Abstract

Background For translating an overall trial result into an individual patient's expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field-Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (<i>P</i>=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE-LY trial (<i>P</i>=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE-LY trial (<i>P</i>&lt;0.001) for major bleeding. Quartile-specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26-0.61) to 1.04 (95% CI, 0.83-1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42-0.88) to 1.20 (95% CI, 0.97-1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.