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

BackgroundCardiovascular 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. MethodsUsing 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. FindingsIn 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). InterpretationWe 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. FundingGlaxoSmithKline Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSTrial replication is an important methodology increasingly used to validate findings from observational studies against target trials. Unlike many naive 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 studyWith 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 evidenceOur 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.