European Journal of Internal Medicine 15 (2004) 348 – 357

www.elsevier.com/locate/ejim

Review article

White-coat hypertension: a clinical review

Hilde Celis*, Robert H. Fagard
Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven,
U.Z. Gasthuisberg – Dienst Hypertensie, Herestraat 49, 3000 Leuven, Belgium

Received 1 June 2004; received in revised form 15 July 2004; accepted 2 August 2004

Abstract

White-coat hypertension (WCHT), also called disolated office or clinic hypertensionT, is defined as the occurrence of blood pressure (BP)
values higher than normal when measured in the medical environment, but within the normal range during daily life, usually defined as
average daytime ambulatory BP (ABP) or home BP values (b135 mm Hg systolic and b85 mm Hg diastolic). The prevalence of WCHT
varies from 15% to over 50% of all patients with mildly elevated office BP (OBP) values. In untreated hypertensive patients, the probability
of WCHT especially increases with female gender and a mildly elevated OBP level. The value of other possible determinants such as (non)
smoking status, duration of hypertension, left ventricular mass, number of OBP measurements, educational level, etc. is less consistently
shown. Although, for various reasons, studies evaluating the long-term effects of WCHT are not always easy to interpret, most data indicate
that persons with WCHT have a worse or equal cardiovascular prognosis than normotensives, but a better one than those with sustained
hypertension. WCHT is sometimes considered a prehypertensive state, but data on the long-term evolution of subjects with WCHT are scarce.
Patients with WCHT and a high cardiovascular risk or proven target organ damage should be pharmacologically treated. Subjects with
uncomplicated WCHT should probably not receive medical therapy, but a close follow-up, including regular assessment of other risk factors
and measurement of OBP (every 6 months) and ABP (every 1 or 2 years), is warranted.
D 2004 Elsevier B.V. All rights reserved.

Keywords: White-coat hypertension; Sustained hypertension; Ambulatory blood pressure; Home blood pressure; Diagnosis; Prognosis

Contents

1. Definition and prevalence of white-coat hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

2. Correctly diagnosing WCHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3. Identification of patients with WCHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4. Prognostic relevance of WCHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.1. Target organ damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.2. Cardiovascular outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.3. Relation to other risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
5. Evolution of WCHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
6. Treatment and follow-up of WCHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
7. What about the white-coat effect? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

1. Definition and prevalence of white-coat hypertension

White-coat hypertension (WCHT) is defined as the

* Corresponding author. Tel.: +32 16 34 36 31; fax: +32 16 34 37 66. occurrence and persistence of blood pressure values higher
E-mail address: hilde.celis@med.kuleuven.ac.be (H. Celis). than normal (dhypertensiveT) when measured in the
0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2004.08.001
 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357
medical environment and in the presence of a physician
[the so-called office blood pressure (OBP)], but within the
normal range during daily life [1,2]. Most experts agree on
the definition of elevated OBP values, i.e., above 140 mm
Hg systolic and/or above 90 mm Hg diastolic [1,2].
However, normal dout of the officeT BP values are not, and
have not always been, defined in a consistent way. BP
during normal daily activities is usually evaluated by 24-h
ambulatory BP (monitoring) [ABP(M)], but different
expert committees have used different cutoff points of
normalcy [1,3,4]. Today, most experts define WCHT as an
elevated OBP in the presence of a normal average daytime
ABP (b135 mm Hg systolic and b85 mm Hg diastolic
[2,5]); yet, normal average 24-h values (b125 mm Hg
systolic and b80 mm Hg diastolic) [1,4] have also been
used as cutoff points. Home or self-measurement of BP
has been proposed as a useful alternative for ABPM to
detect WCHT. Home BP (HBP) values of 135/85 mm Hg
should probably be considered as the upper limit of
normalcy [1,3,4].
Depending on the thresholds used to diagnose the
condition and the characteristics of the study population
(e.g., treated versus untreated subjects), the prevalence of
WCHT varies from 15% to over 50% of patients with mildly
elevated OBP [6–10].
Recently, some investigators suggested using the term
disolated office or clinic hypertensionT instead of
WCHT [11–13]. This term takes into account that it
is not only the dwhite coatT of the doctor that causes
the difference between OBP and ABP, but that there
are also other factors involved, such as (physical and
mental) activity during the day and the circumstances
of the measurement.
2. Correctly diagnosing WCHT
The correct diagnosis of WCHT requires the application
of several logical, but nevertheless important, guidelines.
Elevated OBP values should be confirmed on subsequent
measurements, usually at several visits [1,4]. If ABPM is
used to diagnose WCHT, some quality requirements should
be implemented to assure accurate measurements [1,4]. The
most important are:
(1) the use of an accurate and internationally and
independently validated device;
(2) the use of cuffs of appropriate size (larger cuff for
obese arms, smaller cuff for lean adult arms and
children);
(3) the need to obtain an adequate number of readings (the
interval between readings should probably not exceed
30 min during day and night);
(4) the need for patients to engage in normal daily
activities, but refrain from strenuous exercise, and
keep the arm still during the measurement; and
349
(5) the need for patients to keep a diary in which
symptoms and unusual events, duration and quality
of night sleep, etc. are noted.
However, using ABPM for the diagnosis of WCHT may
also raise problems. Some authors question whether one
ABPM (for only 24 h) is sufficient to properly characterize
usual daily BP. Results from a study by Hermida et al. [14]
based on 48-h ABPM indicate that if a person wears an
ABPM device for the very first time, this significantly affects
the BP measured. This so-called dABPMT or dpressorT effect
increases BP on average by 7/4 mm Hg for the first 4 h of
measurement and can persist for up to 9 h after the person
starts wearing the device. Hermida et al. documented such an
ABPM effect in 73% of their hypertensive patients. The
pressor effect is no longer obvious when hypertensive
patients are evaluated for the second and subsequent times.
These results suggest that diagnosing or refuting the
diagnosis of WCHT using ABPM should not be based on
only one ABPM since, due to the ABPM effect, average day
ABP might be higher and patients could be mistakenly
classified as having sustained hypertension (SHT) instead of
WCHT.
In a substudy of the HARVEST trial, Palatini et al. [15]
also investigated the reproducibility of the diagnosis of
WCHT. Five hundred and sixty five mild hypertensive
subjects and 95 normotensive controls underwent two
ABPM 3 months apart. Due mainly to regression to the
mean, 58% of the 90 patients who were diagnosed as having
WCHT based on the first ABPM (daytime ABP b130 mm
Hg systolic and b80 mm Hg diastolic) became sustained
hypertensives on repeated recording. Conversely, among the
sustained hypertensives, 11% had daytime ABP below 130
mm Hg systolic and below 80 mm Hg diastolic on the
second recording. These data indicate that the diagnosis of
WCHT is subject to selection bias and that one ABPM may
not always be sufficient to correctly identify persons with
WCHT.
Some guidelines propose the alternative use of home (or
self) blood pressure measurement (HBPM) to diagnose
WCHT [1,3,4]. As for ABPM, the quality of HBPM should
also be guaranteed by:
(1) the use of accurate and validated (preferably upper
arm) devices;
(2) the use of a cuff of appropriate size;
(3) a 5-min rest period before measurements; and
(4) BP measured in duplicate every morning and evening
for a 7-day period. Often measurements of the first day
are not included in the statistical analysis because, due
to anxiety and subsequent familiarization with the new
technique, they may yield measurements that are not
representative.
Instead of using either ABPM or HBPM to diagnose
WCHT, some investigators propose to use an algorithm
350 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357
using both of the above techniques [16–18]. According to
this algorithm, patients with persistently high OBP values
and no evidence of target organ damage should engage in
HBPM (screening test); if this shows normal values,
ABPM is done to confirm the diagnosis (diagnostic test).
However, momentarily, no official international or national
guideline committees have endorsed this approach. Indeed,
it is generally accepted that, although high specificity and
negative predictive value are important for a screening test,
it should predominantly have a high sensitivity. A few
studies [16–18] that tested the above-proposed algorithm
did report high specificity (ranging from 81% [16] to 93%
[18]) and a high negative predictive value (ranging from
77% [16] to 97% [17]), but a rather low sensitivity (ranging
from 43% [18] to 68% [17]). This means that, among the
subjects who had WCHT according to the dformalT
definition (high OBP, normal ABP), only 43% [18] to
68% [17] will be diagnosed when the proposed algorithm is
used, thus leaving an unacceptably high proportion of 32–
57% of WCHT undetected. Furthermore, the Kappa
coefficient suggested only moderate agreement between
HBPM and ABPM in the diagnosis of WCHT (Kappa
coefficient ranging from 0.38 [17] to 0.42 [16]). Thus,
although ABPM and HBPM may classify comparable
percentages of patients as being WCHT or SHT, both
techniques nevertheless identify different subsets of WCHT
patients.
In conclusion, the optimal strategy for detecting
WCHT has not yet been established and more research
is needed.
3. Identification of patients with WCHT
Although several investigators have tried to identify
possible determinants of WCHT [9,19–24], data allowing
an estimate of the probability of WCHT according to
patientsT characteristics are relatively scarce. Already in
1988, Pickering et al. [6] reported that in 292 subjects with
diastolic OBP between 90 and 104 mm Hg, female gender,
young age, and short duration of hypertension were
independent predictors of WCHT. A few years later, Julius
et al. [21] showed that participants in the Tecumseh Blood
Pressure Study (none of them receiving antihypertensive
drug treatment) with WCHT (systolic OBPN140 mm Hg
or diastolic OBPN90 mm Hg and HBP below the upper
decile of the whole population) were very similar to those
with SHT and differed significantly from normotensive
controls. Both dhypertensiveT groups had higher weight,
faster heart rates, elevated total cholesterol, triglyceride,
and insulin levels, and lower HDL-cholesterol levels. They
also had elevated BP levels on previous examinations as
compared to their normotensive counterparts. Subjects
with WCHT did not, however, differ from normotensives
with respect to reactivity to psychological stress or
personality characteristics.
Staessen et al. [24] analyzed a large international
database consisting of 2492 subjects with OBP above
140 mm Hg systolic or above 90 mm Hg diastolic. They
showed that the probability of having WCHT (24-h ABP
below the 95th percentile of a normotensive control group)
was higher in women and was positively associated with
age and inversely related to systolic and diastolic OBP
values and to the number of visits and OBP measurements
per visit.
Martinez et al. [9] examined the clinical factors that
may identify patients with WCHT (OBP 140–170 mm Hg
systolic or 90–109 mm Hg diastolic on repeated measure-
ment and day systolic ABPb135 mm Hg systolic and b85
mm Hg diastolic) in a primary care setting. They showed
that the diagnosis of WCHT was independently related
only to female gender, lower educational level, and lower
systolic and diastolic OBP values. Conversely, patients
with SHT and WCHT were similar with regard to BMI,
smoking habits, family history of hypertension, the
previous use of antihypertensives, and several metabolic
parameters (glucose, cholesterol, triglycerides, etc.). All
patients in the Martinez study were either untreated or
had antihypertensive drugs withdrawn for at least 3
weeks.
Verdecchia et al. [19] performed a joint analysis of the
large HARVEST and PIUMA databases. WCHT was
defined as an OBP (on at least two visits) of 140–159
mm Hg systolic or 90–99 mm Hg diastolic and day ABP
below 130 mm Hg systolic and below 80 mm Hg diastolic.
All participants had to be free of diabetes, renal failure, and
previous cardiovascular disease. Multivariate logistic
regression showed that female gender, non-smoking status,
lower diastolic OBP, and lower left ventricular (LV) mass
on echocardiography were the sole independent predictors
of WCHT.
More recently, Bjfrklund et al. [20] investigated, in a
longitudinal way, a population-based cohort of men not
treated with antihypertensive agents at baseline. They
observed consistently higher heart rate, OBP, and a
prevalence of abnormalities of glucose metabolism in
both patients with WCHT and SHT as opposed to
normotensives. However, LV mass and the prevalence
of micro-albuminuria did not differ between those with
WCHT (OBPz140 mm Hg systolic or z90 mm Hg
diastolic and daytime ABPb135 mm Hg systolic and b85
mm Hg diastolic) and the normotensive control group.
They also reported that a lower BMI and a more
favorable lipid profile characterized subjects with future
development of WCHT (after 20 years) as compared to
those with future SHT.
Segré et al. [23] carried out a retrospective study
including 670 treated and untreated hypertensive patients.
In the group of 183 patients taking no antihypertensive
medication, the prevalence and the determinants of WCHT
(OBPz140 mm Hg systolic or z90 mm Hg diastolic and
awake ABPb135 mm Hg systolic and b85 mm Hg
 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357
diastolic) were assessed. WCHT was only significantly
associated with familial history of hypertension; there was
no association between WCHT and sex, age, lipid profile,
and indices of target organ damage such as echocardio-
graphic parameters of LV mass, changes in fundoscopy,
creatinine level, etc.
Overall, the previous data indicate that, in untreated
hypertensive subjects, the probability of WCHT especially
increases with female sex [9,19,24] and mildly elevated
OBP levels [9,19,24]. Evaluation of other possible
determinants, such as (non)smoking status [9,19], age
[6,23,24], lipid levels [9,21,23], family history of hyper-
tension [9,23], number of OBP measurements [24],
educational level [9], and LV mass [19,23], was less
consistently carried out and sometimes showed contra-
dictory results.
4. Prognostic relevance of WCHT
Several studies have tried to evaluate the long-term
effects of WCHT on target organ damage (i.e., subclinical
lesions or functional deterioration of target organs such as
the heart, large arteries, eye, and kidney) and on the
occurrence of future cardiovascular (CV) events. Moreover,
some investigators have examined the relation between
WCHT and other traditional or novel CV risk factors.
Overall, the results of all these studies are not always easy
to interpret because of the use of different definitions of
WCHT (conservative versus liberal), different study
designs (cross-sectional study versus follow-up study),
different methods to quantify the long-term effects (LV
mass by echocardiography, carotid arteriosclerosis by
ultrasonography), differences in (baseline) characteristics
between the study groups (difference in OBP between
WCHT and SHT, difference in ABP between WCHT and
normotension), etc.
4.1. Target organ damage
The majority of trials evaluated LV parameters (echo-
cardiographically assessed LV mass, LV systolic or diastolic
function, prevalence of LV hypertrophy) [7,9,10,12,13,
23,25–43]. An overview of the trial results with respect to
LV mass can be found in Table 1. Data indicate that persons
with WCHT have a lower or similar LV mass compared to
those with SHT, and a higher or similar LV mass compared
to normotensives. Evaluation of systolic or diastolic LV
function or of the prevalence of LV hypertrophy gives
comparable results.
Several trials compared carotid artery structure and
function (intima-media thickness, prevalence of plaques)
[7,11,29,30,33,35,43–46]. They show less or equal carotid
artery damage in normotensive controls and more or equal
carotid artery damage in subjects with SHT in comparison to
those with WCHT.
351
We found only a few trials that looked at vascular
retinopathy [23,25,31,42,43]. The prevalence of vascular
retinopathy is reported to be lower or equal in WCHT as
compared to SHT, but higher (only two trials) in WCHT than
in NT.
Trials assessing renal function (urinary albumin excre-
tion, creatinine) [9,23,28–31,33,36,37,40,43,47–52] usu-
ally indicate that persons with WCHT have fewer or
equal signs of (early) renal damage as compared to those
with SHT, while there are no significant differences
between subjects with WCHT and normotensives.
4.2. Cardiovascular outcome
The majority of trials on cardiovascular (CV) outcome
[7,10,47–49,53–58] compare WCHT to SHT (Table 2)
and most of them indicate a worse (CV) prognosis in
those with SHT. Only one trial [54] reports a higher
mortality in persons with WCHT than SHT, but the
investigators used an unconventional definition of WCHT
based on nursesT BP measurements. Very recently, Bobrie
et al. [58] assessed the prognostic value of HBPM in an
elderly population treated for hypertension. They showed
that subjects with WCHT (high OBP, normal HBP) have
a good prognosis, equal to those with controlled hyper-
tension (normal OBP, normal HBP) and better than those
with masked (normal OBP, high HBP) or uncontrolled
(high OBP, high HBP) hypertension. Trials on (CV)
prognosis comparing WCHT to normotension are scarce
and show an equal or worse prognosis in patients with
WCHT [10,49,54,56].
4.3. Relation to other risk factors
Several investigators compared traditional metabolic
parameters that could influence CV risk, such as glucose
and insulin levels and lipid profile (total cholesterol,
LDL- and HDL-cholesterol, triglycerides) [7,9–11,28–
30,33,35,36,43,45–51,54,56]. The majority of data shows
similar glucose and lipid profiles in patients with WCHT
and SHT [7,9–11,28–30,33,43,45,47–51,56]; a few trials
report less favorable glucose and lipid levels in those
with WCHT as compared to normotensives [28,35,43,45,
46,54,56].
More recently, some dnovelT CV risk factors have also
been studied in WCHT. The majority of studies
evaluating endothelial function indicate that endothelial
dysfunction is more prevalent in WCHT than in
normotension, but that endothelial function is either
equal [51,59] or worse [47,50,60] in SHT as compared
to WCHT. Pierdomenico et al. [52] found lower
circulating homocysteine levels in subjects with WCHT
than in those with SHT, whereas no difference was
found between WCHT and normotension. In contrast,
Çoban et al. [61] report higher levels of plasma
fibrinogen and d-dimer in persons with WCHT than in
352 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357

Table 1
Prognostic significance of WCHT; trials assessing LV mass by echocardiography
Ref id Definition of WCHT Parameter WCHT versus NT WCHT versus SHT
[25] dOBPN90; LV mass index WCHT N NT WCHTbSHT
day sABPb134 and day dABPb90
[26] sOBPz160 or dOBP z90; LV mass index WCHT N NT WCHTcSHT
24 h sABPb140
[27] sOBPz160 and dOBPz95; LV mass index / WCHTcSHT
day sABPV146 and day dABPV87
[10] sOBPN140 or dOBPN90; LV mass WCHTcNT WCHTbSHT d
day sABPb131 (U) and day dABPb86 (U) bSHT ndw
b136 (h) b87 (h)
[28] dOBPz90; 24 h dABPb85 LV mass index WCHTcNT WCHTcSHT
[29] sOBPz140 or dOBPz90; LV mass index WCHTcNT WCHTbSHT
day ABPb90th percentile healthy volunteers
[30] sOBPN140 or dOBPN90; LV mass index WCHTcNT WCHTbSHT
24 h sABPb135 and 24 h dABPb85
[31] sOBP 145–190 or dOBP 90–114; LV mass index WCHT N NT WCHTbSHT
day sABPb134 and day dABPb90
[32] dOBPz90; day sABPb140 and day dABPb90 LV mass index WCHTcNT WCHTbSHT
[33] dOBPz90; day dABPb95 LV mass index WCHTcNT WCHTbSHT
[34] sOBPN140 or dOBPN90; LV mass index WCHTcNT /
day sABPb142 and day dABPb90
[36] sOBP 140–174 and dOBP 90–104; LV mass index WCHTcNT /
awake sABPb132 and awake dABPb84
[7] sOBP 140–180; intra-arterial 24 h sABPb140 LV mass index / WCHTbSHT
[37] sOBP 140–159 or dOBP90–99; LV mass index WCHT N NTx WCHTbSHTx
3 cutoffs day ABP-day sABPb130 and dABPb80
or day sABPb135 and dABPb85
or day sABPb140 and dABPb90
[38] sOBPN140 or dOBPN90; LV mass index WCHT N NT /
day sABPb135 and day dABPb85 and
night sABPb125 and night dABPb70
[39] by doctor: sOBPz160 or dOBPz95; LV mass WCHT N NT (WCHTcSHT)
by nurse: sOBPb140 and dOBPb90
[40] 0BP: mild to moderate HT; LV mass index WCHTcNTh WCHTbSHTh
4 cutoffs: day dABPb90;
day sABPb135 and day dABPb85;
day sABPb135.6 and day dABPb90.4;
day sABPb139.6 and day dABPb89.4
[41] sOBPz140 or dOBPz90; LV mass index / WCHTbSHT
day sABPV136 and day dABPV86
[9] sOBP 140–179 or dOBP 90–109; LV mass index / WCHTbSHT (U)
day sABPb135 and day dABPb85 WCHTcSHT (h)
[12] sOBPN140 or dOBPN90; LV mass index WCHT N NT WCHTbSHT
day sABPV130 and day dABPV80
[13] sOBPz140 or dOBPz90 LV mass index WCHT N NT r WCHTbSHT r
2 definitions: 24 h sABPb125 and 24 h dABPb79
or shomeBPb132 and dhomeBPb83
[42] sOBPz140 or dOBPz90; LV mass index WCHT N NT r WCHTcSHT r
3 definitions: 8 ABP criteria (see ref [42])
or day sABPb130 and day dABPb80
or day sABPb135 and day dABPb85
[23] sOBPz140 or dOBPz90; WCHT NOT associated to LV parameters
awake sABPb135 and awake dABPb85
[43] dOBPz90; day sABPb135 and day dABPb85 LV mass index WCHT N NT WCHTbSHT
WCHT: white-coat hypertension; NT: normotension; SHT: sustained hypertension; OBP: office blood pressure; ABP: ambulatory blood pressure; d: diastolic;
s: systolic; LV: left ventricular; XcY: X and Y comparable prognosis; XNY: X worse prognosis than Y; XbY: X better prognosis than Y; w: nd=non-
dipper=reduction in average s and dABP from day to night ofb10%, d=dipper=reduction in average s and dABP from day to night of z10%; x: data only
shown for cutoffs 130/80 and 135/85; h: for all four cutoff values; r: for all definitions of WCHT.

normotensive controls, yet lower ones than in patients innocent phenomenon, most available data suggest that
with SHT. persons with WCHT have a higher (CV) risk than
In conclusion, the prognostic relevance of WCHT normotensives, but a lower (CV) risk than those with
remains controversial. Although WCHT might still be an SHT.
 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357 353

Table 2
Prognostic significance of WCHT; trials evaluating dhard endpointsT
Ref id Definition of WCHT Parameter WCHT versus NT WCHT versus SHT
[10] sOBPN140 or dOBPN90; CV events WCHTcNT WCHTbSHT dbSHT ndw
day sABPb131 (U) and day dABPb86 (U)
b136 (h) b87 (h)
[47] sOBPz140 or dOBPz90; Silent / WCHTbSHT
24 h sABPb135 and 24 h cerebrovascular
dABPb80 damage
[7] sOBP 140–180; intra-arterial CV events / WCHTbSHT
24 h sABPb140
[53] dOBPN100; day dABPb88 CV events / WCHTbSHT1
WCHTbSHT2
[48] sOBP 160–219 and dOBPb95; CV events / WCHTbSHT
day sABPb140 Stroke / WCHTbSHT
[54] by doctor: sOBPN160 or Mortality WCHTNNT WCHTNSHT (!)
dOBPN95;
by nurse: sOBPb140 and
dOBPb90
[49] sOBPz140 or dOBPz90; Silent cerebral WCHTcNT WCHTbSHT
infarction
24 h sABPb130 and Stroke WCHTcNT WCHTbSHT
24 h dABPb80
[55] dDOBPz95; day sABPb140 CV events / WCHTbSHT
and day dABPb90
[56] sOBPz140 or dOBPz90; CV events WCHTNNTx WCHTcSHTx
2 definitions: day sABPb135 and day dABPb90 Mortality WCHTcNTx WCHTcSHTx
or day sABPb135 and day dABPb85
[57] sOBPN140 or dOBPN90; (% Multiple) silent / WCHT(dm )bSHT(dm )b
24 h sABPb135 and 24 h cerebral infarctions WCHT(dm+)bSHT(dm+)
dABPb80
[58] sOBPz140 or dOBPz90; CV events / WCHTccontrolled HTb
home sBPb135 and home masked HTcuncontrolled HT r
dBPb85
WCHT: white-coat hypertension; NT: normotension; SHT: sustained hypertension; OBP: office blood pressure; ABP: ambulatory blood pressure; d: diastolic;
s: systolic; CV: cardiovascular; XcY: X and Y comparable prognosis; XNY: X worse prognosis than Y; XbY: X better prognosis than Y; w: nd=non-
dipper=reduction in average s and dABP from day to night of b10%, d=dipper=reduction in average s and dABP from day to night of z10%; SHT1 has day
dABP 88–97 and SHT2 has day dABPN97; x: comparable results for both cutoffs; %: prevalence; dm : without diabetes mellitus; dm+: with diabetes mellitus;
r: controlled HT is normal OBP and normal home BP, masked HT is normal OBP and high home BP, uncontrolled HT is high OBP and high home BP.

Different explanations for this intermediate risk profile of 5. Evolution of WCHT

WCHT have been proposed, such as:
(1) increased BP variability [28,38,56] (although normal
average ABP values), but the evidence linking this
with higher target organ damage is limited [28, 56];.
(2) increased sympathetic activity [62, 63]. Recent evi-
dence has shown sympathetic neural hyperactivity in
SHT [64] and, to a lesser extent, in WCHT, which may
lead to the development of target organ damage.
Associations between sympathetic hyperactivity and
abnormalities of glucose and lipid metabolism have also
been reported [21];
(3) enhanced oxidative stress (increased LDL-oxidation,
reduced anti-oxidant activity) [65], leading to increased
risk of arteriosclerosis (via endothelial dysfunction).
However, it is not yet clear whether this enhanced
oxidative stress occurs before or after the development
of (white coat) hypertension. Moreover, Pierdomenico
et al. [66] did not find any difference in oxidative stress
between persons with WCHT and normotensives.
It has been proposed that WCHT is a prehypertensive
state, but data on the long-term evolution of OBP and
ABP of subjects with WCHT are limited and sometimes
contradictory [36,67]. Verdecchia et al. [68] showed that
28% of 64 study subjects with WCHT spontaneously
developed SHT after an average follow-up of 2.7 years.
Polonia et al. [36] assessed the evolution of OBP and
ABP for about 3.5 years both in untreated subjects with
WCHT and in a normotensive control group matched for
age, weight, and other CV risk factors. Their data suggest
that the percentage of patients with WCHT showing a
spontaneous progression towards dambulatory hyper-
tensionT (awake ABPz140/90 mm Hg) does not differ
significantly from normotensive controls. In contrast,
Bidlingmeyer et al. [67] report that over a 5- to 6-year
follow-up period, approximately 75% of their study
subjects with WCHT at baseline evolved towards
dambulatory hypertensionT (daytime ABPN140/90 mm
Hg). The evolution to SHT was associated with female
354 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357
gender and older age. The development of SHT on follow-
up could not, however, be predicted on the basis of OBP
values since these tended to decrease during follow-up.
6. Treatment and follow-up of WCHT
Most experts agree that antihypertensive drug treatment
should be instituted in subjects with WCHT and a high
CV risk (20% over 10 years) or documented target organ
damage [4,41]. However, evidence to date does not allow
us to make firm recommendations regarding drug treat-
ment in patients with uncomplicated WCHT in whom
medical therapy seems unnecessary. Further intervention
studies are needed to determine whether subjects with
WCHT will benefit from drug treatment to prevent the
future development of organ damage and risk of CV
events. In 1997, Staessen et al. [69] showed that
adjustment of antihypertensive treatment, based on either
ABP or OBP, led to less intensive drug treatment in the
ABP group. Nevertheless, BP control and inhibition of
LV enlargement were equal in both groups. In a recently
published similar trial, the same authors [70] found that
adjusting antihypertensive treatment on the basis of HBP
instead of OBP led to less intensive drug treatment, but
also to worse BP control at the end of the 12-month
treatment period. They did not find any difference in
general well-being or in electrocardiographic or echocar-
diographic LV mass. However, since the final difference
in BP between the two treatment groups (ranging between
3.5 and 6.8 for OBP) is considered clinically relevant,
their long-term prognosis might not be equal. Further
evidence comes from the ABPM substudy of the Syst-Eur
trial [48]. In Syst-Eur, elderly patients with isolated
systolic hypertension were randomized to be treated with
a dihydropyridine calcium antagonist or placebo, and
during the study period both OBP and ABP measure-
ments were taken. Active drug treatment lowered OBP in
all patients but had very little effect on ABP in patients
with dnon-sustainedT (white coat) hypertension. Antihy-
pertensive drug treatment reduced the rate of stroke in
patients with SHT, but patients with WCHT, who
experienced a very low stroke rate whether or not they
were treated, showed no significant benefit from medical
therapy. On the basis of the abovementioned studies, the
recommendation not to (pharmacologically) treat patients
with WCHT thus seems reasonable [5], but caution is
warranted. In patients with WCHT in whom antihyper-
tensive drug treatment is not started, a close follow-up
should certainly be implemented, including initiation of
life style changes, regular assessment of other risk factors,
such as lipid profile, and appropriate treatment if
(metabolic) abnormalities are present, regular OBP meas-
urements (at least every 6 months), and probably yearly
or 2-yearly ABPM to detect whether SHT occurs
[1,4,41,42,71].
7. What about the white-coat effect?
Some confusion exists concerning the terms WCHT and
white-coat effect (WCE). These two terms are sometimes
erroneously used as synonyms, but it should be stressed
that they are different entities. The transient BP rise
occurring as an alerting or defense or anxiety reaction
associated with the presence of a doctor is called the WCE.
It can be as high as 30 mm Hg, but usually averages about
20 mm Hg systolic and 10 mm Hg diastolic. The maximal
rise takes place 1–4 min after the doctorTs arrival, can
persist for up to 10–15 min, and is usually accompanied
by a parallel increase in heart rate. The size of the WCE
varies greatly in different subjects, is absent in many
individuals, and is not substantially influenced by reassur-
ance and familiarization with the technique or the circum-
stances of the BP measurement. A WCE can occur in both
normotensive and hypertensive persons. Although WCHT
is a consequence of the WCE, there is no automatic
association between the two. Persons with a high OBP and
a large WCE may show elevated ABP levels and thus have
SHT; persons with a light or moderate OBP elevation and
a small WCE may show a normal ABP level and thus have
WCHT [1,2].
The first attempts to quantify the WCE were done by
intra-arterial ABP measurement [72]. Because of practical
problems, other methods of estimating the WCE were
soon evaluated, such as the difference between OBP and
(daytime) ABP (ambulatory WCE) [72–74] or between
OBP and HBP (home WCE) [72,74]. Den Hond et al.
[75] showed that the ambulatory WCE was greater in
women than in men, and in treated than in untreated
patients. In addition, it increased with higher body mass
index and with advancing age. The (systolic) home WCE
was also significantly higher in females and showed a
slight increase with higher body mass index and with
older age. Methods using ABP or HBP to diagnose a
significant WCE (usually at least 20 mm Hg systolic or
10 mm Hg diastolic) are, however, reported to disagree in
this diagnosis in up to 20% of the subjects [74].
Moreover, recent data also show that there is no
correlation, or a poor one, between the above surrogate
measures of the WCE and a direct measure of the WCE
as assessed by noninvasive, continuous (beat-to-beat)
finger BP measurements (true WCE) [72,73]. This
disagreement is probably due to the fact that ABP
monitoring also includes BP responses to daily life
activities (mental or physical stress), which are absent
when the true (strict) WCE is considered. Several
investigators assessed the prognostic significance of the
dsurrogateT or dtrueT WCE. Most, though not all, data [76–
78] seem to indicate that the WCE does not predict future
target organ damage [72,73,79–81] or CV morbidity or
mortality [82]. Parati et al. [83] showed that the surrogate
(ambulatory and home) WCE is attenuated by antihyper-
tensive treatment but does not predict the treatment-
 H. Celis, R.H. Fagard / European Journal of Internal Medicine 15 (2004) 348–357
induced improvement in LV changes. This observation
also supports the hypothesis that the (surrogate) WCE is
of marginal clinical significance.
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