Real-world effects of ACE inhibitors and Angiotensin Receptor Blockers: protocol for an emulation study of the ONTARGET trial using electronic health records

Introduction Cardiovascular disease (CVD) is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based upon evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those over 75 years, from ethnic minority backgrounds or with low kidney function may be limited. The ONTARGET trial studied the effects of an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) separately and in combination on cardiovascular event reduction. Using individual anonymised data from this study, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within routinely-collected patient data. If the original trial results are replicable, we will assess treatment effects and risk in groups underrepresented and excluded from the original clinical trial. Methods and analysis We will develop a cohort analogous to the ONTARGET trial within CPRD between 1 January 2001 to 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome, as in the trial, is a composite of cardiovascular death, non-fatal MI, non-fatal stroke and hospitalisation for congestive heart-failure, examined in a time-to-event analysis. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include those with advanced kidney dysfunction and increase the proportion of elderly participants and those from ethnicity minority backgrounds. We will then compare the risk of adverse events and association with long-term outcomes in the clinical trial, with that seen in a directly comparable sample of those attending NHS primary care. STRENGTHS AND LIMITATIONS Strengths Large cohort study giving power to look at effects within subgroups underrepresented in the clinical trial Access to individual patient level data from a landmark trial to support creation of a trial-analogous cohort Novelty of studying treatment effects of dual therapy in real-world settings Limitations There may be differences between the trial population and the observational cohort due to the level of detail on inclusion/exclusion criteria provided by the trial Drug-specific effects are unlikely to be able to be investigated due to small numbers in the dual-therapy arm: class-specific effects will be studied instead Misclassification by primary care coding may lead to inaccurate replication of trial inclusion and exclusion criteria.