ARTIKEL 1 Hypertension

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Research Article

Long-term safety of nebivolol and valsartancombination therapy in patients with hypertension:

an open-label, single-arm, multicenter study

Joel M. Neutel, MDa,*, Thomas D. Giles, MDb, Henry Punzi, MDc,d, Robert J. Weiss, MDe,Huiling Li, PhDf , and Amy Finck g

aOrange County Research Center, Tustin, CA, USA;b Department of Medicine, Tulane University, New Orleans, LA, USA;

cTrinity Hypertension and Metabolic Research Institute, Carrollton, TX, USA;d UT Southwestern Medical Center, Carrollton, TX, USA;

e Maine Research Associates, Auburn, ME, USA; f Department of Biostatistics, Forest Research Institute, Jersey City, NJ, USA; and

gTrial Operations, Forest Research Institute, Jersey City, NJ, USA

Manuscript received August 28, 2014 and accepted September 16, 2014

Abstract

Long–term safety of a free–tablet combination of nebivolol and valsartan was assessed in a Phase III, open–label trial

(NCT01415505). Adults with hypertension entered a 4–week placebo run–in phase, followed by a 52–week treatment phase.

Initial dosage (Neb/Val 5/160 mg/d) was titrated up to 20/320 mg/d to achieve blood pressure (BP) goal (JNC7 criteria), with

the addition of hydrochlorothiazide (up to 25 mg/d) if needed. Safety and tolerability parameters included adverse events.

Efficacy assessments included baseline–to–endpoint change in diastolic BP and systolic BP and the percentage of patients

who achieved BP goal. All analyses were performed using descriptive statistics. Study completion rate was 60.4% (489/

810). The most frequent reason for discontinuation was insufficient therapeutic response (8.4%). Adverse events were expe-

rienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratorytract infection (4.6%). Three (0.4%) deaths occurred during the study; none was considered related to study medication.

Mean standard deviation changes from baseline at week 52 (observed cases) were 25.5 15.9 mm Hg (systolic BP)

and 19.0 8.7 mm Hg (diastolic BP). A total of 75.7% nebivolol/valsartan–treated and 57.8% nebivolol/valsartan/hydro-

chlorothiazide–treated completers achieved BP goal. Long–term treatment with nebivolol and valsartan in adults with hyper-

tension was safe and well–tolerated. J Am Soc Hypertens 2014;8(12):915–920. 2014 American Society of Hypertension.

All rights reserved.

Keywords: Angiotensin receptor blocker; beta-blocker; blood pressure; clinical trial.

Introduction

Over two–thirds of individuals with hypertension require

more than one drug to achieve blood pressure (BP) con-

trol.1,2 There is a dearth of data about combining b–

blockers and renin–angiotensin–aldosterone system

(RAAS) inhibitors, but it has been suggested that such com-

binations would be suboptimal, due to a partial overlap inthe mechanism of action.3

This study was funded by Forest Research Institute.

Conflict of Interest: Dr Neutel does not have any significant re-

lationships or affiliations to disclose. Dr Giles has received grants

and personal fees from Forest Research Institute, Inc. Dr Punzi has

received grants/research support from the NIH, Forest Labora-

tories, Inc., Takeda, Boehringer Ingelheim, Daiichi-Sankyo, Astra-

Zeneca, and he is also on the Speakers’ Bureau for Forest

Laboratories, Inc., Daiichi-Sankyo, and AstraZeneca. Dr Weiss

has received grant/research support from Forest Laboratories,

Inc. Wei Chen and Amy Fink are employees of Forest Research

Institute.

*Corresponding author: Joel M. Neutel, MD, 14351 Myford

Rd, Ste B, Tustin, CA 93780. Tel: (714) 550-9990; Fax: (714)

550-1226.

E-mail: [email protected]

Journal of the American Society of Hypertension 8(12) (2014) 915–920

1933-1711/$ - see front matter 2014 American Society of Hypertension. All rights reserved.

http://dx.doi.org/10.1016/j.jash.2014.09.017

mailto:[email protected]://dx.doi.org/10.1016/j.jash.2014.09.017http://dx.doi.org/10.1016/j.jash.2014.09.017http://dx.doi.org/10.1016/j.jash.2014.09.017http://dx.doi.org/10.1016/j.jash.2014.09.017http://dx.doi.org/10.1016/j.jash.2014.09.017http://crossmark.crossref.org/dialog/?doi=10.1016/j.jash.2014.09.017&domain=pdfmailto:[email protected]


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Nebivolol is a b1–selective antagonist with nitric oxide–

dependent vasodilatory properties4 and has been approved

for the treatment of hypertension, alone or in combination

with other antihypertensive agents. The b1:b2 receptor af-

finity for nebivolol has been estimated at 321:1 for doses

up to 10 mg/day, but the high b1 selectivity may be lost

at the highest approved, but clinically rarely used, dose of 40 mg/day.5 Compared with atenolol, nebivolol has been

shown to decrease central pulse pressure and the augmenta-

tion index,6 although the two drugs lower brachial BP, pulse

rate, and plasma renin activity to a similar extent.7 Valsar-

tan is an angiotensin II receptor blocker (ARB), and is

already a component of several fixed–dose combina-

tions.8–10 The antihypertensive efficacy of valsartan and

other ARBs is based on reduction of peripheral resistance11

and, similar to other ARBs,9 valsartan has been shown to

reduce the levels of pro–inflammatory cytokines in patients

with hypertension.12 Both nebivolol and valsartan have an

excellent safety and tolerability profile.13–15

Here we report the results of an open–label study that as-

sessed the long–term safety of nebivolol and valsartan,

administered as a free–tablet, flexible–dose combination, in

adults with stage 1 or 2 hypertension (per JNC7 criteria1).

Methods

Ethical Conduct

This study was conducted in compliance with the Interna-

tional Conference on Harmonisation of Technical Require-

ments for Registration of Pharmaceuticals for Human Use(ICH) guidelines and the US Food and Drug Administration

guidelines for good clinical practice; and in accordance with

the ethical principles that originate from the Declaration of

Helsinki and the US Food and Drug Administration Code

of Federal Regulations Title 21, section 312.120. All enrolled

patients provided voluntary, written informed consent and

Health Insurance Portability and Accountability Act (HI-

PAA) authorization prior to participating in any study proce-

dures. The institutional review boards of all participating

centers approved the study protocol, informed consent

form, and information sheet advertisements.

Study Design

This was a Phase III, multicenter, open–label, single–arm

trial (NAC-MD-02; NCT01415505) conducted in the US.

Following a 1–week screening, participants entered a 4–

week single–blind placebo run–in phase, followed by a

52–week treatment period during which they received the

free–tablet combination of nebivolol 5 mg/day and valsartan

160 mg/day. The initial dosage (Week 0) of 5/160 mg/day

nebivolol/valsartan was doubled to 10/320 mg/day at

Week 2, and it was further increased to 20/320 mg/day if pa-

tients did not achieve BP goal (SBP/DBP 140/90 mm Hg

[without diabetes] or 130/80 mm Hg [with diabetes]) after

at least 4 weeks of treatment at the 10/320 mg/d dosage. If

BP goal was not met after a minimum of 10 weeks on the

20/320 mg/d dosage, 12.5 mg/d hydrochlorothiazide

(HCTZ) was added and doubled 4 weeks thereafter to

25 mg/d if BP goal was still not achieved. Patients who

did not achieve BP goal after 14 weeks of adding HCTZ totheir regimen (starting with the 12.5 mg/d dosage) were dis-

continued from the study. After 52 weeks of treatment, all

patients underwent 1 week of down–titrating their nebivolol

dosage (20 mg to 10 mg to 5 mg to placebo, in 3–day incre-

ments, as applicable), before all study medication was

discontinued.

Participants

Men and women ages 18 years or older were eligible to

participate if they had a heart rate of 55 beats per minute

(except for patients already on b-blockers), a normal phys-ical examination at Screening, and stage 1 or 2 hyperten-

sion, with a recent DBP measurement of 90 mm Hg

and


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disease or active gastritis, pancreatitis, renal impairment,

major gastrointestinal tract surgery within 6 months from

Screening, or pregnancy or breastfeeding.

Safety Assessments

Safety and tolerability were assessed by recording adverseevents (AEs) and monitoring vital signs at each visit; by per-

forming physical examinations at Screening and Week 52; by

performing electrocardiograms at Screening, Weeks 0 and

52, and after the down–titration phase; by measuring clinical

laboratory parameters (blood and urine) at Screening and

Weeks 0, 6, 22, and 52. Height and weight were measured

at each visit between Weeks 0 and 52.

Efficacy Assessments

Efficacy assessments included change from baseline in

trough–seated SBP and DBP at each visit, percentage of pa-tients who achieved BP goal, percentage of DBP responders

(DBP


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were taking and 210/388 (54.1%) were not taking HCTZ,

experienced at least one treatment–emergent AE (TEAE).

The majority of TEAEs were considered mild or moderate

in severity. Common TEAEs (those occurring in 2% of

the Safety population) are listed in Table 2. In addition to

the 19 (2.4%) patients who reported bradycardia

(Table 2), seven (0.9%) reported sinus bradycardia, withoutco–occurrence of those two in the same individual. Two pa-

tients (0.2%) who experienced bradycardia also reported fa-

tigue, but those two AEs did not coincide in either of those

two individuals. Erectile dysfunction was reported by 3/388

(0.8%) patients not taking HCTZ and by 4/419 (1.0%) pa-

tients taking HCTZ.

During the 52–week treatment phase and the 1–week

down-titration phase, 19 (2.4%) patients experienced a

SAE, with only one SAE (bradycardia) deemed related to

study medication. A total of three (0.4%) patients died dur-

ing the study, but all deaths were deemed unrelated to the

study medication.

Clinical Laboratory Parameters

Changes from baseline in major metabolic parameters are

shown in Table 3. MeanSD changes of 1.04.1kginbody

weight and 0.3 1.4 kg/m2 in body mass index were

observed over the course of the study.

A total of 431/784 (55.0%) patients had a potentially clin-

ically significant post–baseline laboratory value, of which

the levels of high–sensitivity C–reactive protein were the

most prevalent: 77/247 (31.2%) had high–sensitivity C–reac-

tive protein levels below 0.8 mg/L and 128/247 (51.8%) hadlevels above 3.0 mg/L. High–density lipoprotein cholesterol

levels 60 mg/dL were recorded in 17.1%

(93/543) and 6.3% (34/543) participants, respectively.

Low–density lipoprotein cholesterol values 159 mg/dL were found in 11.5% (69/599) and 14.0%

(84/599) of participants. Total cholesterol levels that ex-

ceeded the upper limit of normal range by 10% were re-corded in 19.6% (121/616) of patients. A total of 20/664

(3.0%) patients had a post–baseline fasting glucose measure-

ment that represented >50% increase from baseline and was

over 1.2–fold the upper limit of normal; a total of 69/509

(13.6%) participants experienced a baseline–to–endpoint

shift of HbA1c levels from normal to high, and 30/509

(5.9%) experienced a shift from high to normal.

Efficacy

After 52 weeks of open–label treatment, the mean SD

trough–seated SBP and DBP decreased by 25.5 15.9 mm

Hg and 19.0 8.7 mm Hg, respectively. A total of 419

(51.5%) participants received HCTZ at some point in the

study (Table 4), of which 296 completed the trial.

At Week 52, 65.1% (327/502) of participants remaining

in the trial achieved the BP goal, including 75.7% (156/

206) of those who did not need HCTZ addition, 57.8%

(171/296) of those who did, 61.9% (86/139) of blacks

(vs. 66.4% [241/363] of non–blacks), and 61.1% (77/126)

of Hispanics (vs. 66.5% [250/376] of non–Hispanics).

Visit–by–visit changes in BP, the rates of BP goal achieve-

ment, DBP response, SBP response, and the percentage of

patients receiving HCTZ are shown in Figure 2.

Table 2

Common treatment–emergent adverse events (TEAE; 2% of the

total safety population), n (%)

Common TEAEs Nebivolol–Valsartan Combination

Taking

HCTZ

(n ¼ 419)

Not Taking

HCTZ

(n ¼ 388)

Total

(N ¼ 807)

Headache 27 (6.4) 19 (4.9) 46 (5.7)

Nasopharyngitis 20 (4.8) 20 (5.2) 40 (5.0)

Upper respiratory

tract infection

26 (6.2) 11 (2.8) 37 (4.6)

Dizziness 18 (4.3) 17 (4.4) 35 (4.3)

Bronchitis 16 (3.8) 8 (2.1) 24 (3.0)

Cough 14 (3.3) 8 (2.1) 22 (2.7)

Fatigue 9 (2.1) 12 (3.1) 21 (2.6)

Back pain 10 (2.4) 10 (2.6) 20 (2.5)

Urinary tract infection 13 (3.1) 7 (1.8) 20 (2.5)

Bradycardia 7 (1.7) 12 (3.1) 19 (2.4)

Sinusitis 15 (3.6) 4 (1.0) 19 (2.4)

Peripheral edema 7 (1.7) 11 (2.8) 18 (2.2)

Table 3

Changes from baseline to week 52 in glucose and lipid parameters

(safety population)

Parameter Nebivolol–Valsartan

Combination (N ¼ 782)

Baseline Change from

Baseline

Fasting glucose, mg/dL* 101.6 22.2 2.9 26.7

HDL cholesterol, mg/dL* 49.9 13.9 2.3 7.7

LDL cholesterol, mg/dL* 128.0 34.8 9.3 25.9

Total cholesterol, mg/dL* 192.6 36.7 1.2 30.9

HDL, high–density lipoprotein; LDL, low–density lipoprotein.

* Mean standard deviation.

Table 4

Distribution of dosages at endpoint, n (%), safety population

(N ¼ 807)

Nebivolol–Valsartan

Combination (mg/day)

HCTZ Addition (mg/d)

0 12.5 25

5/160 45 (5.6) – –

10/320 162 (20.1) 1 (0.1) 1 (0.1)

20/320 181 (22.4) 204 (25.3) 213 (26.4)

Total 388 (48.1) 205 (25.4) 214 (26.5)

HCTZ, hydrochlorothiazide.

918 J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915–920


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Discussion

Our data suggest that nebivolol–valsartan combination is

safe and well–tolerated for long–term use (including a

neutral metabolic effect), which is consistent with the favor-able safety and tolerability profile of the individual compo-

nents.15,16 The observed reductions in SBP and DBP are

comparable with those attained in similarly designed, 52–

week trials of valsartan combined with agents from other

classes,17,18 and consistent with the results of shorter, pla-

cebo–controlled trials in which nebivolol was added to an

ongoing treatment with an ARB or an angiotensin–convert-

ing enzyme inhibitor (ACEI).19,20 The subset of participants

in our trial who discontinued treatment due to insufficient

response had a higher proportion of blacks and individuals

with diabetes compared with the entire trial population

(blacks, 42.6% vs. 30.4%; diabetes, 42.6% vs. 17.0%), whichis in agreement with the reported difficulties of attaining BP

control in those patients.1 However, the rates of BP control

between blacks and non–blacks who completed the trial

were similar (61.9% vs. 66.4%, respectively).

The relatively low occurrence of b–blocker-typical AEs

(bradycardia, erectile dysfunction, fatigue, weight

gain)21,22 in our study is consistent with the results of shorter

head–to–head trials, in which nebivolol had lower rates of

those AEs than other b1–selective blockers (atenolol, meto-

prolol).23 In addition, the favorable safety and tolerability

profile of nebivolol15 is possibly reflected in 1.5– to 8–fold

lower rates of some common AEs (peripheral edema,

nasopharyngitis, and dizziness) reported in a similarly de-

signed, 52–week valsartan–amlodipine trial.18

Limitations of this study are inherent to the open–label

design (lack of randomization, blinding, and control groups)

but its duration and treatment scheme (titration to response,

addition of a third drug as needed) mirror clinical practice

and support a notion that the results could be generalized to

the out–of–trial population. In addition, screening was not

performed by means of ambulatory blood pressure moni-

toring, which suggests that possibly up to one–third of partic-

ipants may have had white–coat hypertension.24

In conclusion, a 52–week treatment with a free combina-

tion consisting of an ARB (valsartan) and a vasodilatory b–

blocker (nebivolol), with the addition of HCTZ as needed,

was well–tolerated. The combination resulted in significant

decreases in both systolic and diastolic BP, which were sus-

tained over the 52–week period. The majority of patients

were able to achieve recommended BP goals.

Acknowledgments

Writing assistance and editorial support for the prepara-

tion of this manuscript was provided by Prescott Medical

Communications Group, Chicago, Illinois.

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Figure 2. Blood pressure (BP) changes and percentages of responders, BP goal achievers, and recipients of additional medication

(HCTZ), by visit (intent–to–treat [ITT] population, observed cases). Diastolic blood pressure (DBP) and systolic blood pressure

(SBP) responders were those patients who achieved DBP


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ARTIKEL 1 Hypertension