Prevention of heart failure in hypertension – disentangling the role of evolving left ventricular hypertrophy and blood pressure lowering: the ALLHAT study

Abstract Background Hypertension (HTN) is a known risk factor for heart failure (HF), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy (LVH). We studied how much blood pressure (BP) change and evolving LVH contribute to the effect that lisinopril, doxazosin, amlodipine have on HF compared to chlorthalidone. Methods We conducted causal mediation analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) data. ALLHAT participants with available serial ECGs and BP measurements were included (n=29,892; mean age 67±4 y; 32% black; 56% men): 11,008 were randomized to chlorthalidone, 5,967 – to doxazosin, 6,593 – to amlodipine, and 6,324 – to lisinopril. Evolving ECG-LVH, and BP-lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator-outcome confounders (demographic and clinical characteristics known to be associated both with both LVH/HTN and HF). Results A large majority of participants (96%) had ECG-LVH status unchanged; 4% developed evolving ECG-LVH. On average, BP decreased by 11/7 mmHg. In adjusted Cox regression analyses, progressing ECG-LVH HR 1.78(1.43-2.22), resolving ECG-LVH HR 1.33(1.03-1.70), and baseline ECG-LVH 1.17(1.04-1.31) carried risk of incident HF. After full adjustment, evolving ECG-LVH mediated 4% of the effect of doxazosin on HF. Systolic BP-lowering mediated 12% of the effect of doxazosin, and diastolic BP-lowering mediated 10% effect of doxazosin, 7% effect of amlodipine, and borderline 9% effect of lisinopril on HF. Conclusions Evolving ECG-LVH and BP change account for 4-13% of the mechanism by which antihypertensive medications prevent HF.