Which thiazide to choose as add-on therapy for hypertension?

Figures & data

Figure 1 Effects of chlorthalidone on cardiovascular outcomes.

Note: Data from Roush et al;⁴² Dorsch et al;⁴⁹ Roush et al;⁵⁹ Dhalla et al.⁶⁰
Abbreviations: Chlorthal, chlorthalidone; HCTZ, hydrochlorothiazide; CV, cardiovascular; HF, heart failure; SHEP, Systolic Hypertension in the Elderly Program; vs, versus; NS, not significant.

Table 1 Summary of the most relevant studies comparing the efficacy of hydrochlorothiazide with chlorthalidone in patients with hypertension

Study	Design	Comments
Ernst et al^Citation51	Randomized, single-blind, 8-week, active treatment, crossover study in which chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and HCTZ 25 mg/day (force-titrated to 50 mg/day) were compared in patients with untreated hypertension. Thirty patients completed the first active treatment period, whereas 24 patients completed both.	Compared with HCTZ 50 mg/day, chlorthalidone 25 mg/day reduced ambulatory systolic BP more effectively (24-hour mean −7.4±1.7 mmHg versus −12.4±1.8 mmHg, respectively, P=0.054; nighttime mean −6.4±1.8 mmHg versus −13.5±1.9 mmHg, respectively, P=0.009). However, these differences were not apparent when office BP measurements were considered (at study end, −10.8±3.5 versus −17.1±3.7, respectively, P=0.84).
Bakris et al^Citation52	Randomized, double-blind, titrate-to-target BP trial. A fixed combination of azilsartan medoxomil and chlorthalidone was compared with coadministration of azilsartan medoxomil and HCTZ in 609 individuals with stage 2 primary hypertension (mean baseline clinic BP 164.6/95.4 mmHg). After 2 weeks of treatment with azilsartan medoxomil 40 mg as monotherapy, 12.5 mg of diuretic for 4 weeks (up to week 6) was added to treatment and then titrated to 25 mg for another 4 weeks (up to week 10) if BP targets were not achieved.	At week 6, the combination containing chlorthalidone achieved greater clinic systolic BP reductions (−35.1 mmHg versus −29.5 mmHg, mean difference −5.6 mmHg; P<0.001), as well as greater 24-hour ambulatory BP reduction (mean difference −5.8 mmHg; P<0.001). More patients in the chlorthalidone group achieved target BP at week 6 (64.1% versus 45.9%, P<0.001). Discontinuation due to adverse events was similar between treated and control groups. (9.3% versus 7.3%, P=0.38).
Peterzan et al^Citation53	Meta-analysis aiming to analyze the dose-response relationships between HCTZ, chlorthalidone, and bendroflumethiazide on BP, serum potassium, and urate. A total of 26 trials examining HCTZ, three investigating chlorthalidone, and one investigating bendroflumethiazide were included, with a total of 4,683 subjects in more than 53 comparison arms.	Metaregression of the effect of thiazides on systolic BP showed various antihypertensive effects, as follows: bendroflumethiazide > chlorthalidone > HCTZ (the dose of each agent estimated to reduce systolic BP by 10 mmHg was 1.4, 8.6, and 26.4 mg, respectively). Similar findings were found regarding diastolic BP.
Ernst et al^Citation54	Meta-analysis that studied the effects of HCTZ and chlorthalidone on systolic BP and potassium. A total of 108 clinical trials with HCTZ and 29 with chlorthalidone were included from 1948 to July 2008.	Equivalence analysis suggested that the systolic BP reductions achieved with HCTZ and chlorthalidone were not equivalent within the low-dose range currently recommended. When evaluated on a milligram-per-milligram basis, chlorthalidone generally produced slightly greater reductions in systolic BP. By contrast, within the same dosing range, the mean changes in potassium were similar.
Matthews et al^Citation55	Retrospective study comparing the effects of changing from HCTZ to chlorthalidone in a veteran population (n=40) from Veterans Affairs Ann Arbor Healthcare System, in which nearly three quarters of patients were taking three or more antihypertensive agents at the time of the medication change.	There was a significant reduction in both systolic BP (−15.8 mmHg; P<0.0001) and diastolic BP (−4.2 mmHg; P=0.0035).
Kwon et al^Citation56	Open-label, randomized, prospective crossover study with an 8-week active treatment (candesartan 8 mg with HCTZ 25 mg or chlorthalidone 12.5 mg) and a 4-week washout period (only candesartan during this period). Twenty-eight treatment-naïve hypertensive patients were included.	Combined with candesartan 8 mg, chlorthalidone 12.5 mg was as effective as HCTZ 25 mg in reducing central aortic pressure. However, whereas chlorthalidone significantly reduced pulse wave velocity, HCTZ only marginally reduced the augmentation index.
Dorsch et al^Citation49	Retrospective cohort analysis from the Multiple Risk Factor Intervention Trial (this trial was a primary prevention cardiovascular trial in which participants were men aged 35–57 years and enrolled in 1973).	Although both drugs reduced cardiovascular events compared to those who took neither drug, chlorthalidone reduced cardiovascular events more effectively than HCTZ (by 49% and 35%, respectively; P<0.0001 in both cases versus neither drug; P=0.0016 between both drugs).
Roush et al^Citation59	Systematic review of randomized trials in which one arm was based on either HCTZ or chlorthalidone, followed by two types of network meta-analyses, ie, a drug-adjusted analysis and an office systolic BP-adjusted analysis. A total of three trials based on HCTZ and six based on chlorthalidone were included.	In the drug-adjusted analysis (n=50,946), compared with HCTZ, chlorthalidone reduced the risk of congestive heart failure by 23% (P=0.032); the risk for all cardiovascular events was 21% (P<0.0001). In the office systolic BP-adjusted analysis (n=78,350), compared with HCTZ, chlorthalidone reduced the risk of cardiovascular events by 18% (P=0.024).
Dhalla et al^Citation60	Propensity score-matched observational cohort study with up to 5 years of follow-up performed in patients ≥66 years who were newly treated with chlorthalidone or HCTZ and had not been hospitalized for heart failure, stroke, or myocardial infarction in the previous year (n=29,873).	Chlorthalidone was not associated with fewer adverse cardiovascular events or deaths compared with HCTZ (adjusted HR 0.93; 95% CI 0.81–1.06).

Abbreviations: HCTZ, hydrochlorothiazide; BP, blood pressure; CI, confidence interval; HR, hazards ratio.

Figure 2 Effects of perindopril and indapamide combination on cardiovascular outcomes.

Note: Data from PROGRESS Collaborative Group;⁷³ Patel A et al;⁷⁴ and Beckett NS et al.⁷⁷
Abbreviations: CV, cardiovascular; VE, vascular events; PROGRESS, Perindopril pROtection aGainst REcurrent Stroke Study; ADVANCE, Action in Diabetes and Vascular Disease study; HYVET, the Hypertension in the Very Elderly Trial.

Table 2 Summary of most relevant studies comparing the efficacy of hydrochlorothiazide with indapamide in patients with hypertension

Study	Design	Comments
Leonetti et al^Citation83	Open, 12-month, follow-up study of 444 patients treated with indapamide SR, who were responders and/or achieved target BP levels following a 3-month, randomized, controlled, double-blind, short-term comparison of indapamide SR versus HCTZ 25 mg and amlodipine 5 mg.	After 12 months of follow-up, treatment with indapamide SR was associated with a reduction of BP (−24.0/−13.1 mmHg); 80.1% of patients achieved their BP goals.
Nedogoda et al^Citation84	Clinical trial in which 40 patients with I–II degree high and very high risk hypertension were randomized to receive fixed-dose combinations of perindopril/indapamide 4/1.25 mg or captopril/HCTZ 50/25 mg.	After 6 months of treatment, the fixed combination of perindopril/indapamide 4/1.25 mg was superior to the combination of captopril/HCTZ 50/25 mg.
Karpov^Citation85	In this study, perindopril arginine/indapamide (10 mg/2.5 mg) was administered instead of an ACEi or ARB plus HCTZ in more than 2,100 patients with inadequately controlled hypertension.	Treatment with the perindopril arginine/indapamide combination significantly reduced BP levels from 177/99 mmHg to 149/89 mmHg after 2 weeks of treatment and to 130/80 mmHg after 3 months of treatment, with good tolerance of medication.
Cremonesi et al^Citation86	In this 12-week randomized study, fixed combinations of delapril/indapamide 30/2.5 mg and fosinopril/HCTZ 20/12.5 mg were compared in 171 patients with mild to moderate hypertension. Normalization of BP was defined as sitting diastolic BP ≤90 mmHg and responders as those having a sitting diastolic BP reduction of 10 mmHg or diastolic BP ≤90 mmHg.	The proportion of patients with normalized BP was similar between the two groups (87.4% versus 81%) and for those who responded to therapy (92% versus 86.9%, respectively). Both combinations were well tolerated.
Circelli et al^Citation87	Meta-analysis comparing the efficacy and safety of a combination of delapril and indapamide with that of different ACEi plus HCTZ combinations in patients with mild to moderate hypertension. Four head-to-head randomized controlled trials (n=643 and n=629, respectively) were included.	The proportions of patients with normalized BP values (OR 1.32; 95% CI 1.04–1.68; P=0.024) and who were responders (OR 1.58; 95% CI 1.22–2.04; P=0.002) were higher with the delapril/indapamide combination. The proportion of patients who withdrew from treatment due to side effects was lower with the delapril/indapamide combination (2.3% versus 4.8%; P=0.018).

Abbreviations: HCTZ, hydrochlorothiazide; BP, blood pressure; CI, confidence interval; OR, odds ratio; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SR, sustained release.

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