1. Nebivolol: A Novel Beta-Blocker with
Nitric Oxide-Induced Vasodilatation
Robert Weiss
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Abstract
Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic
receptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatory
effect that is unique among beta-blockers currently available to clinicians (nebivolol is
approved in Europe and is currently under review in the US). A NO-potentiating agent
such as nebivolol may have an important role in hypertensive populations with reduced
endothelial function such as diabetics, African-Americans and those with vascular
disease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-
isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol is
unique among beta-blockers in that, at doses <10 mg, it does not inhibit the increase in
heart rate normally seen with exercise. The efficacy of nebivolol has been tested
successfully in clinical trials against other agents including other beta-blockers,
angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patients
with hypertension, angina, and congestive heart failure. The tolerability of nebivolol has
been shown to be superior to that of atenolol and metoprolol. In controlled clinical trials,
nebivolol has a side effect profile that is similar to placebo, in particular as it relates to
fatigue and sexual dysfunction. This article will review published clinical data regarding
this cardioselective beta-blocker.
Keywords: nebivolol, hypertension, beta-blocker
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Introduction
Goal blood pressure (BP), defined as <140/90 mm Hg in uncomplicated hypertension, is
attained by only 34% of hypertensive patients in the US (Chobanian et al 2003), 24% of
patients in France (Chamontin et al 1998), and 13% of patients in Canada (Joffres et al
2001). These low rates of achieving goal BP indicate that a more aggressive approach to
BP management is required on a global scale. One of the most important classes of
antihypertensive agents, beta-blockers play a critical role in reducing cardiovascular risk
in hypertensive patients. A meta-analysis including almost 19 000 patients concluded that
beta-blocker therapy was associated with a 42% reduction in heart failure, a 29%
reduction in stroke risk, and a 7% reduction in coronary heart disease in hypertensive
patients (Psaty et al 1997). The specific mechanism of action of beta-blockers that

2. reduces BP is not completely understood, however, likely mechanisms include an effect
on heart rate, inhibition of the sympathetic nervous system, and inhibition of the renin-
angiotensin system. Nebivolol is a novel, highly selective beta-blocker with
nonadrenergic vasodilating properties. It has been approved for the treatment of essential
hypertension and congestive heart failure in Europe and is currently under review for the
treatment of hypertension in the US.
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Pharmacokinetics
Nebivolol is a racemic mixture of equal proportions of d- and l-isomers. The beta-blocker
activity resides in the d-isomer while the facilitation of nitric oxide (NO) release is found
in the l-enantiomer (Van Neuten and De Cree 1998; Mason et al 2005).
Nebivolol is well absorbed after oral administration. Peak plasma concentrations are
reached in 0.5–2 hours and steady-state plasma levels are reached in 24 hours (McNeely
and Goa 1999). Nebivolol has a superior trough-to-peak efficacy ratio compared with
atenolol, allowing for “true” once daily dosing (Simon and Johnson 1993). Absorption of
the drug following oral administration is not affected by food, age, gender or body weight
(McNeely and Goa 1999; Cheymol et al 1997). Nebivolol is metabolized by the liver, and
undergoes extensive first-pass metabolism to active moieties via the cytochrome
(CYP)2D6 enzymatic pathway (Gu et al 2003; Weber 2005). The mean terminal half-life
is approximately 10 hours (Cheymol et al 1997). Less than 0.1% of unchanged drug is
excreted in urine (Shaw, Liu, Zachwieja, et al 2005). Metabolism of nebivolol is subject
to a debrisoquine-type genetic polymorphism (Weber 2005). The small percentage of
patients who are deficient in CYP2D6 enzyme activity (7% of Caucasians, 2% of
African-Americans, 2% of Asians) are considered poor metabolizers of nebivolol
(Relling et al 1991; Evans et al 1993; Mizutani 2003). The absolute oral bioavailability of
nebivolol is 12% in extensive metabolizers and 96% in poor metabolizers (Van Peer
1991). However, a safety trial in both extensive and poor metabolizers has shown no
safety or efficacy differences between these patient groups (Lacourcière et al 2000).
No significant difference in efficacy or safety have been found in patients with mild or
moderate renal disease; patients with severe renal impairment may need a lower initial
dose due to impaired clearance (Shaw, Liu, Zachwieja, et al 2005). Similarly, a lower
starting dose may be needed in patients with mild or moderate hepatic impairment due to
alteration in the drug's pharmacokinetics in these patients (Shaw, Liu, Tu, et al 2005).
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Clinical perspective
Nebivolol has a hemodynamic effect suggestive of direct vasodilatation (Gao et al 1991;
Van Rooy et al 1991). Evidence in the literature indicates that the vasodilation associated

3. with nebivolol is due to its effects on the L-arginine/NO pathway in the endothelium of
various regional vascular beds (Bowman et al 1994; Cockcroft et al 1995; Dawes et al
1999; Ritter 2001; Tzemos et al 2001). Using the dorsal hand vein dilatation model,
researchers found that nebivolol had a venodilator effect on the human hand whereas
atenolol did not. Further, this effect was inhibited by L-NMMA (NG
-monomethyl L-
arginine), an inhibitor of NO synthase, indicating that the increased blood flow was due
to activation of the L-arginine/NO pathway (Bowman et al 1994). This finding was
confirmed in hypertensive patients who showed signs of vasodilatation in forearm
arteries after nebivolol infusion. The fact that this vasodilatation was inhibited by L-
NMMA supports that it is due to activation of the L-arginine/NO pathway (Cockcroft et
al 1995; Dawes et al 1999). The endothelial-dependent vasoconstrictive response seen
with L-NMMA infusion was inhibited by nebivolol and not by atenolol (Ritter 2001;
Tzemos et al 2001).
In another study, the effect of nebivolol on small artery distensibility in patients with
hypertension was compared with that of atenolol. Both drugs were equivalent in reducing
BP, but only nebivolol improved small artery distensibility, a measure of arterial
compliance or “stiffness” (Arosio et al 2002). Arterial stiffness has been shown to be an
independent predictor of mortality in patients with essential hypertension. Drugs that
reduce stiffness may therefore confer a survival advantage (Laurent et al 2001). In an
animal model comparison with atenolol, nebivolol infusion showed a statistically
significant reduction in a measure of arterial distensibility, namely pulse wave velocity,
with no change in mean arterial pressure (McEniery et al 2004). In contrast, atenolol had
no effect on pulse wave velocity despite a small drop in mean arterial pressure. This
difference suggests that the release of NO mediated by nebivolol, independent of a beta-
adrenoceptor-dependent mechanism, an effect not seen with older beta-blockers such as
atenolol, may be of particular benefit in patients with impaired arterial compliance, such
as those with isolated systolic hypertension (McEniery et al 2004).
Clinical trials also show that nebivolol has an anti-oxidative effect (de Groot et al 2004;
Pasini et al 2005). In a study of 20 hypertensive patients compared with 20 matched
healthy subjects, nebivolol reduced the oxidative inactivation of NO, a result not seen
with atenolol (Pasini et al 2005). In addition, nebivolol inhibited vascular smooth muscle
proliferation in a rat aortic smooth muscle cell model via an apparent NO-dependent
mechanism (Ignarro et al 2002). Both of these findings suggest that nebivolol may offer
anti-atherosclerotic activity, a particular benefit, if verified, in patients with arterial
disease.
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Nebivolol comparative efficacy
Clinical trials suggest that on a weight-for-weight basis, nebivolol is ten times more
potent than atenolol. In one study, the effect of doses of nebivolol (2.5 mg/day, 5.0
mg/day, and 10.0 mg/day) on exercise-induced increases in heart rate and blood pressure
in 25 male hypertensive volunteers was compared with that of atenolol 50 mg/day and

4. 100 mg/day and of placebo using a double-blind, crossover design and a parallel, placebo
group (n=7) (Simon and Johnson 1993). At 24 hours after dosing, sitting and standing
diastolic and systolic blood pressures and heart rates (at rest and during submaximal
exercise) were reduced to the same extent by nebivolol and atenolol.
However, the hemodynamic effect of nebivolol appears to be different from that of
atenolol. In a double-blind, randomized, prospective study in patients with essential
hypertension, atenolol reduced cardiac output, stroke volume, and heart rate. In contrast,
nebivolol reduced peripheral resistance and increased stroke volume, preserving cardiac
output (Kamp et al 2003). The effects of nebivolol demonstrated in this study suggest that
the drug may be important in treating heart failure, where preservation of cardiac output
is critical.
Nebivolol 5 mg/day was compared with metoprolol 100 mg twice daily (BID) in 155
patients with mild-to-moderate essential hypertension (Uhlir et al 1991). Target blood
pressure was attained in 79% of nebivolol-treated patients and 66% of those in the
metoprolol group. There were fewer adverse events reported by patients in the nebivolol
group. In a second study, nebivolol 5 mg/day was compared with metoprolol 100 mg BID
in 80 newly diagnosed hypertensive patients (Celik et al 2006). After 6 months of
treatment, the researchers found that both drugs significantly reduced BP and heart rate,
with a more profound bradycardic effect seen in the metoprolol group. In contrast, only
nebivolol significantly reduced oxidative stress, insulin resistance index, and plasma
levels of P-selectin, a cell-surface adhesion molecule believed to play a role in the
initiation of atherosclerosis (Celik et al 2006).
Nebivolol 5 mg/day was also compared with the angiotensin-converting enzyme (ACE)
inhibitor lisinopril 20 mg/day in 68 patients with uncomplicated mild-to-moderate
hypertension, treated for 12 weeks. The primary endpoints of the study were response
rate, where patients were defined as “normalized” responders if their blood pressure
values were <140/90 mm Hg at study end, or as “non-normalized” responders if the
reduction in blood pressure was ≥10 mm Hg compared with baseline; and changes in
sitting blood pressure at the end of the study. Patients were randomly assigned to one of
the study arms, however, a significant difference in sitting diastolic blood pressure (DBP)
was found between the 2 groups at baseline. Analysis of covariance of the raw data
including baseline values as covariate suggested that DBP and heart rate were
significantly lower in the nebivolol-treated group at week 8. This difference disappeared,
however, when an analysis of variance for repeated measures was performed, which
indicated a significant reduction in systolic blood pressure (SBP), DBP, and heart rate in
both groups. There was a statistically significant difference in favor of the nebivolol
group in the distribution of responders and non-responders at week 8. Lisinopril and
nebivolol were equally well tolerated (Rosei et al 2003).
Nebivolol 2.5–5 mg/day was compared with the calcium channel antagonist, amlopidine,
5–10 mg/day (Mazza et al 2002) in elderly patients (≥65 years). In this double-blind,
multicenter, randomized trial, efficacy was similar between the two groups. Both drugs
were well tolerated, however, there was a higher incidence of adverse events such as

5. headache and ankle edema in the group treated with amlodipine. In a double-blind study,
the efficacy of nebivolol 5 mg/day was compared with that of the sustained-release
calcium channel antagonist, nifedipine, 20 mg/BID in 51 patients with mild-to-moderate
hypertension over a 12 week-treatment period (Lacourcière et al 1992). The treatment
response rate was 69% for nebivolol and 59% for nifedipine. Both treatment groups
showed a significant reduction in BP, with no significant difference in BP reduction
between the groups either in clinic BP or in 24-hour ambulatory BP. Nebivolol appeared
to be superior to nifedipine in preventing the usual early morning increase in BP. Beta-
blockers have usually been found to increase plasma cholesterol (Ames 1986;
Lacourcière et al 1990). However, both agents were associated with a significant decrease
in cholesterol after 12 weeks of treatment, 5% and 3%, for nebivolol and nifedipine,
respectively.
The largest double-blind study in hypertension included 909 patients with mild-to-
moderate hypertension (Weiss et al 2005). Nebivolol in doses of 1.25–40 mg/day were
compared with placebo over 12 weeks. Placebo-subtracted reductions in trough sitting BP
(SBP/DBP) ranged from 6.6/5.1–11.7/8.3 mm Hg and were dose dependent. Reported
adverse events were: headache (7.1 vs 7.4% placebo, fatigue (3.6 vs 2.5% placebo,
nasopharyngitis (2.9% vs 7.4% placebo), diarrhea (2.8% vs 2.5% placebo) and dizziness
(2.8 vs 3.7% placebo). The incidence of typical beta-blocker adverse effects was very low
and no different from placebo including erectile dysfunction (0.2% vs 0.0% placebo),
decreased libido (0.1% vs 0.0% placebo), dyspnea (1.0% vs 0.0% placebo) and
bradycardia (0.7% vs 0.0% placebo).
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Nebivolol tolerability
In controlled clinical trials, nebivolol demonstrates a side effect profile similar to
placebo, most notably in regards to side effects commonly associated with beta-blockers,
such as fatigue and sexual dysfunction (Weber 2005). Quality of life was evaluated in a
double-blind, randomized trial of 314 patients with hypertension who were treated with
either nebivolol 5 mg/day or losartan 50 mg/day for 12 weeks (Van Bortel et al 2005).
The two agents had an equivalent effect in reducing SBP but the decrease in DBP was
slightly greater with nebivolol. Interestingly, the side effect profile of losartan, an
angiotensin receptor antagonist known for few side effects, was no different than that of
nebivolol. In a separate study, nebivolol (5 mg/day) was compared with atenolol (50
mg/day) and placebo in 364 patients in general practice (Van Nueten et al 1998). There
was no significant difference in BP or in sitting heart rate between the treatment groups,
and there was no significant difference in the incidence of side effects between the
groups, except for significantly more complaints of sexual dysfunction in the atenolol
group.
Beta-blockers have been associated in the past with a risk of sexual dysfunction, however
recent meta-analysis suggests that the risk of this adverse event is not substantial (Ko et
al 2002). A recent clinical trial studied 29 out of 44 hypertensive men who complained of

6. erectile dysfunction while taking atenolol, metoprolol or bisoprolol. The researchers
found that after switching to nebivolol therapy, 20 of the 29 noted significant
improvement in erectile function without a significant change in BP (Doumas et al 2006).
It is reasonable to speculate that this improvement in erectile function may be due to the
involvement of NO in erectile dysfunction and its potentiation with nebivolol therapy
(Doumas et al 2006).
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Nebivolol in other cardiovascular diseases
Nebivolol (5 mg/day) versus placebo has been evaluated in the treatment of angina
(Cherchi et al 1991). In a placebo-controlled trial of 16 patients, nebivolol therapy
significantly prolonged treadmill time to 1 mm ST depression from 555 ± 37sec to 667.5
± 49 sec (p<0.05). Anginal threshold was also significantly delayed from 697 ± 51 sec to
767 ± 64 sec (p<0.05). Further testing of nebivolol in a dose ranging, single-blind trial
(2.5 mg/day, 5 mg/day, and 10 mg/day) was performed in 10 patients with stable angina;
5 of the patients also had a history of myocardial infarction (Ulvenstam 1991). The doses
were titrated in 2 week intervals in this trial. The time to 1 mm ST change increased at all
3 doses of nebivolol compared with placebo.
In a double-blind, placebo-controlled study of maximal and submaximal exercise testing
conducted in patients with ischemic left ventricular dysfunction but no overt signs of
heart failure, both atenolol and propanolol reduced resting heart rate and improved left
ventricular ejection fraction compared with placebo. Only nebivolol produced a parallel,
downward shift of the pressure-volume relationship during early diastolic filling and
improved the early peak filling rate compared with placebo (Rousseau et al 1996). In
addition, compared with baseline, nebivolol therapy increased maximal exercise duration
by 44 sec, a statistically significant difference from baseline (p=0.007 vs baseline),
whereas the improvements seen with placebo and atenolol, 7 sec and 13 sec respectively,
were not statistically significant changes from baseline.
In patients with ischemic left ventricular dysfunction without clinical congestive heart
failure (Stoleru et al 1993), maximal exercise function increased more in those treated
with nebivolol 5 mg/day than in those treated with atenolol 50 mg/day (p<0.0077). This
was associated with an improved pressure-volume relationship during early diastolic
filling and improved early peak filling rate. An improvement in left ventricular ejection
fraction and cardiac output was found with nebivolol, but not with atenolol.
The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in
Seniors with Heart Failure (SENIORS) was a double-blind, randomized, multicenter
placebo-controlled trial conducted in Europe. SENIORS was the first randomized,
controlled clinical trial with the power to demonstrate efficacy specifically in elderly
patients with heart failure. The aim of the study was to assess the effect of nebivolol on
mortality and cardiovascular hospital admissions in elderly patients (≥70 years) with
heart failure, regardless of ejection fraction (Flather et al 2005). The SENIORS

7. researchers note that this age inclusion criterion makes the study population closely
resemble the actual population of heart failure patients, where the average age is 76
years; in contrast, the average age of patients enrolled in previous, large heart failure
studies was 63 years.
All 2128 patients enrolled in the SENIORS study had a history of chronic heart failure, as
evidenced by hospital admission within the past 12 months with a diagnosis of congestive
heart failure on discharge or a documented ejection fraction of 35% or less within the
previous 6 months. Following randomization, 1067 patients received nebivolol 1.25
mg/day titrated to 10 mg/day; 1061 patients received placebo. The primary outcome of
the study was a composite of all-cause mortality or cardiac hospitalization (time to first
event) during a 21 month follow up period. At baseline, the mean ejection fraction was
36%, with 35% of patients having an ejection fraction >35%. More than two thirds of
patients (68%) had a history of coronary artery disease. The primary outcome occurred in
31.1% (n=332) of nebivolol-treated patients and 35.3% (n=375) of patients receiving
placebo (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.74–0.99; p=0.039). The
all-cause mortality rate was 15.8% (n=169) in the nebivolol group and 18.1% (n=192) in
the placebo group (HR 0.88, 95% CI 0.71–1.08; p=0.21) Subgroup analysis by age less
than the median age in SENIORS (75.2 years) in patients with an ejection fraction less
than 35% allowed comparison with the results of previous trials; the HR for primary
outcome was 0.73 (95% CI, 0.56–0.96), the HR for all cause mortality alone was 0.62
(95% CI, 0.43–0.89). These results suggest that the efficacy of nebivolol in this patient
subgroup is similar to that seen in previous studies conducted with bisoprolol,
metoprolol, and carvedilol (Flather et al 2005).
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Nebivolol efficacy in black hypertensive patients
The efficacy and tolerability of nebivolol in black hypertensive patients was assessed in a
randomized, placebo-controlled, multicenter trial conducted in Europe and the US that
included 509 patients with essential hypertension (Van Neuten et al 1997). Doses of 0.5
mg/day, 1.0 mg/day, 2.5 mg/day, 5 mg/day and 10 mg/day of nebivolol were compared
with placebo. Doses of nebivolol at 2.5 mg/day, 5 mg/day, and 10 mg/day were shown to
be more effective than placebo in a dose-dependent manner. There was no significant
difference in efficacy seen between black (22% of the study population) and white
patients, with response rates of 58% and 62%, respectively (response defined as reduction
of DBP to <90 mm Hg or by ≥10 mm Hg from baseline). The drug was well tolerated.
The efficacy of nebivolol in black patients may in part be due to improved NO levels.
The importance of NO in black patients has been shown in the treatment of congestive
heart failure where a regimen of hydralazine and nitrates reduced mortality by 43% over
a standard regimen including an ACE inhibitor and a beta-blocker (Taylor et al 2004).
Nebivolol has been shown to restore NO bioavailability in blacks to the level observed in
whites, independent of beta1-selective blockade, by augmenting NO release and reducing
nitroxidative stress in the vascular endothelium (Mason et al 2005). These findings

8. suggest that nebivolol may be a more effective antihypertensive in black patients than
older beta-blockers.
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Conclusions
Beta-blockers are important agents in cardiovascular medicine, proving critically
important in the management of hypertension and heart failure and in reducing
cardiovascular risk. Nebivolol is a novel highly cardioselective beta-blocker with
antihypertensive efficacy similar to that of other beta-blockers, but with tolerability better
than older agents in its class, which may permit nebivolol to be used more widely and
effectively than other beta-blockers. Nebivolol's vasodilating effect, its anti-
atherosclerotic effect, and its positive effects on arterial compliance suggest that it may
provide more cardiovascular benefits than traditional beta-blockers, particularly in
patients with isolated systolic hypertension, diabetics, black patients, and patients with
known vascular disease.
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36. Shaw AA, Liu S, Zachwieja LF, et al. Effects of varying degrees of renal
impairment on the pharmacokinetic disposition of nebivolol. Clin Pharmacol
Ther. 2005;77:P38.
37. Shaw AA, Liu S, Tu HC, et al. Effects of hepatic impairment on the
pharmacokinetic disposition of nebivolol: A dual acting nitric oxide
modulating/cardioselective beta1-antagonist. Clin Pharmacol Ther. 2005;77:P41.
38. Simon G, Johnson ML. Comparison of antihypertensive and B1-adrenoreceptor
antagonist effect of nebivolol and atenolol in essential hypertension. Clin Exper
Hypertens. 1993;15:501–9. [PubMed]

11. 39. Stoleru L, Wijns W, van Eyll C, et al. Effects of d-nebivolol and lnebivolol on left
ventricular systolic and diastolic function: comparison with d-l-nebivolol and
atenolol. J Cardiovasc Pharmacol. 1993;22:183–90. [PubMed]
40. Taylor AL, Ziesche S, Yancy C, et al. the African-American Heart Failure Trial
Investigators Combination of isosorbide dinitrate and hydralazine in blacks with
heart failure. N Engl J Med. 2004;351:2049–57. [PubMed]
41. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction
in essential hypertension. A randomized, double-blind, crossover study.
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42. Uhlir O, Fejfusa M, Havranek K, et al. Nebivolol versus metoprolol in the
treatment of hypertension. Drug Invest. 1991;3(Suppl 1):107–10.
43. Ulvenstam G. A single-blind dose-ranging study of the effect of nebivolol in
patients with angina pectoris. Drug Invest. 1991;3(Suppl 1):199–200.
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nebivolol and losartan. Am J Hypertens. 2005;18:1060–6. [PubMed]
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nebivolol in essential hypertension. J Human Hypertens. 1997;11:139–44.
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d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases in
heart rate and systolic blood pressure. Cardiovasc Drugs Therapy. 1998;12:339–
44. [PubMed]
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essential hypertension: a double-blind randomized trial. J Human Hypertens.
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nebivolol: a review. Drug Invest. 1991;3(Suppl 1):25–30.
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relation to beta blockade in healthy volunteers. Drug Invest. 1991;3(Suppl
1):174–76.
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controlled study. Am J Hypertension. 2005;18:A96.
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--------------------------------------------------------------------------------------------------------------------------------
Differential Effects of Nebivolol and
Metoprolol on Central Aortic Pressure
and Left Ventricular Wall Thickness

12. 1. Priit Kampus,
2. Martin Serg,
3. Jaak Kals,
4. Maksim Zagura,
5. Piibe Muda,
6. Külliki Karu,
7. Mihkel Zilmer,
8. Jaan Eha
+ Author Affiliations
1. From the Department of Cardiology (P.K., M.S., M.Za., P.M., J.E.) and
Department of Biochemistry, Centre of Excellence for Translational Medicine
(P.K., M.S., J.K., M.Za., M.Zi.), University of Tartu, Tartu, Estonia; Heart Clinic
(P.K., P.M., K.K., J.E.) and Clinic of Vascular Surgery (J.K.), Tartu University
Hospital, Tartu, Estonia.
1. Correspondence to Priit Kampus, Department of Cardiology, University of Tartu, 8
Puusepa St, Tartu 51014, Estonia. E-mail Priit.Kampus@kliinikum.ee
Next Section
Abstract
The aim of this study was to investigate the effects of the vasodilating β-blocker
nebivolol and the cardioselective β-blocker metoprolol succinate on aortic blood pressure
and left ventricular wall thickness. We conducted a randomized, double-blind study on 80
hypertensive patients. The patients received either 5 mg of nebivolol or 50 to 100 mg of
metoprolol succinate daily for 1 year. Their heart rate, central and brachial blood
pressures, mean arterial pressure, augmentation index, carotid-femoral pulse wave
velocity, and left ventricular wall thickness were measured at baseline and at the end of
the study. Nebivolol and metoprolol significantly reduced heart rate, brachial blood
pressure, and mean arterial pressure to the same degree. However, reductions in central
systolic and diastolic blood pressures, central pulse pressure, and left ventricular wall
thickness were significant only in the nebivolol group. The change in left ventricular
septal wall thickness was significantly correlated with central systolic blood pressure
change (r=0.41; P=0.001) and with central pulse pressure change (r=0.32; P=0.01). No
significant changes in augmentation index or carotid-femoral pulse wave velocity were
detected in either treatment group. This proof-of-principle study provides evidence to
suggest that β-blockers with vasodilating properties may offer advantages over
conventional β-blockers in antihypertensive therapy; however, this remains to be tested in
a larger trial.
Key Words:

13. antihypertensive therapy
central blood pressure
pulse wave velocity
β-blockers
left ventricular mass
See Editorial Commentary, pp 1047–1048
Blood pressure (BP) varies throughout the arterial tree because of pulse wave
amplification, a phenomenon of wave reflection and arterial stiffness.1
Because of pulse
wave amplification, reduction in brachial BP does not reflect changes in central BP,
which may become a more important target in the treatment of hypertension. Recent data
from the Strong Heart Study2
confirm earlier results from smaller studies on high-risk
patients3,4
that central pulse pressure is superior to brachial pulse pressure in the
prediction of further cardiovascular events. Moreover, several studies have demonstrated
that brachial BP is not a good surrogate for the hemodynamic effects of drug therapies on
central circulation. The recently published EXPLOR Study5
and the Conduit Artery
Function Evaluation Study6
clearly demonstrated that angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, and calcium channel blockers have a more
pronounced effect on reducing central BP compared with the cardioselective β-blocker
(BB) atenolol. Different effects of BB on central BP can explain the findings of a recent
meta-analysis published by Law et al,7
which demonstrates a slight inferiority of BB in
preventing stroke. The detrimental effect of BB on central BP has generated criticism
regarding its use as first line therapy for essential hypertension. Dhakam et al8
questioned
the hypothesis that the inferiority of atenolol in reducing central BP is a class effect of
BB. They demonstrated that the novel vasodilating BB nebivolol (NEB) reduces central
BP significantly more than atenolol, despite their similar effects on brachial BP.
However, in the above-mentioned and other studies, the BB as the investigated
comparison drug was in most cases atenolol. No data are available about metoprolol
(MET), which is a more widely used cardioselective BB in the Northern and Eastern
European countries.
The main aim of the present study was to investigate the effect of the BB NEB and MET
succinate on central hemodynamics, arterial stiffness, and left ventricular wall thickness
in patients with essential hypertension during 1-year follow-up.
Previous SectionNext Section
Methods
Study Design
The study participants, aged 30 to 65 years, with never-treated mild-to-moderate essential
hypertension, were included in a randomized, double-blind, active controlled trial
(NCT01248338). The trial was investigator initiated and was driven and supported by

14. Berlin-Chemie AG (please see Figure S1 in the online Data Supplement at
http://hyper.ahajournals.org).
A total of 80 patients were randomly assigned into 2 treatment groups receiving either
NEB (Nebilet, dL-nebivolol hydrochloride, Berlin-Chemie AG) or MET (Betaloc zoc,
MET succinate, Astra Zeneca). The NEB-treated patients received 5 mg of the drug daily,
and the MET-treated patients started with 50 mg of the drug daily with possible up-
titration to 100 mg daily 2 weeks after randomization. If the target BP of <140/90 mm Hg
was not achieved, the investigator was free to add 12.5 to 25 mg of hydrochlorothiazide
(Hypothiazid, Chinon Pharmaceuticals and Chemical Works Private Co Ltd) daily 4
weeks after randomization. The duration of the study was 52 weeks plus the screening
period of 2 weeks. The patients attended follow-up visits at weeks 2, 4, 12, 24, 40, and
52. After 15 minutes of rest, BP was measured at each visit; pulse wave analysis and
carotid-femoral pulse wave velocity (PWV) registration were performed at baseline and
at weeks 24 and 52. Echocardiography was performed at baseline and at the end of the
study (please see Figure S2).
Mild or moderate hypertension was defined as systolic BP 140 to 179 mm Hg and/or
diastolic BP 90 to 109 mm Hg on ≥2 occasions separated by 1 month. Patients were
excluded during the screening period in case they had diabetes mellitus; adiposity;
ischemic heart disease; clinically relevant heart failure; chronic pulmonary disease; valve
disease; arrhythmias; secondary hypertension; clinically relevant atherosclerotic disease
of the lower extremities; acute or chronic inflammatory disease; hypercholesterolemia;
known hypersensitivity or allergic reaction to BB; pregnancy or breastfeeding; history of
hepatic, renal, metabolic, or endocrine diseases; heavy smoking; and excessive alcohol
consumption (please see the online Data Supplement at http://hyper.ahajournals.org).
The subjects were studied and the plasma samples were collected between 8:00 and 10:00
am after an overnight fast and abstinence from tobacco, alcohol, tea, or coffee. The study
was approved by the local research ethics committee, and written informed consent was
given by all of the subjects before the study.
Measurements of Hemodynamics
Brachial BP
Brachial BP was measured in a sitting position from the nondominant arm as a mean of 3
consecutive measurements at 5-minute intervals using a validated oscillometric technique
(OMRON M4-I; Omron Healthcare Europe BV). The mean of the 2 closest BP readings
was used in further analysis. Brachial pulse pressure was calculated as the difference
between brachial systolic BP and diastolic BP.
Central Pressure and Augmentation Index
Radial artery waveforms were recorded with a high-fidelity micromanometer
(applanation tonometry) from the wrist of the dominant arm, and pulse wave analysis was

15. performed of the systolic portion (SphygmoCor, version 7.1, AtCor Medical) of the pulse
curve in accordance with established guidelines.9
The corresponding ascending aortic
waveforms were then generated, using a validated transfer function,9,10
from which
central systolic and diastolic BPs, central pulse pressure, and augmentation index (AIx)
were calculated. The AIx, a composite measure of wave reflection and systemic arterial
stiffness, was defined as the difference between the second and the first systolic peaks of
the central arterial waveform, expressed as the percentage of central pulse pressure.9
Because AIx depends on heart rate (HR), it was corrected for a HR of 75 bpm
(AIxHR75). Mean arterial pressure was calculated from the integration of the radial
artery waveform. The degree of pulse pressure amplification was calculated as brachial
pulse pressure/central pulse pressure.
Carotid-Femoral PWV
Carotid-femoral PWV, a direct measure of aortic stiffness, was determined by sequential
acquisition of pressure waveforms from the carotid and femoral arteries using the same
tonometer (SphygmoCor, version 7.1, AtCor Medical). The timing of these waveforms
was compared with that of the R wave on a simultaneously recorded ECG. The PWV was
determined by calculation of the difference between the carotid and the femoral path
lengths divided by the difference in the R wave to waveform foot times. The difference
between the carotid and the femoral path lengths was estimated from the distance of the
sternal notch to the femoral pulse measured in a direct line.9
The pulse wave analysis and
PWV measurements were made in duplicate, and their mean values were used in
subsequent analysis.
Echocardiography
Echocardiographic examination was performed by 2 experienced sonographers, who
were blinded to patient characteristics, using a commercially available device
(Sonos7500, Philips Medical Systems, Inc) with a 3.5-MHz transducer and digital
recording capabilities. The images were stored digitally, coded with a random number,
and read by 2 blinded observers. Using the 2D and the M-mode, long-axis measurements
were obtained at the level distal to the mitral valve leaflets. Left ventricular internal
dimension and septal and posterior wall thicknesses were measured at the end of the
diastole (subscript “d”) according to the recommendations of the American Society of
Echocardiography.11
Left ventricular mass was calculated using the following formula:
0.8{1.04 [(LVIDd+PWTd+SWTd)3
−(LVIDd)3
]}+0.6 g, where LVIDd indicates left
ventricular internal dimension, PWTd indicates posterior wall thickness, and SWTd
indicates septal wall thickness. Left ventricular mass was indexed for the power of its
allometric or growth relation to height (height in meters2.7
)12
; this method was used to
adjust for differences in body size. Relative wall thickness was calculated using the
formula (2×PWTd)/LVIDd.11

16. Biochemical Analysis
White blood cell and red blood cell counts, hematocrit, hemoglobin, and platelets were
estimated with a Sysmex XE 2100 autoanalyzer (Sysmex Corporation). Plasma glucose,
total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol,
triglycerides, creatinine, and high-sensitivity C-reactive protein were determined by
standard laboratory methods, using certified assays, in a local clinical laboratory.
Statistical Analysis
The statistics were performed using the Software SAS, version 9.1 (SAS Institute Inc),
and R (www.r-project.org). All of the analyses were performed on an intention-to-treat
basis. All of the data were tested for normality. Normally distributed data are presented as
mean±SD; nonnormally distributed data are presented as the median with the
interquartile range. For categorical variables, contingency tables were composed and the
χ2
or Fisher exact test, was used to compare the distributions for the 2 randomized
groups. For continuous variables, which were not normally distributed for ≥1 group, the
Wilcoxon rank-sum test was used to test the difference between the groups. In other
cases, the t test was used to test for difference. Changes from the baseline to the end point
were also tested for the difference from 0 using the t test or the signed-rank test. The 2-
way ANOVA with repeated measures was used to test the interaction between time and
drug, as well as error (drug × time). Correlations between the variables were examined
using univariate linear regression analysis. Multivariate regression analysis was
performed using enter method to determine whether the change in baseline factors
influenced the change in hemodynamic parameters. Significance was defined as P<0.05.
Previous SectionNext Section
Results
The baseline characteristics of the untreated hypertensive subjects are presented in Table
1. Before randomization there were no statistically significant differences in the
demographic and clinical characteristics between the treatment groups. A total of 40
patients (50%) were enrolled in the NEB arm, and 40 (50%) were enrolled in the MET
arm. Of the 80 patients enrolled, 63 (79%) completed the study. Seventeen patients were
withdrawn from the study for various reasons (please see the online Data Supplement).
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Table 1.
Baseline Characteristics

17. Up-titration of MET to 100 mg was performed for 13 patients (32%). During the
treatment period, 30.0% of the patients (12 subjects) in the NEB group and 22.5% of the
patients (9 subjects) in the MET group (P=0.5) received an additional 12.5 to 25 mg of
hydrochlorothiazide.
The hemodynamic indices for each treatment group before and after 1 year of therapy are
presented in Table 2. Brachial and central systolic or diastolic BP were not different for
the groups at baseline. The AIx, AIxHR75, and central pulse pressure were significantly
higher in the NEB group at baseline.
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Table 2.
Hemodynamic Indices and Left Ventricular Wall Thickness Before and After the 1-Year
Treatment Period
Both drugs significantly reduced HR, brachial systolic and diastolic BP, and mean arterial
pressure (Table 2), without differences between the groups (Figure 1). However, only the
patients of the NEB treatment group showed significantly decreased brachial pulse
pressure (P=0.02). The reduction in central systolic BP, central diastolic BP (Figure 2),
and central pulse pressure was significant only in the NEB group. At the same time, these
parameters did not display significant changes in the MET group (Table 2). Mean
reduction in central pulse pressure was 6.2 mm Hg in the NEB group and 0.3 mm Hg in
the MET group (P=0.01). Pulse pressure amplification did not change during the
treatment period in either treatment arm.
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18. Figure 1.
Mean reduction in brachial systolic and diastolic blood pressures measured during the
study period. Both treatment groups display significantly reduced brachial systolic and
diastolic blood pressures (P<0.001) during 52 weeks of treatment, without difference
between the treatment arms. ■ indicates nebivolol; -●-, metoprolol; S, screening period;
BP, blood pressure.
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Figure 2.
Mean reduction in central systolic and diastolic blood pressures measured at baseline and
at weeks 24 and 52. Only the nebivolol group displays significantly reduced central
systolic (P<0.001) and diastolic blood pressures (P=0.01) after 52 weeks of treatment
compared with baseline values. ■ indicates nebivolol; -●-, metoprolol; BP, blood
pressure.
The AIxHR75 (22.88±11.89% to 18.60±11.25%; P=0.02) and PWV (7.5±1.51 to
6.80±1.17 m/s; P=0.03) were significantly decreased after 6 months of treatment only in
the NEB group. However, no significant change was detected in AIx, AIxHR75, or PWV
after the 1-year treatment period for either treatment group (Table 2). There was a trend
for correlation (not significant) between the HR change and the AIx change for the whole
study group (r=−0.24; P=0.06). However, the correlation was significant only for the
NEB treatment arm (r=−0.40; P=0.03).
There occurred significant reduction in left ventricular posterior wall thickness and left
ventricular relative wall thickness, as well as a trend for reduction in left ventricular
septal wall thickness and indexed left ventricular mass compared with the baseline values
only for the NEB group (Table 2). Moreover, changes in septal wall thickness were more
significantly correlated with changes in central systolic BP (r=0.41; P=0.001) and with

19. changes in central pulse pressure (r=0.32; P=0.01; Figure 3) compared with changes in
brachial BP values (r=0.32, P=0.01 and r=0.26, P=0.04, respectively). Multiple
regression analysis showed that only changes in central systolic BP (P=0.009) were
independently correlated with changes in septal wall thickness as the dependent variable
but not with medication used, body mass index, changes in mean arterial pressure, or
changes in heart rate (R2
for model=0.2; P<0.01). Finally, no correlation was revealed
between changes in brachial systolic BP and changes in septal wall thickness after
adjustment for changes in mean arterial pressure in multiple regression analysis.
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Figure 3.
A, Correlation between central systolic blood pressure change and IVS thickness change
(r=0.41; P=0.001) for the whole study group. B, Correlation between central pulse
pressure change and IVS thickness change (r=0.32; P=0.01) for the whole study group.
IVS indicates interventricular septal thickness; BP, blood pressure.
Previous SectionNext Section
Discussion
The aim of the present study was to investigate the effects of NEB and MET on central
hemodynamics in patients with essential hypertension during a 1-year treatment period.
The main findings were that both drugs reduced similarly brachial systolic and diastolic
BP; however, only the patients receiving NEB showed a significant reduction in central
BP. The decrease in central BP was correlated with degree of reduction in left ventricular
wall thickness. At the same time, neither drug had an effect on AIx, AIxHR75, or PWV
after the 1-year treatment period.

20. BB and Reduction in Central Aortic Pressure
The results of the present study generally indicate that the novel third generation BB
NEB significantly reduces central BP. However, it is the first attempt to explore the
effects of the cardioselective BB MET on central BP. The results of the study confirm
that BB without vasodilating properties have less impact on central BP. Two short-term
studies (4 to 5 weeks) reported that NEB had a significantly greater effect on central
pulse pressure compared with the cardioselective BB atenolol.8,13
Dhakam et al8
in their
study demonstrated that overall aortic pulse pressure was 4 mm Hg lower after NEB
therapy than after atenolol therapy.8
Moreover, the results from the Conduit Artery
Function Evaluation Study6
indicate that even a 3-mm Hg reduction in central pulse
pressure was associated with better cardiovascular outcome. In the present study, the
effect of BB was tested during a 1-year period. Overall central pulse pressure reduction
was 6.2 mm Hg in the NEB group and only 0.3 mm Hg in the MET group. The recently
published EXPLOR Study5
demonstrated that treatment with the calcium channel blocker
amlodipine combined with the cardioselective BB atenolol during 24 weeks had less
impact on central BP than amlodipine combined with valsartan (the difference in
reducing central systolic BP was also 4 mm Hg). The authors concluded that the addition
of amlodipine to atenolol did not abolish the adverse effect of cardioselective BB on
central BP through bradycardia and changes at reflection sites. In the present study both
treatment arms similarly reduced HR and mean arterial pressure. It could be suggested
that the main mechanism for the reduction in central BP in the nebivolol arm acted
through vasodilation and structural remodeling of the small arteries, leading to the
reduction in reflection site intensity. It has been demonstrated that nebivolol vasodilates
the human forearm vasculature through the l-arginine pathway,14
improves small artery
distensibility index, and increases endothelium-dependent cutaneous vasodilation.15
At
the same time, cardioselective BB do not reduce total peripheral resistance or
sympathetic activity,16
which may lead to small artery vasoconstriction and increased
media:lumen ratio.17
The AIx and pulse pressure amplification are related to wave reflection depending on the
amplitude and site of wave reflection and on the speed at which pressure waves travel
along the arterial tree. In the present study, AIx and pulse pressure amplification did not
change during the 1-year treatment period in either treatment arm. Previous data about
the effect of NEB on AIx and pulse pressure amplification have been conflicting. In
patients with isolated systolic hypertension, Dhakam et al8
showed a slight increase of
AIx and no effect on pulse pressure amplification after 5 weeks of treatment with NEB.
On the contrary, Mahmud and Feely13
demonstrated, after treatment with NEB, a
significant reduction in AIx and an increase in pulse pressure amplification in patients
with essential hypertension. In the above studies, pulse pressure amplification and AIx
were found to be very strongly correlated with HR change, which could explain the
described controversial results. The present study also revealed a trend for correlation,
although not significant, between HR change and AIx change for the whole study group.
Moreover, the correlation was significant only for the NEB treatment arm. No correlation
was detected between central pulse pressure change and HR change, which may suggest
that more intensive central BP reduction in the NEB-treated patients appeared to be a

21. concomitant effect of HR and AIx change and reduction in peripheral vascular resistance
rather than PWV change. It should be noted that there was already a difference in
baseline AIx and that the reduction in HR was not sufficient to produce significant AIx
change after 1-year therapy.
The PWV is considered a gold standard measure of arterial stiffness,9
which
independently predicts outcome in hypertensive patients.18
In the present study, there
occurred a significant reduction in PWV after 6 months of treatment in the NEB group.
However, after the 1-year treatment period there was no significant difference in the
change in PWV, radial-carotid PWV (data not shown), or pulse wave transit time
between the 2 treatment arms. Previous studies have demonstrated a significant reduction
in PWV after treatment with NEB.8,13
It has been suggested that the effect of BB on PWV
may be related to the concomitant effect of reduction in mean arterial pressure,
sympathetic tone, and HR. Consequently, one possible explanation for the nonsignificant
change in PWV in the present study is also the significantly smaller reduction in HR
during the 1-year treatment period (≈6 bpm). It should be noted that previous studies
were of short duration, and long-term use of BB may not have such a significant effect on
HR and sympathetic activity, which are considered important determinants of PWV. The
time-dependent effect of BB on vascular stiffness was also suggested in a recent review
by Protogerou et al.19
Another possibility is that, in the present study, baseline mean
PWV was in the normal range. Also, because of the very strict inclusion criteria of the
present study, the patients were at low total cardiovascular risk, which may also explain
the weak effect of treatment on PWV.
BB and Left Ventricular Mass Reduction
The present study provides the first long-term evidence that the reduction in central
systolic BP in the NEB group was directly related to the reduction in left ventricular
septal and posterior wall thicknesses. It has been demonstrated previously that, compared
with brachial BP, central BP is a stronger determinant for left ventricular hypertrophy.20
Recent data from the Strong Heart Study also indicate that, in terms of reduction in left
ventricular hypertrophy, it is more important to target central systolic than brachial BP.21
Moreover, a recent study has shown that the BB atenolol was less effective than losartan
to reduce left ventricular hypertrophy,22
despite the fact that both drugs reduced brachial
BP to a similar degree. In a small open study, NEB monotherapy ≤12 months resulted in
a reduction in left ventricular wall thickness,23
and NEB was as effective as telmisartan in
reducing left ventricular mass after 3 months of treatment.24
However, a recent meta-
analysis provides evidence that BBs show less regression of left ventricular mass
compared with other antihypertensive drugs.25
Regrettably, the results of 20 of the
reviewed 31 studies were obtained with atenolol, the results of 3 studies with MET, and
the results of only 1 study with NEB. One plausible explanation for the lesser regression
of left ventricular hypertrophy by BB in the above meta-analysis is that central BP may
not be reduced as effectively as brachial BP, which ensures less afterload reduction with
a cardioselective BB without vasodilating properties. Moreover, the failure to reduce
central BP with conventional BB was probably also the main reason for the inferiority of
BB in preventing stroke in a recent meta-analysis by Law et al.7
Regarding the

22. diabetogenic role of BB and diuretics,26
there was no change in fasting plasma glucose
after the 1-year treatment period in either group, because we excluded patients
predisposed to diabetes mellitus (eg, those with metabolic syndrome or with increased
fasting glucose level).
Limitations
The current study has several limitations. The number of patients recruited in the study
was small. When this study was designed in 2005, there were no studies of appropriate
size providing the data about the effect of antihypertensive drugs on aortic pressure
derived from applanation tonometry to undertake formal power calculation; larger studies
are therefore needed to confirm our results. Also, 17 of the 80 study patients were
withdrawn, which is quite a high proportion. The main reason for poor treatment
compliance was that the study patients were relatively young, with newly diagnosed
mild-to-moderate hypertension, who did not have any symptoms or complaints attributed
to high BP. In the case of mild adverse events after the initiation of treatment, they tended
to withdraw their consent.
Also, the inclusion criteria of the study were very strict, and the patients were at low
cardiovascular risk, which may explain the relatively normal mean values of central
hemodynamics and account for the disparity between several studied parameters and
those used in other studies. Although both study groups were comparable with regard to
brachial pressure, there occurred a shift in central hemodynamics (AIx and central PP) at
baseline.
We cannot exclude an additional effect of the thiazide diuretic on the results. It has been
proposed that diuretics have a neutral or minimal beneficial effect on central BP, aortic
stiffness, and pressure wave reflection.19,27
Perspectives
Our study expands earlier observations of BB and shows that, despite the similar effect of
both drugs on brachial BP and arterial stiffness, NEB has a more significant impact on
central BP and left ventricular wall thickness than MET. This proof-of-principle study
provides evidence to suggest that BB with vasodilating properties may offer advantages
over conventional BB in reduction of target organ damage in antihypertensive therapy;
however, this remains to be tested in a larger trial. Moreover, noninvasive assessment of
central BP change might become a good surrogate for estimating reduction in left
ventricular wall thickness in the future.
Previous SectionNext Section
Sources of Funding

23. This study is an independent, investigator-initiated trial supported by the Berlin-Chemie
AG Menarini Group, by the Estonian Scientific Foundation (grants 7480 and 8273), and
by target financing grants 0180105s08 and SF0180001s07.
Previous SectionNext Section
Disclosures
None.
Previous SectionNext Section
Acknowledgments
We acknowledge the invaluable support of the physicians who conducted the clinical trial
(Drs Kristina Lotamõis and Ingmar Lindström), the study nurse (Eva-Brit Mölder), and
the statistician (Mart Kals) for their important contributions. Also, we thank all of the
patients who participated in the study.
Previous SectionNext Section
Footnotes
Continuing medical education (CME) credit is available for this article. Go to
http://cme.ahajournals.org to take the quiz.
Received April 30, 2010.
Revision received May 22, 2010.
Accepted April 7, 2011.
© 2011 American Heart Association, Inc.
Previous Section
References
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1. NicholsWW,
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Comparison of the Effects of Nebivolol
and Bisoprolol on Systemic Vascular
Resistance in Patients with Essential
Hypertension: -Blockade and
Haemodynamics in Hypertension

33. Authors: Brett S.1
; Forte P.2
; Chowienczyk P.1
; Benjamin N.2
; Ritter J.1
Source:Clinical Drug Investigation, Volume 22, Number 6, 1 June 2002 , pp. 355-359(5)
Publisher: Adis International
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Abstract:
Objective: To compare the haemodynamic effects of nebivolol, a highly selective antagonist of
-adrenergic receptors with additional actions caused via the L-arginine/nitric oxide pathway,
with those of bisoprolol, another selective -adrenergic receptor antagonist.
Patients and methods: The study had a double-blind, randomised, crossover design, and was
performed in an outpatient setting. Study participants comprised 15 patients (11 men, four
women, aged 29 to 69 years) with uncomplicated mild essential hypertension. Patients were
randomised to receive nebivolol (5mg orally daily) or bisoprolol (10mg orally daily) for 2 weeks,
followed by a 2-week washout and 2 weeks of the other treatment. Measurements (by mercury
sphygmomanometer and bioimpedance) were made at the end of each baseline and each active
treatment period.
Results: Mean heart rate fell during active treatment (from 65 ± 2 to 53 ± 3 beats/min during
bisoprolol, p < 0.05, and from 64 ± 3 to 59 ± 3 beats/min during nebivolol). Systolic/diastolic
blood pressure fell during active treatments to a similar extent with each treatment (bisoprolol:
143 ± 3/90 ± 2mm Hg to 127 ± 3/80 ± 2mm Hg; nebivolol: 144 ± 4/92 ± 2mm Hg to 131 ± 4/83 ±

34. 3mm Hg; each p < 0.01). In contrast, the systemic vascular resistance index fell during nebivolol
(from 2854 ± 201 to 2646 ± 186 dyn•sec•cm5•m, p < 0.05), but did not change significantly
during bisoprolol treatment (baseline 2848 ± 177, with treatment 2787 ± 159 dyn•sec•cm5•m).
Conclusion: The fall in systemic vascular resistance index during nebivolol (but not bisoprolol)
treatment can be explained on the basis of a systemic vasodilator action of nebivolol. The
clinical importance of this action requires further investigation.
Keywords:Antihypertensives, pharmacodynamics; Bisoprolol, pharmacodynamics;
Nebivolol, pharmacodynamics
Document Type: Original article
Affiliations:1: Department of Clinical Pharmacology, Centre for Cardiovascular Biology
and Medicine,St Thomas's Hospital, London, UK 2: Department of Clinical
Pharmacology, St Bartholomew's Hospital, London, UK
Publication date: 2002-06-01
Comparison of the new cardioselective
beta-blocker nebivolol with bisoprolol in
hypertension: the Nebivolol, Bisoprolol
Multicenter Study (NEBIS).
Czuriga I, Riecansky I, Bodnar J, Fulop T, Kruzsicz V, Kristof E, Edes I; NEBIS Investigators; NEBIS
Investigators Group.
Source
Department of Cardiology, University of Debrecen, Hungary.
Abstract
OBJECTIVES:
The aim of the present study was to evaluate the antihypertensive efficacy of the highly
beta(1)-selective adrenergic antagonist nebivolol in comparison with bisoprolol in the
treatment of mild to moderate essential hypertension.

35. METHODS:
This multicenter, single-blind, randomized, parallel-group 16-week study involved a 4-
week placebo run-in, followed by a 12-week treatment period (5 mg nebivolol or 5 mg
bisoprolol). Patients (n = 273) eligible for the study had a sitting diastolic blood pressure
(DBP) between 95 and 110 mm Hg and a systolic blood pressure (SBP) </=180 mm Hg
at the end of the placebo run-in period. The primary endpoint of the study was the
percentage of responders achieving DBP normalization (</=90 mm Hg) or a DBP
reduction of at least 10 mm Hg.
RESULTS:
The baseline SBP and DBP were similar in the two groups. Both SBP and DBP decreased
gradually and significantly upon treatment. The two treatments had similar effects on the
mean change from the baseline for both DBP (nebivolol -15.7 +/- 6.4 mm Hg vs.
bisoprolol -16.0 +/- 6.8 mm Hg) and SBP. A high proportion of responders was noted in
both groups (nebivolol 92.0% vs. bisoprolol 89.6%) and there was no significant
difference between the treatments. The overall number and incidence of spontaneously
reported adverse events were slightly, but not significantly lower for nebivolol (8 events;
5.8%) than for bisoprolol (12 events; 8.9%).
CONCLUSIONS:
The findings of the present trial indicate that 5 mg nebivolol once daily is an effective
antihypertensive agent. It can therefore be recommended as a useful alternative first-line
treatment option for the management of patients with mild to moderate essential
hypertension.
PMID:
14574084
[PubMed - indexed for MEDLINE]
Nebivolol Versus Metoprolol:
Comparative Effects on Fatigue and
Quality of Life
This study has been completed.
Sponsor:
Weill Medical College of Cornell University
Collaborator:
Forest Laboratories

36. Information provided by:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT00999102
First received: October 20, 2009
Last updated: March 16, 2012
Last verified: March 2012
History of Changes
Full Text View
Tabular View
No Study Results Posted
Disclaimer
How to Read a Study Record
Purpose
Beta-blockers are prescribed to millions of people for treatment of hypertension. Fatigue
is a recognized and common side effect of beta-blockers that can have significant effects
on quality of life. Worse, many people taking a beta-blocker for years are not even aware
of the reduction of energy with which they are living.
A new vasodilating beta-blocker, nebivolol, which is approved by the FDA for treatment
of hypertension, appears to be far less associated with fatigue than are most currently
available beta-blockers. The purpose of this study is to compare nebivolol with the
current best-selling beta-blocker, metoprolol, and determine whether there is a significant
difference in side effects including fatigue, reduced exertion tolerance, and reduced
quality of life.
In this study, 30 subjects will take each of the 2 study drugs for 8 weeks, consisting of 4
weeks at a lower dose, and 4 weeks ata higher dose. All dosages are FDA-approved for
treatment of hypertension. Subjects and investigators will not know which drug is being
administered until completion of the study. Subjects will undergo a treadmill stress test
and will complete fatigue and quality of life questionnaires after each 4 weeks of
treatment. An echocardiogram and non-invasive measurement of aortic blood pressure
will be performed after 8 weeks on each drug. Also, blood will be drawn and stored for
possible measurement of drug levels, after 4 and 8 weeks on each drug. Results on each
drug will then be compared. If nebivolol is found to cause significantly less fatigue, it
would be of substantial importance to the many millions of people who are on life-long
beta-blocker therapy, and are living with reduced energy.
Condition Intervention Phase
Hypertension Drug: Metoprolol
Drug: Nebivolol
Phase 4

37. Study Type: Interventional
Study
Design:
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Asse
ssor)
Primary Purpose: Supportive Care
Official
Title:
Nebivolol Vs. Metoprolol: Comparative Effects on Fatigue and Quality
of Life
Resource links provided by NLM:
MedlinePlus related topics: Blood Pressure MedicinesFatigueHigh Blood Pressure
Drug Information available for:
Succinic acidMetoprololMetoprolol tartrateMetoprolol succinateNebivololMetoprolol fu
marateNebivolol Hydrochloride
U.S. FDA Resources
Further study details as provided by Weill Medical College of Cornell University:
Primary Outcome Measures:
To determine whether fatigue scores differ during treatment with nebivolol versus
metoprolol succinate [ Time Frame: Baseline, 4 weeks, 8 weeks, 12 weeks, 16
weeks ] [ Designated as safety issue: No ]
To determine whether treadmill exercise time differs during treatment with
nebivolol versus metoprolol succinate [ Time Frame: Baseline, 4 weeks, 8 weeks,
12 weeks, 16 weeks ] [ Designated as safety issue: No ]
Enrollment: 37
Study Start Date: October 2009
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary
outcome measure)
Arms Assigned Interventions

38. Active Comparator: Nebivolol then
Metoprolol
Nebivolol will be given at a dose of 5 mg
and 10mg daily. After 8 weeks,
participants will then be given metoprolol
succinate will be given at a dose of 50 mg
daily for 4 weeks, then 100 mg daily for 4
weeks.Identical-appearing pills will be
given, and the drugs will be given in
randomized order without a placebo run-
in. At the end of each 4-week treatment
period on each drug, subjects will undergo
a treadmill stress test (using the standard
Cornell protocol), complete Quality of
Life and fatigue questionnaires, and have
blood drawn and frozen for later analysis
for drug levels.
At the end of 8 weeks of treatment on each
drug, subjects will undergo
echocardiography and applanation
tonometry (non-invasive measurement of
aortic blood pressure) to assess heart
function.
Drug: Metoprolol
Comparison of Metoprolol and Nebivolol.
Metoprolol succinate will be given at a dose
of 50 mg daily for 4 weeks, then 100 mg
daily for 4 weeks. For nebivolol, dosage will
be 5 mg and 10mg daily. Identical-appearing
pills will be given, and the drugs will be
given in randomized order without a placebo
run-in.
Other Names:
Lopressor
Toprol-XL
Drug: Nebivolol
Comparison of Metoprolol and Nebivolol.
Metoprolol succinate will be given at a dose
of 50 mg daily for 4 weeks, then 100 mg
daily for 4 weeks. For nebivolol, dosage will
be 5 mg and 10mg daily. Identical-appearing
pills will be given, and the drugs will be
given in randomized order without a placebo
run-in.
Other Name: Bystolic
Active Comparator: Metoprolol then
Nebivolol
Metoprolol succinate will be given at a
dose of 50 mg daily for 4 weeks, then 100
mg daily for 4 weeks. After 8 weeks, the
participants will take nebivolol, dosage
will be 5 mg and 10mg daily. Identical-
appearing pills will be given, and the
drugs will be given in randomized order
without a placebo run-in. At the end of
each 4-week treatment period on each
drug, subjects will undergo a treadmill
stress test (using the standard Cornell
protocol), complete Quality of Life and
fatigue questionnaires, and have blood
drawn and frozen for later analysis for
drug levels.
At the end of 8 weeks of treatment on each
drug, subjects will undergo
echocardiography and applanation
tonometry (non-invasive measurement of
Drug: Metoprolol
Comparison of Metoprolol and Nebivolol.
Metoprolol succinate will be given at a dose
of 50 mg daily for 4 weeks, then 100 mg
daily for 4 weeks. For nebivolol, dosage will
be 5 mg and 10mg daily. Identical-appearing
pills will be given, and the drugs will be
given in randomized order without a placebo
run-in.
Other Names:
Lopressor
Toprol-XL
Drug: Nebivolol
Comparison of Metoprolol and Nebivolol.
Metoprolol succinate will be given at a dose
of 50 mg daily for 4 weeks, then 100 mg
daily for 4 weeks. For nebivolol, dosage will
be 5 mg and 10mg daily. Identical-appearing
pills will be given, and the drugs will be

39. aortic blood pressure) to assess heart
function.
given in randomized order without a placebo
run-in.
Other Name: Bystolic
Detailed Description:
Hypothesis: the beta-blocker nebivolol is associated with less fatigue than
metoprolol, the most widely-prescribed beta-blocker
Methods: a double-blinded crossover trial comparing nebivolol with metoprolol.
Experimental procedures: Subjects will undergo electrocardiogram and routine
blood testing, unless such tests have been performed within 6 months and are
available for review. Subjects entered into the study will receive each of the 2
study drug for 8 weeks. Metoprolol succinate will be given at a dose of 50 mg
daily for 4 weeks, then 100 mg daily for 4 weeks. For nebivolol, dosage will be 5
mg and 10mg daily. Identical-appearing pills will be given, and the drugs will be
given in randomized order without a placebo run-in.
At the end of each 4-week treatment period on each drug, subjects will undergo a
treadmill stress test (using the standard Cornell protocol), complete Quality of Life and
fatigue questionnaires, and have blood drawn and frozen for later analysis for drug levels.
At the end of 8 weeks of treatment on each drug, subjects will undergo echocardiography
and applanation tonometry (non-invasive measurement of aortic blood pressure) to assess
heart function.
At the end of the study, the blinded subjects will be asked which of the 2 study drugs they
prefer, and the extent to which their energy differed between the 2 drugs.
-Rationale: Millions of hypertensive patients are on life-long beta-blocker therapy. In
many, it reduces cardiac output and increases peripheral resistance to blood flow (1). It is
well-established that beta-blockers cause fatigue in many patients and reduce exertion
tolerance. Every physician knows this, and tacitly accepts that many patients are living
with this unwelcome side effect.
A new beta-blocker, nebivolol, has the standard beta-blocking effects, but also produces
blood vessel relaxation (vasodilation), probably through increased secretion of the
vasodilator nitric oxide. Studies indicate that nebivolol, unlike most beta-blockers, does
not cause constriction of peripheral blood vessels, and is associated with improved heart
function (2). Studies suggest that it is also less likely to cause fatigue (3).
Personal experience is consistent with this, as I have observed marked improvement in
energy in patients in whom I have prescribed nebivolol in place of a different beta-
blocker. The possibility of placebo effect of course cannot be excluded. Nevertheless, the
known hemodynamic differences between nebivolol and other beta-blockers, and the
positive clinical experience, warrant formal study to determine whether nebivolol is
kinder than other beta-blockers in terms of the important side effect of fatigue.
Eligibility

40. Ages Eligible for Study: 21 Years to 80 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Individuals who are taking, or are about to begin taking, a beta-blocker, and who
have the approved indication of hypertension
Exclusion Criteria:
Orthopedic ailments that would interfere with performance of treadmill testing
Stroke or heart attack within the previous 1 year
Symptomatic coronary disease within the past year (angina, shortness of breath)
Clinically significant pulmonary disease (e.g. emphysema or asthma).
Poorly controlled hypertension (blood pressure above 160 systolic or 100
diastolic)
Patients with contra-indications to taking a beta-blocker (asthma or
bradyarrhythmia)
History of tachyarrhythmia (abnormal rapid heart rate)
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00999102
Locations
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10065
Sponsors and Collaborators
Weill Medical College of Cornell University
Forest Laboratories
Investigators
Principal
Investigator:
Samuel J Mann,
MD
Weill Medical College of Cornell
University
More Information
No publications provided
Responsible Party: Samuel Mann, MD, Weill Cornell Medical College
ClinicalTrials.gov Identifier: NCT00999102 History of Changes

41. Other Study ID Numbers: 0901010162
Study First Received: October 20, 2009
Last Updated: March 16, 2012
Health Authority: United States: Institutional Review Board
Keywords provided by Weill Medical College of Cornell University:
hypertension
beta blockers
Metoprolol
blood pressure, high
antihypertensive agents
vascular resistance
adrenergic beta-receptor blockaders
beta-Adrenergic blockers
beta-Adrenergic Blocking Agents
beta-Adrenergic Receptor Blockaders
beta-Blockers, Adrenergic
Bystolic
Nebivolol
Nebivololum
Nebivololum [Latin]
R65,824
Beloc- Zok
H 93/26 succinate
Metoprolol succinate
Seloken ZOC
Selozok
Spesicor Dos
Toprol XL
Toprol-XL
UNII-TH25PD4CCB
Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Adrenergic beta-Antagonists
Metoprolol
Metoprolol succinate
Nebivolol
Antihypertensive Agents
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of
Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Cardiovascular Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists
Vasodilator Agents
ClinicalTrials.gov processed this record on May 12, 2013
Nebivolol (Bystolic), a Novel Beta Blocker
for Hypertension
Olga Hilas, PharmD, BCPS, CGP and Danielle Ezzo, PharmD, BCPS, CGP
Author information ►Copyright and License information ►

42. Go to:
INTRODUCTION
Hypertension is an asymptomatic condition of persistently elevated blood pressure (BP)
that affects approximately 50 million Americans and one billion people worldwide.
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It has been associated with other diseases and events such as myocardial
infarction (MI), heart failure, stroke, and kidney disease.
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Although hypertension the most common primary care diagnosis in the
U.S., most patients are undertreated (fewer than 60% of patients receive any treatment),
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and only about 31% have BP that is adequately controlled.
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The management of hypertension involves lifestyle modifications, pharmacological
treatment, or both. Weight reduction for overweight or obese patients, adherence to the
Dietary Approaches to Stop Hypertension (DASH) diet, moderate consumption of
alcohol, and physical activity are all essential to decreasing BP and enhancing the
efficacy of pharmacotherapeutic regimens.
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43. Destroy user interface control1
Pharmacological treatment includes management with one or more agents belonging to
the following drug classes: thiazide diuretics, beta blockers, calcium-channel blockers,
angiotensin-converting enzyme (ACE)–inhibitors, and angiotensin receptor blockers
(ARBs). These medications can reduce BP as well as the complications of hypertension.
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Although thiazide diuretics are recommended as the first-line therapy for most patients
with hypertension, beta blockers have a compelling indication for use in patients with
high-risk conditions such as heart failure, MI, coronary disease, and diabetes.
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Beta blockers exert antihypertensive effects by reducing myocardial
contractility, heart rate, and cardiac output.
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Central inhibition of sympathetic nervous system outflow, inhibition of the
renin–angiotensin system by reducing renin release from the juxtaglomerular apparatus, and
resetting or altered sensitivity of baroreceptors may also contribute to the BP-lowering effects
of this drug class.
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Beta blockers differ in many of their pharmacological properties, including beta1- and
beta2-adrenergic receptor selectivity and vasodilatory capabilities. Currently, all available
beta blockers can be categorized into one of four principal groups based on their receptor
affinity and hemodynamic properties:
noncardioselective, nonvasodilatory
cardioselective, nonvasodilatory
noncardioselective, vasodilatory
cardioselective, vasodilatory
A fifth category includes nonselective beta blockade with intrinsic sympatho-mimetic
activity; however, this group of agents is not favored for use because of data
demonstrating their potential to increase peripheral vascular resistance and to attenuate
decreases in heart rate and cardiac output that may negate any benefits in cardiovascular
disease.
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Nebivolol (Bystolic, Forest Laboratories), a third-generation beta blocker, is approved by
the FDA for the treatment of hypertension.
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The medication’s unique chemical structure is composed of a racemic
mixture of d-nebivolol and l-nebivolol (Figure (Figure11).
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Nebivolol exerts nitric oxide (NO)–mediated vasodilation in addition to
conventional beta-blocking effects.
Figure 1
Chemical structure of nebivolol.

45. Go to:
PHARMACOLOGY AND MECHANISM OF ACTION
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Beta blockers are typically categorized as selective or nonselective to beta receptors.
Nebivolol may be considered both, depending on the drug’s concentration in the body. At
low concentrations, typically achieved in extensive metabolizers (the majority of the
population), and at doses of 10 mg and below, nebivolol is beta1-selective. However, at
higher concentrations, in poor metabolizers and at higher doses, nebivolol loses its
selectivity and blocks both beta1 and beta2 receptors.
Nebivolol also possesses novel vasoactive factors. It provides vasodilation by releasing
endothelial nitric oxide. The vasodilation properties result in an overall positive
hemodynamic side-effect profile, including cold extremities and a reduction in exercise
intolerance.
Go to:
PHARMACOKINETICS AND
PHARMACODYNAMICS
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The pharmacokinetic features of nebivolol vary according to the phenotype of the
metabolizer. After a 15-mg dose, peak plasma concentrations were reached at 0.5 to 2
hours in extensive metabolizers and in 3 to 6 hours in poor metabolizers. Absorption of
nebivolol is very similar to that of an oral solution. The presence or absence of food does
not alter the drug’s kinetic profile; therefore, nebivolol may be taken without regard to
meals.
Nebivolol is highly protein-bound, mostly to albumin at 98%, independent of its
concentrations. The half-life of nebivolol varies as well: 10.3 hours in extensive
metabolizers and 31.9 hours in poor metabolizers.
Nebivolol undergoes extensive first-pass metabolism through the cytochrome P450 2D6
enzyme system. There is a great difference in bioavailability (12% for extensive
metabolizers and 96% for poor metabolizers). However, the lower concentration of
unchanged drug in extensive metabolizers is balanced by the formation of active
hydroxyl metabolites, yielding insignificant clinical differences in therapeutic endpoints.
Metabolism pathways differ according to the phenotype. The predominant metabolic
pathway in extensive metabolizers is aromatic hydroxylation, whereby glucuronidation
and alicyclic hydroxylation are secondary; N-dealkylation is less important. The
predominant metabolic pathway in poor metabolizers is glucuronidation and alicyclic
hydroxylation; both N-dealkylation and aromatic hydroxylation are less important.
Nebivolol is excreted mostly as metabolites (38% urine and 44% feces in extensive
metabolizers vs. 67% urine and 13% feces in poor metabolizers).
Go to:
CLINICAL EFFICACY
The FDA’s approval of nebivolol was based on its antihypertensive effectiveness in the
two pivotal randomized, double-blind, multicenter, placebo-controlled trials conducted in
the U.S. Both studies concluded that nebivolol was safe, well tolerated, and effective for
patients with mild-to-moderate hypertension.

47. Weiss et al.
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A total of 909 patients with a diastolic BP of between 95 and 109 mm Hg received
nebivolol 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, or placebo once daily for up to
84 days in 70 sites in the U.S. All participants entered a four-week, single-blind, placebo
run-in/washout phase following screening and before randomization. The patients were
instructed to return to their treatment sites on days 14, 28, 56, and 84. BP and heart rate
were monitored, and compliance and the use of concomitant medications were assessed.
Concomitant agents that exerted antihypertensive effects were prohibited at all times
during the study.
Eight-five percent (777 patients) completed the study. After 84 days of treatment, all
nebivolol groups had significantly higher percentages of patients who responded to
therapy (i.e., a diastolic BP of 90 mm Hg or below or a reduction of 10 mm Hg or more
from baseline) compared with the placebo group. Significant decreases in peak diastolic
and systolic BP were also observed in a dose-dependent manner (least-squares [LS] mean
reductions from baseline of 9.1 to 13.9 mm Hg and 7.6 to 14 mm Hg compared with
placebo, respectively).
The nebivolol groups, with doses ranging from 1.25 to 20 mg once daily, also had
significantly greater LS mean reductions in trough diastolic and systolic BP, compared
with placebo patients, from baseline to day 84. Placebo-subtracted LS mean reductions in
trough diastolic and systolic BP ranged from 5.1 to 8.3 mm Hg and 6.6 to 11.7 mm Hg,
respectively. Little difference was noted in diastolic BP with 2.5 to 20 mg, compared
with placebo. No significant differences were observed in the incidence of adverse drug
events between treated and placebo groups.
Saunders et al.
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The Saunders study aimed to assess the antihypertensive efficacy of nebivolol at doses of
2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg once daily in 300 African-American patients with
a diastolic BP of between 95 and 109 mm Hg for 12 weeks in 38 sites in the U.S. As a
result of evidence suggesting a poor response to monotherapy with beta-blockers in
African-Americans, the investigators selected this population in order to investigate their
response to a selective vasodilatory beta blocker.