Equal Effectiveness of Chlorthalidone and Hydrochlorothiazide for Treating Hypertension

Hypertension (high blood pressure) affects around 116 million U.S. adults — nearly half of adults in the United States — and is a major risk factor for heart disease, stroke and chronic kidney disease.[1]

For those patients who cannot control their blood pressure though dietary changes, exercising, losing weight and other lifestyle interventions, there are drugs in many Food and Drug Administration (FDA)-approved medication classes that help lower blood pressure.[2] These include thiazide diuretics (sometimes known as water pills), angiotensin-converting enzyme inhibitors (such as captopril [generic only]), angiotensin receptor blockers (such as losartan [COZAAR and generics]) and calcium channel blockers (such as amlodipine [KATERZIA, NORLIQVA, NORVASC and generics]) or diltiazem [CARDIZEM, CARTIA XT, TAZTIA XT, TIAZAC and generics]).[3]

Worst Pills, Best Pills News recommends low-dose thiazide diuretics as the initial therapy for hypertensive patients (except those with chronic kidney disease) because of their greater effectiveness in preventing acute heart failure.[4] A study published in December 2022 in the New England Journal of Medicine (NEJM) found that chlorthalidone and hydrochlorothiazide are equally effective for treating hypertension.

Prior evidence about thiazides for treating hypertension

Thiazides can be divided into thiazide-like diuretics, including chlorthalidone (THALITONE and generics), and thiazide-type diuretics, such as hydrochlorothiazide (MICROZIDE and generics).[5] Because chlorthalidone is cleared more slowly from the body than hydrochlorothiazide, it is a more potent and longer-acting diuretic.

Thiazides cause the kidneys to excrete sodium (a component of salt) and water into the urine, which may help reduce blood pressure.[6] However, because this mechanism also can lead to decreased levels of potassium in the blood, common adverse events associated with thiazides are hypokalemia (low levels of potassium) and hyponatremia (low levels of sodium). Previous research has shown that chlorthalidone is more likely to cause hypokalemia and hyponatremia than hydrochlorothiazide.

Despite the higher risks of hyponatremia and hypokalemia and inconclusive efficacy data, current guidelines for treating high blood pressure recommend chlorthalidone as the preferred diuretic, not hydrochlorothiazide.[7] For example, although a 2015 meta-analysis (which combined data from multiple studies) showed that thiazide-like diuretics, such as chlorthalidone, led to a significantly greater reduction in the risk of cardiovascular events and heart failure than thiazide-type diuretics, such as hydrochlorothiazide,[8] a 2020 observational study found that both types of drugs were equally effective in preventing the serious complications of hypertension.[9]

As was the case with other earlier studies, the meta-analysis and the observational study only indirectly compared the two drugs.

Evidence from the 2022 NEJM study

The recent study comparing chlorthalidone with hydrochlorothiazide found no difference between the two drugs in their effectiveness for preventing major adverse cardiovascular events.[10] This study was an open-label comparative-effectiveness trial including 13,523 adults 65 years or older in the Department of Veterans Affairs health system. The participants had previously been treated for hypertension with either 25 or 50 mg of hydrochlorothiazide daily.[11]

The participants were randomly assigned to either continue taking their daily dose of hydrochlorothiazide or to switch to a daily dose of 12.5 or 25 mg of chlorthalidone.[12] After a median follow-up of 2.4 years, subjects who switched to chlorthalidone did not have a lower incidence of adverse cardiovascular events than those who continued taking hydrochlorothiazide.[13] Moreover, subjects in the chlorthalidone (10.4%) and the hydrochlorothiazide (10.0%) groups were equally likely to experience adverse events (such as nonfatal myocardial infarction, stroke or hospitalization for heart failure) or death from causes other than cancer.

Nonetheless, patients in the chlorthalidone group had a significantly higher incidence of hypokalemia (6.0%) and were slightly more likely to be hospitalized for hypokalemia (1.5%) than those in the hydrochlorothiazide group (4.4% and 1.1%, respectively).[14] Subjects taking chlorthalidone also were more likely to receive prescriptions for potassium supplements.

The generalizability of these results is limited by several factors.[15] For example, the study involved almost exclusively men (97%), and most subjects were on one or more additional blood pressure medication. The medication doses in the trial were also relatively low, even though the subjects’ average systolic blood pressure at the beginning and throughout the trial remained higher than desired.[16] Thus, the study’s findings may not apply to other groups of patients, such as women or those on higher dosages of these medications.

What You Can Do

If you have been newly diagnosed with hypertension and have no other medical conditions (such as diabetes or high cholesterol), discuss with your doctor whether to try lifestyle interventions (healthy diet, exercise, reduced salt intake) before considering medical therapy. If these changes do not work, talk with your doctor about also taking a low-dose thiazide diuretic as a first-line treatment. If you wish to consider either chlorthalidone or hydrochlorothiazide, you can discuss this article with your doctor.

During treatment with thiazides, it is important that you monitor for signs of hypokalemia (including irregular pulse rate, palpitations and weakness) and hyponatremia (including abdominal pain, vomiting, dizziness and weakness). Before and after initiating thiazide therapy, you should have blood tests to monitor your blood levels of sodium and potassium.

If you are being treated with chlorthalidone and experience problems with either low levels of potassium or sodium in the blood, you should discuss with your doctor alternatives, such as decreasing the dose, taking potassium supplements, switching to hydrochlorothiazide or taking another medication.
 

References

[1] Centers for Disease Control and Prevention. High blood pressure. January 5, 2023. https://www.cdc.gov/bloodpressure/facts.htm. Accessed June 20, 2023.

[2] Mann, J., Flack, J. Choice of drug therapy in primary (essential) hypertension. UpToDate. Updated March 7, 2023.

[3] Food and Drug Administration. High blood pressure. February 1, 2021. https://www.fda.gov/consumers/free-publications-women/high-blood-pressure. Accessed June 20, 2023.

[4] Thiazides (water pills): Best initial treatment for high blood pressure, study finds. Worst Pills, Best Pills News. May 2020. https://www.worstpills.org/newsletters/view/1332. Accessed June 20, 2023.

[5] Olde Engberink RH, Frenkel WJ, van den Bogaard B, et al. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015;65(5):1033-1040.

[6] Chlorthalidone versus hydrochlorothiazide for hypertension. Worst Pills, Best Pills News. July 2013. https://www.worstpills.org/newsletters/view/859. Accessed June 20, 2023.

[7] 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: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension. 2018,71(6):e13-e115.

[8] Olde Engberink R., Frenkel W., van den Bogaard B, et al. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015;65(5):1033-1040.

[9] Hripcsak G, Suchard MA, Shea S, et al. Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension. JAMA Intern Med. 2020;180(4):542-551.

[10] Ishani A, Cushman WC, Leatherman SM, et al. Chlorthalidone vs. hydrochlorothiazide for hypertension–cardiovascular events. N Engl J Med. 2022;387(26):2401-2410.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Ibid.

[16] Mann J, Flack J. Choice of drug therapy in primary (essential) hypertension. UpToDate. Updated March 7, 2023.