Clinical Trials

Amlodipine-Valsartan Combination Decreases Central

Systolic Blood Pressure More Effectively Than the
Amlodipine-Atenolol Combination
The EXPLOR Study
Pierre Boutouyrie, Assya Achouba, Patrick Trunet, Stéphane Laurent, for the EXPLOR Trialist Group

Abstract—The ␤-blocker atenolol is less effective than angiotensin-receptor blockers and calcium-channel blockers for
reducing central blood pressure (BP). The trial was designed to determine whether the advantages of angiotensin-
receptor blockers over atenolol remained significant when both were combined with the calcium-channel blocker
amlodipine. A prospective, randomized, blinded endpoint (PROBE design) parallel group, multicenter trial including
393 patients with essential hypertension resistant to 4 weeks of 5 mg of amlodipine was set out. Central systolic BP,
augmentation index (AIx; either rough or adjusted on heart rate), and carotid-to-femoral pulse wave velocity were
measured with applanation tonometry (SphygmoCor) at inclusion and after 8 and 24 weeks of active treatment with an
amlodipine-valsartan combination (5/80 mg and then 10/160 mg) or an amlodipine-atenolol combination (5/50 mg and
then 10/100 mg). From baseline to week 24, central systolic BP decreased significantly more in the amlodipine-valsartan
group (⫺13.70⫾1.15 mm Hg; P⬍0.0001) than in the amlodipine-atenolol group (⫺9.70⫾1.10 mm Hg; P⬍0.0001;
difference: ⫺4.00 mm Hg [95% CI: ⫺7.10 to ⫺0.90]; P⫽0.013), despite similar changes in brachial systolic BP. The
difference in rough AIx reduction was ⫺6.5% (95% CI: ⫺8.3 to ⫺4.7; P⬍0.0001) in favor of amlodipine-valsartan. AIx
adjusted on heart rate was significantly reduced in favor of amlodipine-valsartan (⫺2.8% [95% CI: ⫺4.92 to ⫺0.68];
P⬍0.01). Heart rate decreased significantly more with amlodipine-atenolol (difference: ⫺11 bpm [95% CI: ⫺14 to ⫺8
bpm]; P⬍0.001). Pulse wave velocity decreased by 0.95 m/s in both groups with no significant difference. Differences
in central systolic BP and rough AIx remained significant after adjustment to the changes in heart rate. The
amlodipine-valsartan combination decreased central (systolic and pulse) pressure and AIx more than the amlodipine-
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atenolol combination. (Hypertension. 2010;55:1314-1322.)

Key Words: hypertension 䡲 blood pressure 䡲 aorta 䡲 arteries 䡲 antihypertensive agents 䡲 compliance
䡲 randomized, controlled trial

C entral aortic systolic and pulse pressures are independent

predictors of cardiovascular events in various popula-
tions.1 Antihypertensive agents differ in their ability to lower
central aortic blood pressure (BP), despite similar reduction
in brachial BP.1,2 Angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin receptor blockers (ARBs), and calcium
channel blockers (CCBs), which are powerful vasodilators,
have been shown to improve wave reflection and central
aortic pressure.3–5 By contrast, the ␤-blocker atenolol, pre-
scribed alone6,7 or in combination with thiazides,8 is less
effective than ACEIs, ARBs, and CCBs for lowering central
pressure and wave reflection. It is now well accepted that
antihypertensive therapy based on brachial artery recordings
may overestimate the effect of ␤-blocking drugs on central
aortic systolic BP (SBP) and underestimate those of ACEIs,
ARBs, and CCBs.9,10
A common explanation for the lesser effect of ␤-blockers
on central BP is the bradycardia-induced dyssynchrony or
uncoupling between outgoing and reflected waves, increasing
central systolic and pulse pressures.11 In addition, atenolol
does not reduce total peripheral resistance and sympathetic
drive and fails to induce a long-term remodeling of large6,7
and small arteries,12 which is required for the functional and
structural improvement of arterial stiffness and resistance
and the consequent reduction in augmentation index (AIx)
and central aortic BP.10,13
Although the effects of antihypertensive agents on central
BP have been studied in several clinical trials as monothera-

Received December 11, 2009; first decision December 26, 2009; revision accepted March 31, 2010.
From the Université Paris-Descartes (P.B., S.L.), Paris, France; Institut National de la Santé et de la Recherche Médicale U970 (P.B., S.L.), Paris,
France; Assistance Publique-Hôpitaux de Paris (P.B., S.L.), Hôpital Européen Georges Pompidou, Paris, France; Novartis-Pharma (A.A., P.T.), Paris,
France.
Correspondence to Pierre Boutouyrie, Department of Pharmacology, INSERM U970 (team 7), Hôpital Européen Georges Pompidou, Assistance
Publique-Hôpitaux de Paris, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France. E-mail pierre.boutouyrie@egp.aphp.fr
© 2010 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.109.148999

1314
 Boutouyrie et al
Screened patients
n = 473
Randomized patients
N = 393
Amlodipine-Valsartan
N = 193
Early termination: n=24
• Adverse event/side effect: n=18
• Treatment failure: n=2
• Consent withdrawal: n=3
• other: n=1
Figure 1. Study flowchart.
pies,2–5,11,14,15 very few long-term randomized, controlled
clinical trials have studied drug strategies and combination
therapies. The REASON Study compared an ACEI/diuretic
combination with atenolol as monotherapy but not with
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atenolol included in a combination.6,7 In the Conduit Artery
Functional Endpoint Study,8 an ancillary study of the Anglo-
Scandinavian Cardiac Outcomes Trial,16 an ACEI/CCB com-
bination was compared with atenolol combined with a
diuretic.
An important unanswered question is whether the lesser
effect of atenolol on central aortic BP is dampened or
reversed when combined with CCBs or whether it remains
significant despite associated vasodilatation. Different mech-
anisms with opposite effects may be surmised, and the
relative weight of each is unknown. Atenolol-mediated bra-
dycardia may persist despite CCB-induced baroreflex activa-
tion. On the other hand, baroreflex-induced vasoconstriction
in response to atenolol might not be attenuated by CCBs.
Thus, both bradycardia and increased wave reflection may
increase central aortic BP in response to atenolol despite its
combination with a CCB. By contrast, associating an ARB
with a CCB can potentiate their vasodilating effects and
further reduce central BP. Our working hypothesis was that
the ARB valsartan would be more effective than atenolol on
central aortic BP, when both drugs are combined with
amlodipine.
Thus, the EXPLOR Trial aimed at comparing the effects of
amlodipine-valsartan with those of amlodipine-atenolol on
aortic SBP in hypertensive patients under prospective, ran-
domized, blinded endpoint (PROBE), parallel group condi-
tions. Patients were treated for 6 months to increase the
possibilities of unmasking a difference between the 2 drug
regimens. In addition, to better analyze the pharmacodynam-
ics of both combinations, we measured central aortic SBP,
Central BP After Amlodipine-Valsartan 1315
Excluded patients n = 80
• Not fulfilling inclusion criterions N = 55
• Withdrawal of consent: N = 16
• Adverse event or lost to follow-up N = 13
Amlodipine-Atenolol
N = 200
Early termination: n=38
• Adverse event/side effect: n=28
• Treatment failure: n=1
• Consent withdrawal: n=3
• Other: n=6
diastolic BP (DBP), pulse pressure (PP), AIx, and carotid-
femoral pulse wave velocity (PWV).
Methods
Study Design
This study was a national, multicenter, randomized, probe-type
(prospective, randomized, open-label, blinded end point) trial (NCT
00687973) with parallel groups versus the reference medication. It
was investigator initiated and driven and sponsored by Novartis
Pharma. Patients fulfilling inclusion criteria underwent a 2-week
washout period before entering a 4-week open-label run-in period
with amlodipine 5 mg (once daily). At the end of this period, patients
whose SBP and/or DBP were not adequately controlled (defined by
SBP ⱖ140 mm Hg and/or DBP ⱖ90 mm Hg and SBP ⱖ130 mm Hg
and/or DBP ⱖ80 mm Hg in the case of diabetes mellitus or renal
insufficiency) were randomized to amlodipine-valsartan 5/80 mg or
amlodipine-atenolol 5/50 mg (once daily) treatment groups for a
period of 8 weeks. After 8 weeks, patients were force titrated to
either amlodipine-valsartan 10/160 mg or amlodipine-atenolol 10/
100 mg for an additional 16-week period and up to completion of the
study. Patients not able to tolerate forced titration were withdrawn
from the study (amlodipine valsartan, n⫽18; amlodipine-atenolol,
n⫽28; Figure 1). All of the patients took the scheduled dosage. All
of the patients who terminated the study early were invited to
undergo an investigation with applanation tonometry within 48 hours
of study termination.
Patients
Between January 11, 2008, and January 15, 2009, general practitio-
ners from 100 general practitioner centers connected with 10
tonometry centers across France were asked to recruit all of their
consenting consecutive patients aged 18 to 75 years with essential
hypertension resistant to 2 drugs belonging to 2 different pharmaco-
logical classes. After a 2-week washout period followed by a 4-week
open-label run-in period with amlodipine 5 mg, patients still pres-
enting an uncontrolled office BP (defined as SBP ⱖ140 mm Hg or
DPB ⱖ90 mm Hg) were selected. Exclusion criteria included the
following: BP controlled by 5 mg of amlodipine, contraindication to
one of the drugs used in the protocol, women of childbearing
 1316 Hypertension June 2010

Table 1. Baseline Population Characteristics

Parameters Amlodipine-Valsartan Amlodipine-Atenolol P
Sex, male/female, n (%) 111 (57)/82 (43) 99 (50)/101 (50) 0.11
Age, mean⫾SD, y 57.5⫾9.9 56.2⫾11.1 0.22
Weight, mean⫾SD, kg 79⫾14 81⫾16 0.18
Height, mean⫾SD, cm 168⫾9 167⫾9 0.27
Body mass index, mean⫾SD, kg/m2 28.0⫾4.4 28.8⫾5.3 0.10
Duration of hypertension, mean⫾SD, y 5.1⫾5.6 5.5⫾6.2 0.50
Smoking, current/past or never, n (%) 42 (22)/151 (78) 56 (28)/143 (72) 0.14
Dyslipidemia, yes/no, n (%) 54 (28)/139 (72) 57 (29)/142 (71) 0.88
Diabetes mellitus, yes/no, n (%) 24 (12)/169 (88) 32 (16)/167 (84) 0.30
Family history of premature CVD, yes/no, n (%) 21 (11)/172 (89) 21 (11)/178 (89) 0.91
Abdominal obesity, yes/no, n (%) 72 (37)/121 (63) 86 (43)/113 (57) 0.23
Previous cardiovascular or renal disease, yes/no, n (%) 17 (9)/176 (91) 21 (11)/178 (89) 0.47
High cardiovascular risk, yes/no, n (%) 89 (46)/104 (54) 99 (50)/100 (50) 0.83
Previous antihypertensive treatments, yes/no, n (%) 107 (55)/86 (45) 113 (56)/87 (44) 0.85
ACEI or ARB, n (%) 77 (40) 76 (38) 0.72
CA, n (%) 16 (8) 21 (11) 0.45
␤-Blockers, n (%) 12 (6) 12 (6) 0.92
Diuretics, n (%) 43 (22) 29 (15) 0.05
Others, n (%) 1 (1) 2 (1) …
Office blood pressure at screening, mean⫾SD, mm Hg
SBP 158⫾13 156⫾12 0.18
DBP 91⫾9 92⫾9 0.21
PP 66⫾14 64⫾13 0.15
Heart rate, mean⫾SD, bpm 76⫾12 75⫾13 0.42
CVD indicates cardiovascular disease; CA, calcium channel blockers.
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potential not using effective contraception, any active chronic
disease, and SBP ⱖ180 mm Hg or DBP ⱖ110 mm Hg after the
run-in period. The protocol was approved by the ethics committee of
Saint-Germain-en-Laye Hospital in France. All of the patients gave
their informed written consent.
Central Pressure and Arterial
Stiffness Measurement
BP was measured using an Omron 705 C oscillometric device, both
at the general practitioner’s office and the tonometry center. Three
measurements were performed, and the average of measures 2 and 3
was retained. Applanation tonometry was performed using a Sphygmo-
Cor device (Atcor), as described previously5 and recommended.9,17
Briefly, the applanation probe is positioned on the radial artery (right
arm), and optimal applanation is obtained using visual inspection and
following built-in quality control indices. Radial waveforms are
calibrated using brachial SBP and DBP measured before and after
applanation (average). The central aortic waveform is calculated by
the device software using the generalized transfer function. BP
values are derived from the curve. AIx is measured, and AIx at heart
rate 75 (AIx@75) is calculated through the software. The procedure
is repeated at the level of the carotid artery, and the calibration is
made using the DBP and the mean BP obtained from the radial
tracings.5,9 Applanation is then performed immediately afterward on
the femoral artery, pulse transit times from concomitant ECG are
calculated using the intersecting tangent, and PWV is calculated
from the direct (carotid-to-femoral) path length.
Certification of Centers and Quality Control and
Blinding Procedures
The description of procedures can be found in the online Data
Supplement (available at http://hyper.ahajournals.org).
Statistical Methods
The number of patients to be included in the study was calculated on
the basis of a 13-mm Hg SD for the fall in central SBP between
inclusion and week 24 according to a previous study.5 The power
was set at 80% using a 2-sided ␣ risk of 5%. We estimated that 334
patients were necessary to demonstrate a difference of 4 mm Hg
between the 2 groups for the reduction in central SBP and a
difference in the reduction in brachial SBP ⱕ2 mm Hg. The
estimated dropout rate after randomization (16%) lead us to include
398 patients.
Statistics were performed using the SAS 9.01 package and NCSS
2004 software. All of the analyses were performed on the intent-to-
treat population. Data are presented as mean⫾SD, unless otherwise
specified. Changes are expressed as W24 minus baseline (negative
means decrease) and their 95% CIs. Baseline (W0) characteristics
were compared using unpaired Student t tests and ␹2 tests, as
appropriate. The main comparisons were performed using a mixed
model including time as the within factor and drug as the between
factor. A center effect was systematically included. We used multi-
variate robust models to determine the changes in arterial parame-
ters, after adjustment to initial values (W0), potential confounders
(eg, changes in heart rate, age, and sex), and drug treatment as
dummy variables. All of the tests were bilateral using ␣⫽0.05.
Results
We initially screened 473 patients because the rate of dropout
was lower than expected (Figure 1). Eighty patients (16%)
were excluded at the end of the washout and 5-mg amlodipine
run-in period, including 55 patients (11%) adequately con-
trolled with 5 mg of amlodipine. After randomization, the 2
populations were of comparable age and BP. Forty-six percent
of patients were at high cardiovascular risk, as predicted from
the frequency of associated risk factors (Table 1). The 2 groups
were matched for all of the important cardiovascular risk
factors.
 Boutouyrie et al Central BP After Amlodipine-Valsartan 1317

Office blood pressure (mmHg) 12.93 mm Hg in the amlodipine-atenolol and amlodipine-

180 valsartan groups, respectively, with no significant difference
between the groups (1.14 mm Hg [95% CI: ⫺4.28 to
1.99 mm Hg]; P⫽0.47; Table 2 and Figures 2 and 3). This
160 value is lower than the predetermined level of 2-mm Hg
equivalence. Brachial DBP was reduced to a lesser extent,
140 down by ⫺7.9 mm Hg with both treatments. The difference
between the drug regimens was close to 0 (Table 2). The fall
in brachial BP was time and dose dependent (Figure 2). Most
120 of the decrease in brachial BP was achieved with the low
dosage, but the higher dosage added a further significant
100 decrease of 2.6 mm Hg for brachial SBP and 2.0 mm Hg for
brachial DBP (P⬍0.05). The rates of BP control after the
valsartan-amlodipine and amlodipine-atenolol combinations
80 were similar after 8 weeks (47% and 43%, respectively) and
remained similar at 24 weeks (56% and 59%, respectively).
60 As expected, heart rate was more reduced in the amlodipine-
-4 0 8 16 24
atenolol group than in the amlodipine-valsartan group ⫺9.4
Time (weeks) bpm (95% CI: [⫺11.6 to ⫺7.1 bpm]; P⬍0.001; Table 2).
Amlodipine 5
By contrast to brachial SBP, aortic SBP decreased more
Amlodipine 5/Valsartan 80
or after amlodipine-valsartan than after amlodipine-atenolol
Amlodipine 5/Atenolol 50 (Table 2). The difference between the groups reached the
Amlodipine 10/Valsartan 160
prespecified threshold of 4 mm Hg (⫺3.95 mm Hg [95% CI:
or ⫺7.08 to ⫺0.83 mm Hg]) and was significant (P⫽0.02).
Amlodipine 10/Atenolol 100 Aortic PP decreased more after amlodipine-valsartan than
Figure 2. Brachial BP in response to amlodipine-valsartan (red) after amlodipine-atenolol (Table 2), with a significant differ-
and amlodipine-atenolol (blue). Values were obtained at a gen- ence between the groups (⫺3.74 mm Hg [95% CI: ⫺5.33 to
eral practitioner office using an Omron 705C device. ⫺2.15 mm Hg]; P⬍0.001). By contrast, no significant dif-
ference in the fall in aortic DBP was observed between the
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At week 24, the decreases in brachial BP either at office
(Figure 2) or at tonometry center (Figure 3 and Table 2) were
not significantly different between the groups. Drug tolerance
was good (please see the online Data Supplement). At the
tonometry center, brachial SBP decreased by 11.78 and
groups (Table 2). The AIx significantly decreased after
amlodipine-valsartan, whereas it significantly increased after
amlodipine-atenolol (Table 3 and Figure 4), with a significant
difference between the groups (⫺6.50% [95% CI: ⫺8.28%
to ⫺4.72%]; P⬍0.001). After adjustment of the AIx to

Systolic pressure (mmHg) Pulse pressure (mmHg)

150 65
Brachial SBP Brachial PP
Mean difference -1.14 [-4.28 to 1.99] p=NS Mean difference -1.36 [-3.33 to 0.6] p=NS

145
60

140
55

135
50
130

45
125

40
120
Aortic SBP Aortic PP
Mean difference -3.95 [-7.08 to -0.83], p=0.02 Mean Difference -3.74[-5.33 to -2.15] p<0.001
115 35
Baseline W8 W24 Baseline W8 W24
Figure 3. Brachial (dotted lines) and aortic BPs (continuous lines) in response to amlodipine-valsartan (red) and amlodipine-atenolol
(blue). Values were obtained at a tonometry center using an Omron 705C device.
 1318 Hypertension June 2010

Table 2. BP Response to Amlodipine-Valsartan or Atenolol-Amlodipine

Baseline Change vs Baseline
Difference
Amlodipine-Valsartan, Amlodipine-Atenolol, Amlodipine-Valsartan, Amlodipine-Atenolol,
Parameters Mean⫾SD Mean⫾SD Mean⫾SD Mean⫾SD Mean 95% CI P
Aortic parameters
SBP, mm Hg 134⫾16 134⫾16 ⫺13.70⫾1.15 ⫺9.70⫾1.09 ⫺3.95 ⫺7.08 to ⫺0.83 0.02
DBP, mm Hg 87⫾9 86⫾9 ⫺7.92⫾0.76 ⫺8.11⫾0.73 0.19 ⫺1.88 to 2.27 0.85
PP, mm Hg 47⫾12 48⫾13 ⫺5.51⫾0.65 ⫺1.77⫾0.63 ⫺3.74 ⫺5.33 to ⫺2.15 ⬍0.001
AIx, % 27⫾10 28⫾11 ⫺4.10⫾0.72 2.4⫾0.7 ⫺6.5 ⫺8.28 to ⫺4.72 ⬍0.001
AIx@75, % 26⫾9 26⫾10 ⫺5.65⫾0.84 ⫺2.81⫾0.84 ⫺2.8 ⫺4.92 to ⫺0.68 0.01
PP amplification 1.30⫾0.14 1.26⫾0.15 0.05⫾0.13 ⫺0.05⫾0.13 0.1 0.07 to 0.12 ⬍0.001
CF-PWV, m/s 12.50⫾3.00 11.9⫾10.8 ⫺0.98⫾0.18 ⫺0.95⫾0.17 ⫺0.02 ⫺0.46 to 0.41 0.92
Brachial BP
SBP, mm Hg 145⫾16 144⫾16 ⫺12.90⫾1.14 ⫺11.80⫾1.11 ⫺1.14 ⫺4.28 to 1.99 0.47
Mean BP, mm Hg 107⫾11 107⫾11 ⫺10.10⫾0.94 ⫺10.10⫾0.91 ⫺0.36 ⫺2.94 to 2.21 0.65
DBP, mm Hg 85⫾9 85⫾9 ⫺7.85⫾0.70 ⫺7.94⫾0.68 0.09 ⫺1.83 to 2.01 0.93
PP, mm Hg 60⫾13 59⫾13 ⫺5.02⫾0.71 ⫺3.66⫾0.70 ⫺1.36 ⫺3.33 to 0.60 0.17
HR, bpm 75⫾11 73⫾11 ⫺0.47⫾0.64 ⫺9.82⫾0.93 9.35 7.11 to 11.58 ⬍0.001
Differences are calculated as amlodipine-valsartan minus amlodipine-atenolol. CF indicates carotid-femoral; HR, heart rate.

heart rate, both drug regimens significantly reduced this
parameter, and the difference in AIx@75 between the groups
remained significant (⫺2.80% [95% CI: ⫺4.92% to
⫺0.68%]; P⫽0.01). Amplification of SBP was enhanced
after amlodipine-valsartan (2.03% [95% CI: 1.42% to
2.65%]; P⬍0.001). Results obtained at the common carotid
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tion in carotid-femoral PWV was positively associated with
the reduction in aortic SBP and heart rate and was larger in
women; treatment was not significantly associated with
changes in carotid-femoral PWV. Results were similar if the
final value of parameter was used instead of changes in
parameter (Table S2).

level paralleled those observed at the aortic level but with

lower probability values (except for the AIx; please see Table
S1 in the online Data Supplement). Both amlodipine-
valsartan and amlodipine-atenolol regimens decreased aortic
PWV by 1 m/s; however, no significant difference between
drugs was observed (⫺0.02 m/s [95% CI: ⫺0.46 to 0.41];
P⫽0.92; Figure 4).
Changes were slightly different after 8 weeks of treatment
only. Indeed, central aortic SBP was nonsignificantly decreased
(⫺2.62 mm Hg [95% CI: ⫺5.81 to 0.58]; P⫽0.11), whereas the
difference in central aortic PP was already significant
(⫺3.98 mm Hg [95% CI: ⫺5.76 to ⫺2.21 mm Hg]; P⬍0.0001).
The raw AIx was significantly decreased with amlodipine-
valsartan compared with amlodipine-atenolol (⫺5.83% [95%
CI: ⫺7.79% to ⫺3.87%]’ P⬍0.0001), although this differ-
ence was no longer significant after correction for heart rate
changes.
At week 24, the between-group differences in the reduction
of aortic SBP, PP, and AIx remained significant after adjust-
ment to baseline values, changes in heart rate, and other
significant covariates in a multivariate regression analysis
(Table 3). Indeed, although the reduction in aortic SBP, PP,
and AIx were negatively correlated with the changes in heart
rate (the larger the reduction in heart rate, the lower the
reduction in aortic PP and AIx), the reduction in aortic SBP,
PP, and AIx remained significantly larger with amlodipine-
valsartan than with amlodipine-atenolol. Patients previously
treated had similar changes as patients previously untreated.
Additional adjustment on changes in mean BP did not alter
these results. After adjustment on baseline value, the reduc-
Discussion
The major finding of the present study is that, despite a
similar reduction in brachial BP in both groups, aortic SBP,
PP, AIx, and AIx@75 were more reduced in the amlodipine-
valsartan group than in the amlodipine-atenolol group. These
results were observed with similar and considerable reduc-
tions in brachial BP with both combinations and remained
significant after adjustment to heart rate reduction.
ARBs, Atenolol, and Reduction of Central
Aortic Pressure
The amlodipine-valsartan combination lowered central aortic
SBP and PP and the AIx more than the amlodipine-atenolol
combination. By contrast, no significant difference between
the groups was observed with regard to aortic stiffness and
brachial BP. The ability of amlodipine-atenolol to lower
PWV to a similar extent as amlodipine-valsartan is not
surprising, because both regimens had similar effects on
mean BP, which represents the main load exerted on the stiff
material of the aortic wall, which, in turn, determines aortic
stiffness. In a multivariate model predicting the regression of
PWV in the present study, we observed that baseline PWV
value, mean BP reduction, and heart rate reduction were the
3 major determinants, explaining 19.0%, 8.0%, and 4.3% of
variance, respectively. This confirms the prominent role of
mean BP reduction on aortic stiffness changes. The similar
reductions in aortic stiffness by both drug regimens are
comparable to previous observations in the REASON6,7 and
Conduit Artery Functional Endpoint 8 studies.
 Boutouyrie et al Central BP After Amlodipine-Valsartan 1319

Table 3. Determinants of Changes in BP and Carotid-Femoral PWV Between Week 24 and Inclusion
Parameters In/Out R2 increment, % ␤-Coefficient Lower CI Upper CI P
Change in aortic systolic pressure
(R2⫽0.26, RMSE⫽11.4)
Baseline aortic systolic In 24.8 ⫺0.45 ⫺0.53 ⫺0.37 ⬍0.001
pressure, mm Hg
Age at inclusion, y In 1.8 0.18 0.06 0.31 0.006
Valsartan/atenolol In 1.0 ⫺3.34 ⫺6.1 ⫺0.6 0.03
Change in heart rate, bpm Out … … … … 0.90
Sex Out … … … … 0.95
BMI Out … … … … 0.85
Change in aortic PP (R2⫽0.40,
RMSE⫽6.6)
Baseline aortic PP, mm Hg In 27.5 ⫺0.41 ⫺0.47 ⫺0.34 ⬍0.0001
Change in heart rate, bpm In 3.4 ⫺0.15 ⫺0.21 ⫺0.34 ⬍0.0001
Age at inclusion, y In 3.2 0.16 0.09 0.24 ⬍0.0001
Valsartan/atenolol In 2.0 ⫺2.65 ⫺4.22 ⫺1.07 0.001
Sex Out … … … … 0.81
BMI Out … … … … 0.89
Change in aortic AIx (R2⫽0.46,
RMSE⫽6.4)
Baseline AIx, % In 19.8 ⫺0.42 ⫺0.50 ⫺0.35 ⬍0.0001
Change in heart rate, bpm In 7.9 ⫺0.25 ⫺0.32 ⫺0.18 ⬍0.0001
Sex In 4.9 4.4 2.9 5.9 ⬍0.0001
Valsartan/atenolol In 4.8 ⫺4.4 ⫺6.0 ⫺2.9 ⬍0.0001
Age at inclusion, y In 2.9 0.15 0.08 0.22 ⬍0.0001
Downloaded from http://ahajournals.org by on March 23, 2020

BMI Out … … … … 0.75

Change in aortic PWV (R2⫽0.38,
RMSE⫽1.87)
Baseline PWV, m/s In 19.3 ⫺0.32 ⫺0.39 ⫺0.26 ⬍0.0001
Change in aortic SBP, mm Hg In 7.9 0.037 0.024 0.048 ⬍0.0001
Change in heart rate, bpm In 4.3 0.031 0.016 0.33 0.0001
Sex In 1 ⫺0.36 ⫺0.69 ⫺0.031 0.03
Valsartan/atenolol Out … … … … …
Age at inclusion, y Out … … … … …
“In” indicates entered the model; “Out,” did not enter the model; RMSE, root mean square error. Changes are calculated as final
minus baseline. A negative ␤-coefficient for baseline SBP means a larger decrease in the more hypertensive subjects; atenolol and
valsartan are coded 0 and 1, men and women 0 and 1, respectively.

There was no significant difference in the reduction of
brachial SBP or PP between the 2 regimens despite a
significant difference in central aortic SBP or PP. This was
also expected. Central pressure is lower than peripheral
pressure, which is consistent with the amplification phenom-
enon according to which the amplitude of the pressure wave
is higher in peripheral arteries than in central arteries18 (Table
2). After treatment, amplification was enhanced by valsartan
compared with atenolol. Drugs exert differential effects on
the PP amplification between central and peripheral arter-
ies.7,8 Altogether these findings indicate that the addition of
CCBs to atenolol did not abolish the adverse effect of
atenolol on central BP10,11,13 and suggest that it occurred
either through bradycardia or increased wave reflection.
The bradycardia-induced dyssynchrony or uncoupling be-
tween outgoing and reflected waves can by itself increase
central SBP and PP.11,19 Indeed, the reduction in heart rate
allows more time during systole for early return of the
reflected wave. Bradycardia is also associated with an in-
creased ejection volume, which translates into an increased
peak SBP. A recent analysis of the Conduit Artery Functional
Endpoint Trial suggests that most of the differences between
the treatment groups were attributable to changes in heart
rate.20 This is indeed not the case in our study, because
adjustment to the change in heart rate only marginally
lessened the improvement in central BP and AIx with
amlodipine-valsartan. In the present study, heart rate was 10
bpm lower with amlodipine-atenolol than with amlodipine-
valsartan. We checked whether differences in central aortic
BP and AIx between the drug regimens could be attenuated
by adjustment to heart rate. This was done by building a
multivariate model with changes in aortic SBP, PP, or AIx as
 1320 Hypertension June 2010
Carotid to femoral pulse wave velocity (m/s)
16
14
12
10
8 10
Mean difference at W24 : -0.02 m/s
[-0.46 to 0.41], p=NS
6 0
Baseline W8 W24
Figure 4. Changes in PWV and AIx in response to amlodipine-valsartan (red) and amlodipine-atenolol (blue).
dependent variables and changes in mean BP, heart rate,
baseline values of central pressure parameters, and treatment
as independent variables. We showed that part of the differ-
ence in aortic PP reduction between the 2 treatment arms was
significantly independent of the changes in heart rate. Indeed,
Downloaded from http://ahajournals.org by on March 23, 2020
in a fully adjusted model for aortic PP changes (Table 3),
treatment with amlodipine-valsartan (versus amlodipine-
atenolol) accounted for 2.65 mm Hg (␤-coefficient,
P⬍0.001) of the total 3.74 mm Hg (Table 2), whereas a
10-bpm reduction in heart rate explained only 1.50 mm Hg
(␤-coefficient, P⬍0.001).
In the present study, AIx significantly decreased with
amlodipine-valsartan, whereas it significantly increased after
amlodipine-atenolol, with a significant difference between
groups (Table 3 and Figure 3). The influence of heart rate was
analyzed in 2 ways. First, we adjusted AIx to heart rate and
calculated AIx@75. The difference in AIx@75 reduction
between the groups remained significant, although it was half
that of unadjusted AIx (⫺2.80% versus ⫺6.50%, respec-
tively; Table 2) Second, in a fully adjusted model for aortic
AIx (Table 3), treatment with amlodipine-valsartan (versus
amlodipine-atenolol) explained a large part of the difference,
that is, 4.40% (␤-coefficient; P⬍0.001) out of 6.50% (Table 2),
whereas a 10-bpm reduction in heart rate only explained
2.50% (␤-coefficient, P⬍0.001). Because bradycardia ex-
plained only part of the difference in central pressures and
AIx between the 2 drug regimens, other mechanisms need to
be discussed, particularly changes in reflection sites.
Vasodilatation, Arterial Remodeling, and
Wave Reflection
Reduction in reflection sites intensity can be obtained phar-
macologically either through vasodilatation or long-lasting
structural remodeling, that is, decreased wall:lumen ratio of
small arteries. Although atenolol is known to prevent the
Aortic augmentation index (%)
50
40
30
20
Mean difference at W24 -6.50%
[-8.28 to -4.72], p<0.001
Baseline W8 W24
deleterious effects of catecholamines on the heart, it does not
reduce total peripheral resistance and sympathetic drive21; it
is less effective than blockers of the renin-angiotensin system
to reduce small artery damage, that is, vasoconstriction and
increased media:lumen ratio12; and it is less effective than
vasodilators in reducing aortic and carotid stiffness, carotid
intima-media thickness, and cerebrovascular resistance in
hypertensive patients.22 That a significant difference in aortic
PP and AIx between the 2 regimens was already observed
after 8 weeks in the present study suggests a difference in
vasomotor tone rather than in structural changes. Indeed, the
pharmacological remodeling of small arteries leading to a
reduction in wall:lumen ratio is a long-lasting process requir-
ing several months.23–25 Thus, the difference in central
pressure and AIx between the 2 regimens suggests that the
amplitude of vasodilatation and, therefore, the reduction of
wave reflection were higher when an ARB was combined
with a CCB than when the ␤-blocker atenolol was combined
with a CCB. A recent report mentioned a better improvement
of PWV and central pressure with CCB combined with ARB
than with diuretics26; however, the difference in central
pressure was of the same magnitude as changes in peripheral
pressure. By contrast, in the EXPLOR Trial, differences in
central SBP were larger than those in brachial SBP, DBP, and
mean BP. Furthermore, they were independent of baseline
value, changes in mean BP, and heart rate. The same holds
true for AIx.
Both bradycardia and increased wave reflection may have
increased central aortic BP and AIx in response to atenolol
despite its combination with a CCB. This may reflect the
persistence of a relative vasoconstriction and bradycardia
with atenolol despite chronic treatment and association with
potent vasodilatators, such as amlodipine. These results are
unlikely to apply to vasodilating ␤-blockers. Indeed, vasodi-
 Boutouyrie et al
lating ␤-blockers, including celiprolol,27 dilevalol,28 and
nebivolol,11,29 have been reported to reduce central PP and
AIx, and it is very likely that combining them with a CCB
will reinforce their beneficial effects. Increased heart rate has
been associated with increased arterial stiffness, mainly
because of arterial wall viscosity phenomenon.30 Therefore,
bradycardia and reduction in cardiac output with ␤-blockers
may explain the similar reduction in aortic PWV as with
vasodilating drugs and may also explain part of their benefi-
cial effect.
Reduction of Central BP and Outcomes
Meta-analyses of hypertension treatment trials have con-
firmed the lower impact of ␤-blocker– based therapies in
preventing stroke, particularly with atenolol, and showed that
the risk of myocardial infarction was not significantly differ-
ent.31 In particular, the Losartan Intervention for Endpoint
Reduction in Hypertension Study32 and Anglo-Scandinavian
Cardiac Outcomes Trial16 showed that losartan- and
amlodipine-based treatments, respectively, proved to be more
effective than atenolol-based treatments in reducing the
incidence of stroke. Because brachial BP was lowered to a
similar extent on both arms, and because central aortic BP is
an independent predictor of cardiovascular events in various
populations,1 it has been suggested that the difference in
outcomes could be attributed to the difference in the reduc-
tion of central aortic BP.1,8,10 Although a differential effect on
central BP has been reported in the Conduit Artery Function
Evaluation Study, in favor of the amlodipine-perindopril
Downloaded from http://ahajournals.org by on March 23, 2020
combination, the lack of measurement of central pressure at
the initiation of the Anglo-Scandinavian Cardiac Outcomes
Trial limits the validity of conclusions.
Methodological Issues
The present study is, to our knowledge, the first one to
provide data on the long-term effects of ␤-blockers in
combination therapies on central BP. Previous studies could
not address this issue, because the drugs to be compared were
not combined with the same antihypertensive agent. For
instance, the Conduit Artery Function Evaluation Study8
compared an ACEI/CCB combination with atenolol com-
bined with a diuretic. The REASON study7 compared an
ACEI/diuretic combination with atenolol as monotherapy but
not with atenolol included in a combination. This is why the
present study was designed with both parallel groups, includ-
ing amlodipine.
Although the PROBE design has been successfully used in
the past, this was mainly in clinical trials with “hard” end
points like in the Hypertension Optimal Treatment Study.33
The true double-blind nature of trials involving ␤-blockers
has been questioned before because of the evident reduction
in heart rate. In the present study, tonometry centers in charge
of measuring the central BP were not responsible for deliv-
ering the drug to the patients and were asked (by procedures)
not to enquire about drugs that patients were receiving. We
also ensured that the core laboratory was never in direct
contact with any of the investigators (general practitioners
or tonometry centers). All of the feedback information
from the core laboratory to the investigator transited
Central BP After Amlodipine-Valsartan 1321
through the contract research organization executive. As
detailed above, tracings were blinded as to the center, the
period, and the identity of the patient, as well as to all of the
queries to the core laboratory from investigators or the CRO.
Thus, the end point was truly blinded, according to the
PROBE design. AIx is not a pure index of wave reflection,
and proving that the differential effect of atenolol and
valsartan, added to amlodipine, is attributed to a differential
effect on wave reflection would need a concomitant measure-
ment of aortic blood flow to separate forward and backward
waves with more precision.34 Radial artery tonometry cali-
brated on brachial pressure leads to imperfect calibration.35
However, this was similarly done in both groups, and it is
unlikely to influence the differential effect of drugs on central
pressure. In conclusion, the amlodipine-valsartan combina-
tion improves central systolic and PP, together with AIx (a
surrogate measure of wave reflection), more than the
amlodipine-atenolol combination.
Clinical Perspectives
Because central aortic SBPs and PPs are independent predic-
tors of cardiovascular events in various populations, it is
important to determine to what extent antihypertensive agents
differ in their ability to lower central aortic BP, despite
similar reduction in brachial BP. The present study is, to our
knowledge, the first one to provide data on the long-term
effects of ␤-blockers in combination therapies on central BP.
We have demonstrated that a 24-week treatment with an
amlodipine-valsartan combination improved central SBP and
PPs, together with wave reflection, more than the amlodipine-
atenolol combination and that differences were independent
of the reduction in heart rate. The lesser effects of ␤-blockers
on outcomes in hypertension have been put in evidence by
recent meta-analyses; the present study strongly suggests that,
even when combined with a CCB, atenolol might not reduce
central BP enough to effectively protect against cardiovascu-
lar events. An outcome trial is required to determine whether
the differences in central BP between the treatment groups
translate into clinical benefit.
Appendix
The EXPLOR Trialist Group consists of the following individuals: P.
Gosse, Bordeaux; G. London and B. Pannier, Fleury-Mérogis; P.
Poncelet, Henin-Beaumont; P. Lantelme and L. Legedz, Lyon; P.
Fesler, Montpellier; B. Levy, Paris; C. Thuillez and R. Joannides,
Rouen; D. Stephan, Strasbourg; P. Laurent, Toulon; and G.
Doll, Tours.
Acknowledgments
We warmly thank Fatima Hamza and Julie Perucca for their
excellent technical work, as well as Erwan Bozec, Kim Thanh Ong,
and Cédric Collin for their help during the training sessions.
Sources of Funding
This investigator-initiated study was funded by Novartis Pharma.
Disclosures
A.A. and P.T. are employees of Novartis-Pharma France. P.B. has
received honorariums from Novartis Pharma for scientific consultation.
 1322 Hypertension June 2010
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