Protection and delay of aortic complications in the Marfan syndrome: a new indication for angiotensin receptor blockers on top of β blockers

Comment on ‘Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials’ which was published in the Lancet; https://doi.org/10.1016/S0140-6736(22)01534-3. In this individual patient data meta-analysis,1 a systematic search was performed using Embase, MEDLINE, and CENTRAL from database inception until November 2021. Seven relevant randomized trials (RCTs) assessing the effects of angiotensin receptor blockers (ARBs) vs. control or ARBs vs. β blockers (BB) in patients with Marfan syndrome were identified. The study focused on Marfan patients with no prior aortic root surgery, in order to estimate the effects of ARBs and BB on the annual rate of change in aortic root dimension, adjusted for body surface area (aortic root Z score) as the primary endpoint of the intervention. Of the seven eligible RCTs (1442 patients), four trials (676 patients) compared ARBs with controls, and three trials (766 patients) compared ARBs with BBs. For the first group of studies, the mean age of participants was 29 years [Standard Deviation (SD), 14], with 54% female and 75% receiving BB at baseline (in all trials patients were allowed to remain on BB). Moreover, of 630 genotyped individuals, 83% had a fibrillin-1 (FBN1) pathogenic variant that causes progressive enlargement of the aortic root. As for the second group of trials, the mean age of participants was 14 years (SD 10), with 44% female and 86% of genotyped individuals (327 patients) having a pathogenic variant in FBN1. During a median follow-up of 3 years, when compared with controls, ARB use was associated with half the annual rate of change in aortic root Z score [mean annual increase 0.07 for ARBs, standard error (SE) 0.02; vs. 0.13 for control, SE 0.02; absolute difference, −0.07; 95% confidence interval (CI), −0.12 to −0.01; P = 0.012], with larger effects for those patients with FBN1 pathogenic variant compared with those without the variant (P for heterogeneity = 0.005), and similar results irrespective of whether or not patients were on BB at baseline (P for heterogeneity = 0.54). These results were statistically significant for all specified aortic root measurement methods. Over a similar follow-up, the annual change in the aortic root Z score was similar in the ARB and BB groups (−0.08 in ARBs vs. −0.11 in BBs, P = 0.48). Moreover, by combining the results of the RCTs of ARBs vs. control with RCTs of ARBs vs. BB to indirectly assess BB vs. control, a difference in mean absolute annual change in the aortic root Z score between BB and control of −0.09 (95% CI, −0.18 to 0.00; P = 0.042) was estimated, similar to the direct estimate for the comparison of ARBs vs. control. Marfan syndrome is a genetically determined disease and is one of the most common systemic disorders of the connective tissue affecting about 1.6 million people. Its incidence ranges between 2 and 3 cases per 10 000 individuals. It is caused by pathogenic variants in the FBN1 gene leading to multiorgan abnormalities with prominent involvement of the cardiovascular system.2 Aortic complications, such as progressive aortic dilatation and dissection, are the leading causes of premature death and disability of Marfan patients. Moreover, high morbidity and mortality are associated with the only effective therapeutic approach, i.e. the prophylactic surgical aortic replacement, to be considered in case of a large or rapidly expanding aortic aneurysm with an imminent risk of dissection.3 Since transforming growth factor β (TGFβ) is involved in the pathogenesis of some aortic aneurysms, previous studies in animal models have focused on the role of the ARB losartan in modulating/blocking aortic growth, in view of a dampening effect of this drug on TGFβ activity.4 In spite of the promising results in animal models and in small observational studies suggesting a delay in the development of aortic wall abnormalities,4,5 RCTs testing drug options for Marfan disease failed to show relevant effects in the prevention of aortic complications.6–9 Furthermore, previous meta-analyses were not able to define the effects of ARBs, by relying only on published data and being limited in scope by high data heterogeneity.10 In the current meta-analysis, individual patient data from eligible RCTs were used in a study protocol designed to overcome data heterogeneity.1 Following this approach, the authors were able to show that the increase in the annual Z score with ARBs compared with control was approximately halved, with the greatest benefit being observed among those patients with a pathogenic FBN1 variant.1 A similar reduction was documented for ARBs and BB in a limited number of head-to-head comparisons. However, given the young age of the patients in the two groups of RCTs (mean age of 29 years in the ARB vs. control subgroup and 14 years in the ARB vs. BB subgroup), the indirect comparison of BB vs. controls is poorly informative and the generalisability of the findings to older adults with Marfan syndrome is somewhat uncertain, as only 11% of the randomly assigned patients were aged 40 years or older and only 6% were aged 50 years or older.1 Moreover, the present study does not clarify whether the protective effect of ARBs is linked to specific agents or reflects a class effect. In addition, it cannot address the question of whether higher doses of ARBs may produce better results than BB or the combination of the two. On the other hand, the finding of no significant heterogeneity of the effects of ARBs depending on concomitant use of BB might suggest that the mechanisms of action of these drugs are independent of each other and potentially additive, thus leading to a greater benefit in decreasing the rate of progression in aortic root dilation, when used in combination. Additional relevant information comes from a sample size calculation performed by the Pediatric Heart Network investigators that suggests that a reduction in the annual rate of change of the Z score from 0.20 to 0.12 (i.e. an annual reduction of 0.08, similar to the effect size of both ARBs and BB) would lead to a delay of about 10 years in the need for aortic surgery.11 By considering that both ARBs and BB are easily accessible, inexpensive drugs, and are safe and well tolerated, the clinical relevance of the data provided in this meta-analysis strongly supports this combination therapy as the standard of care for patients with Marfan syndrome, especially those with FBN1 pathogenic variants. All authors declare no funding for this contribution. No new data were generated or analysed in support of this research.