Do angiotensin receptor blockers prevent cardiac events in patients with Marfan syndrome?

Malik et al. pooled 10 randomised clinical trials with 1370 patients with Marfan syndrome (MFS) to examine the effects of angiotensin receptor blockers (ARBs) and beta-blockers (BBs) through network meta-analysis of the change in aortic root growth. The pooled results indicated that BBs plus ARBs is an effective treatment for the prevention of aortic root growth in MFS. We found a similar trend in our previous work and drew a similar conclusion. Their synthesis retrieved an early trial comparing propranolol and placebo to form a four-group consistency model, and this network model may provide a more complete comparison of MFS medications than other syntheses in recent years. Nevertheless, the change in aortic root growth is a relative parameter. To foster an understanding of common medications for MFS, we still need to examine the outcomes of cardiac events (aortic dissection and aortic surgery during or after treatment). Unfortunately, the authors’ work did not discuss cardiac events. In addition, an important trial comparing propranolol and placebo for patients with MFS in the Johns Hopkins Hospital did not provide available information about aortic root growth, but it clearly reported cardiac events. The trial should be added to an updated synthesis on this topic. The purpose of this letter was to examine further the effect of common medications on the cardiac event rate among patients with MFS through network meta-analysis. We conducted a contrast-based network meta-analysis and surface under the cumulative ranking (SUCRA) using STATA. We reviewed full reports of relevant randomised clinical trials and found data on cardiac events in six trials. The pooled estimate of the cardiac event rate in our network meta-analysis showed a similar trend favouring BBs plus ARBs, but the results did not achieve statistical significance (see Figure 1 and Supplementary File 1). In a further analysis of SUCRA, BBs plus ARBs seemed to be the most effective (SUCRA 81.7), followed by BBs (SUCRA 74.9), ARBs (SUCRA 30.9) and placebo (SUCRA 12.6; see Supplementary File 2). We did not detect any inconsistency (P1⁄4 0.115) or small study effect in the pooled estimate (P1⁄4 0.970; see Supplementary Files 3 and 4). Taken together, adding ARBs to BBs in treating MFS might be a suitable option according to our evidence, and we agree with the conclusion: ‘ARBs should be added to the treatment regimen if tolerated by the patient’ of Malik et al. Based on current evidence, we only know that BBs and ARBs have a synergistic effects on the prevention of aortic dissection in patients with MFS. Unfortunately, how BBs and ARBs work together in preventing aortic dissection remains unclear, although there are some possible explanations for BBs and ARBs, respectively. BBs may improve elastic properties of the aorta by decreasing myocardial contractility and pressure impulse. ARBs may reduce aortic dilation by blocking angiotensin II receptor because angiotensin II influences transforming growth factor b (TGF-b) synthesis and receptor expression. Then, it may result in activation of various matrix metalloproteinases which injure the layers of vessels, such as the aorta. Moreover, angiotensin II may induce aortic dilation and cause endothelial cell hypertrophy when it acts on the renin–angiotensin–aldosterone system by way of the NADH/NADPH oxidase system. Thus, ARBs may prevent rupture of the aorta by multiple approaches. However, different kinds of ARBs may affect MFS differently. The trials in our synthesis mostly compared ARBs or BBs plus ARBs to BBs by using losartan,