Comparative effectiveness of ARB and ACEi for cardiovascular outcomes and risk of angioedema among different ethnic groups in England: an analysis in the UK Clinical Practice Research Datalink with emulation of a reference trial (ONTARGET)

Objective To study the comparative effectiveness of angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEi) in ethnic minority groups in the UK. Design Observational cohort study using a reference trial emulation approach benchmarked against the ONTARGET trial. Setting UK Clinical Practice Research Datalink Aurum data from 01/01/2001-31/07/2019. Participants Black, South Asian, or White patients treated with ARB or ACEi who met the ONTARGET trial criteria. Main outcome measures The primary composite outcome was: cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using a propensity-score—weighted Cox proportional hazards model for ARB vs ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. Results 17,593 Black, 30,805 South Asian, and 524,623 White patients were included. We benchmarked results against ONTARGET comparing ARB with ACEi for the primary outcome (hazard ratio [HR] 0.96, 95% CI: 0.95 to 0.98) and found no evidence of treatment effect heterogeneity ( Pint =0.422). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, there was strong evidence of heterogeneity ( Pint =0.002), with ARB associated with more events in Black individuals and with fewer events in White individuals compared to ACEi, and no differences in South Asian individuals. For angioedema, HR 0.56 (95% CI: 0.46 to 0.67) for ARB vs ACEi ( Pint =0.306). Absolute risks were higher in Black individuals, with number-needed-to-harm of 204 in Black individuals compared with 2000 in South Asian individuals and 1667 in White individuals ( Pint =0.023). Conclusions These results demonstrate variation in drug effects of ACEi and ARB by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals. What is already known on this topic What this study adds ### Competing Interest Statement PB was funded by a GSK PhD studentship at the time of writing. AS is employed by LSHTM on a fellowship sponsored by GSK. EP was an employee of Compass Pathways at the time of the review. CC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter. In 2018 CC co-chaired a KDIGO potassium controversies conference sponsored at arm's length by Fresenius Medical Care, AstraZeneca, Vifor Fresenius Medical Care, Relypsa, Bayer HealthCare and Boehringer Ingelheim. JFEM reports honoraria from AstraZeneca, Bayer, Boehringer, Novo Nordisk, UpToDate Inc., Idorisia, Labchem, Parexel, Roche, Sanofi. MC was an employee of GSK at the time of the study. All other authors have no conflicts. ### Clinical Protocols ### Funding Statement This work was supported by the funding from a GlaxoSmithKline PhD studentship held by PB as part of an ongoing collaboration between GSK and the London School of Hygiene and Tropical Medicine. This research was funded in whole, or in part, by the Wellcome Trust [Senior Research Fellowship 224485/Z/21/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20_012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators and complies with institutional review board approved informed consent forms provided by the individuals from whom the data were collected. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes No additional data available