Individual participant-level analysis of four randomized clinical trials examined therapeutic effects of blood pressure lowering on hierarchical kidney outcome using win statistics

Introduction: Despite established cardiovascular benefits, the effects of intensive blood pressure (BP) lowering and specific agents on kidney function remain debated. Here, we assessed these effects using a validated hierarchical composite kidney endpoint (HCE) that prioritizes clinical severity. 

Methods: This post hoc analysis used individual-level data from four large randomized clinical trials: SPRINT, ACCORD-BP, SHEP, and ALLHAT. The seven-tier HCE ranked components by clinical severity: all-cause mortality, kidney failure, estimated glomerular filtration rate (eGFR) under 15 mL/min/1.73m², eGFR declines of 57%/50%/40% or more, and three-year total eGFR slope. We estimated Win Odds (WO) for all randomized participants, with missing outcomes handled as ties. 

Results: A total of 61,248 participants were included with median follow-ups of 46 to 60 months across trials. Intensive BP treatment yielded unfavorable WO compared with standard treatment in SPRINT (WO, 0.61 [95% confidence interval, 0.58–0.64]) and ACCORD-BP (WO, 0.64 [0.59–0.68]. In SHEP, chlorthalidone was inferior to placebo (WO, 0.89 [0.84–0.95]). In ALLHAT, doxazosin (WO, 1.29 [1.25–1.33]) and amlodipine (WO, 1.38 [1.34–1.42]) outperformed chlorthalidone, while lisinopril was slightly less favorable (WO, 0.96 [0.93–0.98]). The eGFR slope component contributed over 50% to the win statistics across trials. Results were broadly consistent across subgroups and sensitivity analyses. 

Conclusions: Our hierarchical analysis indicated that intensive BP lowering and chlorthalidone were associated with less favorable mid-term eGFR trajectories. Driven largely by the eGFR slope, which represents a sensitive signal of kidney reserve depletion, our findings support monitoring kidney function to optimize the balance between cardiovascular protection and kidney preservation. 

Trial Registration: Registered at Clinicaltrials.gov with study numbers NCT01206062, NCT00000620, NCT00000514, and NCT00000542.