Prevention of Heart Failure in Hypertension—Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering: The ALLHAT Study

Kyle Johnson, Suzanne Oparil, Barry R. Davis, Larisa Tereshchenko

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    Abstract

    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 ECGs 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: NCT00000542.

    Original languageEnglish (US)
    Article numbere011961
    JournalJournal of the American Heart Association
    Volume8
    Issue number8
    DOIs
    StatePublished - Apr 16 2019

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    Left Ventricular Hypertrophy
    Ventricular Pressure
    Heart Failure
    Blood Pressure
    Electrocardiography
    Doxazosin
    Lisinopril
    Amlodipine
    Chlorthalidone
    Antihypertensive Agents
    Hypertension
    Linear Models
    Logistic Models
    Myocardial Infarction
    Regression Analysis
    Demography
    Clinical Trials
    Lipids

    Keywords

    • antihypertensive agent
    • ECG
    • heart failure
    • hypertension
    • left ventricular hypertrophy

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    @article{3afe6250337f46a3a5463388c43c9d7a,
    title = "Prevention of Heart Failure in Hypertension—Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering: The ALLHAT Study",
    abstract = "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 ECGs 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: NCT00000542.",
    keywords = "antihypertensive agent, ECG, heart failure, hypertension, left ventricular hypertrophy",
    author = "Kyle Johnson and Suzanne Oparil and Davis, {Barry R.} and Larisa Tereshchenko",
    year = "2019",
    month = "4",
    day = "16",
    doi = "10.1161/JAHA.119.011961",
    language = "English (US)",
    volume = "8",
    journal = "Journal of the American Heart Association",
    issn = "2047-9980",
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    TY - JOUR

    T1 - Prevention of Heart Failure in Hypertension—Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering

    T2 - The ALLHAT Study

    AU - Johnson, Kyle

    AU - Oparil, Suzanne

    AU - Davis, Barry R.

    AU - Tereshchenko, Larisa

    PY - 2019/4/16

    Y1 - 2019/4/16

    N2 - 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 ECGs 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: NCT00000542.

    AB - 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 ECGs 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: NCT00000542.

    KW - antihypertensive agent

    KW - ECG

    KW - heart failure

    KW - hypertension

    KW - left ventricular hypertrophy

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