Blood Pressure Lowering by Thiazide-type Diuretics: Chlorthalidone vs Hydrochlorothiazide

Linda Brookes, MSc


May 28, 2004

Editorial Collaboration

Medscape &

Presenter: Nitin Khosla, MD, Rush University Medical Center (Chicago, Illinois)

The thiazide-type diuretics hydrochlorothiazide (HCTZ) and chlorthalidone are often considered to be interchangeable. The investigators in the huge Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT) extrapolated their highly publicized positive results with chlorthalidone to the whole drug class,[1] and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) does not differentiate between the 2 drugs in its recommendation of a thiazide-type diuretic as a preferred initial antihypertensive agent.[2]

Earlier this year, however, researchers at the University of Iowa concluded in a review that chlorthalidone and HCTZ are "two very different compounds," although "it is uncertain whether they have different effects on clinical outcomes." The authors recommended that studies comparing low doses of both agents be conducted to establish which is superior in the management of hypertension.[3]

There have been no studies directly comparing chlorthalidone against HCTZ, but in 1990, the Multiple Risk Factor Intervention Trial (MRFIT) reported a reduction in nonfatal cardiovascular events when the diuretic treatment protocol was changed to replace HCTZ with chlorthalidone in men at high risk for coronary heart disease.[4] Now, the results of an observational study appear to support the superiority of chlorthalidone over HCTZ, suggesting that it is more effective at lowering systolic blood pressure (SBP).[5]

Nitin Khosla, MD, and colleagues at Rush University Medical Center (Chicago, Illinois), reviewed 2000 charts from patients referred to the University's Hypertension/Clinical Research Center. All of the patients had been referred to the specialist clinic with refractory hypertension. Within this database, patients were sought who had been switched from HCTZ to chlorthalidone at identical dose when they were found not to be at goal blood pressure (< 140/90 mm Hg). A total of 19 patients (approximately 1%) met these criteria, of which 10 were female and 10 were black (some were both). Their mean age [± SD] was 65 ± 11 years.

Seventeen of the 19 patients were on HCTZ 25 mg/day and 2 were on 12.5 mg/day before they were switched to chlorthalidone. They were each on an average of 2 additional antihypertensive medications, which included dihydropyridine or nondihydropyridine calcium channel blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and alpha blockers. Eight patients also had hypocholesterolemia, 5 had cerebrovascular disease, 4 had diabetes, and 1 had microalbuminuria.

Data available for each patient included supine blood pressure readings recorded from both the index visit (prior to the switch) and the first visit after the switch, which took place 6-9 weeks later. Blood pressure was measured in the sitting position according to the American Heart Association guidelines.

Average SBP in patients at the index visit on HCTZ was 160 ± 23 mm Hg compared with 144 ± 15 mmHg at the first visit post switch (average 62 ± 33.5 days later), showing that chlorthalidone produced a greater reduction in blood pressure over HCTZ by 16 ± 23.7 mm Hg (P = .0085). After the switch to chlorthalidone, 32% of patients achieved their target blood pressure; patients with SBP within 10 mm Hg of target level were more likely to reach this goal.

No hypokalemia or symptoms related to gout were recorded in any of the 19 patients after they switched to chlorthalidone.

Dr Khosla believes that chlorthalidone has greater efficacy for lowering SBP compared with HCTZ and that chlorthalidone, rather than HCTZ, should be used when blood pressure goal is not achieved. He pointed out that substituting chlorthalidone for HCTZ is equivalent to adding another antihypertensive agent when the patient is already on 3 drugs. He and his colleagues support the proposal for comparative studies of chlorthalidone vs HCTZ to confirm this difference.

In the United States, HCTZ is the most commonly prescribed thiazide-type diuretic, whereas chlorthalidone is rarely used. After publication of the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which were interpreted as favorable for chlorthalidone, prescriptions for the drug remained low, whereas those for the more popular thiazide-type diuretic increased.

  1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:1981-1997.

  2. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.

  3. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43:4-9.

  4. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. 1990;82:1616-1628.

  5. Khosla N, Chua D, Elliott WJ, et al. Greater efficacy of chlorthalidone over hydrochlorothiazide for achieving blood pressure goals. Am J Hypertens. 2004;17(5 Pt 2):114A.


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