Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension | Cardiology | JAMA Internal Medicine | JAMA Network
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    Original Investigation
    February 17, 2020

    Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension

    Author Affiliations
    • 1Department of Biomedical Informatics, Columbia University Medical Center, New York, New York
    • 2Medical Informatics Services, NewYork-Presbyterian Hospital, New York
    • 3Observational Health Data Sciences and Informatics, New York, New York
    • 4Fielding School of Public Health, Department of Biostatistics, University of California, Los Angeles, Los Angeles
    • 5David Geffen School of Medicine, Department of Biomathematics, University of California, Los Angeles, Los Angeles
    • 6Department of Medicine, Columbia University, New York, New York
    • 7Department of Medicine, Weill Cornell Medical College, New York, New York
    • 8Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea
    • 9Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
    • 10Department of Statistics, Columbia University, New York, New York
    • 11Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • 12Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut
    • 13Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut
    • 14Epidemiology Analytics, Janssen Research and Development, Titusville, New Jersey
    JAMA Intern Med. 2020;180(4):542-551. doi:10.1001/jamainternmed.2019.7454
    Key Points

    Question  What are the relative effectiveness and safety of chlorthalidone and hydrochlorothiazide?

    Findings  In this comparative cohort study of 730 255 individuals from multiple large databases, no difference in association with effectiveness between the 2 drugs was found, but a significantly worse safety profile for chlorthalidone was observed.

    Meaning  Recommendations to prefer chlorthalidone to hydrochlorothiazide are not supported by real-world evidence.


    Importance  Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits.

    Objective  To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice.

    Design, Setting, and Participants  This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018.

    Exposures  Chlorthalidone and hydrochlorothiazide.

    Main Outcomes and Measures  The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.

    Results  Of 730 225 individuals (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).

    Conclusions and Relevance  This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.