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Original article 351
A comparison of atenolol and nebivolol in isolated systolic
hypertension
Zahid Dhakam, Yasmin, Carmel M. McEniery, Tim Burton, Morris J. Brown and
Ian B. Wilkinson
Objectives Some b-blockers are less effective in reducing
central blood pressure than other antihypertensive drugs,
which may explain the higher rate of events in subjects
randomized to atenolol in recent trials. We hypothesized
that nebivolol, a mixed b-blocker/nitro-vasodilator, would
be more effective than atenolol in reducing central blood
pressure and augmentation index (AIx). The aim of the
present study was to test this in a double-blind, randomized,
cross-over study, in a cohort of subjects with isolated
systolic hypertension.
Methods Following a 2-week placebo run-in, 16 nevertreated hypertensive subjects received atenolol (50 mg),
nebivolol (5 mg) and placebo, each for 5 weeks, in a random
order. Seated brachial blood pressure and heart rate were
measured. Aortic blood pressure, AIx and pulse wave
velocity (PWV) were assessed non-invasively.
Results The placebo-corrected fall in brachial pressure was
similar between nebivolol and atenolol, as was the
reduction in PWV (mean change W SEM: S1.0 W 0.3 and
S1.2 W 0.2 m/s; P U 0.2). However, there was less reduction
in heart rate (S19 W 2 versus S23 W 2 beats/min; P < 0.01)
and increase in AIx (R6 W 1 versus R10 W 1%; P U 0.04),
following nebivolol. Aortic pulse pressure was significantly
lower (50 W 2 versus 54 W 2 mmHg; P U 0.02) after nebivolol.
N-terminal pro-B-type natriuretic peptide (proBNP) rose on
Introduction
Until recently blood pressure reduction per se rather than
the specific drug used was thought to be the primary
factor influencing outcome in hypertensive subjects.
However, despite similar reductions in peripheral pressure in the LIFE Study, losartan appeared superior to
atenolol in preventing death or future cardiovascular
events, and the difference was most marked in older
patients with systolic hypertension [1,2]. Interestingly, in
the Medical Research Council (MRC)-Elderly Trial,
published some years before, atenolol was no better than
placebo in preventing cardiovascular events in older
hypertensive subjects [3], despite reducing peripheral
blood pressure. This view is supported by a recent
meta-analysis of the early placebo-controlled or drug
comparison trials involving atenolol [4], and the recent
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
study [5]. Overall, these observations have cast doubt on
the efficacy of atenolol in older hypertensive subjects.
both drugs (100 W 33 versus 75 W 80 pg/ml; P < 0.01 for
both, NS for comparison).
Conclusions Nebivolol and atenolol have similar effects on
brachial blood pressure and aortic stiffness. However,
nebivolol reduces aortic pulse pressure more than atenolol,
which may be related to a less pronounced rise in AIx and
bradycardia. Whether this will translate into differences in
clinical outcome requires further investigation. J Hypertens
26:351–356 Q 2008 Wolters Kluwer Health | Lippincott
Williams & Wilkins.
Journal of Hypertension 2008, 26:351–356
Keywords: augmentation index, beta blockers, hypertension, pulse wave
velocity
Abbreviations: AIx, Aortic augmentation index; aPWV, Aortic pulse wave
velocity; BP, blood pressure; MAP, mean arterial pressure; proBNP, Pro
Brain type natriuretic peptide
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital,
Cambridge, CB2 2QQ, UK
Correspondence to Dr Ian Wilkinson, Clinical Pharmacology Unit,
University of Cambridge, Addenbrooke’s Hospital, Cambridge,
CB2 2QQ, UK
Tel: +44 (0)1223336806; fax: +44 (0)8701269863; e-mail: [email protected]
Received 19 March 2007 Revised 31 July 2007
Accepted 21 September 2007
The Conduit Artery Function Evaluation (CAFÉ) study
[6], which was a substudy of the much larger ASCOT
study, confirmed one potential hypothesis for the inferiority of atenolol, namely that it is less effective in
reducing aortic blood pressure [7]. Whether such observations pertain only to atenolol, or are a class effect, is
unclear. However, previous studies suggest that vasodilating b-blockers may be more effective than atenolol in
reducing central blood pressure, due to reduced wave
reflection [8]. Nitrates are also well known to reduce wave
reflection [9], and we have shown recently that the novel,
nitrovasodilating b-blocker nebivolol, but not atenolol,
reduces large artery stiffness in an ovine hindlimb model
[10]. Therefore, we hypothesized that nebivolol would be
more effective in reducing central blood pressure than
atenolol. The aim of the present study was to test this
hypothesis in a cohort of subjects with isolated systolic
hypertension as a model of increased arterial stiffness and
high central blood pressure.
0263-6352 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
352 Journal of Hypertension
2008, Vol 26 No 2
Methods
Study protocol
Study population
All subjects received a 2-week placebo run-in and baseline haemodynamic and biochemical measurements were
then made. Subjects were then randomized, in a doubleblinded, cross-over manner, to 5 weeks’ treatment with
each of atenolol 50 mg, nebivolol 5 mg, and placebo,
given once daily in the morning. Haemodynamic and
biochemical measurements were repeated at the end of
each treatment phase. All measurements were made at
trough, i.e. immediately before that morning’s scheduled
dosing.
Never-treated subjects with isolated systolic hypertension were recruited from the Hypertension Clinic at
Addenbrooke’s Hospital in Cambridge, and local general
practices. Hypertension was defined as a seated systolic
blood pressure (BP) 140 and diastolic BP <90 mmHg,
on at least three occasions separated by a month. Subjects
with secondary hypertension, diabetes mellitus or renal
impairment (creatinine >150 mmol/l) were excluded
a priori. Approval of the local research ethics committee
was obtained and written informed consent was given by
all subjects.
Haemodynamics
Brachial (peripheral) BP was recorded in the dominant
arm using a validated oscillometric method (HEM705CP; Omron Corporation, Kyoto, Japan) after 10 min
of seated rest. Radial artery waveforms were then recorded
with a high-fidelity micromanometer (SPC-301; Millar
Instruments, Houston, Texas, USA) from the wrist of
the dominant arm. Pulse wave analysis (SphygmoCor;
AtCor Medical, Sydney, Australia) was then used to generate a corresponding central (ascending aortic) waveform
using a transfer function. This transfer function has been
validated prospectively for the assessment of ascending
aortic BP [11,12], and the system shows good repeatability
of measurements [13].
Aortic augmentation index (AIx), and heart rate were
determined using the integral software. Augmentation
index, a composite measure of wave reflection and
systemic arterial stiffness [14], was calculated as the
difference between the second and first systolic peaks,
expressed as a percentage of the pulse pressure. Aortic
pulse wave velocity (aPWV) was measured, in the supine
position, using the same device by sequentially recording ECG-gated carotid and femoral artery waveforms,
as previously described in detail [13]. Mean arterial
pressure was calculated by integration of the pressure
waveform.
Data analysis
The primary outcome measure was change in central
blood pressure. Secondary outcomes were change in
peripheral blood pressure, AIx, aPWV and N-terminal
proBNP. Data were analysed using repeated measures
analysis of variance (ANOVA) and custom hypothesis
(post hoc) testing to determine individual drug effects.
Plasma N-terminal proBNP levels were significantly
skewed and were logarithmically transformed before
analysis. Unless otherwise stated, data are presented as
means SEM, and a P value < 0.05 was considered
significant.
Results
Sixteen subjects were entered into the study, and all
completed it. Baseline data following the 2-week placebo
run-in are presented in Table 1. There was no order
effect, or influence of gender.
Compared to placebo, there was a significant reduction in
brachial systolic, diastolic, mean and pulse pressures following treatment with atenolol and nebivolol (Table 2).
Importantly, the effect on these peripheral haemodynamic
indices did not differ significantly between the two drugs.
Aortic systolic and diastolic pressure fell significantly
during the study, but the effects of nebivolol and atenolol
Table 1
Baseline characteristics
Parameter
All measurements were made in duplicate, unless they
differed by more than 5%, in which case a third reading
was taken, and the mean values were used in the subsequent analysis.
Biochemical analysis
Venous blood (10 ml) was drawn from the antecubital
fossa into lithium-heparin tubes, centrifuged immediately at 48C, and the plasma separated and stored at
808C for subsequent analysis. The N-terminal fragment
of pro-B-type natriuretic peptide (proBNP) was assayed
using a commercially available immunochemiluminescence technique (Roche Diagnostics, Burgess Hill,
Sussex, UK). All samples were analysed as a single
batch.
Age (years)
Gender (men/women)
Height (m)
Weight (kg)
Body mass index (kg/m2)
Smokers (n)
Brachial SBP (mmHg)
Brachial DBP (mmHg)
Brachial PP (mmHg)
Aortic SBP (mmHg)
Aortic DBP (mmHg)
Aortic PP (mmHg)
Pulse pressure amplification
Aortic PWV (m/s)
AIx (%)
N-terminal proBNP (pg/ml)
70 6
10/6
1.67 0.09
78 11
29 4
2
158 12
84 6
74 6
140 10
86 6
54 5
1.36 0.14
10.2 1.53
24 8
62 [76]
Data represent means SD, or medians [interquartile range]. AIx, augmentation
index; DBP, diastolic blood pressure; PP, pulse pressure; proBNP, pro-B-type
natriuretic peptide; PWV, pulse wave velocity; SBP, systolic blood pressure.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atenolol and nebivolol in hypertension Dhakam et al. 353
Table 2
Haemodynamic and biochemical parameters following therapy
Significance
Parameter
Atenolol (A)
Nebivolol (N)
Placebo
Overall
A versus N
Brachial SBP (mmHg)
Brachial DBP (mmHg)
Brachial PP (mmHg)
MAP (mmHg)
Aortic SBP (mmHg)
Aortic DBP (mmHg)
Aortic PP (mmHg)
PP amplification
Heart rate (beats/min)
AIx (%)
Aortic PWV (m/s)
N-terminal proBNP (pg/ml)
137 3M
73 2
64 2M
94 3M
127 3M
73 2
54 2M
1.20 0.02
57 1
32 2M
8.9 0.3M
157 [123]M
136 3M
75 2
61 3M
95 2M
125 3M
75 2
50 2
1.22 0.02
61 2
28 2M
9.1 0.3M
138 [201]M
149 3
82 2
67 3
104 2
131 2
82 2
49 2
1.39 0.03
80 3
22 2
10.0 0.4
75 [61]
0.003
< 0.001
0.2
< 0.001
0.03
< 0.001
0.03
< 0.001
< 0.001
< 0.001
< 0.001
< 0.001
0.4
0.5
–
0.8
0.4
0.3
0.02
0.7
0.009
0.04
0.2
0.6
Data represent means SEM, or medians [interquartile range]. AIx, augmentation index; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure;
proBNP, pro-B-type natriuretic peptide; PWV, pulse wave velocity; SBP, systolic blood pressure. M Indicates a significant change compared with the placebo phase for
individual treatments based on custom hypothesis testing. Significance was determined using repeated-measures ANOVA for the two active drugs compared with the
placebo phase.
were similar. Aortic pulse pressure was 4 mmHg higher
following atenolol than after nebivolol (P ¼ 0.02). As
expected, administration of both active drugs was associated with significant reduction in heart rate, but this was
less marked with nebivolol (19 2 versus 23 2 beats/
min; P ¼ 0.03). Combining the data from all three phases,
there was a modest correlation between the change in heart
rate and change in aortic pulse pressure (r ¼ 0.27; P ¼ 0.04),
and between the change in AIx and change in aortic pulse
pressure (r ¼ 0.24; P ¼ 0.04).
There was a significant, but similar, reduction in the
aPWV following nebivolol and atenolol (1.0 0.3 and
1.2 0.2 m/s respectively; P ¼ 0.2 for comparison), but a
less marked increase in AIx after nebivolol (þ6 1 versus
þ10 1%; P ¼ 0.04). The change in AIx was significantly
correlated with the change in heart rate during the study,
as was the change in pulse pressure amplification (Fig. 1).
Following 5 weeks’ treatment with both active drugs
there was an increase in plasma N-terminal proBNP
levels and a trend for this to be less pronounced following
nebivolol, although this difference failed to achieve significance. N-terminal proBNP levels were significantly
associated with the change in aortic pulse pressure on
treatment (r ¼ 0.40; P < 0.013). Stepwise multiple linear
regression analysis was used to identify predictors of the
Fig. 1
(b)
20
0.2
15
0.1
10
0.0
Delta amplification
Delta AIx (%)
(a)
5
0
--5
--0.1
--0.2
--0.3
--10
--0.4
--15
--0.5
--50
--40
--30
--20
--10
0
Delta heart rate (beats/min)
10
20
--50
--40
--30
--20
--10
0
10
20
Delta heart rate (beats/min)
Influence of heart rate on augmentation index (AIx) and pulse pressure amplification. Relationship between the change in heart rate following atenolol
(*), nebivolol (~) and placebo (&) and the change in augmentation index (a) and pulse pressure amplification (b). The regression lines are for the
whole data set (all treatment phases combined): (a) r ¼ 0.83, P < 0.001; (b) r ¼ 0.54, P < 0.001.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
354 Journal of Hypertension
2008, Vol 26 No 2
change in N-terminal proBNP. Parameters entered into
the model were drug, and changes in the following: mean
arterial pressure (MAP), aortic pulse pressure, heart rate,
AIx, and aPWV. Only change in aortic pulse pressure was
independently associated with N-terminal proBNP
levels (P ¼ 0.009; R2 for model ¼ 0.59, P < 0.001).
Discussion
The aim of the present study was to compare the central
haemodynamic effects of atenolol and the novel, nitrovasodilator b-blocker nebivolol in a cohort of subjects
with systolic hypertension. The main findings were that,
despite similar reductions in peripheral blood pressure
and aortic stiffness, nebivolol had a significantly greater
effect on aortic pulse pressure than atenolol, and less
effect on aortic AIx. Plasma N-terminal proBNP rose
following both active drugs and was independently correlated with the change in aortic pulse pressure, but not in
mean pressure, heart rate or aPWV.
Brachial systolic pressure is routinely measured in clinical
practice, and is well established as a surrogate measure of
future cardiovascular risk [15]. However, systolic blood
pressure varies along the arterial tree [16], due primarily
to increasing vessel stiffness and wave reflection. Therefore, aortic systolic pressure and pulse pressure, in
particular, may provide a more accurate measure of risk
[17]. Indeed, the brain, heart and kidneys are exposed to
central and not brachial pressure, and surrogate measures
of cardiovascular risk correlate more closely with central
pulse pressure [18,19].
In the present study, both atenolol and nebivolol significantly reduced brachial systolic, diastolic and pulse pressures, by a similar amount. Compared with placebo, aortic
pulse pressure actually increased following atenolol and
was no different after nebivolol. Although previous
studies with atenolol have reported a modest reduction
in central pulse pressure [20,21], placebo-corrected
values were not provided, making direct comparisons
difficult. Overall, aortic pulse pressure was 4 mmHg lower
after nebivolol than atenolol. This is similar to the observations of Kelly et al. [8], who compared the vasodilating
b-blocker dilevalol (now withdrawn) with atenolol, and
noted a 6 mmHg greater reduction in carotid pressure
with dilevalol. Although these may seem trivial differences, similar disparities in brachial artery pressure are
associated with an 20% variation in cardiovascular
events [22]. Moreover, the average difference between
the amlodipine/perindopril and atenolol/bendrofluazide
arms of the ASCOT study reported by the CAFÉ investigators was only 4 mmHg, suggesting that such modest
differences between drugs may be important [6]. Unfortunately, comparative data for other vasodilating b-blockers against atenolol are not available. However, celiprolol
appears as effective as enalapril in reducing central
pressure [23].
The shape of the aortic pressure wave depends on local
aortic stiffness and pressure waves reflected from the
periphery. In older subjects, the summated reflected
wave arrives back at the aortic root in systole, augmenting
peak aortic pressure. Consequently, aortic systolic pressure depends on the degree of wave reflection. In contrast, brachial systolic pressure is largely uninfluenced by
such wave reflections, but is higher than aortic pressure
partly because the brachial artery is stiffer. By altering
local vessel stiffness and wave reflection, drugs can have
different effects on central and peripheral pulse pressure
[24]. Therefore, in order to investigate the potential
mechanisms underlying changes in aortic pressure, we
assessed aortic stiffness, using the current ‘gold-standard’
technique of aPWV [25], and aortic AIx – a composite
measure of wave reflection and systemic arterial stiffness
[14].
Both b-blockers reduced aPWV by a similar amount
(1 m/s) over the 5-week treatment period. This observation is consistent with previous studies utilizing both
non-dilating and vasodilating b-blockers in hypertensive
subjects [8,21,26,27], and suggests that the differential
effect on aortic pulse pressure did not result from a
greater reduction in large vessel stiffness (aPWV) by
nebivolol. This may appear to contradict our previous
animal observations [10], but these were based on local
(intra-arterial) rather than systemic drug administration to
minimize any influence of concomitant reductions in
blood pressure or reflex autonomic effects. The present
data suggest that such direct effects are either overwhelmed by the passive effects of a fall in MAP
(15 mmHg), or any reduction in sympathetic tone that
may accompany systemic administration of b-blockers
[28–30]. Alternatively, the fall in heart rate with systemic
b-blockade may be, in part, responsible for the reduction
in aPWV, although this remains controversial [31–33].
Acute and chronic treatment with atenolol has been
associated with an increase in central AIx in most
[8,20,21,27,34], but not all studies [35]. This is in contrast
to other antihypertensive drugs, which tend to reduce AIx
[20,34]. However, only one previous study compared the
effects of different b-blockers on central haemodynamics. Kelly et al. [8] reported a greater increase in
carotid AIx after acute and chronic therapy with atenolol
than with dilevalol. Similarly, in the present study,
although there was an increase in aortic AIx with both
b-blockers, the magnitude of this effect was significantly
greater with atenolol. This rise in AIx following b-blockade suggests a greater influence of reflected pressure
waves on the systolic portion of the central waveform.
Although the mechanisms responsible for this effect
remain to be elucidated, aortic stiffening and faster travel
of the reflected waves seem unlikely to be involved since
aPWV fell following b-blockade, consistent with previous
observations.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atenolol and nebivolol in hypertension Dhakam et al. 355
An alternative explanation for the change in AIx is the
reduction in heart rate that accompanies b-blockade.
Indeed, we have previously demonstrated that AIx is
confounded by heart rate, due to alterations in the
absolute duration of systole. As heart rate slows, systole
lengthens, giving more time for the reflected wave to
return to the ascending aorta, and thus augment central
pressure, independently of any effect on stiffness. For
each 10 beat/min reduction in heart rate, AIx increases by
4% [36]. This is exactly what was observed with atenolol in the present study (a 20 beat/min fall in heart rate
and an 8% increase in AIx). In contrast, nebivolol had less
impact on AIx than predicted from the measured 16 beat/
min reduction in heart rate. Given that both drugs had
similar effects on MAP and aPWV, this suggests that the
magnitude of the reflected pressure wave was lower after
nebivolol. This may be due to nitric oxide-induced
relaxation of the small arteries and better impedance
mismatch between small arteries and arterioles. Further
work is required to substantiate this view, and different
approaches, such as wave intensity analysis [37], may also
provide alternative explanations. Nevertheless, the lower
central pulse pressure after therapy with nebivolol
appears to be due to changes in wave reflection rather
than a differential impact on aortic stiffness per se.
nebivolol, and less change in AIx and heart rate, these
observations require further evaluation in a much larger
cohort with significantly longer duration of therapy.
Indeed, Chen et al. [35] noted a fall in AIx with atenolol
after 8 weeks of therapy, although they did not placebocorrect their data. Finally, we did not assess flow and
pressure simultaneously and, therefore, could not resolve
forward and backward going waves or undertake wave
intensity analysis. Such approaches may allow a better
understanding of the precise mechanisms responsible for
the changes in AIx.
To investigate the potential importance of the changes in
haemodynamic indices, we also compared the effect of
therapy on plasma N-terminal pro-BNP levels – an index
of left ventricular stretch and cardiac afterload [38].
Amongst hypertensive subjects, BNP levels correlate
with left ventricular mass [39], and BNP levels predict
outcome in subjects with cardiovascular disease [40].
Treatment with both b-blockers was associated with a
significant increase in pro-BNP levels, which is consistent
with previous observations [21,34,41]. Although the rise
was less marked with nebivolol, this difference did
not achieve significance. Nevertheless, the change in
N-terminal pro-BNP levels was independently associated with the change in central pulse pressure. This
suggests that central haemodynamic changes following
b-blockade are sensed by the myocardium, and may,
therefore, have adverse long-term consequences.
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clearly required to substantiate these observations and
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