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. 2020 Feb 17;180(4):542-551.
doi: 10.1001/jamainternmed.2019.7454. Online ahead of print.

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

Free PMC article

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

George Hripcsak et al. JAMA Intern Med. .
Free PMC article


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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hripcsak reports grants from the National Library of Medicine during the conduct of the study and grants from Janssen Research outside the submitted work. Dr Suchard reports grants from the National Science Foundation and the National Institutes of Health during the conduct of the study and grants from Janssen Research and Development outside the submitted work. Dr Shea reports grants from the National Heart, Lung, and Blood Institute and the US Health Resources and Services Administration not directly relevant to the published work. Dr Madigan reports personal fees from Simon Greenstone Panatier; Williams Hart; Lanier Law Firm; Kazan, McClain, Satterley & Greenwood; Shire; and Bayer outside the submitted work. Dr Krumholz reports personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jenson Law Firm, Arnold & Porter Law Firm, Ben C. Martin Law Firm, and the National Center for Cardiovascular Diseases (Beijing); cofounder of Hugo Health and Refactor Health; contracts with US Centers for Medicare & Medicaid Services; and grants from Medtronic/US Food and Drug Administration, Medtronic/Johnson & Johnson, and Shenzhen Center for Health Information outside the submitted work. Dr Ryan is an employee of Janssen Research and Development and shareholder of Johnson & Johnson during the conduct of the study. Dr Schuemie is an employee and shareholder of Janssen Research and Development outside the submitted work. No other disclosures were reported.


Figure 1.
Figure 1.. Comparability of the Populations for Commercial Claims and Encounters Database (CCAE)
A, The preference score is a transformation of the propensity score that adjusts for differences in the sizes of the 2 treatment groups. A higher overlap indicates individuals in the 2 groups were more similar in terms of their predicted probability of receiving 1 treatment over the other. This plot shows sufficient equipoise (majority of both distributions being between 0.25 and 0.75) in CCAE that propensity score stratification should be able to create balance without discounting a large proportion of the population, but it shows sufficient difference (nonoverlap) that propensity score stratification is necessary. B, Same plot as panel A but showing essentially perfect overlap after adjustment (matching shown here). This illustrates the success of the adjustment in achieving balance. C, Each dot represents the standardized difference of the means for a single covariate before and after stratification on the propensity score. The panel shows poor balance before but excellent balance after stratification, with all 63 069 under 0.1 and most under 0.05. All measured variables were successfully balanced by the adjustment, and the 2 cohorts were in fact similar on all measured aspects.
Figure 2.
Figure 2.. Homogeneity on Effectiveness
Hazard ratios (HRs) and forest plot of the 3 databases and the meta-analysis for chlorthalidone vs hydrochlorothiazide on the composite cardiovascular disease outcome. The 3 databases showed excellent agreement. CCAE indicates Commercial Claims and Encounters Database.
Figure 3.
Figure 3.. Forest Plot of Safety and Effectiveness Outcomes
Forest plot of hazard ratio estimates and calibrated 95% CIs for chlorthalidone vs hydrochlorothiazide for 55 safety and effectiveness outcomes. The safety signals predominantly favored hydrochlorothiazide.

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    1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines. Hypertension. 2018;71(6):1269-1324. doi:10.1161/HYP.0000000000000066 - DOI - PubMed
    1. Lederle FA, Cushman WC, Ferguson RE, Brophy MT, Fiore Md LD. Chlorthalidone Versus hydrochlorothiazide: a new kind of Veterans Affairs cooperative study. Ann Intern Med. 2016;165(9):663-664. doi:10.7326/M16-1208 - DOI - PubMed
    1. Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015;65(5):1033-1040. doi:10.1161/HYPERTENSIONAHA.114.05122 - DOI - PubMed
    1. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-1117. doi:10.1161/HYPERTENSIONAHA.112.191106 - DOI - PubMed
    1. Dhalla IA, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med. 2013;158(6):447-455. doi:10.7326/0003-4819-158-6-201303190-00004 - DOI - PubMed