Meta-Analysis

. 2022 Sep 10;400(10355):822-831.

doi: 10.1016/S0140-6736(22)01534-3. Epub 2022 Aug 29.

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

Alex Pitcher¹, Enti Spata², Jonathan Emberson², Kelly Davies², Heather Halls², Lisa Holland², Kate Wilson³, Christina Reith³, Anne H Child⁴, Tim Clayton⁵, Matthew Dodd⁵, Marcus Flather⁶, Xu Yu Jin⁷, George Sandor⁸, Maarten Groenink⁹, Barbara Mulder⁹, Julie De Backer¹⁰, Arturo Evangelista¹¹, Alberto Forteza¹², Gisela Teixido-Turà¹³, Catherine Boileau¹⁴, Guillaume Jondeau¹⁴, Olivier Milleron¹⁴, Ronald V Lacro¹⁵, Lynn A Sleeper¹⁵, Hsin-Hui Chiu¹⁶, Mei-Hwan Wu¹⁷, Stefan Neubauer¹⁸, Hugh Watkins¹⁹, Hal Dietz²⁰, Colin Baigent²¹; Marfan Treatment Trialists’ Collaboration

Affiliations

¹ The Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴ Royal Brompton and Harefield Hospitals Unit, Guy's and St Thomas' NHS Trust and Department of Surgery and Oncology, Imperial College London, London, UK.
⁵ Clinical Trials Unit, Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
⁶ Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
⁷ The Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁸ Children's Heart Centre, British Columbia's Children's Hospital, Vancouver, BC, Canada; Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁹ Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Amsterdam, The Netherlands.
¹⁰ Center for Medical Genetics and Department of Cardiology, Ghent University Hospital, Ghent, Belgium; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Ghent, Belgium.
¹¹ Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Barcelona, Spain.
¹² Hospital Puerta de Hierro, Majadahonda, Spain.
¹³ Department of Cardiology, Hospital Universitari Vall d'Hebron, CIBER-CV, Vall d'Hebron institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Barcelona, Spain.
¹⁴ Université Paris Cité and Université Sorbonne Paris Nord, Inserm U1148, LVTS, F-75018 Paris, France; Service de Cardiologie, AP-HP Hôpital Bichat-Claude Bernard, F-75018, Paris, France; CRMR Syndrome de Marfan et apparentés. AP-HP Hôpital Bichat-Claude Bernard, F-75018, Paris, France; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Paris, France.
¹⁵ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
¹⁷ Department of Pediatrics and Adult Congenital Heart Center, National Taiwan University Hospital, Taipei, Taiwan.
¹⁸ Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
¹⁹ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
²⁰ Howard Hughes Medical Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹ MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address: colin.baigent@ndph.ox.ac.uk.

PMID: 36049495
PMCID: PMC7613630
DOI: 10.1016/S0140-6736(22)01534-3

Meta-Analysis

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

Alex Pitcher et al. Lancet. 2022.

. 2022 Sep 10;400(10355):822-831.

doi: 10.1016/S0140-6736(22)01534-3. Epub 2022 Aug 29.

Authors

Affiliations

¹ The Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
² MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴ Royal Brompton and Harefield Hospitals Unit, Guy's and St Thomas' NHS Trust and Department of Surgery and Oncology, Imperial College London, London, UK.
⁵ Clinical Trials Unit, Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
⁶ Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
⁷ The Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁸ Children's Heart Centre, British Columbia's Children's Hospital, Vancouver, BC, Canada; Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁹ Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Amsterdam, The Netherlands.
¹⁰ Center for Medical Genetics and Department of Cardiology, Ghent University Hospital, Ghent, Belgium; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Ghent, Belgium.
¹¹ Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Barcelona, Spain.
¹² Hospital Puerta de Hierro, Majadahonda, Spain.
¹³ Department of Cardiology, Hospital Universitari Vall d'Hebron, CIBER-CV, Vall d'Hebron institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Barcelona, Spain.
¹⁴ Université Paris Cité and Université Sorbonne Paris Nord, Inserm U1148, LVTS, F-75018 Paris, France; Service de Cardiologie, AP-HP Hôpital Bichat-Claude Bernard, F-75018, Paris, France; CRMR Syndrome de Marfan et apparentés. AP-HP Hôpital Bichat-Claude Bernard, F-75018, Paris, France; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Paris, France.
¹⁵ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
¹⁷ Department of Pediatrics and Adult Congenital Heart Center, National Taiwan University Hospital, Taipei, Taiwan.
¹⁸ Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
¹⁹ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
²⁰ Howard Hughes Medical Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹ MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address: colin.baigent@ndph.ox.ac.uk.

PMID: 36049495
PMCID: PMC7613630
DOI: 10.1016/S0140-6736(22)01534-3

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.

Funding: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

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Conflict of interest statement

Declaration of interests 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).

Figures

**Figure 1**
Annual rate of change of body surface area-adjusted aortic root dimension Z score at the sinuses of Valsalva Indirect effect of β blocker vs control is –0·09 (95% CI –0·18 to 0·00); p value=0·042 (β blocker minus control). ARB=angiotensin receptor blocker.

**Figure 2**
Annual rate of change of BSA-adjusted aortic root dimension Z score at the sinuses of Valsalva, by subgroups (ARB vs control) ARB=angiotensin receptor blocker. BSA=body surface area.

**Figure 3**
Annual rate of change of BSA-adjusted aortic root dimension Z score at the sinuses of Valsalva, by subgroups (ARB vs β blocker) ARB=angiotensin receptor blocker. BSA=body surface area.

See this image and copyright information in PMC

Comment in

Marfan syndrome meta-analysis: individual patient data analysis reduces heterogeneity.
Pees C. Pees C. Lancet. 2022 Sep 10;400(10355):790-791. doi: 10.1016/S0140-6736(22)01642-7. Epub 2022 Aug 29. Lancet. 2022. PMID: 36049496 No abstract available.

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

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

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Conflict of interest statement

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