Irfan A. Dhalla, MD, MSc; Tara Gomes, MHSc; Zhan Yao, MD, MS; Jeff Nagge, PharmD; Navindra Persaud, MD, MSc; Chelsea Hellings, MSc; Muhammad M. Mamdani, PharmD, MA, MPH; David N. Juurlink, MD, PhD
Disclaimer: Dr. Dhalla had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The opinions, results, and conclusions reported here are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.
Acknowledgment: The authors thank Brogan Inc., Ottawa, Ontario, Canada, for the use of its Drug Product and Therapeutic Class Database.
Grant Support: This study was funded by a grant from the Ontario Ministry of Health and Long-Term Care to the Ontario Drug Policy Research Network, which is led by Drs. Mamdani and Juurlink. The project was supported by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Dhalla was supported by a New Investigator Award from the Canadian Institutes of Health Research.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1038.
Reproducible Research Statement: Study protocol: Available from Dr. Dhalla (e-mail, firstname.lastname@example.org). Statistical code and data set: Not available.
Requests for Single Reprints: Irfan A. Dhalla, MD, MSc, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; e-mail, email@example.com.
Current Author Addresses: Drs. Dhalla, Persaud, and Mamdani and Ms. Gomes: St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
Drs. Yao and Juurlink and Ms. Hellings: Institute for Clinical Evaluative Sciences, G1 06, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Dr. Nagge: University of Waterloo, School of Pharmacy, 10 Victoria Street South, Kitchener, Ontario N2G 1C5, Canada.
Author Contributions: Conception and design: I.A. Dhalla, T. Gomes, J. Nagge, N. Persaud, M.M. Mamdani, D.N. Juurlink.
Analysis and interpretation of the data: I.A. Dhalla, T. Gomes, Z. Yao, J. Nagge, C. Hellings, M.M. Mamdani, D.N. Juurlink.
Drafting of the article: I.A. Dhalla, N. Persaud, D.N. Juurlink.
Critical revision of the article for important intellectual content: I.A. Dhalla, T. Gomes, Z. Yao, J. Nagge, N. Persaud, C. Hellings, M.M. Mamdani, D.N. Juurlink.
Final approval of the article: I.A. Dhalla, T. Gomes, Z. Yao, J. Nagge, N. Persaud, C. Hellings, M.M. Mamdani, D.N. Juurlink.
Statistical expertise: T. Gomes, Z. Yao, M.M. Mamdani.
Obtaining of funding: T. Gomes, M.M. Mamdani, D.N. Juurlink.
Administrative, technical, or logistic support: I.A. Dhalla, T. Gomes, C. Hellings.
Collection and assembly of data: I.A. Dhalla, T. Gomes, Z. Yao, C. Hellings, M.M. Mamdani, D.N. Juurlink.
Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for the treatment of hypertension.
To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide in older adults.
Propensity score–matched observational cohort study with up to 5 years of follow-up.
All individuals aged 66 years or older who were newly treated with chlorthalidone or hydrochlorothiazide and were not hospitalized for heart failure, stroke, or myocardial infarction in the prior year were eligible for inclusion. Each chlorthalidone recipient was matched to up to 2 hydrochlorothiazide recipients on the basis of age, sex, year of treatment initiation, and propensity score.
The primary outcome was a composite of death or hospitalization for heart failure, stroke, or myocardial infarction. Safety outcomes included hospitalization with hypokalemia or hyponatremia.
A total of 29 873 patients were studied. During follow-up, chlorthalidone recipients (n = 10 384) experienced the primary outcome at a rate of 3.2 events per 100 person-years of follow-up, and hydrochlorothiazide recipients experienced 3.4 events per 100 person-years of follow-up (adjusted hazard ratio, 0.93 [95% CI, 0.81 to 1.06]). Patients treated with chlorthalidone were more likely to be hospitalized with hypokalemia (adjusted hazard ratio, 3.06 [CI, 2.04 to 4.58]) or hyponatremia (adjusted hazard ratio, 1.68 [CI, 1.24 to 2.28]). In 9 post hoc analyses comparing patients initially prescribed 12.5, 25, or 50 mg of chlorthalidone per day with those prescribed 12.5, 25, or 50 mg of hydrochlorothiazide per day, the former were more likely to be hospitalized with hypokalemia for all 6 comparisons in which a statistically significant association was found. The results of other effectiveness and safety outcomes were also consistent with those of the main analysis.
Unmeasured differences in baseline characteristics or physician treatment approaches or an insufficiently large sample may have limited the ability to detect small differences in the comparative effectiveness of the drugs.
As typically prescribed, chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia.
Ontario Ministry of Health and Long-Term Care.
Dhalla IA, Gomes T, Yao Z, Nagge J, Persaud N, Hellings C, et al. Chlorthalidone Versus Hydrochlorothiazide for the Treatment of Hypertension in Older Adults: A Population-Based Cohort Study. Ann Intern Med. ;158:447–455. doi: 10.7326/0003-4819-158-6-201303190-00004
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Published: Ann Intern Med. 2013;158(6):447-455.
Cardiology, Coronary Risk Factors, Endocrine and Metabolism, Fluid and Electrolyte Disorders, Geriatric Medicine.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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