TY - JOUR
T1 - Angiotensin receptor blockers and β blockers in Marfan syndrome
T2 - an individual patient data meta-analysis of randomised trials
AU - Pitcher, Alex
AU - Spata, Enti
AU - Emberson, Jonathan
AU - Davies, Kelly
AU - Halls, Heather
AU - Holland, Lisa
AU - Wilson, Kate
AU - Reith, Christina
AU - Child, Anne H.
AU - Clayton, Tim
AU - Dodd, Matthew
AU - Flather, Marcus
AU - Jin, Xu Yu
AU - Sandor, George
AU - Groenink, Maarten
AU - Mulder, Barbara
AU - de Backer, Julie
AU - Evangelista, Arturo
AU - Forteza, Alberto
AU - Teixido-Turà, Gisela
AU - The Marfan Treatment Trialists’ Collaboration
AU - Boileau, Catherine
AU - Jondeau, Guillaume
AU - Milleron, Olivier
AU - Lacro, Ronald V.
AU - Sleeper, Lynn A.
AU - Chiu, Hsin-Hui
AU - Wu, Mei-Hwan
AU - Neubauer, Stefan
AU - Watkins, Hugh
AU - Dietz, Hal
AU - Baigent, Colin
N1 - Funding Information: The work of the MTT is supported by the Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council (MC_UU_00017/4). AP acknowledges funding support from the Marfan Foundation, the British Heart Foundation, including from the Oxford British Heart Foundation Centre for Research Excellence (RE/13/1/30181), the UK National Institute for Health and Care Research Biomedical Research Centre, Oxford, the Gibson fund, Oxford University Hospitals Charitable Fund, and from an Academy of Medical Sciences Clinical Lecturer Starter Grant scheme, which is administered by the Academy on behalf of the Academy, the Wellcome Trust, the Medical Research Council, the British Heart Foundation, Arthritis Research UK, Prostate Cancer UK, and the Royal College of Physicians. We would like to thank all the participants who originally took part in the included trials, without whom this research would not have been possible. We would like to thank the clinicians, scientists, and all those who worked on the original trials. JDB would like to thank Laura Muiño Mosquera for her contributions to the Ghent Marfan trial. We would also like to thank Samantha Briggs and Clare Mathews for their valuable administrative assistance in preparing this report. Funding Information: AP has received grants paid to his institutions from the Marfan Foundation, the British Heart Foundation, the UK National Institute for Health and Care Research Biomedical Research Centre, the Gibson fund, Oxford University Hospitals Charitable Fund, and the Academy of Medical Sciences Clinical Lecturer Starter Grant scheme (which is administered by the Academy on behalf of the Academy, the Wellcome Trust, the UK Medical Research Council [MRC], the British Heart Foundation, Arthritis Research UK, Prostate Cancer UK, and the Royal College of Physicians). CR has received institutional grants from the British Heart Foundation and UK MRC. CBa has received institutional grants from the British Heart Foundation, UK MRC, NIHR, and Boehringer Ingelheim (EMPA-KIDNEY trial). Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2022/9/10
Y1 - 2022/9/10
N2 - 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. Funding: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.
AB - 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. Funding: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.
UR - http://www.scopus.com/inward/record.url?scp=85137288244&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S0140-6736(22)01534-3
DO - https://doi.org/10.1016/S0140-6736(22)01534-3
M3 - Article
C2 - 36049495
SN - 0140-6736
VL - 400
SP - 822
EP - 831
JO - The Lancet
JF - The Lancet
IS - 10355
ER -