Effect of intensive blood pressure and blood glucose control on cardiovascular outcomes driven by reductions in cardiovascular death and nephropathy: win ratio analysis of ADVANCE trial

AIMS: This study aims to re-analyse the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial using the win ratio approach to better understand the relative contributions of individual outcomes in a composite endpoint. METHODS AND RESULTS: We applied an unmatched win ratio analysis to the 11 140 participants of the ADVANCE trial, comparing intervention and control groups for blood pressure and glucose control. Outcomes were prioritized hierarchically by severity: cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, nephropathy, and retinopathy. The ADVANCE trial is registered with ClinicalTrials.gov, number NCT00145925. For blood pressure lowering, the perindopril-indapamide group had a win ratio of 1.11 [95% confidence interval (CI) 1.01-1.22, P = 0.028] compared to placebo and a net benefit of 1.5% (95% CI 0.2%-2.8%) for a number needed to treat (NNT) of 68 patients. For intensive glucose control, the win ratio was 1.10 (95% CI 1.01-1.20, P = 0.027) compared to standard glucose control with a net benefit of 1.6% (95% CI 0.2%-3.0%) for a NNT of 63 patients. When both interventions were combined, the win ratio increased to 1.19 (95% CI 1.04-1.35, P = 0.010) and the NNT decreased to 41 patients. Cardiovascular death and nephropathy were the main contributors to the observed benefits. CONCLUSION: The win ratio approach confirms the robustness of the original ADVANCE findings while providing a more detailed understanding of the relative importance of individual outcomes. This method enhances the interpretation and communication of composite endpoint analyses.