Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Abstract

SummaryBackgroundAngiotensin Receptor Blockers (ARBs) and β-blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments.MethodsMeta-analysis of individual data from 1,442 patients with Marfan syndrome and no prior aortic surgery in seven randomised trials was performed. Estimates were obtained of the effects of: (i) ARB versus control (placebo or open control), (ii) ARB versus β-blocker, and (iii) indirectly, β-blocker versus control. The primary endpoint was the annual rate of change of body surface area (BSA)-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva.FindingsFour trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (annual increase +0.07 (SE 0.02) ARB versus +0.13 (SE 0.02) control, absolute difference -0.07 [95% CI: -0.12 to -0.01, p=0.01]). The effect of an ARB on change in aortic root Z score was larger in those with a known FBN1 pathogenic variant than in those without such a variant (p for heterogeneity = 0.005), but there was no evidence that the effect was modified by any other patient characteristic. In particular, the effect of an ARB was similar whether or not a patient was also prescribed a β-blocker at baseline. Few patients experienced the composite outcome of aortic dissection, aortic root surgery or death during study follow-up (30 [8%] ARB vs 27 [8%] control, p=0.86). Three trials involving 766 eligible participants compared ARB vs β-blocker. During a median followup of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0.08 (SE 0.03) ARB vs -0.11 (SE 0.02) β-blocker, absolute difference 0.03 [95% CI -0.05 to 0.10], p=0.48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β-blocker and control was -0.09 (95% CI -0.18 to 0.00, p=0.04).InterpretationIn patients with Marfan syndrome and no prior aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β-blocker. The effects of β-blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β-blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery.