 16-9-2016 26-9-2016

Please cite this article as: Basmah El-Aloul, Luis Altamirano-Diaz, Eugenio Zapata-Aldana, Rebecca Rodrigues, Monali S. Malvankar-Mehta, Cam-Tu Nguyen, Craig Campbell, Pharmacological therapy for the prevention and management of cardiomyopathy in duchenne muscular dystrophy: a systematic review, Neuromuscular Disorders (2016), http://dx.doi.org/doi: 10.1016/j.nmd.2016.09.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Pharmacological therapy for the prevention and management of cardiomyopathy in Duchenne muscular dystrophy: a systematic review

Basmah El-Aloula, Luis Altamirano-Diazb, Eugenio Zapata-Aldanab,d, Rebecca Rodriguesa, Monali S. Malvankar-Mehtaa,c, Cam-Tu Nguyenb,d, Craig Campbella,b,d

a

Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

b

Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

c

Department of Ophthalmology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada

d

Clinical Neurological Sciences, Children’s Hospital, London Health Sciences Center, London, Ontario, Canada

Corresponding author:

Craig Campbell B1-177, Children’s Hospital, London Health Sciences Center 800 Commissioners Road East, London, Ontario, Canada, N6A 5W9 Tel: +1 519 685 8332 Fax: +1 519 685 8350 [email protected]

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Abstract

Cardiomyopathy is a major source of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients now that respiratory care has improved. There is currently no definitive evidence guiding the management of DMD-associated cardiomyopathy (DMD-CM). The objective of this systematic review was to evaluate the efficacy of pharmacotherapies for the prevention and/or management of DMD-CM and to determine the optimal timing to commence these interventions. A systematic search was conducted in January 2016 using MEDLINE, EMBASE and CINAHL databases and grey literature sources for studies evaluating the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta-blockers (BB) or aldosterone antagonists (AA). Study quality assessment was conducted using the Downs and Black quality assessment checklist. PRISMA reporting guidelines were used. Of the 15 studies included in this review, most were of low methodological quality. Meta-analysis was not possible due to heterogeneity of studies. ACE inhibitor, ARB, BB and/or AA therapy tended to improve or preserve left ventricular systolic function and delay the progression of DMD-CM. While there is evidence supporting the use of heart failure medication in patients with DMD, data regarding these interventions for delaying the onset of DMD-CM and when to initiate therapy is lacking. PROSPERO registration: CRD42015029555.

Keywords: Duchenne muscular dystrophy; cardiomyopathy; heart failure.

Abbreviations: DMD, Duchenne muscular dystrophy; DMD-CM, Duchenne muscular dystrophy-associated cardiomyopathy; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BB, beta-blocker; AA, aldosterone antagonist.

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1. Introduction Duchenne muscular dystrophy (DMD) is the most common and severe form of childhood muscular dystrophies, affecting 1 in 3,600 to 6000 live male births [1]. DMD is an X-linked recessive disease characterized by the absence of or defect in the sarcolemmal protein dystrophin. The lack of dystrophin ultimately results in progressive muscle degeneration [2,3]. Patients are typically diagnosed between the ages of 3 and 7 years, when their physical ability diverges noticeably from their peers. Loss of independent ambulation occurs by 13 years of age [4–6]. Without intervention, premature death associated with respiratory or cardiac failure occurred in the late teens [7]. Improved medical management with long-term glucocorticoid therapy and non-invasive ventilation has prolonged survival, with patients now having a possible life expectancy into their fourth decade [1,8]. Improved respiratory care has unmasked cardiomyopathy as a major source of morbidity and mortality [9]. In the dystrophin-deficient myocardium, fibrosis caused by the degeneration of cardiomyocytes proceeds to dilated cardiomyopathy and is further complicated by heart failure and arrhythmia [10,11]. Onset of DMD-associated cardiomyopathy (DMD-CM) occurs at a mean age of 14 to 15 years and is a universal consequence by adulthood [12,13]. There is currently no consensus regarding the appropriate pharmacological management of DMD-CM and the optimal time to initiate pharmacotherapy [1,14]. In 2010, the DMD Care Considerations Group published consensus-based recommendations for DMD patients, which advised the use of angiotensinconverting enzyme (ACE) inhibitors as first-line therapy for DMD-CM [1,15]. The use of ACE inhibitors has now become widespread in the DMD population. In patients who are unable to tolerate ACE inhibitors, angiotensin receptor blockers (ARBs) may be used [16]. An expert Working Group recently published updated cardiac care recommendations, which recommend that ACE inhibitor/ARB therapy should be initiated by the age of 10 years, however it is unclear if earlier therapy is warranted. While a beta-blocker (BB) is often initiated after ACE inhibitor/ARB therapy for progressive cardiac decline, recommendations for their use remain variable [14]. Aldosterone antagonism has recently demonstrated favourable effects on cardiac function in DMD and the use of an aldosterone antagonist (AA) is currently under further investigation [17].

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The objective of this systematic review is to evaluate the effectiveness of pharmacological therapies for the prevention and management of DMD-CM and to determine the optimal timing to commence these interventions. This review aims to summarize and critically appraise the current body of scientific literature relating to the use of ACE inhibitors, ARBs, BBs and AAs in the DMD population. 2. Materials and Methods This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. The protocol of this systematic review was registered in PROSPERO (CRD42015029555), an international database of prospectively registered systematic reviews in health and social care. 2.1. Search strategy A systematic search was conducted using MEDLINE (Ovid), EMBASE and CINAHL databases. A grey literature search was conducted using Web of Science™ Core Collection, BIOSIS Previews®, ClinicalTrials.gov, International Clinical Trials Registry Platform, UK Clinical Trials Gateway, UK Clinical Research Network Study Portfolio, Cochrane Center Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Electronic Theses Online Services (EThoS), Networked Digital Library on Theses and Dissertations, Theses Canada Portal, ProQuest Dissertations and Theses, Centers for Disease Control and Prevention, and U.S. Food and Drug Administration. Searches were conducted in October 2015, and updated in January 2016. A comprehensive search strategy was developed with guidance from a research librarian using terms related to DMD, cardiomyopathy, ACE inhibitor, ARB, BB, AA and additional heart failure medications. The search strategies employed database- and platform-specific terminology and syntax. Alerts were set up for each database to receive publication notifications for relevant newly published articles. See Appendix A for detailed search strategies and search results. 2.2. Inclusion and exclusion criteria

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The PICOS (population, intervention, comparator, outcomes, study design) approach was used to specify the inclusion and exclusion criteria [19]. The population was defined as male patients of any age who have a diagnosis of DMD confirmed by mutation analysis of the DMD gene or by the absence of dystrophin protein expression on muscle biopsy, and a phenotype consistent with DMD. The interventions under investigation were ACE inhibitors, ARBs, BBs and AAs. Studies were not excluded based on types of control groups used or lack thereof. Outcomes of interest included both surrogate measures of cardiac function and clinical outcomes. The primary outcomes were changes in left ventricular ejection fraction (LVEF) and fractional shortening (FS) measured using echocardiography, cardiac magnetic resonance imaging (cMRI) or radionuclide ventriculography. Canadian Cardiovascular Society paediatric heart failure guidelines define left ventricular (LV) systolic dysfunction as LVEF<50% and/or FS<25% [20], while abnormal LVEF in adults is commonly defined as <55% by echocardiography or <60% by cMRI [21–24]. Secondary outcomes included the following measures by echocardiography, cMRI or radionuclide ventriculography: left ventricular end diastolic and systolic diameters (LVEDd and LVESd), left ventricular end diastolic and systolic volumes (LVEDv and LVESv), left ventricular mass (LVM) and heart rate (HR). Peak left ventricular circumferential strain (εcc) and myocardial fibrosis evident by late gadolinium enhancement were also of interest as they have been found to be early markers of myocardial damage before the onset of ventricular dysfunction [25,26]. Additional clinical outcomes of interest included levels of blood biomarkers indicative of heart failure, adverse events, hospital admissions due to heart failure, signs and symptoms of congestive heart failure, arrhythmias and survival. Types of records included were full-text research studies (experimental or observational) with a sample size greater than 1 DMD patients, published in English. Non-research articles such as review articles, editorials, commentaries and case reports were excluded. Records were not excluded based on country or date of publication. 2.3 Study selection All records were imported into EPPI Reviewer 4 [27]. Duplicate records were removed prior to screening. Two authors (BE and RR) independently screened records against the inclusion and exclusion criteria in three consecutive stages by title, abstract and full-text. Kappa statistics were calculated following

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each stage to measure agreement between authors. Kappa values between 0.40 and 0.59 were considered to reflect fair agreement, between 0.60 and 0.74 to reflect good agreement and 0.75 or more to reflect excellent agreement [28]. Any disagreements at each stage were resolved by consensus. Reference lists of included studies and excluded non-original data studies were searched to ensure no records were omitted from the search strategy. When full-text articles corresponding to relevant conference abstracts could not be located, authors were contacted and asked to provide full reports. Authors of studies that included patients with other muscular dystrophies were contacted and asked to provide data on DMD patients exclusively when a subgroup analysis was not already provided. 2.4 Data abstraction Two authors (BE and EZ) independently extracted data from the included studies in the following areas: study description (year, language, study location, study centers, publication status, study design), population (sample size, method of diagnosis, disease severity, background medical therapies), intervention (medication, dosage, duration), comparator (placebo/medication, dosage, duration), baseline characteristics (age, echocardiography, cMRI or radionuclide ventriculography measures) and outcomes (echocardiography, radionuclide ventriculography and cMRI measures, clinical outcomes). In cases where little numerical data was presented, study authors were contacted to provide summary statistics. 2.5 Study quality One reviewer (BE) completed a quality assessment for each included study using the Downs and Black quality assessment checklist, which is composed of 27 items comprising five subdomains: reporting (10 items), external validity (3 items), bias (8 items), confounding (6 items) and power (1 item) [29]. Randomized and non-randomized studies can be assigned maximum scores of 28 and 25, respectively. Scores of 26 to 28 were considered excellent, 20 to 25 good, 15 to 19 fair and 14 or below were considered poor [30].

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2.6 Statistical analyses Due to heterogeneity of the included studies, meta-analyses could not be performed to obtain pooled intervention effect estimates. Similarly, publication bias could not be assessed using a funnel plot. Heterogeneity of the included studies, with respect to patient populations, interventions, comparators, outcome measures and study designs, is addressed further in the results and discussion. 3. Results 3.1 Study selection and quality A total of 384 records were retrieved from databases (86 from MEDLINE (Ovid), 280 from EMBASE and 18 from CINAHL) and an additional 329 records were retrieved from grey literature sources. Of the 499 abstracts remaining after duplicate records were removed, 78 met eligibility criteria for full-text review (Fig. 1). Fifteen studies (16 records) met all eligibility criteria and were included in the systematic review [16,17,31–44]. Kappa statistics, computed to measure inter-rater reliability between the reviewers, were 0.60, 0.72 and 0.92 for title, abstract and full-text screening, respectively. The characteristics of included studies and their quality assessment according to the Downs and Black quality assessment checklist are presented in Table 1 [29]. The included studies were published between 1995 and 2015, and consisted of three double-blind randomized controlled trials (RCTs), two openlabel RCTs, two non-randomized trials, four retrospective cohort studies, two prospective case series and two retrospective case series. A full quality assessment report is provided in Appendix B. Briefly, two studies were determined to be of poor quality, seven of fair quality and six of good quality. 3.2 Summary of findings

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A summary of methods and results of the included studies is presented in Table 2. A diagnosis of DMD was confirmed by mutation analysis or muscle biopsy in nine studies. Four studies included patients with other muscular dystrophies in their sample—particularly Becker’s, Fukuyama and Emery-Dreifuss muscular dystrophies. The number of patients with other types of muscular dystrophies in these studies was small relative to the number of DMD patients. Echocardiography was the most common mode of cardiac assessment (N=12), followed by cMRI (N=3) and radionuclide ventriculography (N=2). The most common measure of cardiac function used to classify patients by DMD-CM status was LVEF (N=13), followed by FS (N=4). Raman et al. used myocardial fibrosis in one or more LV segment evident by late gadolinium enhancement as an additional criteria for DMD-CM [17]. Ishikawa et al. used abnormal LVEDd, in addition to LVEF, to diagnose DMD-CM. Ishikawa et al. recruited patients with congestive heart failure, which was defined as DMD-CM with elevated atrial natriuretic peptide (ANP) levels [43]. Not only were different imaging modalities used across studies, but different LVEF and FS cut-off points were applied to diagnose DMD-CM. The LVEF cut-off point indicative of DMD-CM ranged from 40% to 55%. The FS cut-off point indicative of DMD-CM ranged from 20% to 28%. Based on the Canadian Cardiovascular Society pediatric heart failure guidelines, which define LV systolic dysfunction as LVEF<50% and/or FS<25% [20], six studies initiated treatment with cardiac medications after the onset of LV systolic dysfunction in all patients [35–37,40,43,44], one study initiated treatment before the onset of LV systolic dysfunction in all patients [39], and the remaining studies included a combination of patients with and without LV systolic dysfunction. The ages at which treatment with cardiac medications were initiated are presented in Table 3. In most patients, treatment was initiated in early to mid-teenage years. However, several studies included patients who started treatment as young as 7 years of age or when they reached adulthood. Because different definitions of cardiomyopathy were applied across studies, it was challenging to clearly distinguish whether studies used cardiac medications prophylactically or for the management of established DMD-CM according to Canadian Cardiovascular Society paediatric heart failure guidelines. However, the distinction between prophylactic use and management was cautiously made based on the objectives of individual studies and the definition of cardiomyopathy applied by the study authors. Accordingly, four studies included in this review evaluated prophylactic effects of cardiac medications [17,32,34,39]. In a two-phase double-blind RCT, Duboc et al. examined the prophylactic effects of the ACE inhibitor perindopril on the onset and progression

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of DMD-CM. All patients had LVEF>55% measured using radionuclide ventriculography and were 9.5 to 13 years of age at baseline. In phase I, patients were randomized to receive perindopril or placebo for three years. In phase II, all patients received open-label perindopril for an additional seven years. No significant difference in mean LVEF was observed at three and five years between patients who received early versus delayed treatment with perindopril. However, one of 27 patients who received early treatment with perindopril had LVEF<45% at five years, compared to eight of 29 who received delayed treatment (P = 0.02). Early initiation of perindopril was also associated with significantly lower mortality [38,39]. The double-blind, placebo-controlled RCT by Raman et al. evaluated the prophylactic effects of an AA (eplerenone) when added to an ACE inhibitor or ARB in patients with normal LV function (LVEF≥45%) and myocardial damage by cMRI, and concluded that eplerenone attenuated the progressive decline in LV systolic dysfunction relative to placebo [17]. In a retrospective cohort study, Kwon et al. reported no significant changes in LVEF during a 3-year follow-up period in a subgroup of seven patients with initial LVEF>50% receiving an ACE inhibitor or ARB either alone or with a BB, along with ventilatory support. This finding suggests that stabilization of LV function may be achieved with optimal cardiac medication therapy and adequate ventilatory support. Hor et al. aimed to assess the effects glucocorticoid use alone or in combination with an ACE inhibitor or ARB on cMRI-derived εcc in a retrospective cohort of patients with normal LV function. Hor et al reported that an ACE inhibitor or ARB plus a glucocorticoid was not more effective in arresting the decline in LV systolic dysfunction compared to glucocorticoid monotherapy [34]. With the exception of Raman et al. who evaluated the effectiveness of an AA [17], all studies evaluated the effectiveness of an ACE inhibitor (lisinopril, enalapril, perindopril, cilazapril or captopril), ARB (losartan) or BB (carvedilol, metoprolol, bisoprolol or atenolol) as either monotherapy or combination therapy for DMD-CM. Adverse effects were reported to be mild and infrequent. Up-titration to maintenance doses, particularly for BBs, was typically performed in an effort to avoid adverse effects. Adverse effects and maintenance doses of medications for each study are summarized in Table 4. Although ACE inhibitors and ARBs were typically used interchangeably in study designs, the double-blind RCT by Allen et al. sought to compare their effectiveness and

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safety in an equivalence trial. No therapeutic difference was observed between lisinopril and losartan in improving LVEF over a one-year period in boys with DMD-CM [16]. Outcomes in 14 out of 15 studies included parameters of LV function measured using echocardiography, cMRI or radionuclide ventriculography (Table 2). Of these 14 studies, 12 measured changes in LVEF as either the only imaging parameter or among other imaging parameters, and the other two studies measured FS. Six studies evaluated levels of a blood biomarker indicative of heart failure. Seven studies evaluated other clinical outcomes including survival, hospital admissions due to heart failure, arrhythmias and cardiopulmonary symptoms. Rhodes et al. incorporated a self-report questionnaire to quantify changes in overall health status [37]. Improvements in LV systolic dysfunction, measured by LVEF or FS, in patients with clinically evident DMD-CM following treatment with cardiac medications were reported in 10 studies [16,31–33,37,40–44]. Rather than observing improvements in LV systolic dysfunction in patients without evidence of DMD-CM or with early DMD-CM, treatment with cardiac medications delayed the onset or attenuated the progressive decline in LV systolic dysfunction in three studies [17,32,39]. Duboc et al. demonstrated that earlier intervention with perindopril was significantly associated with higher survival free from all-cause death over a 10-year follow-up period in patients with preserved LVEF at baseline [38]. Likewise, Ogata et al. reported significantly higher 5-, 7- and 10-year survival free from all-cause death in patients with asymptomatic heart failure compared to patients with symptomatic heart failure when treated with an ACE inhibitor plus BB [36]. While Matsumura et al. observed no differences in LVEF in patients treated with carvedilol plus an ACE inhibitor or ARB compared to patients treated with an ACE inhibitor or ARB alone, 5-year survival free from all-cause death, deterioration of heart failure and severe arrhythmia was significantly higher in patients who received carvedilol compared to those who did not. Survival free from all-cause death was also higher in patients who received carvedilol, although this difference was not significant. [35]. 4. Discussion

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Studies included in this review reported modest improvements in LV systolic dysfunction in patients with established DMD-CM following monotherapy or combination therapy with ACE inhibitors, ARBs or BBs [16,31–33,37,40–44]. In studies where cardiac medications were used prophylactically, treatment did not prevent the deterioration of LV systolic function, but rather attenuated the progressive decline in LV systolic function that is typically observed following the onset of DMD-CM [17,32,39]. Improvements in survival were demonstrated in three scenarios: early initiation of an ACE inhibitor in patients with preserved LVEF, combination therapy of an ACE inhibitor plus BB in patients with asymptomatic heart failure compared to patients with symptomatic heart failure and lastly, combination therapy with an ACE inhibitor or ARB plus BB compared to monotherapy in patients with abnormal LVEF [35,36,38]. However, these results should be interpreted cautiously due to limitations of the studies included in this review. Several studies aimed to investigate the effectiveness of an ACE inhibitor plus BB as combination therapy. Although a survival benefit was reported in patients who received an ACE inhibitor plus BB, neither Viollet et al. nor Matsumara et al. observed a difference in LVEF changes in patients with DMD-CM who received an ACE inhibitor plus BB compared to patients who received an ACE inhibitor alone, making it difficult to directly ascribe the survival benefit to a cardiac mechanism [31,35]. In an open-label RCT, Kajimoto et al. observed a significant improvement in FS in patients who received an ACE inhibitor plus BB, which was not observed in patients who received an ACE inhibitor alone, but this study did not assess survival [40]. Additional studies which evaluated the effectiveness of an ACE inhibitor plus BB did not include monotherapy control groups [32,36,42–44]. Given that only one study [40] evaluating the effectiveness of an ACE inhibitor plus BB for the management of DMD-CM was an RCT, no firm conclusion can be drawn regarding this particular combination therapy compared to monotherapy. Reports of patients unable to reach maintenance doses were rare, indicating that these cardiac medications may be safely initiated in DMD patients. However, carvedilol doses in the trial by Matsumura et al. were lower than doses administered in other studies of DMD patients or children with cardiomyopathy [35,37,40,45,46]. Insufficient doses of carvedilol may therefore be the reason that functional cardiac changes did not accompany lower rates of

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all-cause death, deterioration of heart failure and severe arrhythmia in patients who received carvedilol. Additionally, Matsumura et al. reported that patients who experienced clinical endpoints (all-cause death, deterioration of heart failure and severe arrhythmia) had lower maintenance doses of carvedilol compared to patients free from clinical endpoints [35]. In BB trials of adult heart failure patients, functional cardiac changes and survival were dose-dependent, with higher doses associated with better outcomes [47,48]. Therefore, inconclusive evidence regarding added benefits of a BB when administered with an ACE inhibitor or ARB may have resulted from subtherapeutic doses. Several studies included in this review did not report background medical therapies that patients received during the follow-up period or did not control for uneven distribution of background medical therapies between treatment groups in the analyses. Only four out of 15 studies reported the proportion of patients receiving glucocorticoid therapy [16,17,31,34]. Glucocorticoids have been demonstrated to slow the decline in muscle strength and function in DMD patients, consequently reducing the risk of scoliosis and stabilizing respiratory function [49–51]. Moreover, glucocorticoid therapy has been demonstrated to delay the onset and progression of DMD-CM [52–55]. Glucocorticoids are a part of care recommendations for all patients with DMD and are largely in routine use [1]. Because glucocorticoid therapy is considered a standard of care, results from studies in which patients were not treated with background glucocorticoid therapy may not be externally valid. Hor et al. underscored this concern by demonstrating, albeit retrospectively, that treatment with an ACE inhibitor or ARB in addition to glucocorticoid therapy was not more effective than glucocorticoid therapy alone in arresting the decline in cardiac function. The treatment of respiratory insufficiency and scoliosis can provide indirect cardiac benefits, and should also be considered in the design and analysis of future clinical trials to successfully isolate the treatment effect of cardiac medications [56]. Four studies included patients with other muscular dystrophies, most commonly Becker’s muscular dystrophy (BMD) [33,37,40,42]. Patients with other muscular dystrophies accounted for 4% to 22% of the samples and were included in the same analyses as DMD patients. However, DMD and BMD patients have different prognoses and clinical manifestations of cardiomyopathy [57]. Onset of cardiomyopathy typically occurs in the second decade of life in DMD,

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compared to the third decade of life in BMD [58]. Patients with BMD have more severe LV dilation and valvular regurgitation at the time of cardiomyopathy onset than do DMD patients. Five-year survival from onset of cardiomyopathy is lower in DMD patients compared to BMD patients, for whom cardiac transplantation may be a viable option [13]. Not surprisingly, echocardiography was the most commonly used imagining modality to evaluate cardiac function. Echocardiography, which is widely available clinically, is the first-line technique in the assessment of paediatric heart failure [59]. Cardiac assessment recommendations for DMD patients include a baseline echocardiogram at 6 years of age, with subsequent bi-annual echocardiograms until the age of 10 years and annual echocardiograms after the age of 10 years [15]. However, the technical quality and interpretability of echocardiography may be limited in some DMD patients due to chest wall deformities, scoliosis, obesity, respiratory insufficiency and limited mobility [14]. As a result, advanced imaging techniques such as cMRI are becoming more widely applied to DMD patients [26,60]. Three out of 15 studies in this review utilized cMRI, one of which assessed myocardial damage and fibrosis evident by late gadolinium enhancement [17,34,37]. This enhancement, as well as abnormalities in εcc can be detected by cMRI before an overt decline in LVEF or FS [26,60– 62]. Because late gadolinium enhancement and εcc abnormalities are predicted to reflect the first signs of myocardial involvement in DMD, they have been used to support early initiation of cardiac medications and are warranted outcomes in future clinical trials involving patients with subclinical DMD-CM [14,62]. Furthermore, cMRI provides more reliable and reproducible measurements of ventricular structure and function compared to echocardiography [63]. This allows for unavoidably smaller sample sizes in clinical trials of patients with this rare disease. Radionuclide ventriculography, an imaging modality used by two studies included in this review, has poor resolution in comparison to echocardiography and cMRI [39,43,64]. Studies have suggested that LVEF measurements by echocardiography, cMRI and randionuclide ventriculography are not interchangeable and that assessment of LVEF by one method should not be considered universal [64,65]. This further justifies our decision to not perform a meta-analysis to derive a pooled effect estimate from studies included in this review. 5. Conclusion

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This review highlights the immediate need for robust clinical trials to determine the optimal time to initiate therapy and the optimal regimen of cardiac medications to stabilize LV systolic function and delay the onset of DMD-CM. While there is evidence supporting the use of ACE inhibitors, ARBs, BBs and AAs in patients with DMD-CM, data regarding optimal pharmacological regimens for delaying the onset of DMD-CM and when to initiate therapy is largely insufficient and lacking. Additional RCTs are necessary to inform the development of evidence-based recommendations and guidelines in this area. Additionally, a large-scale prospective cohort study of patients before the onset of εcc abnormalities or late gadolinium enhancement would be beneficial for determining whether early initiation of cardiac medications can change the onset of LV systolic dysfunction, as well as the earliest markers of myocardial disease. The design and analyses of future trials should attempt to isolate the effects of ACE inhibitors, ARBs, BBs and AAs on cardiac function and long-term survival, from those due to standard of care therapies such as glucocorticoids. In addition to biomarkers of cardiac function, it is necessary for future trials to evaluate both long-term survival and patient-reported outcomes, such as quality of life and functional status, using valid and reliable instruments. The choice of LVEF and FS threshold values used to define LV systolic dysfunction should be carefully considered in the design of future trials, as these will influence the prevalence of DMD-CM and subsequently, the number of patients eligible to participate in management and/or prevention studies. Acknowledgements We would like to acknowledge John Costella, Associate Librarian at Western University, for his invaluable assistance and guidance in developing the search strategies. We would also like to acknowledge Dr. Brian Hutton, Associate Scientist at the Ottawa Hospital Research Institute’s Clinical Epidemiology Program and Assistant Professor at the University of Ottawa’s Faculty of Epidemiology and Community Medicine, for providing his expert opinion on metaanalysis.

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APPENDIX A

Table A.1. Database search strategies

Concept Angiotensin Converting Enzyme Inhibitors

CINAHL (MH "AngiotensinConverting Enzyme Inhibitors+")

MEDLINE exp AngiotensinConverting Enzyme Inhibitors/

EMBASE exp Dipeptidyl carboxypeptidase inhibitor/

Beta Blockers

(MH "Adrenergic Beta-Antagonists+")

exp Adrenergic betaAntagonists/

exp Beta adrenergic receptor blocking agent/

Angiotensin Receptor Blockers

(MH "Angiotensin II Type I Receptor Blockers+")

exp Angiotensin Receptor Antagonists/

exp Angiotensin receptor antagonist/

Keywords Angiotensin converting enzyme inhibit* OR dipeptidyl carboxypeptidase inhibit* OR ACE inhibit* OR angiotensin converting enzyme inhibiting agent* OR angiotensin I converting enzyme inhibit* OR peptidyldipeptide hydrolase inhibit* OR converting enzyme inhibit* OR dipeptidyl carboxypeptidase i inhibit* OR kininase ii inhibit* OR peptidyl dipeptidase inhibit* OR Benazepril* OR captopril OR cilazapril* OR enalapril* OR fosinopril* OR lisinopril OR moexipril* OR perindopril OR quinapril* OR ramipril* OR trandolapril OR LCZ696 OR sacubitril Beta block* OR adrenergic beta-antagonis* OR beta adrenergic block* OR Beta adrenergic antagonis* OR beta adrenergic receptor antagonis* OR beta adrenergic receptor block* OR beta adrenoceptor antagonis* OR beta adrenoceptor block* OR beta adrenolytic* OR beta antagonis* OR beta antiadrenergic* OR beta receptor adrenergic block* OR beta receptor block* OR beta sympatholytic* OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR carteolol OR carvedilol OR esmolol OR labetalol OR metoprolol OR nadolol OR nebivolol OR penbutolol OR pindolol OR propranolol OR sotalol OR timolol Angiotensin II type I receptor block* OR Type I angiotensin receptor block* OR angiotensin II receptor block* OR angiotensin II receptor antagonis* OR

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Aldosterone Antagonist

(MH “Aldosterone antagonists”)

exp Mineralocorticoid receptor antagonists/

exp Aldosterone antagonist/

Diuretics

(MH “Diuretics+”)

exp Diuretics/ OR exp sodium potassium chloride symporter inhibitors/

exp Diuretic agent/ OR exp loop diuretic agent/

Ivabradine Digoxin

N/A MH "Digitalis Glycosides+"

N/A exp digitalis glycosides/

Cardiac Complications

(MH "Myocardial Diseases+") OR (MH "Heart Failure+") OR (MH "Ventricular Dysfunction+")

Duchenne Muscular Dystrophy

(MH “Muscular Dystrophy, Duchenne”)

exp Ivabradine/ exp digitslis glycoside/ OR exp digoxin/ OR exp digitoxin/ exp exp Cardiomyopathies/ Cardiomyopathy/ OR exp Heart failure/ OR exp congestive OR exp Ventricular cardiomyopathy/ Dysfunction/ OR exp heart failure/ OR exp heart ventricle function/ Muscular Dystrophy, exp Duchenne Duchenne/ muscular dystrophy/

angiotensin receptor antagonis* OR angiotensin receptor block* OR azilsartan OR candesartan OR eprosartan OR forasartan OR irbesartan OR losartan OR olmesartan OR saprisartan OR tasosartan OR telmisartan OR valsartan Mineralocorticoid receptor antagonis* OR spironolactone OR eplerenone OR canrenone OR canrenoic acid OR fin aldosterone antagonis* OR aldosterone receptor antagonis* OR anti aldosterone OR antialdosterone OR antialdosterone agent OR selective aldosterone receptor antagonis* OR mineralocorticoid antagonis* Diuretic* OR carbonic anhydrase inhibit* OR thiazide OR loop diuretic* OR high ceiling diuretic* OR sodium potassium chloride symporter inhibit* OR potassium sparing diuretic* OR chlorthalidone OR hydrochlorothiazide OR indapamide OR metolazone OR amiloride OR triamterene OR acetazolamide OR methazolamide OR bumetanide OR ethacrynic acid OR furosemide OR torsemide OR torasemide Ivabradine Digoxin OR digitoxin OR digitalis*

Myocardial disease* OR cardiomyopath* or dilated cardiomyopath* OR heart failure OR congestive heart failure OR heart function OR heart dysfunction OR ventricular function OR ventricular dysfunction OR ventricle function or ventricle dysfunction OR cardiac

Duchenne muscular dystrophy

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APPENDIX A

Table A.2. Database and grey literature sources search results

Source CINAHL January 20, 2016 EMBASE January 20, 2015 MEDLINE (Ovid) January 20, 2016 Web of Science Core Collection January 20, 2016 Search: (DMD keywords) AND (Cardiac complications keywords) AND (Drug keywords) BIOSIS Previews January 20, 2016 Search: (DMD keywords) AND (Cardiac complications keywords) AND (Drug keywords) ClinicalTrials.gov October 21, 2015 Search: Duchenne muscular dystrophy AND angiotensin converting enzyme inhibitor Duchenne muscular dystrophy AND beta blocker Duchenne muscular dystrophy AND angiotensin receptor blocker Duchenne muscular dystrophy AND diuretic International Clinical Trials Registry Platform October 21, 2015 Search:

Total Records 18 280 86 121

90

9

4

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Duchenne muscular dystrophy AND angiotensin converting enzyme Inhibitor Duchenne muscular dystrophy AND beta blocker Duchenne muscular dystrophy AND ARB Duchenne muscular dystrophy AND diuretic UK Clinical Trials Gateway October 21, 2015 Search: Duchenne muscular dystrophy AND angiotensin converting enzyme Inhibitor Duchenne muscular dystrophy AND beta blocker Duchenne muscular dystrophy AND ARB Duchenne muscular dystrophy AND diuretic UK Clinical Research Network Study Portfolio October 21, 2015 Search: Duchenne muscular dystrophy Cochrane Library Reviews October 22, 2015 Search: Duchenne muscular dystrophy AND cardiac complications keywords Trials October 21, 2015 Search: Duchenne muscular dystrophy AND drug keywords Electronic Thesis Online Service (EThoS) October 22, 2015 Search: Duchenne muscular dystrophy AND angiotensin converting enzyme inhibitor (0) Duchenne muscular dystrophy AND beta blocker (0) Duchenne muscular dystrophy AND diuretic (0) Duchenne muscular dystrophy AND angiotensin receptor blocker (0) Duchenne muscular dystrophy AND cardiomyopathy (3) Networked Digital Library of Theses and Dissertations October 22, 2015 Search: Duchenne Muscular Dystrophy AND (“Angiotensin converting enzyme inhibitor” OR “dipeptidyl carboxypeptidase

2

17

2

8 3

7

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inhibitor” OR “ACE inhibitor” OR “angiotensin converting enzyme inhibiting agent” OR “angiotensin I converting enzyme inhibitor” OR “peptidyldipeptide hydrolase inhibitor” OR “converting enzyme inhibitor” OR “dipeptidyl carboxypeptidase i inhibitor” OR “kininase ii inhibitor” OR “peptidyl dipeptidase inhibitor” OR Benazepril OR captopril OR cilazapril OR enalapril OR fosinopril OR lisinopril OR moexipril OR perindopril OR quinapril* OR ramipril* OR trandolapril OR “Beta blocker” OR “adrenergic beta-antagonist” OR “beta adrenergic blocker” OR “Beta adrenergic antagonist” OR “beta adrenergic receptor antagonist” OR “beta adrenergic receptor blocker” OR “beta adrenoceptor antagonist” OR “beta adrenoceptor blocker” OR “beta adrenolytic” OR “beta antagonist” OR “beta antiadrenergic” OR “beta receptor adrenergic blocker” OR “beta receptor blocker” OR “beta sympatholytic” OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR carteolol OR carvedilol OR esmolol OR labetalol OR metoprolol OR nadolol OR nebivolol OR penbutolol OR pindolol OR propranolol OR sotalol OR timolol OR “Angiotensin II type I receptor blocker” OR “Type I angiotensin receptor blocker” OR “angiotensin II receptor blocker” OR “angiotensin II receptor antagonist” OR “angiotensin receptor antagonist” OR “angiotensin receptor blocker” OR azilsartan OR candesartan OR eprosartan OR forasartan OR irbesartan OR losartan OR olmesartan OR saprisartan OR tasosartan OR telmisartan OR valsartan OR Diuretic OR “carbonic anhydrase inhibitor” OR thiazide OR loop diuretic OR potassium sparing diuretic OR chlorthalidone OR hydrochlorothiazide OR indapamide OR metolazone OR amiloride OR spironolactone OR triamterene OR acetazolamide OR methazolamide OR bumetanide OR ethacrynic acid OR furosemide) Theses Canada Portal October 22, 2015 Search: Duchenne muscular dystrophy AND angiotensin converting enzyme inhibitor (0) Duchenne muscular dystrophy AND beta blocker (0) Duchenne muscular dystrophy AND diuretic (0) Duchenne muscular dystrophy AND angiotensin receptor blocker (0) Duchenne muscular dystrophy AND cardiomyopathy (3) ProQuest Dissertations and Theses October 22, 2015 Search: (duchenne muscular dystrophy) AND (Cardiac OR cardiomyopathy OR ventricular dysfunction OR heart failure OR myocardial disease OR dilated cardiomyopathy OR congestive cardiomyopathy) Centers for Disease Control and Prevention October 22, 2015 Google search: Duchenne muscular dystrophy guidelines US Food and Drug Administration October 22, 2015

3

60

2

1

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Google search: Duchenne muscular dystrophy guidelines Total (Before Duplicate Removal) Total (After Duplicate Removal)

713 499

APPENDIX B

Allen HD et al. (2013)

Viollet L et al. (2012)

Kwon SW et al. (2012)

Kwon HW et al. (2012)

Hor KN et al. (2011)

Matsumura T et al. (2010)

Ogata H et al. (2008)

Rhodes J et al. (2007)

Duboc D et al. (2007, 2005)

Kajimoto H et al. (2006)

Ramaciotti C et al. (2006)

Jefferies JL et al. (2005)

Ishikawa Y et al. (1999)

Ishikawa Y et al. (1995)

Reporting Is the hypothesis/aim/objective of the study clearly described Are the main outcomes to be measured clearly described in the introduction or methods section? Are the characteristics of the patients included in the study clearly described? Are the interventions of interest clearly described Is the distribution of principal confounders in each group of subjects to be compared clearly described? Are the main findings of the study clearly described? Does the study provide estimates of the random variability in the data for the main outcomes? Have all important adverse events that may be a consequence of the intervention been reported? Have the characteristics of patients lost to follow-up been described? Have actual probability values been reported? External Validity Were the subjects asked to participate in the study representative of the entire population from which they were recruited? Were those subjects who were prepared to participate representative of the entire population from which they were recruited Were the staff, places and facilities where the patients were treated representative of the treatment the majority of patients receive? Internal Validity: Bias Was an attempt made to blind study subjects to the intervention they have received? Was an attempt made to blind those measuring the main outcomes of the intervention? If any of the results of the study were based on "data dredging", was this made clear?

Raman SV et al. (2015)

Table B.1. Study quality assessment report conducted using the Downs and Black quality assessment checklist

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1

1 1 1 1 0 1 1 0 0 1

1 1 1 1 1 1 1 0 1 1

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 0 0 1

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 0 1 0

1 1 1 1 0 1 1 1 1 0

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 0

1 1 1 1 0 1 0 1 0 1

1 1 1 1 1 1 1 1 0 1

1 1 1 1 0 1 1 1 1 0

1 1 0 1 0 1 0 0 0 0

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1 1 1

1 1 1

0 0 1

0 0 1

0 0 1

0 0 1

0 0 1

0 0 1

0 0 1

1 1 1

0 0 1

0 0 1

0 0 1

0 0 1

0 0 1

Page 20 of 38

In trials and cohort studies, do the analysis adjust for different lengths of follow-up of patients, or in case-control studies is 1 0 0 1 1 0 1 1 1 1 1 0 0 1 the time period between the intervention and outcome the same for cases and controls? Were the statistical tests used to assess the main outcomes appropriate? 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Was compliance with the intervention(s) reliable? 0 0 0 0 0 0 0 0 0 1 0 0 0 0 Were the main outcome measures used accurate (valid and reliable)? 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Internal Validity: Confounding (Selection Bias) Were the patients in different intervention groups (trials and cohort studies) or were the cases and controls (case-control 1 1 1 1 1 1 1 1 0 1 1 0 0 0 studies) recruited from the same population? Were study subjects in different intervention groups (trials and cohort studies) or were the cases and controls (Case-control 1 0 1 1 1 1 1 1 0 0 1 0 0 0 studies) recruited over the same period of time? Were study subjects randomized to intervention groups? 1 1 0 0 1 0 0 0 0 1 1 0 0 0 Was the randomized intervention assignment concealed from both patients and health care staff until recruitment was 1 1 0 0 0 0 0 0 0 0 0 0 0 0 complete and irrevocable? Was there adequate adjustment for confounding in the analyses from which the main findings were drawn? 0 0 0 0 1 1 0 0 0 0 0 0 0 0 Were losses of patients to follow-up taken into account? 0 1 0 1 1 0 1 1 1 1 1 0 0 0 Power Did the study have sufficient power to detect a clinically important effect where the probability value for a difference being 1 0 0 0 0 0 0 0 0 0 0 0 0 0 due to chance is less than 5%? * Total Score 24 22 15 19 22 17 20 18 16 23 20 13 15 15 * Randomized and non-randomized studies can be assigned maximum scores of 28 and 25, respectively. Scores of 26 to 28 are considered excellent, 20 to 25 good, 15 to 19 fair and 14 or below are considered poor.

0 0 0 1 0 0 0 0 0 0 0 9

Page 21 of 38

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Viollet L, Thrush PT, Flanigan KM, Mendell JR, Allen HD. Effects of angiotensin-converting enzyme inhibitors and/or beta blockers on the cardiomyopathy in Duchenne muscular dystrophy.

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Kwon SW, Kang S-W, Kim J-Y, Choi E-Y, Yoon YW, Park YM, et al. Outcomes of cardiac involvement in patients with late-stage Duchenne muscular dystrophy under management in the pulmonary rehabilitation center of a tertiary referral hospital. Cardiology 2012;121:186–93. doi:10.1159/000336810.

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Figure 1. Flow chart of study selection

Page 30 of 38

Table 1. Characteristics of included studies Author [Publication]

Year

Country

Journal

2015

USA

The Lancet Neurology

2013

USA

PLoS Currents

Viollet L et al. [31]

2012

USA

The American Journal of Cardiology

Kwon SW et al. [32]

2012

Kwon HW et al. [33]

2012

Hor KN et al. [34]

2011

USA

2010

Japan

Internal Medicine

Ogata H et al. [36]

2008

Japan

Journal of Cardiology

Rhodes J et al. [37]

2007

USA

Pediatric Cardiology

Duboc D et al. [38, 39]

2007, 2005

France

American Heart Journal, Journal of the American College of Cardiology

Kajimoto H et al. [40]

2006

Japan

Ramaciotti C et al. [41]

2006

USA

Jefferies JL et al. [42]

2005

USA

Ishikawa Y et al. [43]

1999

Japan

Ishikawa Y et al. [44]

1995

Japan

Raman SV et al. [17] Allen HD et al. [16]

Matsumura T et al. [35]

Republic of Korea Republic of Korea

Cardiology Korean Circulation Journal Journal of Cardiovascular Magnetic Resonance

Circulation Journal The American Journal of Cardiology Circulation American Heart Journal American Journal of Physical Medicine & Rehabilitation

Study Design Double-blind, placebo-controlled RCT Double-blind, equivalence RCT Retrospective cohort study Retrospective cohort study

Quality Assessmenta Good Good Fair Fair

Open-label RCT

Good

Retrospective cohort study

Fair

Open-label, nonrandomized trial Retrospective cohort study Open-label, singlearm trial Phase I: Doubleblind, placebocontrolled RCT Phase II: Openlabel, single-arm trial Open-label RCT Retrospective case series Retrospective case series Prospective case series Prospective case series

Good Fair Fair

Good

Good Poor Fair Fair Poor

Abbreviations: RCT, randomized controlled trial a

Quality assessment of studies was completed using the Downs and Black quality assessment checklist, which evaluates reporting, external validity, bias, confounding and power.

Page 31 of 38

Table 2. Methods and results of included studies Study

Raman SV et al. (2015)

Allen HD et al. (2013)

Viollet L et al. (2012)

Samp le Size

Diagnos tic Method

Cardiac Assessment

DMD-CM Severity

Interventio ns/ Treatments

Backgroun d Medical Therapy

Outcome Measures

Follo w-up

εcc, LVEF, LVEDV, LVESV, LV fibrosis, blood biomarkers (creatine kinase, creatine kinase MB fraction, troponin I, osteopontin), adverse events, hospital admissions due to heart failure, arrhythmias, death, hyperkalaemia

12 month s

42

Mutation analysis or DMD phenoty pe

LGE-cMRI

LVEF≥45%, LV fibrosis

Eplerenone (20), placebo (20)

ACEi or ARB (42), BB (17), glucocortico id (35), noninvasive ventilation (2)

23

Mutation analysis or muscle biopsy, and DMD phenoty pe

Echocardiogra phy

40%
Lisinopril (12), losartan (10)

BB (2), glucocortico id (10)

LVEF

12 month s

42

Mutation analysis or muscle biopsy

LVEF<55%

Lisinopril (30), Lisinopril + metoprolol or atenolol (24)

Glucocortic oid (13)

LVEF

6 to 48 month s

Echocardiogra phy

Findings In boys with preserved LVEF, addition of eplerenone (AA) to ACEI or ARB therapy significantly reduced the 12-month decline in LV systolic function (LVEF and εcc) in comparison to placebo. Significant changes in LV fibrosis by LGE or blood biomarkers were not observed. Significant improvemen ts in LVEF over 12 months were observed in both treatment groups. There was no difference in LVEF improvemen t between ACEi and ARB. Significant improvemen t in LVEF was observed after 12 months of treatment with ACEi or ACEi + BB compared to 12 months before initiation of treatment. There was no difference in LVEF improvemen t between ACEi and

Page 32 of 38

Kwon SW et al. (2012)

Study

Kwon HW et al. (2012)

Hor KN et al. (2011)

31

Mutation analysis or muscle biopsy

Echocardiogra phy

LVEF 42.2 ± 18.0%* LVEF<50% (16)

ACEi or ARB (17), ACEi or ARB + BB (6), no cardiac medication (8)

Samp le Size

Diagnos tic Method

Cardiac Assessment

DMD-CM Severity

Interventio ns/ Treatments

a

23

136

-

Mutation analysis

Echocardiogra phy

cMRI

LVEF<55% FS<28%

LVEF 62.8 ± 7.5%* (ACEi/ARB), LVEF 64.2 ± 6.1%* (no ACEi/ARB)

Enalapril (13), carvedilol (10)

Lisinopril or enalapril or losartan + glucocortic oid (31), glucocortic oid alone (28)

ACEi + BB. Over 3 years, no significant changes in LVEF were observed in boys with normal baseline LVEF (>50%), regardless of cardiac medication status. Significant improvemen t in LVEF was observed in boys with reduced baseline LVEF (<50%) taking cardiac medication.

Diuretic (1), Digoxin (5), Antiarrhyth mic drug (1), noninvasive ventilation (30)

LVEF

46.5 ± 9.1 month s*

Backgroun d Medical Therapy

Outcome Measures

Follo w-up

Findings

-

LVEF, FS, LV peak global longitudinal strain, systolic myocardial velocities, E/A ratio, diastolic myocardial velocities, myocardial performance index, LVM index, LVEDd, LVESd, LVEDv, LVESv, BNP

40.1 ± 8.9 month s*

FS improved significantly in all patients, even though the improvemen t was not significant in individual treatment groups.

15 month s (5.8 to 35.8 month s)

ACEi/ARB therapy did not arrest the decline in cardiac function in patients receiving glucocorticoi ds. In patients who underwent serial cMRI exams (59/136), significant worsening of εcc was observed in patients taking both

(patients receiving BB excluded)

LVEF, εcc, LVEDv, LVM, HR

Page 33 of 38

Matsum ura T et al. (2010)

Ogata H et al. (2008)

Study

54

-

52

Mutation analysis or muscle biopsy

Sample Size

Echocardiogra phy

LVEF<50%

Carvedilol + ACEi or ARB (41), ACEi or ARB alone (13)

Echocardiogra phy

LVEF≤45%, Symptomatic (12) or asymptomatic (40) heart failure

ACEi + BB (52)

Diagnostic Method

Cardiac Assessment

DMD-CM Severity

Pimobendan (9)

All-cause death, deterioration of heart failure requiring intravenous catecholamine, phosphodiester ase III inhibitor or diuretics >15 days, arrhythmia requiring cardioversion or intravenous arrhythmic agents >15 days, LVEF, BNP

Diuretic (38), digoxin (49)

All-cause mortality

Interventions/ Treatments

5 years

10 years

Background Medical Therapy

Outcome Measures

Rhodes J et al. (2007)

22b

-

cMRI and echocardiography

LVEF<50% (cMRI)

Carvedilol (22)

Invasive ventilation (4), noninvasive ventilation (3), ACEi (10), digoxin (8), diuretics (4)

Duboc D et al. (2007,

57

Mutation analysis

Radionuclide ventriculography

LVEF>55%

Phase I (3 years): Perindopril

BB (9), invasive ventilation

ACEi/ARB + glucocorticoi d. Survival free from death, deterioration of heart failure and arrhythmia was significantly higher in the BB group. Although not significant, survival free from allcause death was higher in the BB group. Carvedilol significantly reduced HR. No differences in LVEF or BNP were observed. Long-term survival was significantly higher in boys who received ACEi + BB therapy before developing heart failure symptoms than in boys who were symptomatic when therapy was initiated.

Followup

Findings

LVEF, FS, LVEDv, LVESv, SV, myocardial performance index, dP/dt, E/E’ ratio, IVRT, HR, pulmonary function, quality of life and cardiopulmonary symptoms

6 months

BB was associated with modest improvements in systolic and diastolic ventricular function. Significant improvements were detected in LVEF.

LVEF, survival

10 years

At 5 years, a single patient who received

Page 34 of 38

2005)

(28), Placebo (29)

(13)

Phase II (2 years): Perindopril (52)

Kajimoto H et al. (2006)

28c

-

Echocardiography

Ramaciotti C et al. (2006)

23

Mutation analysis

Echocardiography

Jefferies JL et al. (2005)

69d

Mutation analysis

Echocardiography

FS<26%

Cirazapril or enalapri + carvedilol (13), cirazapril or enalapril alone (15)

Furosemide (3), spironolactone (19)

FS, LVEDd, LVPWTd, HR, systolic blood pressure, BNP, cardiac symptoms

2-3 years

FS<28%

Enalapril (23)

-

FS, LVEDd

8 to 96 months

LVEF<55%

Enalapril or captopril or lisinopril + carvedilol or metoprolol (18), Enalapril or captopril or lisinopril alone (13)

-

LVEF, LVEDd, myocardial performance index, sphericity index

3.3 years

Study

Sample Size

Diagnostic Method

Cardiac Assessment

DMD-CM Severity

Interventions/ Treatments

Ishikawa Y et al. (1999)

11

-

Echocardiography or radionuclide ventriculography

LVEF<40% or FS<20%

Enalapril or lisinopril + metoprolol or bisoprolol (11)

Background Medical Therapy Digitalis (11), diuretic (11), aspirin (11), non-

early treatment with ACEi had LVEF<45%, compared to 8 patients who received delayed treatment. At 10 years, survival was significantly higher in patients who received early treatment with ACEi compared to delayed treatment. Significant improvement in FS was observed in patients who received ACEi + BB. No significant change in FS was observed in patients who received ACEi monotherapy. Among patients with LV systolic dysfunction, 43% responded to enalapril with normalization of function (FS≥28%). No specific mutation was associated with response to ACEi. Significant improvement in LVEF was observed in all patients after receiving ACEi + BB or ACEi alone.

Outcome Measures

Followup

Findings

LVEF, LVEDd, ANP, BNP,

60 months

Following treatment with an ACEi + BB, LVEF

Page 35 of 38

invasive ventilation (4)

PNE, pulmonary function

transiently increased, LVEDd was preserved, and elevated ANP, BNP and PNE levels decreased. Improvements in LVEF, Ishikawa Enalapril + Digoxin (3), LVEF, 18 ANP and Y et al. 3 Echocardiography LVEF<40% bisoprolol or furosemide ANP, months PNE were (1995) metoprolol (3) (3) PNE observed in all patients. Abbreviations: DMD-CM, Duchenne muscular dystrophy-associated cardiomyopathy; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; BB, beta-blocker; AA, aldosterone antagonist; LGE-cMRI, cardiac magnetic resonance imaging with late gadolinium enhancement; LVEF, left ventricular ejection fraction; FS, fractional shortening; LVEDd, left ventricular end diastolic diameter; LVESd, left ventricular end systolic diameter; LVEDv, left ventricular end diastolic volume; LVESv, left ventricular end systolic volume; LVM, left ventricular mass; HR, heart rate; εcc, left ventricular circumferential strain; SV, stroke volume; dP/dt, change in LV pressure during isovolumetric contraction; IVRT, isovolumetric relaxation time; LVPWTd, left ventricular posterior wall thickness in diastole; BNP, brain natriuretic peptide; ANP, atrial natriuretic peptide; PNE, plasma norepinephrine *

Mean ± standard deviation Included 1 Becker’s muscular dystrophy patient b Included 5 Becker’s muscular dystrophy patients c Included 2 Fukuyama and 1 Emery-Dreifuss muscular dystrophies patients d Included 7 Becker’s muscular dystrophy patients a

Numbers in parenthesis represent numbers of patients. A dash represents that no data was provided.

Table 3. Age at initiation of cardiac medications Study Raman SV et al. (2015) Allen HD et al. (2013) Viollet L et al. (2012) Kwon SW et al. (2012) Kwon HW et al. (2012) a Hor KN et al. (2011) Matsumura T et al. (2010) Ogata H et al. (2008) Rhodes J et al. (2007) b Duboc D et al. (2007) Kajimoto H et al. (2006)c Ramaciotti C et al. (2006) Jefferies JL et al. (2005)d Ishikawa Y et al. (1999)

Mean ± SD (Years) 14.5* (AA + ACEi or ARB), 15* (placebo + ACEi or ARB) 12.5* (ACEi), 15.5* (ARB)

15.7 ± 3.9 (ACEi + BB), 14.1 ± 4.6 (ACEi alone) 12.2 ± 3.6 (ACEi) 13.6 ± 3.9 (BB) 19.3 ± 4.7 (ACEi + BB), 23.2 ± 8.5 (ACEi alone) 19.5 ± 5.8 21.5 ± 8.4 10.7 ± 1.2 18 ± 6 (ACEi + BB), 15 ± 4 (ACEi alone) 13.2 ± 2.4 15.4 ± 2.8 17.0 ± 3.3

Range (Years)

12 to 18.5† (AA + ACEi or ARB), 11 to 19† (placebo + ACEi or ARB) 10 to 21 (ACEi), 7 to 27 (ARB) 9.8 to 23.7 (ACEi + BB), 7 to 27.3 (ACEi alone) 11 to 29 (ACEi + BB), 15 to 35 (ACEi alone) 14 to 46 9.5 to 13 8 to 29 (ACEi + BB), 7 to 27 (ACEi alone) 8 to 19 10.4 to 21.2 12.6 to 22.8

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Ishikawa Y et al. (1995)

-

-

*

Median † Interquartile range a Included 1 Becker’s muscular dystrophy patient b Included 5 Becker’s muscular dystrophy patients c Included 2 Fukuyama and 1 Emery-Dreifuss muscular dystrophies patients d Included 7 Becker’s muscular dystrophy patients A dash represents that no data was provided.

Table 4. Medication maintenance dosages and adverse events Study Raman SV et al. (2015)

Medication

Dosage

Eplerenone

Lisinopril Metoprolol Atenolol -

25 mg/day 5 mg/day (0.07 mg/kg/day) 25 mg/day (0.7 mg/kg/day) 0.16 ± 0.1 mg/kg/day* 1.1 ± 0.6 mg/kg/day* -

Enalapril

0.05 to 0.1 mg/kg/day

Carvedilol Lisinopril or Enalapril

0.15 to 1 mg/kg/day 0.04 to 1.23 mg/kg/day (0.16 ± 0.08 mg/kg/day*) 0.34 to 1.23 mg/kg/day (0.73 ± 0.29 mg/kg/day*)

Lisinopril Allen HD et al. (2013) Losartan Viollet L et al. (2012) Kwon SW et al. (2012) Kwon HW et al. (2012)a

Hor KN et al. (2011)

Losartan

Matsumura T et al. (2010)

Carvedilol

7.85 ± 2.80 mg/daya

Ogata H et al. (2008)

Enalapril Lisinopril Bisoprolol Metoprolol Carvedilol

3.7 ± 1.8 mg/day* 6.1 ± 4.3 mg/day* 3.0 ± 1.3 mg/day* 20.8 ± 2.0 mg/day* 10.0 ± 0 mg/day*

Rhodes J et al. (2007)b

Carvedilol

25 to 50 mg/day

Duboc D et al. (2007, 2005)

Perindopril

2 to 4 mg/day

Cilazapril Enalapril Carvedilol Enalapril Enalapril Captropril Lisinopril Carvedilol Metoprolol Enalapril Lisinopril

0.03 mg/kg/day 0.3 mg/kg/day 0.5–1 mg/kg/day 5 to 20 mg/day 18 to 30 mg/day 5 mg/day 10 to 100 mg/day 6.25 to 12.5 mg/day 20 mg/day 10 mg/day

Kajimoto H et al. (2006) Ramaciotti C et al. (2006)

Jefferies JL et al. (2005)

Ishikawa Y et al. (1999)

Adverse Effects (Number of Cases/Sample Size) Headaches (1/20; Placebo: 0/22) None reported by patients Hives (1/11) Headaches (2/42) Mild intermittent cough (2/13) Mild transient dizziness (1/13) None reported by patients Bradycardia (1/41) Worsened general fatigue (1/41) Mild fatigue Faintness Headaches Increase in expectorated sputum Respiratory infection (Not all expected to be caused by carvedilol) Mild, transient hypotension Pneumonia (2/22) Bronchitis (2/28; Placebo: 5/29) Cough (2/28; Placebo: 3/29) Rhinitis (2/28; Placebo: 3/29) Weight loss (3/28; Placebo: 2/29) Fever (2/28; Placebo: 2/29) Headache (2/28; Placebo: 2/29) None reported by patients None reported by patients

None reported by patients

-

Page 37 of 38

Metoprolol 25 mg/day Bisoprolol 2.5 mg/day Enalapril 10 to 20 mg/day Ishikawa Y et al. (1995) Bisoprolol 2.5 mg/day Metoprolol 25 mg/day * Mean dosage achieved ± standard deviation a Included 1 Becker’s muscular dystrophy patient b Included 5 Becker’s muscular dystrophy patients c Included 2 Fukuyama and 1 Emery-Dreifuss muscular dystrophies patients d Included 7 Becker’s muscular dystrophy patients

Hypotension None reported by patients

A dash represents that no data was provided.

Page 38 of 38