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Am Fam Physician. 2021;104(2):203

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Clinical Question

Is hydrochlorothiazide more effective than chlorthalidone for the treatment of hypertension?

Evidence-Based Answer

Chlorthalidone reduces systolic blood pressure (SBP) by 10 mm Hg more than hydrochlorothiazide at equal dosages (12.5 to 25 mg daily) in patients using monotherapy. (Strength of Recommendation [SOR]: B, meta-analysis of randomized controlled trials [RCTs].) Low-dose chlorthalidone (6.25 mg daily) and controlled-release hydrochlorothiazide (12.5 mg daily; not currently available in the United States) reduce 24-hour ambulatory SBP and diastolic blood pressure (DBP), whereas immediate-release hydrochlorothiazide (12.5 mg daily) may only reduce daytime SBP. (SOR: B, single RCT.)

Evidence Summary

A 2010 meta-analysis (137 RCTs; N = 10,443) evaluated the effect of hydrochlorothiazide and chlorthalidone on SBP and serum potassium.1 Adult patients were on hydrochlorothiazide or chlorthalidone monotherapy. Further patient demographics were not defined. Chlorthalidone dosing ranged from 12.5 to 200 mg daily (mean dosage = 31.6 mg daily) with an average baseline SBP of 166 mm Hg (29 RCTs; n = 4,380). Hydrochlorothiazide dosing ranged from 3 to 450 mg daily (mean dosage = 42.7 mg daily) with an average baseline SBP of 163 mm Hg (108 RCTs; n = 6,063). Studies lasted four to 52 weeks. Pooled results showed that chlorthalidone (12.5 to 25 mg daily) reduced SBP more than hydrochlorothiazide at the same dosage (137 RCTs; N = 10,443; −24 mm Hg vs. −14 mm Hg, respectively; P < .05). However, chlorthalidone also caused larger decreases in serum potassium levels (−0.4 mEq per L [–0.4 mmol per L] vs. −0.2 mEq per L [–0.2 mmol per L], respectively; P < .05). Heterogeneity was not reported. The analysis was limited to patients with hypertension who were on monotherapy.

A 2016 RCT (N = 54) evaluated the effect of low-dose chlorthalidone and hydrochlorothiazide on mean 24-hour ambulatory blood pressure.2 Patients were 18 to 65 years of age (mean = 45 years of age) with essential hypertension (SBP of 140 to 159 mm Hg, DBP of 90 to 99 mm Hg) and an average blood pressure of 148/93 mm Hg. Patients were excluded if they had secondary hypertension, diabetes mellitus, hyperuricemia, gout, chronic kidney disease, parathyroid disease, or recent cardiovascular disease. Patients were randomized to receive chlorthalidone, 6.25 mg (n = 16), hydrochlorothiazide, 12.5 mg (n = 18), or controlled-release hydrochlorothiazide, 12.5 mg (n = 20). Ambulatory (24-hour) blood pressure monitoring was done at baseline and after four and 12 weeks of therapy. Chlorthalidone and controlled-release hydrochlorothiazide reduced SBP and DBP during the day and at night at four and 12 weeks. Hydrochlorothiazide showed a significant improvement in SBP only during the day at four weeks. The study was limited by excluding many disease processes often present as comorbid conditions in patients with hypertension.

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