Cardiorenal Effects of Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers in people underrepresented in trials: analysis of routinely collected data with validation against a target trial

Background Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial populations may not be representative of the general population. Methods Using trial replication methods within routine-care data, we explored replicability of the ONTARGET trial. For people prescribed an ACEi and/or an ARB in the UK Clinical Practice Research Datalink CPRD GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, using Cox-proportional hazards models, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), as well as secondary outcomes. As the pre-specified criteria were met confirming trial replicability, we then explored treatment effect heterogeneity of ACEi and ARB among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease. Findings In the trial-eligible population (n=137,155), results for the primary outcome met pre-specified criteria for similarity to the ONTARGET trial and demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]). When extending to trial-underrepresented groups, similar treatment effects of ARB and ACEi were observed by sex (P=0.09), age (P=0.70) and chronic kidney disease status (P=0.10). Interpretation We were able to replicate the results of the ONTARGET trial using routinely-collected healthcare data. Results suggest that trial findings were generalisable to population subgroups underrepresented in the trial. Funding GlaxoSmithKline Evidence before this study Trial replication is an important methodology increasingly used to validate findings from observational studies against target trials. Unlike many naïve observational comparisons, a previous study demonstrated replicability of the ONTARGET trial using United States insurance claims data. However, it is unknown whether trial replicability can be extended to UK routinely-collected healthcare data. In addition, little work has been done to extend findings of comparative effectiveness among trial-underrepresented subgroups such as women, the elderly and those with chronic kidney disease despite high rates of prescribing of ACE Inhibitors and angiotensin receptor blockers among these groups in routine-care. Added value of this study With access to the individual patient data from the ONTARGET study and using propensity-score methods to address confounding, we demonstrated trial replicability using routinely-collected primary care data, representative of a large proportion of the UK population. We were then able to leverage the large sample size of the trial-eligible cohort to extend findings to trial-underrepresented groups and demonstrated similar comparative effectiveness for subgroups of patients treated with ARB and ACEi among women, those aged ≥75 years and those with chronic kidney disease. Implications of all the available evidence Our findings support similar effectiveness for cardiovascular and renal outcomes for patients receiving an ARB compared to an ACEi in a trial-eligible cohort and subgroups for which there is currently a lack of evidence of treatment effectiveness. Trial-replication methodology can be used to provide evidence for populations underrepresented in clinical trials. ### Competing Interest Statement PB is funded by a GSK PhD studentship. AS is employed by LSHTM on a fellowship sponsored by GSK. 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. CC co-chairs the cloth mask knowledge exchange, a stakeholder group that includes cloth mask manufacturers and fabric distributors. MC was an employee of GSK at the time of the study. All other authors have no conflicts. ### Clinical Protocols ### Funding Statement This project is funded by a GlaxoSmithKline PhD studentship as part of a collaboration between GlaxoSmithKline and the London School of Hygiene and Tropical Medicine. 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: An application for scientific approval related to the use of the Clinical Practice Research Datalink (CPRD) data has been approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency in January 2020 (protocol no. 20_012). CPRD are already approved via a National Research Ethics Committee for purely non-interventional research if this type. Ethical approval for this study has been obtained from the London School of Hygiene & Tropical Medicine Ethics Committee (Ref. 22658). Access to the individual patient data from the ONTARGET trial has been obtained by the trial investigators via a data sharing agreement. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data was provided by CPRD under terms of the LSHTM license and can be requested from CPRD. ONTARGET trial data was obtained via a data sharing agreement with the sponsor, Hamilton Health Sciences Corporation.