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英国牛津大学Colin Baigent团队研究了血管紧张素受体阻滞剂和β阻滞剂治疗马凡氏综合征的效果。2022年8月29日出版的《柳叶刀》杂志发表了这项成果。

血管紧张素受体阻滞剂（ARBs）和β阻滞剂被广泛用于马凡氏综合征的治疗，以试图降低该病特征性进展性主动脉根部扩大率，但它们单独和联合作用尚不确定。该研究旨在通过对这些治疗随机试验的协作个体患者数据进行荟萃分析来确定这些效应。

在这项荟萃分析中，研究组通过在MEDLINE、Embase和CENTRAL中检索从数据库建库到2021年11月2日的相关文献，确定了马凡氏综合征患者的相关试验。如果涉及ARB与对照组或ARB与β受体阻滞剂的随机比较，则试验合格。研究组使用来自既往无主动脉手术患者的个体患者数据来评估ARB与对照组（安慰剂或开放对照）、ARB与β受体阻滞剂、间接的β受体阻滞剂与对照组间的效果。主要终点是Valsalva窦测量的经体表面积校正的主动脉根部尺寸Z评分的年变化率。

研究组确定了10个潜在合格的试验，包括1836名患者，其中7个试验及1442名患者有资格纳入主要分析。涉及676名合格参与者的4项试验将ARB与对照组进行了比较。在3年的中位随访期间，ARB使主动脉根部Z评分的年变化率大约减半，平均每年增加0.07，而对照组为0.13，组间差异显著。

预先指定的二级亚组分析显示，与无此类变体的患者相比，具有原纤蛋白-1致病性变体的患者ARB作用尤其显著，并且没有证据表明ARB作用随β受体阻滞剂的使用而变化。涉及766名合格参与者的三项试验比较了ARB和β受体阻滞剂。在为期3年的中位随访中，两组主动脉根部Z评分的年变化相似，ARB组的年增长率为-0.08，β受体阻滞剂组为-0.11。因此，间接地，β受体阻滞剂和对照组之间主动脉根部Z评分的年变化差异为-0.09。

研究结果表明，在马凡氏综合征和既往无主动脉手术史的患者中，ARB将主动脉根部Z评分增加率降低约一半，包括服用β受体阻滞剂的患者。β受体阻滞剂的作用与ARB相似。假设具有可加性，从诊断时起，ARB和β受体阻滞剂的联合治疗将比单独治疗更能降低主动脉扩大率，如果维持多年，预计将延迟主动脉手术的必要性。

附：英文原文

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

Author: Alex Pitcher, Enti Spata, Jonathan Emberson, Kelly Davies, Heather Halls, Lisa Holland, Kate Wilson, Christina Reith, Anne H Child, Tim Clayton, Matthew Dodd, Marcus Flather, Xu Yu Jin, George Sandor, Maarten Groenink, Barbara Mulder, Julie De Backer, Arturo Evangelista, Alberto Forteza, Gisela Teixido-Turà, Catherine Boileau, Guillaume Jondeau, Olivier Milleron, Ronald V Lacro, Lynn A Sleeper, Hsin-Hui Chiu, Mei-Hwan Wu, Stefan Neubauer, Hugh Watkins, Hal Dietz, Colin Baigent

Issue&Volume: 2022-08-29

Abstract:

Background

Angiotensin 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.

Methods

In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva.

Findings

We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four 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 (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference –0·07 [95% CI –0·12 to –0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up 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] in ARB groups vs –0·11 [SE 0·02] in β-blocker groups; 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 blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042).

Interpretation

In people with Marfan syndrome and no previous 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.

DOI: 10.1016/S0140-6736(22)01534-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01534-3/fulltext

LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
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