Key result
Evolving ECG LVH and blood pressure change mediated 4% to 13% of the effect of doxazosin, amlodipine, and lisinopril on preventing incident symptomatic heart failure compared to chlorthalidone.
Why the study?
Hypertension is a risk factor for HF, possibly via cardiac remodeling and LVH, but the extent to which BP change and evolving LVH explain treatment effects on HF was unknown.
Does lisinopril, doxazosin, or amlodipine compared with chlorthalidone affect incident heart failure via evolving ECG LVH and BP lowering in hypertensive patients?
RCT (n=29,892)
randomized
Does lisinopril, doxazosin, or amlodipine compared with chlorthalidone affect incident heart failure via evolving ECG LVH and BP lowering in hypertensive patients?
Evolving ECG LVH and blood pressure changes account for only a small proportion (4-13%) of the mechanism by which different antihypertensive medications prevent heart failure, suggesting other mechanisms drive the differences in HF prevention between drug classes.
Limited mediation by ECG LVH and BP changes suggests other pathways predominate; leaves open mechanisms of differential HF prevention by antihypertensives.
Background Hypertension is a known risk factor for heart failure ( HF ), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy ( LVH ). We studied the extent to which blood pressure ( BP ) change and evolving LVH contribute to the effect that lisinopril, doxazosin, and amlodipine have on HF compared with chlorthalidone. Methods and Results We conducted causal mediation analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data (1994-2002; in-trial follow-up). ALLHAT participants with available serial ECG s and BP measurements were included (n=29 892; mean age 67±4 years; 32% black; 56% men): 11 008 were randomized to chlorthalidone, 5967 to doxazosin, 6593 to amlodipine, and 6324 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 /hypertension and HF ). A large majority of participants (96%) had ECG LVH status unchanged, but 4% developed evolving ECG LVH . On average, BP decreased by 11/7 mm Hg. In adjusted Cox regression analyses, progressing ECG LVH (hazard ratio [ HR ] 1.78 [95% CI 1.43-2.22]), resolving ECG LVH ( HR 1.33 [95% CI 1.03-1.70]), and baseline ECG LVH (1.17 [95% CI 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% of the effect of doxazosin, 7% of the effect of amlodipine, and borderline 9% of the effect of lisinopril on HF . Conclusions Evolving ECG LVH and BP change account for 4% to 13% of the mechanism by which antihypertensive medications prevent HF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00000542.
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Johnson et al. (2019) conducted an RCT in Hypertension (n=29,892). lisinopril, doxazosin, and amlodipine vs. chlorthalidone was evaluated on Incident symptomatic HF. Evolving ECG LVH and blood pressure change mediated 4% to 13% of the effect of doxazosin, amlodipine, and lisinopril on preventing incident symptomatic heart failure compared to chlorthalidone.
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