Pairwise comparison of hydrochlorothiazide and chlorthalidone responses among hypertensive patients.

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone.

BACKGROUND: Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. METHODS: We compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17-65-year-old mild-moderate uncomplicated hypertensive whites and blacks. RESULTS: Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10-6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e-7). CONCLUSION: Compared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.