Pharmacotherapeutics for prevention of aortic root enlargement in Marfan Syndrome – A network meta-analysis of randomized controlled trials

Marfan syndrome (MFS) is a life-threatening autosomal dominant condition with a prevalence ranging from one every 3000 to one every 5000 persons. Aortic root dissection due to progressive aortic enlargement is the leading cause of premature death in MFS. There is no curative therapy for MFS, and aortic dilatation is the primary therapeutic target in these patients. Despite this, the lifespan of MFS patients has dramatically increased from 32 to 72 years, and this has mostly been attributed to early diagnosis, improved lifestyle guidance, and non-invasive aortic imaging along with elective aortic root repair. The evidence for the medical treatment in reducing aortic root dilatation remains unclear. Beta-blockers are considered first-line for the prevention of aortic root dilatation despite the inconsistent evidence. More recently, angiotensin receptor blockers (ARBs) have been tested with limited success in several trials due to their antagonizing properties against transforming growth factorbeta (TGF-b). Habashi et al. in 2006 found that the clinical manifestations of MFS are due to altered activation and signaling of TGF-b and losartan was noted to antagonize the TGF-b signaling in a mouse model. In MFS, a defect in FBN1 glycoprotein leads to a reduction or alteration in fibrillin-1, which can cause an increase in the level and activity of TGF-b. Several studies failed to show an advantage of beta-blockers or ARBs over each other for the prevention of aortic root growth (ARG), adding to the confusion as to which is the preferred treatment choice. Therefore, the objective of this network meta-analysis from all the randomized controlled trials (RCTs) is to synthesize evidence from existing studies and to compare the efficacy of various therapeutic options for the prevention of aortic root dilatation in patients with MFS. We performed a comprehensive literature search in PubMed, Cochrane library, and Embase. The keywords utilized included ‘Marfan syndrome’ with the limits for human and RCTs. The RCTs were considered for inclusion in our meta-analysis if they studied the effects of medical therapy for the prevention of aortic root dilatation. Our outcome of interest was the change in aortic root dilatation. Throughout this process, we followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for all stages of the design and implementation. We extracted the relevant data from the finally selected studies. We used the overall change in aortic root dilatation as a continuous variable with a standard deviation. Software R version 3.5. 1 (R Development Core Team, 2010) was used to determine treatment effects and the standard error of these treatment effects. We converted all pairwise comparisons for a given study into contrastbased data for our analysis. The frequentist approach exploits the analogy between treatment networks and electrical networks to construct a network meta-analysis model accounting for the correlated treatment effects. Due to expected heterogeneity between studies, we decided on reporting results from a random-effects model and this was an a priori decision. The initial search yielded 394 articles. After full-text review, 10 RCTs with 1370 randomized patients were selected for analysis. Table 1 shows the characteristics of the trials and participants. Figure 1(a) summarizes the result that compared with control both beta-blockers and