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.