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Journal of the American Society of Hypertension 8(12) (2014) 915920

Research Article

Long-term safety of nebivolol and valsartan

combination 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 Finckg

Orange County Research Center, Tustin, CA, USA;

Department of Medicine, Tulane University, New Orleans, LA, USA;
Trinity Hypertension and Metabolic Research Institute, Carrollton, TX, USA;
UT Southwestern Medical Center, Carrollton, TX, USA;
Maine Research Associates, Auburn, ME, USA;
Department of Biostatistics, Forest Research Institute, Jersey City, NJ, USA; and
Trial Operations, Forest Research Institute, Jersey City, NJ, USA
Manuscript received August 28, 2014 and accepted September 16, 2014

Longterm safety of a freetablet combination of nebivolol and valsartan was assessed in a Phase III, openlabel trial
(NCT01415505). Adults with hypertension entered a 4week placebo runin phase, followed by a 52week 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 baselinetoendpoint 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 experienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratory
tract 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/valsartantreated and 57.8% nebivolol/valsartan/hydrochlorothiazidetreated completers achieved BP goal. Longterm treatment with nebivolol and valsartan in adults with hypertension was safe and welltolerated. J Am Soc Hypertens 2014;8(12):915920. 2014 American Society of Hypertension.
All rights reserved.
Keywords: Angiotensin receptor blocker; beta-blocker; blood pressure; clinical trial.

Over twothirds of individuals with hypertension require
more than one drug to achieve blood pressure (BP) control.1,2 There is a dearth of data about combining b
This study was funded by Forest Research Institute.
Conflict of Interest: Dr Neutel does not have any significant relationships 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 Laboratories, Inc., Takeda, Boehringer Ingelheim, Daiichi-Sankyo, AstraZeneca, and he is also on the Speakers Bureau for Forest
Laboratories, Inc., Daiichi-Sankyo, and AstraZeneca. Dr Weiss

blockers and reninangiotensinaldosterone system

(RAAS) inhibitors, but it has been suggested that such combinations would be suboptimal, due to a partial overlap in
the mechanism of action.3
has received grant/research support from Forest Laboratories,
Inc. Wei Chen and Amy Fink are employees of Forest Research
*Corresponding author: Joel M. Neutel, MD, 14351 Myford
Rd, Ste B, Tustin, CA 93780. Tel: (714) 550-9990; Fax: (714)

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


J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915920

Nebivolol is a b1selective 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 affinity 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 augmentation index,6 although the two drugs lower brachial BP, pulse
rate, and plasma renin activity to a similar extent.7 Valsartan is an angiotensin II receptor blocker (ARB), and is
already a component of several fixeddose combinations.810 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 proinflammatory cytokines in patients
with hypertension.12 Both nebivolol and valsartan have an
excellent safety and tolerability profile.1315
Here we report the results of an openlabel study that assessed the longterm safety of nebivolol and valsartan,
administered as a freetablet, flexibledose combination, in
adults with stage 1 or 2 hypertension (per JNC7 criteria1).

Ethical Conduct
This study was conducted in compliance with the International Conference on Harmonisation of Technical Requirements 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 (HIPAA) authorization prior to participating in any study procedures. 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, openlabel, singlearm
trial (NAC-MD-02; NCT01415505) conducted in the US.
Following a 1week screening, participants entered a 4
week singleblind placebo runin phase, followed by a
52week treatment period during which they received the
freetablet 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 patients 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 to
their regimen (starting with the 12.5 mg/d dosage) were discontinued from the study. After 52 weeks of treatment, all
patients underwent 1 week of downtitrating their nebivolol
dosage (20 mg to 10 mg to 5 mg to placebo, in 3day increments, as applicable), before all study medication was

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 physical examination at Screening, and stage 1 or 2 hypertension, with a recent DBP measurement of 90 mm Hg
and <110 mm Hg if currently receiving hypertension treatment, DBP 95 mm Hg and <110 mm Hg at Screening if
currently untreated or if previously diagnosed but untreated
for at least 4 weeks prior to Screening. Individuals were
enrolled in the treatment phase if during the runin phase
they demonstrated 80% and 120% adherence to singleblind placebo treatment and if their mean seated DBP
measurements at the end of the runin phase and at Week
0 (study enrollment visit) were 95 mm Hg and
<110 mm Hg. Treatmentnave patients and patients who
were untreated for at least 4 weeks were eligible for early
enrollment if SBP measured 180 mm Hg or DBP
110 mm Hg (safety value) and if a repeat measurement
within 3 days was below the safety value, or if DBP
measured 95 mm Hg and <110 mm Hg and SBP
<180 mm Hg for at least two consecutive visits during
the runin phase. Major reasons for exclusion were secondary hypertension, severe hypertension (SBP 180 mm Hg
or DBP 110 mm Hg), current treatment with four or
more antihypertensive medications (including components
of fixeddose combinations), contraindication to discontinuing current antihypertensive treatment, upper arm circumference >42 cm, the presence of coronary artery disease
requiring treatment with a b-blocker, calcium channel
blocker, or chronic nitrates, reactive airway disease,
chronic obstructive pulmonary disease, second- or thirddegree heart block or sick sinus syndrome, clinically significant cardiovascular disease, event, or procedure within
6 months from Screening, heart failure, hypertensive retinopathy (KeithWagener grade III or IV), type 1 diabetes,
poorly controlled type 2 diabetes (HbA1C 8%), uncontrolled thyroid disease within 3 months of Screening, record
of substance abuse within 2 years from Screening or a positive urine drug test at Screening, inflammatory bowel

J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915920


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 adverse
events (AEs) and monitoring vital signs at each visit; by performing physical examinations at Screening and Week 52; by
performing electrocardiograms at Screening, Weeks 0 and
52, and after the downtitration 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
troughseated SBP and DBP at each visit, percentage of patients who achieved BP goal, percentage of DBP responders
(DBP <90 mm Hg [<80 mm Hg if with diabetes] and
10 mm Hg reduction from baseline), percentage of SBP responders (SBP <140 mm Hg [<130 mm Hg if with diabetes]
and 10 mm Hg reduction from baseline), change from baseline in standing SBP/DBP at Weeks 28 and 52, and proportion
of patients who received additional treatment with HCTZ.

Sample Size Determination

Figure 1. Study flow. ITT, Intenttotreat.

(Figure 1). The most frequent reason for discontinuation

was insufficient treatment response (8.4%; Figure 1), with
a majority of patients discontinuing treatment due to an
inability to achieve BP goal after 14 weeks of receiving additional (HCTZ) medication. Among the patients who discontinued treatment due to insufficient response, 42.6% (29/68)
were black and 42.6% (29/68) had diabetes. Baseline demographic and clinical characteristics are summarized in
Table 1.

The sample size of 800 participants was chosen to meet the

US Food and Drug Administration regulatory requirement
for determining drug exposure, and therefore was not based
on statistical considerations. A sample size of 800 provides
a 95% chance that an AE will appear as a common AE (occurring in 2% of patients) if the true AE rate is 2.9%.

Safety and Tolerability

Data Analysis

Table 1
Baseline demographic

Analyses of safety measures were based on the safety

population, defined as all randomized participants who
took at least one dose of doubleblind study medication,
and are presented using descriptive statistics. Analyses of
efficacy measures were based on the intenttotreat population, defined as all patients in the safety population who had
at least one postbaseline BP measurement, using descriptive statistics and the observedcases approach.

Study Flow and Baseline Characteristics
This study was conducted between August 11, 2011 (first
patient, first visit) and January 28, 2013 (last patient, last
visit) at 118 US sites. Of the 2264 participants screened for
eligibility, 810 were enrolled in the 52week openlabel
treatment phase, and 489 (60.4%) completed treatment

Adverse Events
During the 52week treatment phase, the rate of discontinuations due to an AE was 6.5% (53/810; Figure 1). A total of 478 (59.2%) participants, of which 267/419 (63.7%)






Combination (N 807)

Age (y), mean  SD

Women, n (%)
Race, n (%)
Ethnicity, n (%)
Hispanic or Latino
Weight (kg), mean  SD
BMI (kg/m2), mean  SD
Diabetes, n (%)
SBP (mm Hg), mean  SD*
DBP (mm Hg), mean  SD*

52.7  9.5
359 (44.5)
531 (65.8)
245 (30.4)
197 (24.4)
94.1  20.89
32.5  6.4
138 (17.1)
157.8  11.5
100.3  3.8

BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation.
* Values based on the intenttotreat population (n 799).


J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915920

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

experienced at least one treatmentemergent 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, without
cooccurrence of those two in the same individual. Two patients (0.2%) who experienced bradycardia also reported fatigue, 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%) patients taking HCTZ.
During the 52week treatment phase and the 1week
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 during 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. Mean  SD changes of 1.0  4.1 kg in body
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 clinically significant postbaseline laboratory value, of which
the levels of highsensitivity Creactive protein were the
most prevalent: 77/247 (31.2%) had highsensitivity Creactive protein levels below 0.8 mg/L and 128/247 (51.8%) had
levels above 3.0 mg/L. Highdensity lipoprotein cholesterol
levels <35 mg/dL and >60 mg/dL were recorded in 17.1%
(93/543) and 6.3% (34/543) participants, respectively.
Table 2
Common treatmentemergent adverse events (TEAE; 2% of the
total safety population), n (%)
Common TEAEs

Upper respiratory
tract infection
Back pain
Urinary tract infection
Peripheral edema

NebivololValsartan Combination
(n 419)

Not Taking
(n 388)

(N 807)

27 (6.4)
20 (4.8)
26 (6.2)

19 (4.9)
20 (5.2)
11 (2.8)

46 (5.7)
40 (5.0)
37 (4.6)







Table 3
Changes from baseline to week 52 in glucose and lipid parameters
(safety population)

Combination (N 782)

Fasting glucose, mg/dL*

HDL cholesterol, mg/dL*
LDL cholesterol, mg/dL*
Total cholesterol, mg/dL*


Change from



HDL, highdensity lipoprotein; LDL, lowdensity lipoprotein.

* Mean  standard deviation.

Lowdensity lipoprotein cholesterol values <77 mg/dL

and >159 mg/dL were found in 11.5% (69/599) and 14.0%
(84/599) of participants. Total cholesterol levels that exceeded the upper limit of normal range by 10% were recorded in 19.6% (121/616) of patients. A total of 20/664
(3.0%) patients had a postbaseline fasting glucose measurement that represented >50% increase from baseline and was
over 1.2fold the upper limit of normal; a total of 69/509
(13.6%) participants experienced a baselinetoendpoint
shift of HbA1c levels from normal to high, and 30/509
(5.9%) experienced a shift from high to normal.

After 52 weeks of openlabel treatment, the mean  SD
troughseated 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 nonblacks), and 61.1% (77/126)
of Hispanics (vs. 66.5% [250/376] of nonHispanics).
Visitbyvisit changes in BP, the rates of BP goal achievement, DBP response, SBP response, and the percentage of
patients receiving HCTZ are shown in Figure 2.
Table 4
Distribution of dosages at endpoint, n (%), safety population
(N 807)
Combination (mg/day)

HCTZ Addition (mg/d)



HCTZ, hydrochlorothiazide.




1 (0.1)
204 (25.3)
205 (25.4)

1 (0.1)
213 (26.4)
214 (26.5)

J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915920


Figure 2. Blood pressure (BP) changes and percentages of responders, BP goal achievers, and recipients of additional medication
(HCTZ), by visit (intenttotreat [ITT] population, observed cases). Diastolic blood pressure (DBP) and systolic blood pressure
(SBP) responders were those patients who achieved DBP <90 mm Hg (<80 mm Hg if with diabetes) and 10 mm Hg reduction
from baseline, or SBP <140 mm Hg (<130 mm Hg if with diabetes) and 10 mm Hg reduction from baseline, respectively. BP
goal indicates the achievement of SBP/DBP values <140/90 mm Hg for patients without diabetes or <130/80 mm Hg for those
with diabetes. Starting with Week 14, hydrochlorothiazide (HCTZ) was added to the treatment regimen of patients receiving
20/320 mg/day nebivolol/valsartan combination who did not achieve the BP treatment goal (see Methods).

Our data suggest that nebivololvalsartan combination is
safe and welltolerated for longterm use (including a
neutral metabolic effect), which is consistent with the favorable safety and tolerability profile of the individual components.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, placebocontrolled trials in which nebivolol was added to an
ongoing treatment with an ARB or an angiotensinconverting 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%), which
is in agreement with the reported difficulties of attaining BP
control in those patients.1 However, the rates of BP control
between blacks and nonblacks who completed the trial
were similar (61.9% vs. 66.4%, respectively).
The relatively low occurrence of bblocker-typical AEs
(bradycardia, erectile dysfunction, fatigue, weight
gain)21,22 in our study is consistent with the results of shorter
headtohead trials, in which nebivolol had lower rates of
those AEs than other b1selective blockers (atenolol, metoprolol).23 In addition, the favorable safety and tolerability
profile of nebivolol15 is possibly reflected in 1.5 to 8fold
lower rates of some common AEs (peripheral edema,

nasopharyngitis, and dizziness) reported in a similarly designed, 52week valsartanamlodipine trial.18

Limitations of this study are inherent to the openlabel
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 outoftrial population. In addition, screening was not
performed by means of ambulatory blood pressure monitoring, which suggests that possibly up to onethird of participants may have had whitecoat hypertension.24
In conclusion, a 52week treatment with a free combination consisting of an ARB (valsartan) and a vasodilatory b
blocker (nebivolol), with the addition of HCTZ as needed,
was welltolerated. The combination resulted in significant
decreases in both systolic and diastolic BP, which were sustained over the 52week period. The majority of patients
were able to achieve recommended BP goals.
Writing assistance and editorial support for the preparation of this manuscript was provided by Prescott Medical
Communications Group, Chicago, Illinois.

1. Chobanian AV, Bakris GL, Black HR, Cushman WC,
Green LA, Izzo JL Jr, et al. Seventh report of the Joint


J.M. Neutel et al. / Journal of the American Society of Hypertension 8(12) (2014) 915920

National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:120652.
2. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control
among United States adults with hypertension: the
National Health and Nutrition Examination Survey,
2001 to 2010. Circulation 2012;126:210514.
3. Gradman AH, Basile JN, Carter BL, Bakris GL,
Materson BJ, Black HR, et al. Combination therapy
in hypertension. J Am Soc Hypertens 2010;4:908.
4. Vanhoutte PM, Gao Y. Beta blockers, nitric oxide, and
cardiovascular disease. Curr Opin Pharmacol 2013;13:
5. Munzel T, Gori T. Nebivolol: the somewhat-different
beta-adrenergic receptor blocker. J Am Coll Cardiol
6. Koumaras C, Tziomalos K, Stavrinou E, Katsiki N,
Athyros VG, Mikhailidis DP, et al. Effects of
renin-angiotensin-aldosterone system inhibitors and
beta-blockers on markers of arterial stiffness. J Am
Soc Hypertens 2014;8:7482.
7. Simon G, Johnson ML. Comparison of antihypertensive
and beta 1-adrenoceptor antagonist effect of nebivolol
and atenolol in essential hypertension. Clin Exp Hypertens 1993;15:5019.
8. Bains J, Smith WB. Valsartan plus hydrochlorothiazide:
a review of its use since its introduction. Expert Opin
Pharmacother 2011;12:197584.
9. Miura S, Saku K. Efficacy and safety of angiotensin II
type 1 receptor blocker/calcium channel blocker combination therapy for hypertension: focus on a single-pill
fixed-dose combination of valsartan and amlodipine.
J Int Med Res 2012;40:19.
10. Neutel JM, Smith DH. Hypertension management:
rationale for triple therapy based on mechanisms of action. Cardiovasc Ther 2013;31:2518.
11. Israili ZH. Clinical pharmacokinetics of angiotensin II
(AT1) receptor blockers in hypertension. J Hum Hypertens 2000;14(Suppl 1):S7386.
12. Manabe S, Okura T, Watanabe S, Fukuoka T, Higaki J.
Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with
essential hypertension. J Cardiovasc Pharmacol 2005;

13. Neutel JM, Bedigian MP. Efficacy of valsartan in patients aged > or 65 years with systolic hypertension.
Clin Ther 2000;22:9619.
14. Pool JL, Glazer R, Chiang YT, Gatlin M. Doseresponse efficacy of valsartan, a new angiotensin II receptor blocker. J Hum Hypertens 1999;13:27581.
15. Weiss RJ, Saunders E, Greathouse M. Efficacy and
tolerability of nebivolol in stage I-II hypertension: a
pooled analysis of data from three randomized,
placebo-controlled monotherapy trials. Clin Ther
16. Black HR, Bailey J, Zappe D, Samuel R. Valsartan: more
than a decade of experience. Drugs 2009;69:2393414.
17. Chrysant SG, Murray AV, Hoppe UC, Dattani D,
Patel S, Hsu H, et al. Long-term safety, tolerability
and efficacy of aliskiren in combination with valsartan
in patients with hypertension: a 6-month interim analysis. Curr Med Res Opin 2008;24:103947.
18. Smith TR, Glazer RD, Koren MJ, Wernsing M, Zhang Y.
Combination therapy with amlodipine/valsartan in
essential hypertension: a 52-week, randomised, openlabel, extension study. Int J Clin Pract 2010;64:136774.
19. Deedwania P, Shea J, Chen W, Brener L. Effects of
add-on nebivolol on blood pressure and glucose parameters in hypertensive patients with prediabetes. J Clin
Hypertens (Greenwich) 2013;15:2708.
20. Weiss RJ, Stapff M, Lin Y. Placebo effect and efficacy
of nebivolol in patients with hypertension not
controlled with lisinopril or losartan: a phase IV, randomized, placebo-controlled trial. Am J Cardiovasc
Drugs 2013;13:12940.
21. Black HR, Greenberg BH, Weber MA. The foundation
role of beta blockers across the cardiovascular disease
spectrum: a year 2009 update. Am J Med 2010;123:S2.
22. Kountz DS. Are tolerability concerns a class effect of
beta-blockers in treating patients with hypertension?
Postgrad Med 2009;121:1424.
23. Ambrosioni E, Borghi C. Tolerability of nebivolol in
head-to-head clinical trials versus other cardioselective
B-blockers in the treatment of hypertension. High
Blood Press Cardiovasc Prev 2005;12:2735.
24. Verberk WJ, Kroon AA, Thien T, Lenders JW, van
Montfrans GA, Smit AJ, et al. Prevalence of the
white-coat effect at multiple visits before and during
treatment. J Hypertens 2006;24:235763.