Journal of the American College of Cardiology Vol. 57, No.

5, 2011
© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.07.053

Cardiovascular Pharmacology

Antihypertensive Efficacy of Hydrochlorothiazide as

Evaluated by Ambulatory Blood Pressure Monitoring
A Meta-Analysis of Randomized Trials

Franz H. Messerli, MD,* Harikrishna Makani, MD,* Alexandre Benjo, MD,* Jorge Romero, MD,*
Carlos Alviar, MD,* Sripal Bangalore, MD, MHA†
New York, New York

Objectives The purpose of this study was to evaluate the antihypertensive efficacy of hydrochlorothiazide (HCTZ) by ambula-
tory blood pressure (BP) monitoring.

Background HCTZ is the most commonly prescribed antihypertensive drug worldwide. More than 97% of all HCTZ prescrip-
tions are for 12.5 to 25 mg per day. The antihypertensive efficacy of HCTZ by ambulatory BP monitoring is less
well defined.

Methods A systematic review was made using Medline, Cochrane, and Embase for all the randomized trials that assessed
24-h BP with HCTZ in comparison with other antihypertensive drugs.

Results Fourteen studies of HCTZ dose 12.5 to 25 mg with 1,234 patients and 5 studies of HCTZ dose 50 mg with 229
patients fulfilled the inclusion criteria. The decrease in 24-h BP with HCTZ dose 12.5 to 25 mg was systolic 6.5
mm Hg (95% confidence interval: 5.3 to 7.7 mm Hg) and diastolic 4.5 mm Hg (95% confidence interval: 3.1 to
6.0 mm Hg) and was inferior compared with the 24-h BP reduction of angiotensin-converting enzyme inhibitors
(mean BP reduction 12.9/7.7 mm Hg; p ⬍ 0.003), angiotensin-receptor blockers (mean BP reduction 13.3/7.8
mm Hg; p ⬍ 0.001), beta-blockers (mean BP reduction 11.2/8.5 mm Hg; p ⬍ 0.00001), and calcium antago-
nists (mean BP reduction 11.0/8.1 mm Hg; p ⬍ 0.05). There was no significant difference in both systolic (p ⫽
0.30) and diastolic (p ⫽ 0.15) 24-h BP reduction between HCTZ 12.5 mg (5.7/3.3 mm Hg) and HCTZ 25 mg
(7.6/5.4 mm Hg). However, with HCTZ 50 mg, the reduction in 24-h BP was significantly higher (12.0/5.4 mm
Hg) and was comparable to that of other agents.

Conclusions The antihypertensive efficacy of HCTZ in its daily dose of 12.5 to 25 mg as measured in head-to-head studies by
ambulatory BP measurement is consistently inferior to that of all other drug classes. Because outcome data at
this dose are lacking, HCTZ is an inappropriate first-line drug for the treatment of hypertension. (J Am Coll
Cardiol 2011;57:590–600) © 2011 by the American College of Cardiology Foundation

Hydrochlorothiazide (HCTZ) has been available for half a million) were written for monotherapy and the remainder in
century and remains the most commonly prescribed antihy- fixed combination, mostly with blockers of the renin-
pertensive drug worldwide. In the U.S. alone, ⬎134.1 angiotensin system. The dose of HCTZ prescribed was
million prescriptions of HCTZ were written in the year almost exclusively (⬎97%) 12.5 to 25 mg/day, and hyperten-
2008 (1). For comparison, the second most commonly sion remains, by far, the most common indication. Over the
prescribed drug was atenolol, with 44 million prescriptions past 30 years, this persistent prescription pattern of HCTZ has
(1). More than a third of the HCTZ prescriptions (47.5 been heavily influenced by reports of the Joint National
Committee for Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure, all 7 of which recommended
From the *Division of Cardiology, St. Luke’s Roosevelt Hospital, Columbia Univer-
sity College of Physicians and Surgeons, New York, New York; and the †Division of “thiazides” or “thiazide-like drugs” or “thiazide-type diuretics”
Cardiology, New York University School of Medicine, New York, New York. Dr. as first-line or as preferred therapy for hypertension. In an
Messerli reports that he has served as an ad hoc consultant for Novartis, Boehringer
attempt to promote the use of thiazide-type diuretics, the
Ingelheim, Daiichi Sankyo, Sanofi, and Takeda; and has received research funding and
grants from Novartis, Boehringer Ingelheim, and Forest. All other authors have reported National Heart, Lung, and Blood Institute sponsored the
that they have no relationships to disclose. None of the authors received any compensation ALLHAT/JNC7 (Antihypertensive and Lipid-Lowering
for their work on this manuscript.
Manuscript received April 7, 2010; revised manuscript received June 29, 2010,
Treatment to Prevent Heart Attack Trial/Joint National Com-
accepted July 5, 2010. mittee Seventh Report) dissemination project, which reached
JACC Vol. 57, No. 5, 2011 Messerli et al. 591
February 1, 2011:590–600 Hydrochlorothiazide for Hypertension

18,524 physicians in 1,698 venues through 147 physician version 5.0.23 (Copenhagen, Nor- Abbreviations
educators (2). This effort resulted in a small increase in dic Cochrane Centre, The Co- and Acronyms
thiazide-type diuretics use that almost exclusively consisted of chrane Collaboration, 2008).
ABP ⴝ ambulatory blood
HCTZ. However, despite the extensive use, little evidence is Heterogeneity was assessed pressure
available regarding the efficacy and safety of HCTZ for the using the I2 statistics. The I2 ACE ⴝ angiotensin-
treatment of essential hypertension, particularly at the dose of statistic is the proportion of total converting enzyme
12.5 to 25 mg. In the following paper, we scrutinize antihy- variation observed between the ARB ⴝ angiotensin-
pertensive efficacy of HCTZ as assessed by 24-h ambulatory trials attributable to differences receptor blocker
blood pressure (ABP) monitoring and the evidence for mor- between trials rather than sam- BP ⴝ blood pressure
bidity and mortality reduction available in the extensive liter- pling error (chance), and we HCTZ ⴝ hydrochlorothiazide
ature on this drug. considered I2 ⬍25% as low and
I2 ⬎75% as high. The random-
effects model of DerSimonian and Laird (5) was used to
Methods
calculate the effect sizes if I2 ⬎25% and/or p ⬍ 0.05.
Search strategy. We searched PubMed, Embase, and Co- Analysis was performed on an intention-to-treat basis. Data
chrane Central Register of Clinical Trials (Cochrane Li- from changes in baseline BP were combined using the
brary, Issue 2, 2009) using the terms “HCTZ,” “hydrochlo- weighted mean difference method. Publication bias was
rothiazide,” “ABP,” “ambulatory blood pressure,” and estimated visually by funnel plots, and/or using Begg’s test
“hypertension.” We limited our search to randomized trials and the weighted regression test of Egger (6). For trials that
in human subjects and in peer-reviewed journals from 1966 did not provide complete information about variance for net
to March 2010. No language restriction was applied. The change in BP, the information was obtained from confi-
reference lists of identified articles and bibliographies of dence intervals (CIs), p value, or t statistics. Variance was
original articles were also reviewed. Trials in the abstract estimated from pre-test–post-test (parallel group and facto-
form without a manuscript published were excluded for this rial design) and crossover designs, as suggested by Follmann
analysis. et al. (7)
Selection criteria. To be included in the analysis, a trial Sensitivity analysis. Sensitivity analysis was performed for
had to fulfill the following criteria: 1) randomized trials BP reduction in HCTZ dose 12.5 to 25 mg based on the
involving patients with hypertension that assessed the anti- quality of study, study design, and type of blinding in the
hypertensive efficacy by 24-h ABP monitoring comparing study. We estimated difference between subgroups accord-
HCTZ with other antihypertensive drug classes; 2) use of ing to the tests of interaction (8).
HCTZ as a monotherapy in the trial; and 3) trial duration
of at least 4 weeks.
Results
Data extraction. Two reviewers (J.R. and C.A.) extracted
the data independently and in duplicate. Data were ex- Study selection. We identified 2,440 articles, out of which
tracted using standardized protocol and reporting form. 86 abstracts were retrieved and reviewed for possible inclu-
Disagreements were resolved by arbitration (H.M. or A.B.), sion (Fig. 1). Nineteen studies (Table 1) enrolling 1,463
and consensus was reached after discussion. We extracted patients (mean age 58 years; 54% men) fulfilled the inclu-
characteristics of each trial, duration of intervention and sion criteria and were included in the analysis.
methods, baseline demographics, and 24-h ABP and office Baseline characteristics. Of the 19 studies, 14 studies
BP at baseline and after the intervention for our analysis. (9 –22) enrolling 1,234 patients evaluated HCTZ dose 12.5
Authors of the papers were individually contacted in case to 25 mg, and 5 studies (23–27) with 229 patients evaluated
the data were unclear. HCTZ dose 50 mg. Of the 14 studies of HCTZ dose of
Outcomes assessed. The main outcome of the present 12.5 to 25 mg, 4 studies evaluated HCTZ 12.5 mg dose, 1
analysis was BP (systolic/diastolic) reduction from baseline evaluated HCTZ 12.5 to 25 mg dose, and the majority (9
to follow-up. studies) evaluated HCTZ 25 mg dose. Fifteen studies
Quality assessment. The criteria used for quality assess- (28 – 42) were excluded because they did not meet the
ment were sequence generation of allocation, allocation inclusion criteria: 5 had inadequate data, 3 were nonran-
concealment, blinding of participants, personnel, and out- domized studies, 2 had HCTZ combined with other drugs
come assessors, incomplete outcome data, selective outcome in case of inadequate response, 2 were duplicate studies, 1
reporting, and other sources of bias (3). We classified had HCTZ compared with placebo, and 1 had HCTZ
studies with high or unclear risk for bias for any of the first compared with exercise.
3 components as low quality. Quality assessment. Of the 14 studies with HCTZ dose
Statistical analysis. The statistical analysis was done in line 12.5 to 25 mg, 4 studies reported adequate generation of
with recommendations from the Cochrane Collaboration allocation sequence and adequate allocation concealment,
and the Quality of Reporting of Meta-analyses (QUO- and 10 reported adequate masking of participants, person-
RUM) guidelines (4) using Review Manager (RevMan) nel, and outcome assessors. On the basis of quality assess-
592 Messerli et al. JACC Vol. 57, No. 5, 2011
Hydrochlorothiazide for Hypertension February 1, 2011:590–600

Figure 1 Selection of Studies

HCTZ ⫽ hydrochlorothiazide.

ment, 4 were deemed as low bias risk trials and the rest as Head-to-head comparisons. In head-to-head compari-
high bias risk. sons with other antihypertensive drug classes, HCTZ in the
Antihypertensive efficacy. The antihypertensive efficacy of usual dose of 12.5 to 25 mg lowered systolic ABP less well
HCTZ in the dose of 12.5 to 25 mg was assessed from 14 than ACE inhibitors by 4.5 mm Hg (p ⫽ 0.001), ARBs by
randomized controlled trials. The mean baseline BP in these 5.1 mm Hg (p ⫽ 0.003), beta-blockers by 6.2 mm Hg (p ⬍
studies was 148 ⫾ 7.5/92 ⫾ 5.6 mm Hg. After treatment 0.00001), and calcium antagonists by 4.5 mm Hg (p ⫽
with HCTZ for a mean duration of 17 weeks, systolic ABP 0.02). HCTZ lowered diastolic ABP less well than ACE
decreased by 6.5 mm Hg (95% CI: 5.3 to 7.7 mm Hg) and inhibitors by 4.0 mm Hg (p ⬍ 0.0001), ARBs by 2.9 mm
diastolic ABP by 4.5 mm Hg (95% CI: 3.1 to 6.0 mm Hg) Hg (p ⫽ 0.002), beta-blockers by 6.7 mm Hg (p ⬍
(Figs. 2 and 3). Other antihypertensive agents such as angio- 0.00001), and calcium antagonists by 4.2 mm Hg (p ⫽
tensin-converting enzyme (ACE) inhibitors, angiotensin- 0.0001) (Figs. 4 and 5).
receptor blockers (ARBs), beta-blockers, and calcium an- Office versus ambulatory pressure. Both office BP and
tagonists were significantly more efficacious than HCTZ in ABP readings were available in 8 studies with HCTZ in the
the dose of 12.5 to 25 mg as shown in Figure 2. commonly used dose of 12.5 to 25 mg evaluating 488
 February 1, 2011:590–600
JACC Vol. 57, No. 5, 2011
Baseline
Table 1 Characteristics of Studies Included
Baseline Characteristics in the
of Studies Meta-Analysis
Included in the Meta-Analysis

Follow-Up Age Men HCTZ Dose Comparison Drug Baseline ABP

First Author (Ref #) Study Design Inclusion Criteria n (Weeks) (yrs) (%) (mg) (mg) (mm Hg)
HCTZ dose 12.5 to 25 mg
Damasceno et al. (9) 1999 P, DB, CO, R, PC Black hypertensive patients 12 4 NR NR 25 Nifedipine 30 148/99
Falconnet et al. (10) 2004 P, SB, RC, CO Hypertensive patients of East African descent 61 4 49 56 25 Lisinopril 20 139/92
Galzerano et al. (11) 2004 P, DB, RC Mild to moderate essential hypertension 69 52 54 55 25 Telmisartan 80 154/95
Kraiczi et al. (12) 2000 P, DB, CO, RC Hypertensive patients with obstructive sleep apnea 40 12 57 100 25 Amlodipine 5, atenolol 50, enalapril 20, losartan 50 145/92
Lacourcière et al. (14) 1995 P, DB, R, PC Mild to moderate primary hypertension 42 32 69 60 12.5–25 Amlodipine 5–10 154/89
Lacourcière et al. (13) 2003 P, OL, PG, RC Uncomplicated systolic hypertension 120 6 61 55 12.5 Losartan 50 150/86
Pelttari et al. (15) 1998 P, DB, CO, RC Hypertensive patients with obstructive sleep apnea 18 8 52 NR 25 Atenolol 50, isradipine 2.5, spirapril 6 152/105
Suonsyrjä et al. (16) 2008 P, DB, CO, R, PC Finnish men with moderate hypertension 233 4 51 100 25 Amlodipine 5, bisoprolol 5, losartan 50 135/93
Tedesco et al. (17) 1998 P, DB, RC Mild to moderate hypertension 77 95 54 53 25 Losartan 50 156/96
Ubaid-Girioli et al. (18) 2007 P, OL, PG, RC Mild to moderate hypertension 63 12 49 46 25 Irbesartan 150, quinapril 20 136/88
White et al. (19) 2008 P, MC, DB, RC Stage II hypertension 354 8 51 55 25 Ramipril 20 148/92
Wing et al. (20) 2003 P, DB, CO, R, PC Elderly with hypertension 19 6 68 58 12.5 Candesartan 8–16 161/85
Abate et al. (21) 1998 P, MC, DM, DB, RC Mild to moderate hypertension 84 8 78 46 12.5 Pinacidil 25 148/85
Radevski et al. (22) 2002 P, OL, R, PC Black patients with mild to moderate hypertension 42 12 57 33 12.5 Indapamide 2.5 147/94
HCTZ dose 50 mg
Lacourcière et al. (23) 1989 P, DB, PG, RC Mild to moderate hypertension 38 12 57 42 25–50 Zofenopril 30–60 150/94
Morgan et al. (24) 2003 P, DB, CO, R, PC Elderly hypertensive patients 24 8 77 75 50 Atenolol 50, felodipine 10, perindopril 8 157/85

Hydrochlorothiazide for Hypertension

Silagy et al. (25) 1992 P, DB, RC Elderly patients with isolated systolic hypertension 24 6 72 38 25–50 Atenolol 50–100, enalapril 10–20, isradipine 2.5–5 156/76
Weir et al. (26) 1998 P, MC, DB, PG, RC Obese patients with hypertension 124 12 51 62 12.5–50 Lisinopril 10–40 145/89
Wing et al. (27) 1997 P, DB, CO, RC Elderly patients with isolated systolic hypertension 19 4 71 26 25-50 Lacidipine 2–4 160/84

ABP ⫽ ambulatory blood pressure; BP ⫽ blood pressure; CO ⫽ crossover; DB ⫽ double blind; DBP ⫽ diastolic blood pressure; DM ⫽ double masked; FT ⫽ forced-titrated; HCTZ ⫽ hydrochlorothiazide; HTN ⫽ hypertension; MC ⫽ multicenter; NR ⫽ not reported; OL ⫽ open
label; P ⫽ prospective; PG ⫽ parallel group; R ⫽ randomized; RC ⫽ randomized controlled; SB ⫽ single blind; SBP ⫽ systolic blood pressure.

Messerli et al.
593
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Hydrochlorothiazide for Hypertension February 1, 2011:590–600

of bias did not make any noticeable difference to these

outcomes (data not shown).

Discussion
The principal findings of our study are that the most
commonly prescribed HCTZ dose of 12.5 to 25 mg has
clinically significant inferior antihypertensive efficacy com-
pared with other drug classes used to treat hypertension.
Our analysis was based on 24-h ABP monitoring, which is
the most thorough and objective way to assess antihyper-
tensive efficacy. In contrast, the reduction of office BP by
Antihypertensive HCTZ Efficacy
Figure 2
as Assessed by 24-h ABP Monitoring
HCTZ (12.4/6.5 mm Hg) was similar to the reduction of
office BP by ACE inhibitors, ARBs, beta-blockers, and
Compared with hydrochlorothiazide (HCTZ) dose 12.5 to 25 mg, p ⬍ 0.001 for calcium-channel blockers.
other antihypertensive drugs, as assessed by 24-h ambulatory blood pressure
(ABP) monitoring. Bars represent 95% confidence intervals; N indicates number
The office BP reduction with ACE inhibitors (11.4/6.4
of studies. ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin-receptor mm Hg) and ARBs (11.6/6.5 mm Hg) obtained from
blocker; DBP ⫽ diastolic blood pressure (blue bars); SBP ⫽ systolic blood Cochrane meta-analysis (43,44) was similar to that obtained
pressure (pink bars).
from our analysis. Thus, when HCTZ is assessed by
outpatient BP measurement, the antihypertensive efficacy
seems comparable to that of other antihypertensive drug
patients followed up for a mean of 8 weeks. The mean
classes. This finding would indicate that HCTZ lowers BP
baseline office BP was 163 ⫾ 7.5/98 ⫾ 6.5 mm Hg and the
well during daytime when patients are seen in the physi-
mean ABP was 149 ⫾ 7.4/89 ⫾ 3.6 mm Hg. In these 8
cian’s office but has less effect during the night and early
studies, office BP reduction by HCTZ was systolic 12.4 mm
morning hours. Indeed, Finkielman et al. (28) documented
Hg (95% CI: 8.1 to 16.6 mm Hg) and diastolic 6.5 mm Hg
that the antihypertensive response to HCTZ is overesti-
(95% CI: 3.9 to 9.2 mm Hg). HCTZ lowered mean office
mated by using office BP measures. In their patient popu-
systolic BP by 4.9 mm Hg (95% CI: 0.8 to 9.0 mm Hg)
lation of 228 subjects treated with HCTZ 25 mg daily, the
better than by ABP monitoring (p ⫽ 0.02). Average office difference between office BP and 24-h ABP was 4.8/2.1 mm Hg
diastolic BP was lowered by 2.5 mm Hg (95% CI: 0.9 to 4.1 (p ⬍ 0.01). This difference is very similar to that found in
mm Hg) better than by ABP monitoring (p ⫽ 0.002) (Fig. 6). our present analysis (4.9/2.5 mm Hg). Thus, assessing the
The mean office systolic and diastolic BP reduction with antihypertensive efficacy of HCTZ by office BP measure-
HCTZ 12.5 to 25 mg of 12.4/6.5 mm Hg was not ments only is deceptive and is prone to provide to physicians
significantly different from the mean office BP reduction and patients a false sense of security.
with ACE inhibitors of 11.8/7.4 mm Hg (p ⫽ 0.65), with Not surprisingly, at a daily dose of 50 mg and above,
ARBs of 13.3/6.7 mm Hg (p ⫽ 0.66), with beta-blockers of HCTZ’s antihypertensive efficacy seems to be similar to
12.9/9.9 mm Hg (p ⫽ 0.71), and with calcium antagonists most other drug classes. However, all biochemical adverse
of 12.0/9.7 mm Hg (p ⫽ 0.36). effects such as hypokalemia, hyponatremia, hyperuricemia,
Dose response. The ABP was not significantly different insulin resistance, and visceral fat accumulation are dose
when compared between the HCTZ 12.5 dose and the dependent and become clinically more significant with daily
HCTZ 25 mg dose. However, with the HCTZ dose of 50 doses exceeding 25 mg (45). Thus, biochemical adverse
mg, the reduction in systolic ABP was 12.0 (95% CI: 8.2 to effects of HCTZ may prohibit the prescription of higher
15.9), and the reduction in diastolic ABP was 5.4 (95% CI: doses in many patients. An additional concern is the risk of
3.2 to 7.7). Thus, there was a significant difference in the sudden cardiac death that has been shown to increase in a
systolic ABP (p ⫽ 0.04), but not diastolic ABP (p ⫽ 0.97) dose dependant fashion with HCTZ doses exceeding 25 mg
(Fig. 7), when compared with the 25 mg dose. daily (46). A recent meta-analysis also showed that the
Significant heterogeneity was found to be present in the chlorthalidone reduces systolic BP significantly better than
ABP reduction with HCTZ (Fig. 3), head-to-head com- the HCTZ at equivalent doses of both drugs without
parison of HCTZ with ACE inhibitors, ARBs, and calcium increase in the risk of hypokalemia (47).
antagonists (Figs. 4 and 5), comparison of office BP with What then is the evidence that HCTZ reduces morbidity
ABP monitoring of HCTZ (Fig. 6), office BP reduction and mortality in hypertension? A thorough scrutiny of the
with HCTZ, and BP reduction with different doses of literature reveals that outcome evidence for low-dose
HCTZ (Fig. 7). There was no evidence of publication bias HCTZ is lacking. All outcome studies were done with
for any of our analyses. Sensitivity analyses for various higher doses than the currently used 12.5 to 25 mg or with
subgroups based on the study design, blinding, and the risk other thiazides such as chlorthalidone or indapamide.
JACC Vol. 57, No. 5, 2011 Messerli et al. 595
February 1, 2011:590–600 Hydrochlorothiazide for Hypertension

Figure 3 Reduction in 24-h ABP With HCTZ 12.5 and 25 mg

Reduction in systolic (top) and diastolic (bottom) 24-h ambulatory blood pressure (ABP) with hydrochlorothiazide (HCTZ) dose 12.5 to 25 mg. Trial references as in
Table 1. ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin-receptor blocker; CCB ⫽ calcium-channel blocker; CI ⫽ confidence interval; df ⫽ degrees of free-
dom; IV ⫽ instrumental variables.

HCTZ was compared with and found to be inferior to cluded that the more favorable mortality trend was due to “a
enalapril in the large Australian National Blood Pressure 2 change in the diuretic treatment protocol about 5 years after
study (48), although the exact dose was not specified. In the randomization which involved replacement of HCTZ with
MRFIT (Multiple Risk Factor Intervention Trial) study chlorthalidone” (50). On the basis of these data, we have to
(49), both HCTZ and chlorthalidone were used, and the conclude that, for the most prescribed antihypertensive drug
highest mortality rates were found in a subset of hyperten- in the U.S., outcome evidence is lacking. In its commonly
sive patients treated with HCTZ, with death most likely used dose of 12.5 to 25 mg once a day, there has been no
from lethal arrhythmias due to hypokalemia. In 9 clinics evidence that HCTZ reduces myocardial infarction, stroke,
whose staff prescribed HCTZ, the trend of mortality was or death. This lack of outcome data together with the poor
unfavorable whereas it was favorable in the 6 clinics whose antihypertensive efficacy should strongly motivate physi-
staff primarily used chlorthalidone (50). The investigators cians to refrain from prescribing HCTZ as initial therapy in
decided to switch everybody to chlorthalidone, and con- hypertension.
596 Messerli et al. JACC Vol. 57, No. 5, 2011
Hydrochlorothiazide for Hypertension February 1, 2011:590–600

Figure 4 Systolic 24-h ABP Reduction by HCTZ at 12.5 to 25 mg Compared With Other Antihypertensive Drugs

Head-to-head comparison of systolic 24-h ambulatory blood pressure (ABP) reduction with hydrochlorothiazide (HCTZ) at the
dose of 12.5 to 25 mg with other classes of antihypertensive drugs. Trial references as in Table 1; abbreviations as in Figure 3.

The fact that our data indicate that HCTZ in its ACE inhibitor, an ARB, or even a direct renin inhibitor.
commonly used dose is a suboptimal antihypertensive drug Numerous, mostly factorial design studies have shown that
should not prevent it from it being useful in combination when combined with these drug classes, HCTZ, even at low
with a blocker of the renin-angiotensin system such as an doses, elicits a distinct incremental fall in BP. That would
JACC Vol. 57, No. 5, 2011 Messerli et al. 597
February 1, 2011:590–600 Hydrochlorothiazide for Hypertension

Figure 5 Diastolic 24-h ABP Reduction by HCTZ at 12.5 to 25 mg Compared With Other Antihypertensive Drugs

Head-to-head comparison of diastolic 24-h ambulatory blood pressure (ABP) reduction with hydrochlorothiazide (HCTZ) at
the dose of 12.5 to 25 mg with other classes of antihypertensive drugs. Trial references as in Table 1; abbreviations as in Figure 3.

indicate that HCTZ is more useful as an “enhancer” or outcome data suggest that HCTZ is inferior to amlodipine, as
“sensitizer” for the antihypertensive effect of renin-angiotensin was reported in the recent ACCOMPLISH (Avoiding Car-
system blockers than as a monotherapeutic agent. However, diovascular Events in Combination Therapy in Patients Living
even when combined with a renin-angiotensin system blocker, With Systolic Hypertension) study (51).
598 Messerli et al. JACC Vol. 57, No. 5, 2011
Hydrochlorothiazide for Hypertension February 1, 2011:590–600

Figure 6 Systolic and Diastolic 24-h ABP Reduction Compared With Office BP Reduction

Comparison of systolic (top) and diastolic (bottom) 24-h ambulatory blood pressure (ABP) reduction with office BP reduction
with hydrochlorothiazide (HCTZ) dose 12.5 to 25 mg. Trial references as in Table 1; other abbreviations as in Figure 3.

Clinical implications. HCTZ still remains the most com-

monly prescribed antihypertensive drug in the U.S. and
worldwide. The National Heart, Lung and Blood Institute
continues to advocate (2) the use of “thiazide-type diuret-
ics,” which, for practicing physicians, simply means HCTZ
in a daily dose of 12.5 to 25 mg. However, because the
BP-lowering effect of HCTZ is inferior to that of every
other drug class and outcome data at commonly used doses
are nonexistent, its use as a first-line antihypertensive agent
is ill advised. On a milligram-per-milligram basis using
pooled data, chlorthalidone, for which solid outcome data
are available, produced greater reductions in systolic BP
than HCTZ did, while mean changes in potassium were
found to be equivalent (47). Thus, if a clinical indication
calls for a thiazide-type diuretic, chlorthalidone or indap-
amide remain the drugs of choice.
Figure 7 Dose Response Curve With Hydrochlorothiazide Study limitations. As in other meta-analyses, given the
Systolic ambulatory blood pressure (ABP) is indicated by yellow bars; diastolic lack of data in each trial, we did not adjust our analyses for
ABP is indicated by red bars. Compared with HCTZ 25 mg ABP: p ⫽ NS versus compliance to assigned therapy. Also, the results are subject
12.5 mg (both systolic and diastolic), p ⫽ 0.0001 versus 50 mg systolic, and
to limitations inherent to any meta-analysis based on
p ⫽ NS versus 50 mg diastolic. N indicates number of patients. HCTZ ⫽ hydro-
chlorothiazide; NS ⫽ not significant. pooling of data from different trials with different designs,
different duration, and different patient groups. The trials
JACC Vol. 57, No. 5, 2011 Messerli et al. 599
February 1, 2011:590–600 Hydrochlorothiazide for Hypertension

did not report cardiovascular outcomes, and hence, the 11. Galzerano D, Tammaro P, Cerciello A, et al. Freehand three-
dimensional echocardiographic evaluation of the effect of telmisartan
superiority of ABP monitoring over office BP measurement compared with hydrochlorothiazide on left ventricular mass in hyper-
for prevention of cardiovascular outcomes cannot be derived tensive patients with mild-to-moderate hypertension: a multicentre
from our study. However, there are solid data establishing study. J Hum Hypertens 2004;18:53–9.
ABP monitoring as a better surrogate end point than office 12. Kraiczi H, Hedner J, Peker Y, Grote L. Comparison of atenolol,
amlodipine, enalapril, hydrochlorothiazide, and losartan for antihyper-
BP measurement (52). There is also evidence that thiazides tensive treatment in patients with obstructive sleep apnea. Am J Respir
are primarily or only effective for patients with low renin, Crit Care Med 2000;161:1423– 8.
salt-volume hypertension, so monotherapy limited to this 13. Lacourcière Y, Poirier L. Antihypertensive effects of two fixed-dose
combinations of losartan and hydrochlorothiazide versus hydrochlo-
group might have shown different results; however, the rothiazide monotherapy in subjects with ambulatory systolic hyperten-
design of the meta-analysis precluded examining such a sion. Am J Hypertens 2003;16:1036 – 42.
possibility (53). Although no clear dose range was estab- 14. Lacourcière Y, Poirier L, Lefebvre J, Archambault F, Cleroux J,
Boileau G. Antihypertensive effects of amlodipine and hydrochlorothi-
lished for other antihypertensive drugs when used for azide in elderly patients with ambulatory hypertension. Am J Hyper-
comparison with HCTZ in this meta-analysis, most of tens 1995;8:1154 –9.
these drugs were used in one-half the maximal dose. 15. Pelttari LH, Hietanen EK, Salo TT, Kataja MJ, Kantola IM. Little
effect of ordinary antihypertensive therapy on nocturnal high blood
pressure in patients with sleep disordered breathing. Am J Hypertens
1998;11:272–9.
Conclusions 16. Suonsyrjä T, Hannila-Handelberg T, Paavonen KJ, et al. Laboratory
tests as predictors of the antihypertensive effects of amlodipine,
HCTZ in its commonly used dose of 12.5 to 25 mg daily bisoprolol, hydrochlorothiazide and losartan in men: results from the
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angiotensin converting enzyme inhibition and diuretic therapy on hypertension y meta-analysis.