ORIGINAL

PAPER

Comparison of the Effect of Thiazide Diuretics and Other

Antihypertensive Drugs on Central Blood Pressure: Cross-Sectional
Analysis Among Nondiabetic Patients
Cristiano S. Moura, PhD;1,2 Stella S. Daskalopoulou, MD, MSc, PhD;3,4 Linda E. Levesque, PhD;5 Sasha Bernatsky, MD, PhD;1,2
Michal Abrahamowicz, PhD;1,2 Meytal A. Tsadok, PhD;1 Shadi Rajabi, BSc;1 Louise Pilote, MD, MPH, PhD1,4
From the Division of Clinical Epidemiology ;1 Department of Epidemiology, Biostatistics and Occupational Health;2 Division of Experimental Medicine;3
Division of General Internal Medicine McGill University, Montreal, QC;4 and Department of Public Health Sciences Queens University, Kingston, ON,
Canada5

Thiazide diuretics (TDs) are a cost-effective first-line therapy

for uncomplicated hypertension; however, they are less
prescribed than other options. The authors aimed to assess
the noninferiority of TDs relative to different classes of
antihypertensive medications in relation to central blood
pressure. Cross-sectional data from the Quebec CARTaGENE project was used. Nondiabetic hypertensive participants on monotherapy for hypertension were studied.
Separate adjusted models were constructed to establish
noninferiority of TDs to non-TD antihypertensive medications for central blood pressure measurements. Models

included a set of potential confounders. Of the 1194

hypertensive participants, 7.4% were taking TDs. We found
that TDs were comparable with non-TD antihypertensive
medications for central systolic blood pressure (adjusted
regression coefficient, 0.45; 95% confidence interval,
1.61 to 2.50). No differences in other central measurements were noted. The results provide additional support
that TDs are at least as effective as other first-line
medications for treating uncomplicated hypertension. J
Clin Hypertens (Greenwich). 2015:17. 2015 Wiley
Periodicals, Inc.

Elevated blood pressure (BP) is a well-known predictor

of cardiovascular risk and mortality and lowering BP is
an effective means of reducing cardiovascular events.1,2
Although lifestyle modification is important in the
management of hypertension, most hypertensive patients
require some level of pharmacologic treatment.3 The use
of antihypertensive medication has remarkably increased
in the past years. A large-scale national survey documented that 77% of US adults with hypertension used at
least one antihypertensive medication.4 In Canada, the
implementation of the Canadian Hypertension Education Program (CHEP), which is responsible for the
generation of the hypertension guidelines in Canada and
their annual update, has resulted in improved diagnosis
and management of hypertension in Canada.5,6 In adults
with hypertension without compelling indications for
specific agents, existing guidelines emphasize that thiazide diuretics (TDs), when used as monotherapy, are as
effective as calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin
receptor blockers (ARBs), in lowering BP and preventing
cardiovascular and renal endpoints.2,7
Some studies have shown measurements of central
systolic BP (cSBP) and central pulse pressure (cPP) to be
better predictors of target organ damage and cardiovascular
disease than peripheral (brachial) systolic BP (pSBP) or

peripheral pulse pressure (pPP).8,9 When compared with

peripheral BP (pBP), central BP (cBP) offers a more accurate
estimation of the load imposed on the aorta and the left
ventricle, and, in turn, of the overall vascular damage and
prognosis.10,11 cBP can be measured noninvasively using
pulse wave analysis (PWA), a technique based on applanation tonometry of the radial artery. PWA provides additional information, in particular the calculation of the
augmentation index (AIx).12 AIx represents wave reflection,
and an indirect measure of arterial stiffness.
In this study, we aimed to assess the noninferiority of
TDs relative to different classes of antihypertensive
medications in relation to cBP and AIx.

Address for correspondence: Louise Pilote, MD, MPH, PhD, V Pavillion

687, Avenue des Pins Ouest, Montreal, QC, Canada H3A1A1
E-mail: louise.pilote@mcgill.ca
Manuscript received: March 11, 2015; revised: May 11, 2015;
accepted: May 12, 2015
DOI: 10.1111/jch.12622

MATERIAL AND METHODS

The CARTaGENE Biobank
The CARTaGENE (CaG) is a large ongoing prospective
health study intended to investigate modifiable environmental and lifestyle factors and the genomic determinants of chronic diseases.13 The CaG baseline assessment
survey was conducted from July 2009 to October 2010 in
a random sample of the adult population of the province
of Quebec, aged between 40 and 69 years, from four
metropolitan areas in the province (Montreal, Quebec,
Sherbrooke, and Saguenay). Specific details regarding the
survey sampling design and methodology have previously been described.13 A total of 19,995 men and
women were enrolled, representing 1% of the Quebec
population of the specific age group. All participants
provided informed consent.
Survey participants completed detailed self-administered and interviewer-administered health questionnaires
The Journal of Clinical Hypertension

Antihypertensive Drugs and Central BP | Moura et al.

covering different areas of health and lifestyle habits.

Participants also underwent noninvasive physical measurements of health indices, including anthropometric
measurements, pBP, and cBP. Biochemical analyses were
performed in one central laboratory and included measurements of circulating glucose, total cholesterol, highdensity lipoprotein cholesterol (HDL), and triglyceride
levels.
Our main analysis was restricted to nondiabetic
hypertensive participants in CaG taking monotherapy
for uncomplicated hypertension and with both pBP and
cBP measurements completed. Individuals with a history
of diabetes were excluded on the basis of self-reported
diagnosis.
Medication Use Assessment
CaG participants were asked to bring containers of all
their current prescription medications. Interviewers
recorded the product names based on labels or verbally
as reported by participants if containers were not
available. We classified antihypertensive medications
within the following categories: ACE inhibitors, ARBs,
b-blockers (BBs), CCBs, TDs, and other antihypertensive medications (including diuretics [excluding TDs],
antiadrenergic agents, and agents acting on the reninangiotensin system [excluding ACE inhibitors and
ARBs]). Participants who reported using only one active
ingredient were defined as receiving monotherapy.
Hypertension Assessment and BP Measurements
Hypertension was considered in cases of a positive
response to the question Has a doctor ever told you
that you had high blood pressure or hypertension?
Peripheral BP was measured in triplicate with an
automated device using the oscillometric method (Omron IntelliSense Blood Pressure Monitor HEM-907XL;
Omron Healthcare, Inc, Lake Forest, IL); the mean of
the three readings was recorded. Radial artery waveforms were recorded using applanation tonometry
(SCOR-Px SphygmoCor; AtCor Medical, Sydney, Australia). Previous studies have shown the validity of the
derived central pressures and arterial waveforms with
this system.14,15 Specifically, the micromanometer
records radial (peripheral) pressure waveforms, which
are averaged and mathematically transformed using a
generalized transfer function to derive an aortic (central)
waveform.16 Mean arterial pressure (MAP), heart rate,
and central AIx (cAIx) were also determined using the
SphygmoCor software system.1719
Covariates
A history of physician-diagnosed stroke, myocardial
infarction, chest pain, and renal disease was assessed by
questionnaires. Participants who had been diagnosed
with at least one of the above health conditions were
classified as having one or more comorbidities. Body
mass index (BMI) was classified into the following
categories: normal/underweight (BMI <25 kg/m2), overweight (BMI between 25 and 30 kg/m2), and obese
2

The Journal of Clinical Hypertension

(BMI 30 kg/m2). The short version of the International

Physical Activity Questionnaire (IPAQ)20 was used to
categorize physical activity levels as low, moderate, or
high. Alcohol intake was recorded as the average
frequency of intake of any beverage (red or white wine,
beer, spirit or liquor, and other kinds of alcohol) over
the preceding 12 months and was divided into the
categories of never drinking alcohol, once a week or
less, and 2 to 3 times a week or more. Cigarette smoking
was categorized as current (occasional or current daily
use) or not smoking (past smokers and never smokers).
Statistical Analysis
Descriptive analysis included estimation of mean and
median values, as well as standard deviations and
interquartile ranges for continuous variables, and
frequencies expressed as percentage for categorical
variables. Multivariable linear models were employed
to compare the mean values of cBP measurements
across the classes of antihypertensive drugs taken as
monotherapy. TDs were first compared with non-TD
antihypertensive medications (ie, ACE inhibitors,
ARBs, BBs, CCBs, and other antihypertensive drugs).
We then compared TDs with ACE inhibitors or ARBs,
while excluding users of other antihypertensive drugs.
The main objective of our analysis was to show
noninferiority of the TDs against other antihypertensive medications in controlling cBP. Specifically, noninferiority would be demonstrated if the upper bound
of the 95% confidence interval (CI) for the adjusted
treatment effect b1 was below the predefined margin,
of D=3 mm Hg, for all cBP measurements.21 We
obtained b1 and its standard error (SE) by estimating
separate multivariable models for each of the following outcomes: cSBP, central diastolic blood pressure
(cDBP), MAP, cPP, and cAIx. All models included a
prespecified set of potential confounders that were
selected based on clinical knowledge. All models were
adjusted for sex, age, BMI, physical activity, smoking
status, alcohol intake, hypercholesterolemia (defined as
a total serum cholesterol 6.5 mmol/L), comorbidities,
and heart rate (beats per minute [bpm]). Model with
AIx as the outcome was adjusted for height instead of
BMI. Interactions between indicators of drug therapy
and sex and between drug therapy and comorbidities
were tested and included in the final multivariable
model only if they were statistically significant
(P<.05).
All statistical analyses were performed using R 2.13
(www.r-project.org) and SAS 9.2 (SAS Institute, Cary,
NC).

RESULTS
Among the 17,910 CaG participants with cBP measurements, 1194 were identified as nondiabetic participants
with uncomplicated hypertension on antihypertensive
monotherapy at the time of enrollment (Figure). Over
50% of these participants were treated with ACE
inhibitors or ARBs. Only 7.4% of the participants were

Antihypertensive Drugs and Central BP | Moura et al.

FIGURE. Study flow chart.

taking TDs (Table I). Of those, 5.6% were taking

hydrochlorothiazide (HCTZ) (n=67) and 1.8% were
taking indapamide (n=21).
cBP means are shown for each antihypertensive group
in Table II. cSBP was 4.2 mm Hg higher in participants
taking TDs when compared with BBs and 3.8 mm Hg
higher when compared with ACE inhibitors, but in both
cases the differences were not statistically significant.
We found significant differences for cAIx in participants
taking TDs than that of users of ACE inhibitors (P=.02).
In addition, the average cDBP and MAP values for
participants taking TDs were significantly higher than
that of BB users (P=.01 in both cases).
Table III summarizes the results of the multivariable
linear regression analyses, with each row reporting the
adjusted mean difference between users of TDs and nonTDs and users of TDs and ACE inhibitors or ARBs,
respectively, for each outcome. The use of TD monotherapy did not appear to be associated with different
cBP measurements or AIx, as all upper 95% CIs were
below the noninferiority margin previously defined
(Table III). Similarly, measures of cBP as well as AIx
were comparable between participants taking TDs and
those taking ACE inhibitors or ARBs. Interactions terms
were not statistically significant and not reported.

DISCUSSION
In this population survey, we found that TDs were
noninferior when compared with other antihypertensive
drugs in terms of cBP measurements and AIx. In our
multivariate models, the 95% CIs excluded differences
3 mm Hg for central SBP, which has been shown to be
epidemiologically and clinically significant.21 These
results provide additional support for the growing body
of evidence that suggests that TDs are at least as
effective as other pharmaceutical options for treating
mild to moderate uncomplicated hypertension.22,23
Pharmacologic management of hypertension has dramatically improved worldwide in the past years, with
increasing treatment and control rates, following recent
guidelines and large trial findings.4,24 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend a
thiazide-type diuretic as initial or concomitant therapy
in most patients with hypertension.22,25 These recommendations had a significant impact on antihypertensive
prescription patterns, with increased utilization of TDs,
especially in recently diagnosed patients,2630 although
the magnitude of impact may be smaller and of more
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Antihypertensive Drugs and Central BP | Moura et al.

TABLE I. Characteristics of the Study Population According to Antihypertensive Therapy

Class of Antihypertensive Medicationsa
ACE Inhibitors

ARBs

BBs

CCBs

Other

TDs

Variables

268 (22.4)

449 (37.6)

156 (13.1)

187 (15.7)

46 (3.9)

88 (7.4)

Women
Age, y

104 (38.8)b
57.4 (7.9)

219 (48.8)b
57.7 (7.5)

76 (48.7)b
56.7 (7.8)

106 (56.7)
58.4 (7.3)

37 (80.4)
56.5 (7.7)

56 (63.6)
58.3 (7.2)

1.7 (0.1)

1.7 (0.1)

1.7 (0.1)

1.7 (0.1)

1.6 (0.1)

1.6 (0.1)

48 (19.4)
119 (48)

81 (19.2)
193 (45.8)

31 (22.6)
51 (37.2)

39 (22.5)
75 (43.4)

3 (7.5)
24 (60.0)

16 (18.8)
34 (40.0)

81 (32.7)

147 (34.9)

55 (40.1)

59 (34.1)

13 (32.5)

35 (41.2)

36 (13.5)
113 (42.3)

3 (1.1)
76 (17)

193 (43.2)
12 (2.7)

58 (37.2)
63 (40.4)

11 (25.6)
13 (30.2)

14 (16.5)
34 (40.0)

115 (43.1)
25 (10)

166 (37.1)
40 (9.8)

30 (19.2)
23 (16.3)

5 (3.2)
11 (6.4)

19 (44.2)
5 (12.5)

37 (43.5)
8 (9.9)

Comorbidities
Yes

91 (34.0)

124 (27.6)

74 (47.4)b

63 (33.7)

20 (43.5)

28 (31.8)

Current smoking status

Daily smoker

34 (12.7)

46 (10.3)

18 (11.5)

28 (15.1)

8 (17.8)

7 (8.0)

Occasional smoker
Past smoker

12 (4.5)
114 (42.7)

14 (3.1)
212 (47.6)

4 (2.6)
69 (44.2)

7 (3.8)
75 (40.3)

1 (2.2)
15 (33.3)

0 (0)
44 (50.6)

Never smoked
Current alcohol intake

107 (40.1)

173 (38.9)

65 (41.7)

76 (40.9)

21 (46.7)

36 (41.4)

23 times a week
Once a week or less

135 (52.7)
108 (42.2)

180 (42.2)
213 (49.9)

61 (41.2)
72 (48.6)

84 (48.3)
78 (44.8)

17 (39.5)
21 (48.8)

39 (45.9)
41 (48.2)

13 (5.1)
130.8 (14.1)

34 (8.0)
131.1 (14.4)

15 (10.1)
127.4 (15.0)b

12 (6.9)
133.7 (13.5)

5 (11.6)
130.9 (14.2)

5 (5.9)
133.6 (15.8)

77.9 (9.5)
69.4 (10.8)

77.4 (10.5)
69.7 (10.3)

74.5 (10.2)b
61.9 (9.6)b

79.1 (9.6)
71.1 (11.0)

80.4 (7.9)
72.4 (11.3)

79.1 (10.6)
70.6 (11.4)

27 (14.6)

6 (13.0)

12 (14.9)

62 (33.5)
96 (51.9)

17 (37.0)
23 (50.0)

38 (43.7)
36 (41.4)

Height, m
BMI
Normal/underweight
Overweight
Obesity
IPAQ
Low
Moderate
High
Hypercholesterolemia

Never
Peripheral SBP, mm Hg
Peripheral DBP, mm Hg
Heart rate, beats per min
High BP onset
1 y or less
25 y
More than 5 y

48 (18)

74 (16.7)

98 (36.8)
120 (45.1)

165 (37.2)
205 (46.2)

14 (9)
35 (22.6)
106 (68.4)b

Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; BB, b-blockers; BMI, body mass index; BP, blood pressure;
CCBs, calcium channel blockers; DBP, diastolic blood pressure; IPAQ, International Physical Activity Questionnaire; Other, other antihypertensive
agents, including diuretics (other than thiazides), antiadrenergic agents, agents acting on the renin-angiotensin system (excluding ACE inhibitors and
ARBs); SBP, systolic blood pressure; TD, thiazides diuretics. Values are expressed as number (percentage) or mean (standard deviation). aThe
proportion of missing data was less than 10% for all variables. bP value <.05, based on chi-square test for categorical and independent groups or t test
for continuous variables for comparison between each drug class with TDs.

limited duration than initially anticipated.31 In our

study, the use of TDs as antihypertensive monotherapy
was low, only 7.4% of the sample studied. This figure is
lower than the 14% reported in a similar investigation,
which, however, included patients with diabetes.32 A
considerable proportion of nondiabetic hypertensive
participants in CaG reported using TDs as a fixed-dose
combination tablet (19% of adults treated for hypertension), which can partially explain the low rate of TD
monotherapy in our sample. This finding is consistent
with the trend of increasing rates of TDs in fixed-dose
combinations.33
Our results show that cBP and AIx were equivalent in
TD and non-TD users. The comparison between TDs
and ACE inhibitors/ARBs led to similar results. The
effects of diuretics on cBP have not been studied as well
as those on pBP. In placebo-controlled trials, TDs
4

The Journal of Clinical Hypertension

lowered cSBP significantly less than pSBP, whereas other

monotherapies lowered cSBP and pSBP to similar
extents.34 The largest published trial in which cBP
measurements were obtained was the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, Conduit Artery Function Evaluation (CAFE), in which two
different regimens were compared (atenolol+thiazidebased vs amlodipine+perindopril-based therapy).9 There
was a substantial reduction in cBP with the amlodipinebased therapy compared with the atenolol-based regimen, but this finding may be the result of BBs causing a
slowing of heart rate.35 The substudy cohort of the
Second Australian National Blood Pressure Trial
(ANBP2) showed that neither pBP nor cBP differed
between ACE inhibitor and diuretic-based regimens
after approximately 4 years of treatment.36 Other
small-scale studies have also reported inconsistent

Antihypertensive Drugs and Central BP | Moura et al.

TABLE II. Central Blood Pressure Measurements According to Antihypertensive Therapy

Class of Antihypertensive Medications
ACE Inhibitors
(n=268)

ARBs (n=449)

BBs (n=156)

CCBs (n=187)

Other (n=46)

TDs (n=88)

120.0 (118.3121.7)
79.0 (77.880.2)

120.6 (119.3121.9)
78.5 (77.579.5)

119.6 (117.3121.9)
75.4 (73.877.0)a

123.5 (121.6125.4)
80.2 (78.881.6)

121.9 (118.3125.5)
81.5 (79.283.8)

123.8 (120.5127.1)
80.2 (78.082.4)

Central PP, mm Hg
MAP, mm Hg

41.0 (39.742.3)
96.4 (95.197.7)

42.1 (41.143.1)
96.6 (95.697.6)

44.1 (42.345.9)
94.1 (92.395.9)a

43.2 (41.744.7)
98.8 (97.3100.3)

40.4 (36.943.9)
99.1 (96.8101.4)

43.6 (41.246.0)
99.1 (96.7101.5)

Central AIx, %

25.8 (24.527.1)a

27.2 (26.228.2)

32.0 (30.333.7)

28.4 (26.929.9)

29.7 (26.832.6)

30.1 (27.932.3)

Central SBP, mm Hg
Central DBP, mm Hg

Abbreviations: ACE, angiotensin-converting enzyme; AIx, augmentation index; ARBs, angiotensin receptor blockers; BBs, b-blockers; CCBs, calcium
channel blockers; DBP, diastolic blood pressure; MAP, mean arterial pressure; Other, other antihypertensive agents, including diuretics (other than
thiazides), antiadrenergic agents, agents acting on the renin-angiotensin system (excluding ACE inhibitors and ARBs); PP, pulse pressure; SBP, systolic
blood pressure; TDs, thiazide diuretics. Values are expressed as mean (95% confidence interval). Student t test was performed to compare each drug
class with TDs, and significant results are represented as aP<.05.

TABLE III. Adjusted Regression Coefficients for Users of TD Monotherapy Compared With Users of Non-TDs or
ACE Inhibitors or ARBs
Drug Groups: TD vs Non-TD
Outcomes

Adjusted Coefficient

SE

P Value

Central SBP

0.445

1.047

.007

Central DBP
Central PP

0.954a
0.278a

1.161
1.065

<.001
.005

MAP
Central AIx

0.939a
0.254b

1.333
0.956

.002
<.001

Drug Groups: TD vs ACE Inhibitors/ARBs

95% CI

Adjusted Coefficient

SE

P Value

95% CI

1.606 to 2.496

0.265

1.061

.005

1.814 to 2.344

3.229 to 1.321
1.810 to 2.366

1.405b
0.035b

1.201
1.077

<.001
.003

3.759 to 0.949
2.077 to 2.146

3.552 to 1.674
2.127 to 1.619

1.519b
0.308a

1.370
0.961

.001
<.001

4.205 to 1.167
2.191 to 1.575

Abbreviations: AIx, augmentation index; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SE, standard error; SBP,
systolic blood pressure. Non-thiazide diuretic Non-(TD) antihypertensive includes angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), b-blockers, calcium channel blockers, and other antihypertensive agents (diuretics [other than thiazide-type], antiadrenergic agents,
and agents acting on the renin-angiotensin system [excluding ACE inhibitors and ARBs]). In all models, TD was the reference category. aAdjusted for
sex, age, quadratic age, body mass index (BMI), quadratic BMI, International Physical Activity Questionnaire, hypercholesterolemia, comorbidities,
smoking, alcohol intake, heart rate, and high blood pressure onset date. bAdjusted for all previous variables and height instead of BMI.

findings regarding central effect of TDs and other

antihypertensive agents.37,38 This evidence suggests that
the beneficial effect of TDs is mainly attributable to the
decline in BP rather than to a change in the intrinsic
properties of the arterial wall.

STUDY STRENGTHS AND LIMITATIONS

The strengths of our study include the use of a random
sample, detailed ascertainment of baseline characteristics, including cBP measurements and medication data,
which enabled the control of many potential confounders. The use of a population-based sample enhances the
generalizability of our findings beyond results generated
from clinical trials as our study includes a random sample
of the population for the targeted age group. Moreover,
our sample size was adequate for our analyses. For our
bivariate analysis, we estimated that our sample has
sufficient power (>80%) to detect a difference as low as
5 mm Hg between TD and any other comparison
groups, except for the group of other antihypertensive.
For these estimates, we assumed a standard deviation of
13 mm Hg and an a value of 0.05. For the comparison
with the other antihypertensive group, our sample size

may not have had enough power to detect such a small

difference in the BP measurements. For the multivariable
regression analyses, our sample size was also adequate;
we assumed an a value of 0.05 and that the set of
predictors included in our models accounted for 50% of
the variance of the outcomes.39 However, our study is
subject to a number of limitations that should be
highlighted. When selecting antihypertensive therapy,
other factors besides hemodynamic parameters, must be
taken into account. These include clinical endpoints, such
as cardiovascular events, costs involved in the treatment,
and potential side effects of the medications. Nevertheless, our findings provide important information on the
cross-sectional relationship between cBP measurements
and antihypertensive therapy. cBP has been widely
accepted as a surrogate for cardiovascular risk and some
studies have suggested that cBP is a stronger predictor of
cardiovascular events than peripheral BP.8,10 Although
CaG is an ongoing cohort study, with limited availability
of clinical measurements, these topics can be addressed in
future analysis when follow-up and linkage with an
administrative database become available. Confounding
by indication could have potentially biased our results as
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Antihypertensive Drugs and Central BP | Moura et al.

it was not clear whether a given therapy was the first-line

medication or whether it was prescribed after the patient
had failed initial therapy. It is also possible that participants starting on TDs have been prescribed other
antihypertensive agents before. However, it may be
reasonable to assume, at least in the majority of the
cases, that if patients were nonresponders to the first-line
medication, a second class of drugs would have been
added rather than switching to another form of monotherapy. Similarly, BP was measured at a single visit, and
our results may not represent true BP control. Another
limitation of the current study stems from the type of
diuretics used; for example, chlorthalidone was chosen as
the TD under study in the ALLHAT and other trials,
while the diuretic most commonly prescribed in our
population-based sample was HCTZ.22 Whether the
results obtained with chlorthalidone can be extrapolated
to HCTZ is unclear40; however, no randomized controlled trial to date has compared the two medications
head-to-head with respect to cardiovascular events.
Nevertheless, results of two meta-analyses have indicated
no significant or minor differences between the two
agents in preventing cardiovascular events, which can be
related to HCTZs shorter duration of action.41,42

CONCLUSIONS
In this sample of a general nondiabetic population aged
40 to 69 years with uncomplicated hypertension, the
use of TD monotherapy was not associated with either
statistically or clinically significantly higher levels of
either pBP or cBP measurements when compared with
monotherapy with other antihypertensive classes. These
findings reinforce the importance of diuretic agents as
one of the first-line therapies for uncomplicated
hypertension.
Acknowledgments: We thank the CARTaGENE team for the generous support
on data access and Dr Mitesh Shah for his support on drug classification.
Funding Sources: This work was funded by the Government of Canada through
the Canadian Institutes of Health Research/Drug Safety and Effectiveness
Network (CIHR/DSEN; grant number 298283). CARTaGENE project received
 du Que
bec (FRSQ),
financial support from Fonds de la recherche en sante
seau de me
decine ge
 ne
tique applique
e (RMGA), Fonds
Genome Quebec, Re
 be
cois de la recherche sur la nature et les technologies (FQRNT), Canadian
que
Foundation of Innovation, and the Canadian Partnership Against Cancer.
Disclosures: The authors declare no conflicts of interest.

References
1. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian
Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and
treatment of hypertension. Can J Cardiol. 2013;29:528542.
2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline
for the management of high blood pressure in adults: report from the
panel members appointed to the Eighth Joint National Committee
(JNC 8). JAMA. 2014;311:507520.
3. Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness,
treatment, and control of hypertension among United States adults
1999-2004. Hypertension. 2007;49:6975.
4. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive
medication use and blood pressure control among United States adults
with hypertension: the National Health And Nutrition Examination
Survey, 2001 to 2010. Circulation. 2012;126:21052114.

The Journal of Clinical Hypertension

5. Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness,

treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA.
2013;310:959968.
6. McAlister FA, Wilkins K, Joffres M, et al. Changes in the rates of
awareness, treatment and control of hypertension in Canada over the
past two decades. CMAJ. 2011;183:10071013.
7. Daskalopoulou SS, Rabi DM, Zarnke KB, et al. The 2015 Canadian
hypertension education program recommendations for blood pressure
measurement, diagnosis, assessment of risk, prevention, and treatment
of hypertension. Can J Cardiol. 2015;31:549568.
8. Wang KL, Cheng HM, Chuang SY, et al. Central or peripheral
systolic or pulse pressure: which best relates to target organs and
future mortality? J Hypertens. 2009;27:461467.
9. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood
pressure-lowering drugs on central aortic pressure and clinical
outcomes: principal results of the Conduit Artery Function Evaluation
(CAFE) study. Circulation. 2006;113:12131225.
10. McEniery CM, Cockcroft JR, Roman MJ, et al. Central blood
pressure: current evidence and clinical importance. Eur Heart J.
2014;35:17191725.
11. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a
systematic review and meta-analysis. J Am Coll Cardiol.
2010;55:13181327.
12. ORourke MF, Pauca A, Jiang XJ. Pulse wave analysis. Br J Clin
Pharmacol. 2001;51:507522.
13. Awadalla P, Boileau C, Payette Y, et al. Cohort profile of the CARTaGENE study: Quebecs population-based biobank for public health and
personalized genomics. Int J Epidemiol. 2013;42:12851299.
14. Pauca AL, ORourke MF, Kon ND. Prospective evaluation of a
method for estimating ascending aortic pressure from the radial artery
pressure waveform. Hypertension. 2001;38:932937.
15. Sharman JE, Lim R, Qasem AM, et al. Validation of a generalized
transfer function to noninvasively derive central blood pressure during
exercise. Hypertension. 2006;47:12031208.
16. Karamanoglu M, ORourke MF, Avolio AP, Kelly RP. An analysis of
the relationship between central aortic and peripheral upper limb
pressure waves in man. Eur Heart J. 1993;14:160167.
17. Munir S, Guilcher A, Kamalesh T, et al. Peripheral augmentation
index defines the relationship between central and peripheral pulse
pressure. Hypertension. 2008;51:112118.
18. Pauca AL, Kon ND, ORourke MF. The second peak of the radial
artery pressure wave represents aortic systolic pressure in hypertensive
and elderly patients. Br J Anaesth. 2004;92:651657.
19. Yu A, Giannone T, Scheffler P, et al. The effect of oral contraceptive
pills and the natural menstrual cYCLe on arterial stiffness and
hemodynamICs (CYCLIC). J Hypertens. 2014;32:100107.
20. IPAQ. The International Physical Activity Questionnaire. http://
www.ipaq.ki.se/ipaq.htm. Accessed March 9, 2015.
21. Whelton PK, He J, Appel LJ, et al. Primary prevention of hypertension: clinical and public health advisory from The National High
Blood Pressure Education Program. JAMA. 2002;288:18821888.
22. ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium
channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA.
2002;288:29812997.
23. Flack JM, Nasser SA. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT). Major outomes
in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. Curr
Hypertens Rep. 2003;5:189191.
24. Walker RL, Chen G, Campbell NR, et al. Canadian provincial trends
in antihypertensive drug prescriptions between 1996 and 2006. Can J
Cardiol. 2011;27:461467.
25. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report. JAMA.
2003;289:25602572.
26. Furmaga EM, Cunningham FE, Cushman WC, et al. National
utilization of antihypertensive medications from 2000 to 2006 in the
Veterans Health Administration: focus on thiazide diuretics. J Clin
Hypertens (Greenwich). 2008;10:770778.
27. Heidenreich PA, Davis BR, Cutler JA, et al. Cost-effectiveness of
chlorthalidone, amlodipine, and lisinopril as first-step treatment for
patients with hypertension: an analysis of the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
J Gen Intern Med. 2008;23:509516.

Antihypertensive Drugs and Central BP | Moura et al.

28. Muntner P, Krousel-Wood M, Hyre AD, et al. Antihypertensive

prescriptions for newly treated patients before and after the main
antihypertensive and lipid-lowering treatment to prevent heart attack
trial results and seventh report of the joint national committee on
prevention, detection, evaluation, and treatment of high blood
pressure guidelines. Hypertension. 2009;53:617623.
29. Neutel CI, Campbell NR. Antihypertensive medication use by recently
diagnosed hypertensive Canadians. Can J Cardiol. 2007;23:561565.
30. Stafford RS, Bartholomew LK, Cushman WC, et al. Impact of the
ALLHAT/JNC7 Dissemination Project on thiazide-type diuretic use.
Arch Intern Med. 2010;170:851858.
31. Stafford RS, Monti V, Furberg CD, Ma J. Long-term and short-term
changes in antihypertensive prescribing by office-based physicians in
the United States. Hypertension. 2006;48:213218.
32. McInnis NH, Fodor G, Moy Lum-Kwong M, Leenen FH. Antihypertensive medication use and blood pressure control: a communitybased cross-sectional survey (ON-BP). Am J Hypertens. 2008;21:
12101215.
33. Hemmelgarn BR, Chen G, Walker R, et al. Trends in antihypertensive
drug prescriptions and physician visits in Canada between 1996 and
2006. Can J Cardiol. 2008;24:507512.
34. Manisty CH, Hughes AD. Meta-analysis of the comparative effects of
different classes of antihypertensive agents on brachial and central
systolic blood pressure, and augmentation index. Br J Clin Pharmacol.
2012;75:7992.

35. Davies J, Carr E, Band M, et al. Do losartan and atenolol have

differential effects on BNP and central haemodynamic parameters? J
Renin Angiotensin Aldosterone Syst. 2005;6:151153.
36. Dart AM, Cameron JD, Gatzka CD, et al. Similar effects of treatment
on central and brachial blood pressures in older hypertensive subjects
in the Second Australian National Blood Pressure Trial. Hypertension.
2007;49:12421247.
37. Jiang XJ, ORourke MF, Zhang YQ, et al. Superior effect of an
angiotensin-converting enzyme inhibitor over a diuretic for reducing
aortic systolic pressure. J Hypertens. 2007;25:10951099.
38. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different
antihypertensive drug classes on central aortic pressure. Am J
Hypertens. 2004;17:118123.
39. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible
statistical power analysis program for the social, behavioral, and
biomedical sciences. Behav Res Methods. 2007;39:175191.
40. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension.
2004;43:49.
41. Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes
of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic
therapies. JAMA. 2004;292:4344.
42. Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with
hydrochlorothiazide in reducing cardiovascular events: systematic
review and network meta-analyses. Hypertension. 2012;59:11101117.

The Journal of Clinical Hypertension