DESIGN AND METHODOLOGY OF A RANDOMIZED CONTROLLED TRIAL EMULATION WITH REAL-WORLD DATA TO ASSESS COMBINATION THERAPY EFFECTIVENESS WITH BISOPROLOL, PERINDOPRIL AND AMLODIPINE

Objective: The 2023 European Hypertension Guidelines recommends beginning treatment with two drugs combination in most patients and up-titrates the treatment to a three-drug regimen if blood pressure (BP) remains uncontrolled. However, real-world evidence on the effectiveness of adding a third drug to a two-drug regimen is lacking. This study will evaluate the effectiveness and safety of a three-drug combination of bisoprolol, perindopril, and amlodipine compared to two-drug therapy in patients whose hypertension is not controlled with two drugs alone, aiming to assess the contribution of each drug to systolic and diastolic BP reduction. Design and method: A retrospective observational cohort study designed to emulate a randomized clinical trial (RCT) will be conducted. Eligible patients are those with uncontrolled systolic BP (>=140 mmHg) who, after at least four weeks on two drugs, either were prescribed a third drug (bisoprolol, perindopril, or amlodipine) or continued on two drugs. Patients will be identified from those included in Clinical Practice Research Datalink, a database collecting primary care data in the UK, between January 2005 and September 2019 and followed until March 2020. The primary endpoint is the change in systolic BP at eight weeks. Secondary endpoints include changes in diastolic BP and difference in BP control. BP measurements from 4 to 24 weeks post-index will be analyzed using a mixed model for repeated measures. To control for indication and selection bias, a two-stage matching process will be used, with propensity scores and chronological inclusion date used to ensure similar distribution of baseline characteristics between study groups. Feasibility counts indicated a high number of patients on dual therapy suggesting ability to match all triple-therapy patients to dual-therapy patients. Sensitivity analyses and Quantitative Bias Analysis will further assess potential residual confounding. Results: We hypothesize that adding a third drug - bisoprolol, perindopril, or amlodipine - will demonstrate effective BP control in real-world settings. Conclusions: If successful, this study will confirm the use of RCT emulation with real-world data to assess combination therapy effectiveness. This innovative approach could provide valuable insights for the potential registration of a new single-pill combination in hypertension.