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Review
. 2023 Jul 13;7(7):CD008161.
doi: 10.1002/14651858.CD008161.pub3.

First-line diuretics versus other classes of antihypertensive drugs for hypertension

Marcia Reinhart  1 , Lorri Puil  1 , Douglas M Salzwedel  1 , James M Wright  1
Affiliations
Review

First-line diuretics versus other classes of antihypertensive drugs for hypertension

Marcia Reinhart et al. Cochrane Database Syst Rev. .

Abstract

Background: Different first-line drug classes for patients with hypertension are often assumed to have similar effectiveness with respect to reducing mortality and morbidity outcomes, and lowering blood pressure. First-line low-dose thiazide diuretics have been previously shown to have the best mortality and morbidity evidence when compared with placebo or no treatment. Head-to-head comparisons of thiazides with other blood pressure-lowering drug classes would demonstrate whether there are important differences.

Objectives: To compare the effects of first-line diuretic drugs with other individual first-line classes of antihypertensive drugs on mortality, morbidity, and withdrawals due to adverse effects in patients with hypertension. Secondary objectives included assessments of the need for added drugs, drug switching, and blood pressure-lowering.

Search methods: Cochrane Hypertension's Information Specialist searched the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers to March 2021. We also checked references and contacted study authors to identify additional studies. A top-up search of the Specialized Register was carried out in June 2022.

Selection criteria: Randomized active comparator trials of at least one year's duration were included. Trials had a clearly defined intervention arm of a first-line diuretic (thiazide, thiazide-like, or loop diuretic) compared to another first-line drug class: beta-blockers, calcium channel blockers, alpha adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, direct renin inhibitors, or other antihypertensive drug classes. Studies had to include clearly defined mortality and morbidity outcomes (serious adverse events, total cardiovascular events, stroke, coronary heart disease (CHD), congestive heart failure, and withdrawals due to adverse effects).

Data collection and analysis: We used standard Cochrane methodological procedures.

Main results: We included 20 trials with 26 comparator arms randomizing over 90,000 participants. The findings are relevant to first-line use of drug classes in older male and female hypertensive patients (aged 50 to 75) with multiple co-morbidities, including type 2 diabetes. First-line thiazide and thiazide-like diuretics were compared with beta-blockers (six trials), calcium channel blockers (eight trials), ACE inhibitors (five trials), and alpha-adrenergic blockers (three trials); other comparators included angiotensin II receptor blockers, aliskiren (a direct renin inhibitor), and clonidine (a centrally acting drug). Only three studies reported data for total serious adverse events: two studies compared diuretics with calcium channel blockers and one with a direct renin inhibitor. Compared to first-line beta-blockers, first-line thiazides probably result in little to no difference in total mortality (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.84 to 1.10; 5 trials, 18,241 participants; moderate-certainty), probably reduce total cardiovascular events (5.4% versus 4.8%; RR 0.88, 95% CI 0.78 to 1.00; 4 trials, 18,135 participants; absolute risk reduction (ARR) 0.6%, moderate-certainty), may result in little to no difference in stroke (RR 0.85, 95% CI 0.66 to 1.09; 4 trials, 18,135 participants; low-certainty), CHD (RR 0.91, 95% CI 0.78 to 1.07; 4 trials, 18,135 participants; low-certainty), or heart failure (RR 0.69, 95% CI 0.40 to 1.19; 1 trial, 6569 participants; low-certainty), and probably reduce withdrawals due to adverse effects (10.1% versus 7.9%; RR 0.78, 95% CI 0.71 to 0.85; 5 trials, 18,501 participants; ARR 2.2%; moderate-certainty). Compared to first-line calcium channel blockers, first-line thiazides probably result in little to no difference in total mortality (RR 1.02, 95% CI 0.96 to 1.08; 7 trials, 35,417 participants; moderate-certainty), may result in little to no difference in serious adverse events (RR 1.09, 95% CI 0.97 to 1.24; 2 trials, 7204 participants; low-certainty), probably reduce total cardiovascular events (14.3% versus 13.3%; RR 0.93, 95% CI 0.89 to 0.98; 6 trials, 35,217 participants; ARR 1.0%; moderate-certainty), probably result in little to no difference in stroke (RR 1.06, 95% CI 0.95 to 1.18; 6 trials, 35,217 participants; moderate-certainty) or CHD (RR 1.00, 95% CI 0.93 to 1.08; 6 trials, 35,217 participants; moderate-certainty), probably reduce heart failure (4.4% versus 3.2%; RR 0.74, 95% CI 0.66 to 0.82; 6 trials, 35,217 participants; ARR 1.2%; moderate-certainty), and may reduce withdrawals due to adverse effects (7.6% versus 6.2%; RR 0.81, 95% CI 0.75 to 0.88; 7 trials, 33,908 participants; ARR 1.4%; low-certainty). Compared to first-line ACE inhibitors, first-line thiazides probably result in little to no difference in total mortality (RR 1.00, 95% CI 0.95 to 1.07; 3 trials, 30,961 participants; moderate-certainty), may result in little to no difference in total cardiovascular events (RR 0.97, 95% CI 0.92 to 1.02; 3 trials, 30,900 participants; low-certainty), probably reduce stroke slightly (4.7% versus 4.1%; RR 0.89, 95% CI 0.80 to 0.99; 3 trials, 30,900 participants; ARR 0.6%; moderate-certainty), probably result in little to no difference in CHD (RR 1.03, 95% CI 0.96 to 1.12; 3 trials, 30,900 participants; moderate-certainty) or heart failure (RR 0.94, 95% CI 0.84 to 1.04; 2 trials, 30,392 participants; moderate-certainty), and probably reduce withdrawals due to adverse effects (3.9% versus 2.9%; RR 0.73, 95% CI 0.64 to 0.84; 3 trials, 25,254 participants; ARR 1.0%; moderate-certainty). Compared to first-line alpha-blockers, first-line thiazides probably result in little to no difference in total mortality (RR 0.98, 95% CI 0.88 to 1.09; 1 trial, 24,316 participants; moderate-certainty), probably reduce total cardiovascular events (12.1% versus 9.0%; RR 0.74, 95% CI 0.69 to 0.80; 2 trials, 24,396 participants; ARR 3.1%; moderate-certainty) and stroke (2.7% versus 2.3%; RR 0.86, 95% CI 0.73 to 1.01; 2 trials, 24,396 participants; ARR 0.4%; moderate-certainty), may result in little to no difference in CHD (RR 0.98, 95% CI 0.86 to 1.11; 2 trials, 24,396 participants; low-certainty), probably reduce heart failure (5.4% versus 2.8%; RR 0.51, 95% CI 0.45 to 0.58; 1 trial, 24,316 participants; ARR 2.6%; moderate-certainty), and may reduce withdrawals due to adverse effects (1.3% versus 0.9%; RR 0.70, 95% CI 0.54 to 0.89; 3 trials, 24,772 participants; ARR 0.4%; low-certainty). For the other drug classes, data were insufficient. No antihypertensive drug class demonstrated any clinically important advantages over first-line thiazides.

Authors' conclusions: When used as first-line agents for the treatment of hypertension, thiazides and thiazide-like drugs likely do not change total mortality and likely decrease some morbidity outcomes such as cardiovascular events and withdrawals due to adverse effects, when compared to beta-blockers, calcium channel blockers, ACE inhibitors, and alpha-blockers.

PubMed Disclaimer

Conflict of interest statement

Marcia Reinhart: Thermo Fisher Scientific (employment, since October 2020).

Lorri Puil: no relevant interests; Editor of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

Douglas Salzwedel: no relevant interests; Information Specialist of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

James Wright: no relevant interests; Co‐ordinating Editor of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

Figures

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Forest plot of comparison: 1 First‐line thiazides vs active comparators: primary outcomes, outcome: 1.1 Total mortality.
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Forest plot of comparison: 1 Thiazides vs active comparators: primary outcomes, outcome: 1.2 Total serious adverse events.
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Forest plot of comparison: 1 First‐line thiazides vs active comparators: primary outcomes, outcome: 1.3 Total cardiovascular events.
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Forest plot of comparison: 1 Thiazides vs active comparators: primary outcomes, outcome: 1.4 Total stroke events.
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Forest plot of comparison: 1 Thiazides vs active comparators: primary outcomes, outcome: 1.5 Total coronary events.
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Forest plot of comparison: 1 Thiazides vs active comparators: primary outcomes, outcome: 1.6 Total congestive heart failure.
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Forest plot of comparison: 1 First‐line thiazides vs active comparators: primary outcomes, outcome: 1.7 Withdrawal due to adverse effects.
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Forest plot of comparison: 2 Thiazides vs active comparators: secondary outcomes, outcome: 2.1 Dose titration and addition of second or third drug.
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Forest plot of comparison: 2 Thiazides vs active comparators: secondary outcomes, outcome: 2.2 Switching to other antihypertensive therapies.
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Forest plot of comparison: 2 Thiazides vs active comparators: secondary outcomes, outcome: 2.3 Systolic blood pressure.
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Forest plot of comparison: 2 Thiazides vs active comparators: secondary outcomes, outcome: 2.4 Diastolic blood pressure.
1.1
1.1. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 1: Total mortality
1.2
1.2. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 2: Total serious adverse events
1.3
1.3. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 3: Total cardiovascular events
1.4
1.4. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 4: Total stroke events
1.5
1.5. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 5: Total coronary heart disease
1.6
1.6. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 6: Total congestive heart failure
1.7
1.7. Analysis
Comparison 1: First‐line diuretics versus active comparators: primary outcomes, Outcome 7: Withdrawals due to adverse effects
2.1
2.1. Analysis
Comparison 2: First‐line diuretics versus active comparators: secondary outcomes, Outcome 1: Dose titration and addition of second or third drug
2.2
2.2. Analysis
Comparison 2: First‐line diuretics versus active comparators: secondary outcomes, Outcome 2: Switching to other antihypertensive therapies
2.3
2.3. Analysis
Comparison 2: First‐line diuretics versus active comparators: secondary outcomes, Outcome 3: Systolic blood pressure at 1 year
2.4
2.4. Analysis
Comparison 2: First‐line diuretics versus active comparators: secondary outcomes, Outcome 4: Diastolic blood pressure at 1 year
See this image and copyright information in PMC

Update of

Comment in

References

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COPE 2011 {published data only}
    1. Matsuzaki M, Ogihara T, Umemoto S, Rakugi H, Matsuoka H, Shimada K, et al. Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial. Journal of Hypertension 2011;29:1649-59. - PubMed
COSMO‐CKD 2014 {published data only}
    1. Ando K, Nitta K, Rakugi H, Nishizawa Y, Yokoyama H, Nakanishi T, et al. Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in renin-angiotensin system (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (Combination strategy on renal function of benidipine or diuretics treatment with RAS inhibitors in a chronic kidney disease hypertensive population) Study. International Journal of Medical Sciences 2014;11(9):897-904. - PMC - PubMed
Ebbs 2001 {published data only}
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    1. Galzerano D, Tammaro P, Cerciello A, Breglio R, Mallardo M, Lama D, et al. Freehand three-dimensional echocardiographic evaluation of the effect of telmisartan compared with hydrochlorothiazide on left ventricular mass in hypertensive patients with mild-to-moderate hypertension: a multicentre study. Journal of Human Hypertension 2004;18:53-9. - PubMed
GENRES 2007 {published data only}
    1. Donner KM, Hiltunen TP, Suonsyrja T, Hannila-Handelberg T, Tikkanen I, Antikainen M, et al. CYP2C9 genotype modifies activity of the renin-angiotensin-aldosterone system in hypertensive men. Journal of Hypertension 2009;27(10):2001-9. - PubMed
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Grassi 2006 {published data only}
    1. Grassi G, Quarti-Trevano F, Scopelliti F, Seravalle G, Cuspidi C, Mancia G. Effects of long-term lercanidipine or hydrochlorothiazide administration on hypertension-related vascular structural changes. Blood Pressure 2006;15(5):268-74. - PubMed
Iyalomhe 2014 {published data only}
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Jordan 2012 {published data only}
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Khan 2008 {published data only}
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Klingbeil 2000 {published data only}
    1. Klingbeil AU, John S, Schneider MP, Delles C, Weidinger GP, Schmieder RE. Valsartan but not a thiazide improves aortic augmentation pressure index in essential hypertension: a randomized, placebo controlled study. Circulation 2000;102(18):416-7.
LIFE 2002 {published data only}
    1. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, De Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995-1003. - PubMed
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LIVE 1998 {published data only}
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Mahmud 2009 {published data only}
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Mallion 2004 {published data only}
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Mann 2002 {published data only}
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Morgan 2004 {published data only}
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Neaton 1993 {published data only (unpublished sought but not used)}
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NORDIL 2000 {published data only}
    1. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359-65. - PubMed
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Oshchepkova 2007 {published data only}
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PEAR 2012 {published data only}
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Peng 2015 {published data only}
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Pool 2009 {published data only}
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Posadzy‐Malaczynska 2014 {published data only}
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PROGRESS 2001 {published data only}
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Rasmussen 2006 {published data only}
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SALT 2007 {published data only}
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Schram 2005 {published data only}
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Sierra 2004 {published data only}
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Solorzano 2011 {published data only}
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SPREAD 2006 {published data only}
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STOP‐Hypertension‐2 1999 {published data only}
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Syst‐Eur 1997 {published data only}
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Tedesco 1998 {published data only}
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Tedesco 1999 {published data only}
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Trimarco 2011 {published data only}
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Trimarco 2015 {published data only}
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Yurenev 1992 {published data only}
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References to ongoing studies

NCT02217852 {published data only}
    1. NCT02217852. Treatment of hypertension in Tibetan adult population [A randomized, open-label, positive drug controlled clinical trials to compare the efficacy of nitrendipine and hydrochlorothiazide, captopril plus hydrochlorothiazide and Beijing hypotensive No.0 in Tibetan hypertension]. clinicaltrials.gov/show/NCT02217852 (first received 15 August 2014).

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