Tools for Practice

#61 Is Hydrochlorothiazide the Best Thiazide Diuretic for Hypertension?

When choosing a thiazide diuretic for hypertension, is hydrochlorothiazide (HCTZ) the best choice?

The available data suggest that hydrochlorothiazide is at best equal to and very likely inferior to chlorthalidone for improving blood pressure (BP) and clinical outcomes. Consider chlorthalidone when initiating thiazide diuretic therapy for hypertension.

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No trials specifically compare HCTZ to other thiazide diuretics on cardiovascular or mortality outcomes. We must rely on less rigorous study designs and other outcomes: 
  • Chlorthalidone reduces systolic BP better than HCTZ at equivalent doses with similar effects on potassium:1,2 
    • Chlorthalidone 25 mg, compared to HCTZ 50 mg, provided superior BP reduction overall (12 versus 7 mmHg on 24-hr monitor) and at nighttime (13 versus 6 mmHg).3  
  • Retrospective (and thus not considered definitive) analysis of the MRFIT trial: Chlorthalidone-based regimen reduced mortality versus HCTZ-based regimen (HR: 0.79 [95% CI: 0.68 to 0.92]; P=0.0016).4    
  • Retrospective cohort study of 29,873 patients from Ontario found no difference in cardiovascular outcomes but increased risk of electrolyte abnormalities with chlorthalidone.5 
  • Large trials using chlorthalidone (like ALLHAT6 and SHEP7) have demonstrated reductions in cardiovascular endpoints whereas HCTZ evidence is less robust. 
  • Network meta-analysis of nine randomized controlled trials found chorthalidone associated with fewer cardiovascular events than hydrochlorothiazide (Relative risk~0.8).8 However, these were indirect comparisons.  
    • Other indirect comparisons with thiazide diuretics (not just hydrochlorothiazide) have found either no difference in cardiovascular outcomes9 or, in more recent studies, reduced cardiovascular events with chlorthalidone/indapamide.10,11 
  • Thiazide diuretics are first-line for hypertensive patients without compelling indications for an alternate drug.12-14 
  • Meta-analysis15 (19 trials): found 24-hour BP with 12.5-25 mg doses of HCTZ compared to other antihypertensive drugs:  
    • Systolic 4.5-6.2 mmHg and diastolic 2.9-6.7mmHg higher.  
  • Chlorthalidone has a longer half-life than HCTZ (50-60 versus 9-10 hours), which may explain the superior BP control, especially at nightime.16 
  • HCTZ’s advantage is availability in many combination preparations which may improve adherence.17 
  • Indapamide is another thiazide-like diuretic with good evidence for reduction in cardiovascular endpoints as first18 or second-line antihypertensive.19  
June 29 2015 by Adrienne

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  • G. Michael Allan MD CCFP
  • Raj S. Padwal MD MSc FRCP(C)

1. Ernst ME, Carter BL, Zheng S, et al. Am J Hypertens. 2010; 23:440-6.

2. Peterzan MA, Hardy R, Chaturvedi N, et al. Hypertension. 2012 Jun; 59(6):1104-9.

3. Ernst ME, Carter BL, Goerdt CJ, et al. Hypertension. 2006; 47:352-8.

4. Dorsch MP, Gillespie BW, Erickson SR, et al. Hypertension. 2011; 57(4):689.

5. Dhalla IA, Gomes T, Yao Z, et al. Ann Intern Med. 2013; 158:447-55.

6. ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002; 288:2981-97.

7. SHEP Cooperative Research Group. JAMA. 1991; 265:3255-64.

8. Roush GC, Holford TR, Guddati AK. Hypertension. 2012 Jun; 59(6):1110-7.

9. Psaty BM, Lumley T, Furberg CD. JAMA. 2004; 292:43-4.

10. Olde Engberink RH, Frenkel WJ, van den Bogaard B, et al. Hypertension. 2015 May; 65(5):1033-40.

11. Chen P, Chaugai S, Zhao F, et al. Am J Hypertens. 2015 Apr 29. pii: hpv050. [Epub ahead of print]

12. Wright JM, Musini VM. Cochrane Database Syst Rev. 2009; 3:CD001841.

13. Psaty BM, Lumley T, Furberg CD, et al. JAMA. 2003; 289:2534-44.

14. Rabi DM, Daskalopoulou SS, Padwal RS, et al. Can J Cardiol. 2011; 27:415-33.

15. Messerli FH, Makani H, Benjo A, et al. Am Coll Cardiol. 2011; 57:590-600.

16. Ernst ME, Moser M. N Engl J Med. 2009; 361(22):2153-64.

17. Pan F, Chernew ME, Fendrick AM. J Gen Intern Med. 2008; 23(5):611-4.

18. Beckett NS, Peters R, Fletcher AE, et al. N Engl J Med. 2008; 358(18):1887-98.

19. PROGRESS Collaborative Group. Lancet. 2001; 358(9287):1033-41.

Authors do not have any conflicts of interest to declare.