Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes ( P <0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events ( P =0.049) and a 21% additional risk reduction for heart failure ( P =0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.

Introduction

Thiazide diuretics are widely recommended as first-line therapy for hypertension with >48 million prescriptions for hydrochlorothiazide in the United Stated in 2011.1–3 Clinical trials have demonstrated that thiazide diuretics reduce cardiovascular morbidity and mortality in hypertensive patients when given alone or in combination with β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium antagonists.4 Thiazide diuretics can be separated according to their molecular structure in thiazide-type (TT) and thiazide-like (TL) diuretics with TT diuretics being to date the most commonly prescribed diuretic class in the United States.5,6 TT and TL diuretics differ with regard to their pharmacokinetic and pharmacodynamic properties, which may result in different blood pressure (BP)–dependent and BP-independent effects. TL diuretics such as chlorthalidone have a longer elimination half-life compared with TT diuretics resulting in better 24-hour BP reduction, especially during the night.7 In addition, experimental evidence suggests that TL diuretics exert additional effects on the vascular system by reducing platelet aggregation and vascular permeability.8,9 On the basis of the above, it is conceivable that TL diuretics may differentially affect cardiovascular disease compared with TT diuretics. Because prospective trials comparing TT and TL diuretics are lacking, the interchangeability of these 2 classes about cardiovascular risk reduction is subject of debate. Previous retrospective studies have concentrated on differences between hydrochlorothiazide and chlorthalidone and reported conflicting results.10,11 A meta-analysis of prospective studies indirectly comparing hydrochlorothiazide and chlorthalidone concluded that treatment with chlorthalidone resulted in less cardiovascular event (CVE) than treatment with hydrochlorothiazide.12 Because differences in pharmacological and pharmacokinetic properties may not be confined to hydrochlorothiazide and chlorthalidone, we compared the effects of TT and TL diuretics on cardiovascular outcome. To correct for nonequipotent doses, we additionally related the antihypertensive effect of TT and TL diuretics to the achieved cardiovascular risk reduction.

Methods

The primary objective of this systematic review and meta-analysis was to compare the effect of TT and TL diuretics on CVE, coronary events, heart failure, cerebrovascular events, and all-cause mortality in adult hypertensive (BP >140/90 mm Hg) patients.

Data Sources and Searches

In this meta-analysis, we adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Medline, Embase, and Cochrane library were searched (until July 2014) for clinical trials, in which thiazide diuretics were given as first-line antihypertensive treatment (online-only Data Supplement). The electronic search strategy was designed by a medical librarian and reviewed by 2 authors (R.H.G.O.E., W.J.F.) who were trained in systematic review searches. Furthermore, bibliographies of previously published meta-analyses about thiazide diuretics were used to search for eligible clinical trials.4,12 Articles were first evaluated based on title and abstract. Case reports, guidelines, editorials, and reviews were excluded, as well as abstracts with a combination of title and abstract that indicated that there was no possibility that the article could fit the requirements of this review.

Study Selection

For this review, randomized, controlled studies that described the effect of either TT or TL diuretics in hypertensive patients aged ≥18 years on CVE or mortality, were considered. We included studies that used either placebo or other antihypertensive therapy as control treatment. Studies were included if patients had a mean systolic BP of ≥140 mm Hg, a mean diastolic BP of ≥90 mm Hg or received antihypertensive treatment at baseline. Treatment had to include TT or TL diuretics as first-line therapy with a standardized protocol for dose titration or add-on BP-lowering therapy. A minimum follow-up period of 1 year was considered to adequately study the effect of the different BP-lowering treatment regimens on cardiovascular end points and mortality. Two reviewers (W.J.F. and B.v.d.B.) independently assessed each eligible study. Disagreement was resolved through final discussion with a third author (B.J.H.v.d.B.).

Data Extraction and Quality Assessment

Data were extracted using a standardized data extraction form. Data extraction was done by 2 independent reviewers (W.J.F. and R.H.G.O.E.). We extracted data on key demographics, such as age, sex, body mass index, baseline BP, ethnicity, prevalence of cardiovascular disease and diabetes mellitus, and study characteristics such as study size, mean follow-up duration, treatment strategies, publication year, CVE definitions, and inclusion criteria. In addition, we collected data on BP changes and CVE. Because of differences in outcome definitions across trials, we calculated new predefined outcome measures using data that was reported by the authors of included studies. In this meta-analysis, CVE were defined as the aggregate of cerebrovascular events, coronary events, and heart failure. Cerebrovascular events were defined as a composite of stroke and transient ischemic attack, whereas coronary events included myocardial infarction and sudden death. We did not include cardiac angina, peripheral artery disease, coronary artery bypass grafting, coronary revascularization, other cardiovascular procedures, and accelerated hypertension because of differences in definitions and event reporting, or because they were only reported in few studies. Adverse events were defined as discontinuation of the drug because of side effects or serious adverse events. In individual studies, the risk of bias was assessed by R.H.G.O.E. and reviewed by B.v.d.B. according to the Cochrane Handbook Guidelines.13 The risk of bias was assessed for random sequence generation, allocation concealment, blinding of personnel and participants, blinding of outcome assessment, incomplete outcome data, and selective reporting (Table S1 in the online-only Data Supplement).

Data Analysis

Data were analyzed using Cochrane Review Manager Software (Review Manager 5.2) and SPSS (Version 20.0; SPSS, Inc, Chicago, IL). To compare demographics and follow-up duration of studies that investigated TT and TL diuretics, we calculated average values that were weighted by study size. Statistical heterogeneity was quantified by calculating I2 that describes the percentage of total variation across studies that is caused by heterogeneity.14 Quantitative analyses of outcomes were based on intention-to-treat analysis whenever possible, using observational years to correct for differences in study duration. Risk ratios (RRs) and confidence intervals were calculated to combine outcomes across trials using a random effects model. We compared the effects of TT and TL diuretics with placebo and other antihypertensive drugs to test the effects of both diuretic classes on cardiovascular outcome.

Meta-regression analysis was performed to assess if the outcome measures were affected by patient characteristics, such as average patient age, proportion of male and white subjects, annual incidence of CVE, mean follow-up time, and the achieved mean BP reduction between randomized groups. The annual incidence of CVE was calculated for each study separately by dividing the number of CVE by the amount of patients-years of follow-up. For analysis of covariance, RRs were logarithmically transformed and plotted against the antihypertensive effect. This regression was weighted by the inverse variance of the natural logarithm of the RR. The slope and y-intercept of these regression lines were calculated and compared. Differences in y-intercept between TT and TL diuretics were considered to represent an additional effect, independent of BP reductions, whereas slope differences were considered to represent synergistic effects related to the size of BP reduction.

Sensitivity analyses were performed to assess the robustness of the results and to detect factors that may induce heterogeneity. Because the group of other antihypertensive therapy consists of various antihypertensive classes, we performed separate, drug-adjusted analyses for those antihypertensive classes that were compared with both TT and TL diuretics. The analysis comparing calcium antagonists with thiazide diuretics was repeated with dihydropyridine compounds only. In other sensitivity analyses, we excluded studies that were not double-blinded, studies that included patients with a mean age >75 years, the preliminary discontinued arm in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and studies, in which additional drugs were used in combination with thiazide diuretics to assess the effect on the outcome measures.15 In addition, studies were weighted by the inverse variance and Mantel–Haenszel approach.

Results

Description of Studies

A total of 3712 records were found after searching in Medline, Embase, and the Cochrane database, and 350 full-text articles were reviewed (Figure S1). Twenty-one studies, containing 25 comparisons were included (Tables 1 and 2).15–36 Seventeen studies compared TT diuretics with either placebo (8 studies, totalling 105 053 person-years of observation) or other antihypertensive drugs (9 studies, totalling 167 181 patient-years of observation), whereas 8 studies compared TL diuretics with placebo (3 studies, totalling 30 978 patient-years of observation) or other antihypertensive therapy (5 studies, totalling 201 205 patient-years of observation).

Table 1. Study Characteristics of Included Studies: Summary of Studies Comparing Thiazide-Type and Thiazide-Like Diuretics With Placebo Study Study Medication (dose in mg) n FU, y Age, y Men, % BMI SBP/DBP, mm Hg Δ SBP/DBP, mm Hg Thiazide-type diuretics vs placebo ANBP-I 198016 Chlorothiazide 500–1000 1721 4.1 50 63 27 157.7/100.5 NA/−12.2 Placebo 1706 4.0 51 64 27 157.1/100.4 NA/−6.6 EWPHBP 198517 HCTZ 25+Triamterene 50 416 4.7 72 31 26 183.0/101.0 −33.0/−16.0 Placebo 424 4.6 72 30 27 182.0/101.0 −11.0/−6.0 Kuramoto 198118 Trichlormethiazide 1–4 38 4.0 75 52 NA 171.3/86.5 −19.3/−6.5 Placebo 41 4.0 77 57 NA 166.1/85.5 −7.1/−5.5 MRC I 198519 Bendrofluazide 10 4297 5.0 52 52 NA 161.0/98.0 −25.0/−13.0 Placebo 8654 5.0 52 52 NA 161.0/98.0 −12.0/−7.0 MRC II 199220 HCTZ 25–50+Amiloride 2.5–5.0 1081 5.8 70 42 27 185.0/91.0 −34.0/−14.0 Placebo 2213 5.8 70 42 27 185.0/90.0 −19.0/−6.0 USPHSH 197721 Chlorothiazide 500+RS 100 193 7.0 44 77 27 147.7/99.0 −16.5/−10.4 Placebo 196 7.0 45 83 27 146.2/99.0 1.5/−0.6 VA-I 196722 HCTZ 100+Reserpine 0.2+Hydralazine 150 73 1.7 50 100 28 185.6/121.2 −43.0/−29.7 Placebo 70 1.3 51 100 27 186.8/121.0 NA/−1.3 VA-II 197023 HCTZ 50+Reserpine 0.2 + Hydralazine 75 186 3.2 51 100 27 162.1/103.8 −27.2/−17.4 Placebo 194 3.3 52 100 27 165.1/104.7 4.2/1.2 Thiazide-like diuretics vs placebo HYVET 200824 Indapamide 1.5 1933 1.8 84 39 25 173.0/90.8 −29.5/−12.9 Placebo 1912 1.8 84 40 25 173.0/90.8 −14.5/−6.8 SHEP 199125 Chlorthalidone 12.5–25 2365 4.5 72 44 28 170.5/76.7 −26.5/−9.0 Placebo 2371 4.5 72 43 28 170.1/76.4 −15.0/−5.3 SHEP pilot 198926 Chlorthalidone 25 443 2.8 72 37 NA 172.0/75.0 −31.0/−7.0 Placebo 108 2.8 72 37 NA 172.0/75.0 −15.0/−2.0

Table 2. Study Characteristics of Included Studies: Summary of Studies Comparing Thiazide-Type and Thiazide-Like Diuretics With Other Antihypertensive Agents Study Baseline Medication n FU, y Age, y Men, % BMI Mean SBP/DBP, mm Hg Δ SBP/DBP, mm Hg Thiazide-type diuretics vs other antihypertensive agents ACCOMPLISH 200827 Benazepril 40+HCTZ 12.5 5762 3.0 68 61 31 145.4/80.0* −12.9/−5.6 Benazepril 40+Amlodipine 5 5744 3.0 69 60 31 145.3/80.1* −13.7/−6.8 ANBP II 200328 HCTZ 3039 4.1 72 48 27 168.0/91.0 −26.0/−12.0 Enalapril 3044 4.1 72 50 27 167.0/91.0 −26.0/−12.0 Berglund29 Bendroflumethiazide 2.5+KCl 570 53 6.0 NA 100 NA NA NA Propranolol 80 53 6.0 NA 100 NA NA NA HAPPHY 198730 Bendroflumethiazide 5 or HCTZ 25 3272 3.8 52 100 27 166.0/107.0 −26.0/−18.0 Atenolol 100 or Metoprolol 200 3297 3.8 52 100 27 166/0/107.0 −26.0/−19.0 INSIGHT 200031 HCTZ 25+Amiloride 2.5 3164 3.5 65 47 28 173.0/99.0 −33.0/−17.0 Nifedipine 30 3157 3.5 65 46 28 173.0/99.0 −33.0/−17.0 MIDAS 199632 HCTZ 25–50 441 3.0 59 76 28 148.9/96.2 −19.5/−13.0 Isradipine 5–10 442 3.0 58 80 28 150.6/96.7 −16.0/−13.0 MRC I 198519 Bendrofluazide 10 4297 5.0 52 52 NA 161.0/98.0 −25.0/−13.0 Propranolol 80–240 4403 5.0 51 52 NA 158.0/98.0 −20.5/−11.5 MRC II 199220 HCTZ 25–50+Amiloride 2.5–5.0 1081 5.8 70 42 27 185.0/91.0 −34.0/−14.0 Atenolol 50 1102 5.8 70 41 27 185.0/91.0 −34.0/−14.0 NICS EH 200133 Trichlormethiazide 2 210 5.0 70 26 24 172.6/93.4 −25.6/−14.4 Nicardipine 20 204 5.0 70 40 23 171.9/94.2 −24.9/−13.2 Thiazide-like diuretics vs other antihypertensive agents ALLHAT A 200234 Chlorthalidone 12.5–25 15 255 4.9 67 53 30 156.0/89.0 −22.1/−13.6 Amlodipine 2.5–10 9048 4.9 67 53 30 157.0/90.0 −22.3/−15.4 ALLHAT L 200234 Chlorthalidone 12.5–25 15 255 4.9 67 53 30 156.0/89.0 −22.1/−13.6 Lisinopril 10–40 9054 4.9 67 54 30 156.0/89.0 −20.1/−13.6 ALLHAT D 200015 Chlorthalidone 12.5–25 15 268 3.3† 67 53 30 156.0/89.0 −21.0/−13.0 Doxazosin 2–8 9067 3.3† 67 54 NA 145.0/84.0* −8.0/−8.0 SHELL 200335 Chlorthalidone 12.5 940 2.7 72 38 NA 178.2/86.8 −35.8/−7.8 Lacidipine 4 942 2.7 72 40 NA 178.1/86.9 −35.1/−7.9 VHAS 199736 Chlorthalidone 25 707 2.0 54 50 27 168.8/102.3 −28.6/−16.6 Verapamil 240 707 2.0 55 48 27 169.1/102.2 −27.6/−17.0

The weighted average value of mean ages across studies was lower in studies investigating TT diuretics (60 versus 68 years) when compared with studies involving TL diuretics. The average proportion of males across studies was higher in TT diuretic studies (58% versus 50%). Ethnicity was reported in 12 of 21 studies accounting for 73% of all subjects. On the basis of these data, proportionally more white people were included in studies with TT diuretics (91%) than in studies with TL diuretics (63%). Studies with TT diuretics involved patients with a lower mean annual incidence of CVE (1.4%) when compared with studies investigating TL diuretics (3.3%). Treatment with TT diuretics resulted in larger BP reductions than TL diuretics when compared with placebo treatment. The average placebo-subtracted drop across all studies involving TT diuretics was 14.5/6.7 mm Hg (systolic BP/diastolic BP), whereas the average drop in BP in studies investigating TL diuretics was 13.0/4.6 mm Hg. The antihypertensive effect of TT and TL diuretics was comparable with the antihypertensive effect observed in corresponding control arms that received other antihypertensive drugs. Studies about TT diuretics were older (median, 1985; interquartile range, 1980–2000) when compared with studies involving TL diuretics (median, 2000; interquartile range 1991–2003). Mean follow-up time was comparable among studies with TT (4.3 years; SD, 0.9) and TL diuretics (4.2 years; SD, 1.0).

Primary Analysis

In comparison with placebo, TT (RR, 0.67 [0.56–0.81]; I2=37%) and TL diuretics (RR, 0.67 [0.60–0.75]; I2=0%) significantly reduced the number of CVE (Figure S2). In addition, TT and TL diuretics significantly reduced the number of cerebrovascular events (TT: RR, 0.52 [0.38–0.69]; I2=25% and TL: RR, 0.68 [0.57–0.80]; I2=0%) and heart failure (TT: RR, 0.36 [0.16–0.84]; I2=14% and TL: RR, 0.47 [0.36–0.61]; I2=0%) compared with placebo. In contrast to TT diuretics, treatment with TL diuretics also resulted in a significant reduction of coronary events (RR, 0.76 [0.61–0.96]; I2=0%) and all-cause mortality (RR, 0.84 [0.74–0.96]; I2=0%).

Next, we compared thiazide diuretics with studies that used other antihypertensive therapy as control treatment. TT diuretics did not show a significant benefit on any of the outcomes. TL diuretics, however, more effectively reduced heart failure (RR, 0.71 [0.53–0.95]; I2=91%), and showed similar risk reductions for CVEs (RR, 0.86 [0.72–1.04]; I2=88%), cerebrovascular events (RR, 0.93 [0.86–1.01]; I2=0%), coronary events (RR, 1.01 [0.95–1.07]; I2=0%), and all-cause mortality (RR, 1.00 [0.95–1.05]; I2=0%) when compared with studies that used other antihypertensive therapy as control treatment. We were not able to perform separate analyses stratified by ethnicity because of the lack of data. Sensitivity analyses did not result in any significant change in treatment effect.

Meta-Regression

Age, sex, ethnicity, follow-up duration, and annual incidence of CVE did not significantly affect the risk of all outcomes. The difference in MAP at the end of the study between treatment and control group significantly affected the risk of all outcomes. Larger BP differences between treated and control groups at the end of the study were significantly associated with a greater decrease of CVE (P<0.001), coronary events (P=0.025), cerebrovascular events (P<0.001), heart failure (P=0.010), and all-cause mortality (P=0.001).

BP-Adjusted Analysis

Corrected for BP changes, TT diuretics did not result in an additional risk reduction for CVE (RR, 1.00 [0.91–1.09]) and heart failure (RR, 0.90 [0.68–1.21]), whereas treatment with TL diuretics resulted in a significant risk reduction for CVE (RR, 0.88 [0.79–0.98]) and heart failure (RR, 0.71 [0.57–0.89]) independent of BP. Consequently, the risk of CVE was 12% lower with TL diuretics (P=0.049) compared with TT diuretics, whereas the risk of heart failure was 21% lower (P=0.023; Figure) with TL diuretics. In addition, the regression line of TL diuretics had a significant steeper slope when compared with the regression line of TT diuretics for the outcome CVE (P=0.028). TT and TL diuretics did not show a BP-independent risk reduction for coronary events, cerebrovascular events, and all-cause mortality (Figure S4).

Figure. Blood pressure (BP) adjusted analysis. Association between the risk ratios of cardiovascular events (CVEs) and heart failure, and the difference in achieved mean arterial pressure (MAP) reduction between treatment and control group. Circles and squares represent individual trials and have a size proportional to the calculated weight. Analyzing y-intercept, thiazide-like diuretics showed a significant additional 12% risk reduction of CVE (A; P=0.049) and a 21% risk reduction of heart failure (B; P=0.023) when compared with thiazide-type diuretics, independent of office BP reduction. A significant extra risk reduction for CVE (P=0.028) was seen when larger MAP reductions were achieved with thiazide-like diuretic treatment.

In sensitivity analyses, the significant beneficial effect of TL diuretics on CVE disappeared, whereas the beneficial effect about heart failure persisted. If the prematurely terminated doxazosin arm of ALLHAT was excluded (P=0.117) or only nonblack participants of the chlorthalidone, amlodipine, and lisinopril arm were analyzed (P=0.160), the significant benefit for CVE disappeared. However, TL diuretics remained significantly better in reducing heart failure when compared with TT diuretics when excluding the doxazosin arm of ALLHAT (P=0.012) or analyzing only nonblack participants of the chlorthalidone, amlodipine, and lisinopril arm of ALLHAT (P=0.039). When only analyzing double-blind trials, the beneficial effect of TL diuretics on heart failure (P=0.012) was still present, but not for CVE (P=0.182). Likewise, after excluding studies that enrolled patients with a mean age >75 years, the beneficial effect of TL diuretics on heart failure (P=0.018) remained, whereas the benefit for CVE was no longer present (P=0.146).

Drug-Adjusted Analysis

In studies comparing thiazide diuretics with calcium antagonists, treatment with TL diuretics resulted in less CVE and heart failure, whereas studies comparing TT diuretics with calcium antagonists did not show a significant difference in treatment effect (Figure S3). Similar results were found when only dihydropyridine compounds were analyzed or when the analysis was restricted to hospitalized heart failure. In comparison with ACE inhibitors, treatment with TT diuretics was associated with a higher risk of CVE, whereas TL diuretics showed a similar risk reduction in CVE.

Adverse Events

Seventeen studies reported data on adverse events. For the comparison of TL diuretics with placebo, 2 studies reported adverse events. In the Hypertension in the Very Elderly Trial (HYVET), however, 99% of adverse events were considered not to be related to the trial medication. With only one trial left comparing TL diuretics and placebo on adverse events, we were not able to estimate the risk of adverse events for the comparison of TL diuretics and placebo. When compared with other antihypertensive therapy, TT (RR, 0.92 [0.74–1.15]) and TL diuretics (RR, 0.84 [0.68–1.03]) showed a similar amount of adverse events when comparable BP reductions were achieved.

Discussion

This meta-analysis suggests that TL diuretics result in a significantly larger risk reduction of CVE and heart failure when compared with TT diuretics. When similar BP reductions were achieved, treatment with TL diuretics was associated with 12% less CVE and 21% less heart failure than TT diuretics.

Randomized trials directly comparing TT and TL diuretics are lacking. We, therefore, pooled the results of studies comparing thiazide diuretics with placebo or other antihypertensive drugs totalling over 480 000 patient-years of observation. Because subjects were not randomized to receive either TT or TL diuretics, populations differed in baseline characteristics. However, meta-regression analyses showed that differences in age, sex, ethnicity, and annual incidence of CVE among studies did not differently affect cardiovascular outcomes.

Our results are in line with a previous meta-analysis that reported a larger risk reduction of CVE with chlorthalidone compared with hydrochlorothiazide using a network meta-regression analysis.12 Because comparisons between chlorthalidone and hydrochlorothiazide were indirect in both the analyses, differences in outcome definitions among trials may lead to differences in event reporting.12 To ensure compatibility of included studies in this analysis, we included only major CVE. Interventional procedures and minor cardiovascular outcomes, such as cardiac angina, peripheral artery disease, or accelerated hypertension were excluded because of differences in definition and event reporting.

Although placebo groups are homogeneous among trials, various antihypertensive drugs, including β-blockers, calcium antagonists, ACE inhibitors, and α-blockers were used as active comparators. As a result, comparisons between placebo and TT or TL diuretics, showed low heterogeneity (I2<50%), whereas some comparisons between TT or TL diuretics, and the group of other antihypertensive drugs showed significant heterogeneity. Among the studies that used other antihypertensive drugs as control treatment, antihypertensive classes were unequally distributed between comparisons with TT and TL diuretics. Beta-blockers, for example, were used 4× as control treatment in studies investigating TT diuretics, whereas there were no comparisons between TL diuretics and β-blockers. The significant heterogeneity disappeared in the drug-adjusted analysis, suggesting that the different groups of antihypertensive drugs that were included in these comparisons were the main cause of heterogeneity. In comparison with calcium antagonists, TL diuretics resulted in a greater reduction in CVE and heart failure, whereas TT diuretics had comparable efficacy. Because dihydropyridine calcium-channel blockers are known to induce peripheral edema, possible leading to false-positive event reporting for heart failure, hospitalized heart failure was analyzed separately. Despite these more stringent criteria, TL diuretics remained superior in reducing the risk of heart failure. Compared with ACE inhibitors, TT diuretics were less effective in reducing CVE, whereas the efficacy was comparable for TL diuretics.

The beneficial effects of TL diuretics on CVE and heart failure, that were independent of the achieved office BP reduction, may be best explained by the longer elimination half-life of TL diuretics that results in a better 24-hour BP reduction. Treatment with 12.5 and 25 mg hydrochlorothiazide, for example, has been shown to result in less 24-hour BP reduction than ACE inhibitors, angiotensin receptor blockers, β-blockers, and calcium antagonists, whereas the reduction in office BP measurements was comparable.37,38 In a direct comparison, hydrochlorothiazide was equally effective in reducing office BP when compared with chlorthalidone, but less effective in lowering 24-hour ambulatory BP, especially during the night.7 Because BP measurements in large clinical trials are often based on office BP measurements, the decreased efficacy of hydrochlorothiazide to reduce 24-hour BP may be missed by relying on office BP alone. The longer half-life of TL diuretics may also translate in enhanced natriuresis, which may explain the superiority of TL diuretics in reducing heart failure. In addition, pleiotropic effects of TL diuretics may contribute to the greater risk reductions of CVE and heart failure.8,9

Because of the longer half-life of TL diuretics, an increase in adverse events may be anticipated, especially with regard to the occurrence of adverse events related to disturbances in sodium and potassium homeostasis. In this meta-analysis, we observed a similar incidence of adverse events for TT and TL diuretics with comparable reductions in office BP. This is in contrast with a previous retrospective study, which demonstrated a greater incidence of electrolyte abnormalities for chlorthalidone compared with hydrochlorothiazide.11 Because the mean starting dose of the more potent drug chlorthalidone (27.3 mg) exceeded that of hydrochlorothiazide (18.3 mg), it is conceivable that the higher incidence of adverse events was related to differences in dosing.11 This is supported by a meta-analysis of randomized controlled trials involving chlorthalidone and hydrochlorothiazide that concluded that the reduction of potassium levels by chlorthalidone, within the currently recommended doses, is equivalent to that of hydrochlorothiazide.39 In addition, a case-control study in hyponatremic patients showed that the risk of hyponatremia was similar when equally potent doses of hydrochlorothiazide and chlorthalidone were used.40

A limitation in the interpretation of the results from this meta-analysis is the lack of randomized trials directly comparing the effect of TT and TL diuretics on CVE. Comparison of TT and TL diuretics is thus not randomized, which can introduce bias. Meta-regression analyses, however, did not identify a significant influence of demographic heterogeneity among studies. Finally, in sensitivity analyses, the beneficial effect of TL diuretics on CVE did not remain significant. This, however, may also be because of a significant reduction in power after excluding large number of patients. The beneficial effects of TL diuretics on heart failure, however, remained significant in all sensitivity analyses.

Perspectives

Currently, TL diuretics are far outnumbered by TT diuretics for the treatment of hypertension.6 This meta-analysis suggests that the millions of peoples who are treated with TT diuretics may receive suboptimal treatment. Future randomized controlled trials should compare TT and TL diuretics to determine the efficacy on cardiovascular outcome. In addition, these studies should investigate whether a different ability to improve 24-hour BP control and natriuresis, or additional effects of TL diuretics on platelet aggregation underlie the differences in cardiovascular risk reduction. Although awaiting further evidence, the available data seem to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension—especially patients at risk for heart failure.

Sources of Funding Dr. Vogt was supported by Kolff grant KJPB 11.22 from the Dutch Kidney Foundation . Drs Vogt and van den Born are recipients of the Clinical Fellowship grants 90700408 and 90700310 of the Netherlands Organisation for Scientific research ( NWO-ZonMW ). Dr Brewster is a recipient of a Veni fellowship (grant number 916.10.156 ) awarded by NWO as part of its Innovational Research Incentives Scheme .

Disclosures None.

Footnotes