Worsening of kidney function is the major mechanism of heart failure in hypertension: the ALLHAT study

Background We aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function. We hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT participants randomized to lisinopril, amlodipine, and doxazosin, in comparison to those randomized to chlorthalidone. Methods Causal mediation analysis of ALLHAT data (1994-2002) included participants with available baseline and 24-48 month estimated glomerular filtration rate (eGFR) (n=27,918; mean age 66±7.4; 32.4% black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors. Results There were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 38% of the effect of amlodipine, 25.5% of doxazosin, and 6.3% of lisinopril on incident symptomatic HF, and 42% of the effect of amlodipine, 55.3% of doxazosin, and 12.7% of lisinopril on hospitalized/fatal HF. In lisinopril arm, eGFR changes had an opposite effect on symptomatic versus hospitalized/fatal HF outcomes. Reduction in eGFR by at least 40% explained > 50% of increased risk in hospitalized/fatal HF but 18-25% reduction of symptomatic HF risk. Conclusion On the risk difference scale, change in eGFR accounts for more than 50% of the mechanism by which antihypertensive medications affect HF. Clinical Trial Registration URL: www.clinicaltrials.gov Unique identifier: NCT00000542 .