Worsening Kidney Function Is the Major Mechanism of Heart Failure in Hypertension: The ALLHAT Study.

objectivesThe authors 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.

backgroundThe authors hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) participants randomized to lisinopril and chlorthalidone, in comparison with those randomized to amlodipine and doxazosin.

methodsCausal mediation analysis of ALLHAT data (1994 to 2002) included participants with available baseline and 24- to 48-month estimated glomerular filtration rate (eGFR) (N = 27,918; mean age 66 ± 7.4 years; 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.

resultsThere 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 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF. In participants with diabetes, the relative change in eGFR mediated nearly 50% of the effect of lisinopril on incident symptomatic HF, whereas in diabetes-free participants, only 17%.

conclusionsOn the risk difference scale, change in eGFR accounts for up to 50% of the mechanism by which antihypertensive medications affect HF. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542).