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Limitations of the difference between clinic and daytime
blood pressure as a surrogate measure of the ‘white-coat’
effect
Gianfranco Paratia,b, Stefano Ombonib, Jan Staessenc, Lutgarde Thijsc,
Robert Fagardc, Luisa Uliana, Giuseppe Manciad,a on behalf of the
Syst-Eur investigators
Background The difference between clinic and
ambulatory average daytime blood pressures is
frequently taken as a surrogate measure of the ‘whitecoat effect’ (i.e. the pressor reaction triggered in the
patient by the physician’s visit).
Objective To assess the reproducibility of this difference
and its relationship with clinic and average ambulatory
daytime blood pressure levels.
Design and methods These issues were addressed
with two large groups of subjects in whom both clinic
and ambulatory blood pressures were measured,
namely 783 outpatients with systolic and diastolic
essential hypertension [Group 1, aged 50.8 ± 9.4 years
(mean ± SD)], participating in standardized Italian trials of
antihypertensive drugs, and 506 elderly patients (group 2,
age 71 ± 7 years) with isolated systolic hypertension,
participating in the European Syst-Eur trial.
Results The clinic–daytime blood pressure difference for
the essential systolic and diastolic hypertensive patients
(group 1) was 13.6 ± 14.3 mmHg for systolic and
9.1 ± 8.6 mmHg for diastolic blood pressure (P always
< 0.01). This difference for the elderly patients with
isolated systolic hypertension (group 2) was
21.2 ± 16.0 mmHg for systolic and only 1.3 ± 10.2 mmHg
for diastolic blood pressure (P < 0.01 and P < 0.05,
respectively). In both studies little or no systematic
clinic–daytime difference could be observed for heart
rate. The reproducibility of the clinic–daytime blood
pressure difference, tested for 108 essential systolic and
diastolic hypertensive patients from group 1 and 128
isolated systolic hypertensives from group 2, was
Introduction
Ambulatory intra-arterial blood pressure monitoring has
shown that blood pressure measurements by a doctor may
induce an alerting reaction and thus an increase in the
patient’s blood pressure and heart rate [1,2]. It is believed
that this phenomenon (which is known as the ‘white-coat
effect’) can lead to an erroneous diagnosis of hypertension
or an inaccurate estimate of the response to antihyper0263-6352
© 1998 Rapid Science Ltd
invariably lower than that both of daytime and of clinic
blood pressure values. Finally, the clinic–daytime blood
pressure difference was progressively higher for
increasing levels of clinic blood pressure and
progressively lower for higher levels of ambulatory
daytime blood pressure.
Conclusions Thus, the clinic–daytime blood pressure
difference has a limited reproducibility; depends not only
on clinic but also on daytime average blood pressure,
which means that its size is a function of the blood
pressure criteria employed for selection of the patients
in a trial; and is never associated with a systematic
clinic–daytime difference in heart rate, which further
questions its use as a reliable surrogate measure of the
true pressor response induced in the patient by the
doctor’s visit. J Hypertens 16:23–29 © 1998 Rapid
Science Ltd.
Journal of Hypertension 1998, 16:23–29
Keywords: ambulatory blood pressure monitoring, alerting reaction, clinic
blood pressure, hypertension, white-coat effect, blood pressure
reproducibility
d
Cattedra di Medicina Interna, Ospedale S. Gerardo, Monza, University of
Milan, aCentro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore and
University of Milan, bIstituto Scientifico Ospedale S. Luca, Fondazione Istituto
Auxologico Italiano, Milan, Italy, and cUniversitaire Ziekenhuizen, Hypertension
Unit, Gasthuisberg O&N, Leuven, Belgium.
Requests for reprints to Dr Gianfranco Parati, Centro di Fisiologia Clinica e
Ipertensione, Università di Milano, Ospedale Maggiore, Via F. Sforza 35,
20122 Milano, Italy.
Received 6 June 1997 Revised 30 September 1997
Accepted 7 October 1997
tensive treatment [3–5] and that therefore its quantification is clinically useful. However, because intra-arterial
blood pressure monitoring cannot be used on a large scale,
in the clinical setting the quantification of the pressor
effects of the doctor’s visit has generally been obtained
indirectly by computing the difference between blood
pressure values measured in the clinic environment and
the daytime average blood pressure provided by non-
24 Journal of Hypertension 1998, Vol 16 No 1
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invasive ambulatory blood pressure monitoring. Indeed,
it is upon this difference that most hypotheses and conclusions on the prevalence and prognostic value of the
‘white-coat effect’ have been based [6–12].
In spite of its generalized use, few studies have been performed on the reproducibility of the difference between
clinic and daytime average blood pressures [13]. Furthermore, the relationship between the magnitude of this
surrogate measure of the ‘white-coat effect’ and the
concomitant clinic and ambulatory blood pressure values
(i.e. its dependence or independence with respect to the
values from which it is derived) has never been examined systematically. Finally, no study has ever determined
whether and to what extent differences between clinic
and ambulatory systolic blood pressure, diastolic blood
pressure and heart rate relate to each other, thereby
reflecting in a consistent and reliable fashion the cardiovascular response to an alerting condition. In the present
study we have addressed these issues in patients with
systolic and diastolic essential hypertension and in old
patients with isolated systolic hypertension.
Methods
Subjects and study design
The present study included two different groups of
patients. Group 1 consisted of 783 Caucasian patients
of both sexes (476 men and 307 women) aged 18–78 years
(mean ± SD 50.8 ± 9.4 years). The patients were seen in
Italian outpatient clinics participating in multicentre trials
on efficacy of antihypertensive drugs. Mild or moderate
essential hypertension had been diagnosed in all of them,
on the basis of their having a clinic diastolic blood pressure
in the range 91–109 mmHg after a 3-week washout from
previous antihypertensive treatment under placebo and a
lack of a history or signs of cardiovascular complications
and major end-organ damage. Patients were excluded
from the study if they had diabetes mellitus, a body mass
index > 30 kg/m2, atrial fibrillation or other major arrhythmias, a history of excessive alcohol consumption and major
cardiovascular or non-cardiovascular diseases; and if they
had previously been exposed to ambulatory blood
pressure monitoring techniques.
Group 2 consisted of 506 older patients (307 women and
199 men, aged more than 60 years, mean ± SD 70.1 ± 6.9
years) with isolated systolic hypertension who had been
taking part in the Syst-Eur (Systolic Hypertension in
Europe) Trial (i.e. the European outcome trial on antihypertensive treatment of older patients with isolated
systolic hypertension [14,15]). Exclusion criteria for this
group were a history of myocardial infarction or stroke
incidence, retinopathy of degree II–IV, symptoms and
signs of congestive heart failure, evidence of aortic dissecant aneurysms, major concomitant diseases (e.g.
dementia) and poor compliance with the assigned treatment. The patients were recruited from outpatient clinics
and general practices in some countries and from the
general population in others. They were enrolled if, after
a single-blind period of 3 months’ placebo, their clinic
systolic blood pressure was in the range 160–219 mmHg,
with a diastolic blood pressure below 95 mmHg.
Measurements
Blood pressure and heart rate were measured in the outpatient clinics by a doctor with the patient seated. Blood
pressure was measured with a mercury sphygmomanometer, using Korotkoff phases I and V to identify
systolic and diastolic values, respectively, except for a few
patients from group 2, for whom Korotkoff phase V was
substituted by phase IV. Heart rate was measured by the
palpatory method as the frequency of consecutive pulse
waves at the radial artery level for 30 s. For group 1
patients the averages of two measurements performed
during the visit closest to the time when ambulatory blood
pressure monitoring was performed (see below) were
considered the baseline clinic blood pressure and heart
rate values, whereas for patients from group 2 only one
measurement per visit was performed. After the clinic
blood pressure assessment, blood pressure and heart rate
were also monitored for 24 h under ambulatory conditions
by using non-invasive automatic devices for which validation had been achieved in previous studies either by
making use of the comparison with ambulatory intra-arterial blood pressure recordings or by following the guidelines proposed by the American Association for the
Advancement of Medical Instrumentations and by the
British Hypertension Society [16–20]. These devices,
which included SpaceLabs 90202 and 90207 monitors
(SpaceLabs, Redmond, Washington, USA), the Takeda
TM 2020/2420 monitors (A&D Company Ltd, Tokyo,
Japan) and the Accutracker II monitor (Suntech
Instruments, Raleigh, North Carolina, USA), were
programmed to measure blood pressure and heart rate at
15–30 min intervals [15].
Data analysis
Twenty-four-hour blood pressure recordings for the
group 1 patients were excluded from analysis when blood
pressure readings were not available for more than two
consecutive hours, more than 20% of the expected readings were missing or more than 20% of the expected
readings had been discarded by the device software on
the basis of the following criteria: systolic blood pressure
< diastolic blood pressure, systolic blood pressure
> 260 mmHg or < 50 mmHg, diastolic blood pressure
> 160 mmHg or < 40 mmHg, heart rate > 150 beats/min or
< 40 beats/min and pulse pressure < 10% of systolic blood
pressure [15]. Blood pressure recordings for group 2
patients were excluded from analysis only under the first
two conditions mentioned above and when the timing of
sleep and awakening was not known. All unedited values
automatically recorded during the 24 h were considered for
the analysis, on the basis of the observation that presently
Clinic-daytime blood pressure difference and white-coat effect Parati et al. 25
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available oscillometric blood pressure monitoring devices
provide a very low number of identifiable artefactual measurements, whose removal does not produce appreciable
changes in the daytime or 24 h average values [21]. We thus
considered for the final analysis data from 783 patients from
group 1 and 506 patients from group 2.
Daytime and night-time periods were defined according
to patients’ diaries. Average systolic blood pressures, diastolic blood pressures and heart rates were calculated for
the 24 h, daytime and night-time periods. The difference
between clinic and ambulatory average daytime blood
pressures was computed by subtracting average daytime
systolic blood pressure or diastolic blood pressure from
the corresponding clinic values (‘surrogate’ white-coat
effect, SWC). A similar calculation was carried out for
heart rate.
The reproducibilities of clinic and ambulatory blood
pressure values and the reproducibility of their difference (SWC) were assessed by the Bland and Altman technique [22] for data from subgroups of 108 patients from
group 1 [66 men and 42 women, aged 52.2 ± 8.2 years
(mean ± SD)] and 128 patients from group 2 (51 men and
77 women, aged 71 ± 6.5 years), for whom clinic and 24 h
ambulatory blood pressure measurements were repeated
during placebo at 4-week intervals. This was done by calculating the mean differences between the two recordings, taking into account the sign of the difference
(‘change’), and the repeatability coefficients, defined as
twice the SD of the intra-individual differences between
the two recordings. To allow comparisons between various
measurements, these coefficients were expressed as
percentages of the near-maximum variation in the
recorded blood pressures (i.e. they were divided by four
times the SD of average blood pressure obtained for the
group at the time of the first recording and multiplied by
100). Values are expressed as means ± SD. Statistical
analysis was performed by means of the SAS and the
SPSS softwares [23,24]. The differences between clinic
and daytime blood pressure and heart rate values were
tested by Student’s t test. P < 0.05 was considered statistically significant.
Results
In Table 1 we report the average blood pressure and heart
rate values obtained for the two groups of patients. For
group 1 patients, systolic and diastolic average daytime
blood pressure values were both markedly lower than the
corresponding clinic values. In contrast, for group 2
patients, while daytime average systolic blood pressure
was markedly less than clinic systolic blood pressure, the
difference between daytime average and clinic diastolic
blood pressure was very small. For both groups of patients
the difference between clinic and daytime average heart
rate values was also very small. Thus for group 1 patients
a marked SWC was observed both for systolic and for
diastolic blood pressure. For group 2 patients a SWC was
present for systolic blood pressure and only to a minimal
extent for diastolic blood pressure. For both groups little
or no SWC was found for heart rate.
In Table 2 we report the data obtained by testing the
reproducibility of clinic and daytime average blood
pressures, clinic and daytime average heart rate and the
derived SWC. For systolic blood pressure the reproducibility was highest for the daytime average value, less
for the clinic value and lowest for SWC. This was the
case also for diastolic blood pressure. Heart rate reproducibility also tended to be greater for average daytime
than it was for clinic blood pressures and was lowest for
SWC.
Clinic and daytime systolic and diastolic blood pressures
both for group 1 and for group 2 patients displayed a
significant relationship (Fig. 1). For group 1, SWC became
more pronounced with the increase in clinic blood
pressure but less pronounced with the increase in daytime
blood pressure. This was the case both for systolic and
for diastolic blood pressure (Figs 2, 3, upper panels). It
was also the case for systolic SWC for patients from group
2 (Figs 2, 3, lower panels). In contrast, less clear relationships were found for this group for SWC based on
diastolic blood pressure, whose clinic value was on average
only 1.3 mmHg higher than daytime average diastolic
blood pressure. Thus the surrogate measure of the whitecoat effect based on the difference between clinic and
Clinic and ambulatory blood pressure and heart rate (pulse rate) values in untreated
patients with systolic and diastolic hypertension (group 1) and with isolated systolic hypertension (group 2)
Table 1
Systolic
blood pressure
(mmHg)
Systolic and diastolic hypertension (group 1, n = 783)
Clinic
160.2 ± 14.4
Daytime average
146.6 ± 14.5
Difference (clinic minus daytime)
13.6 ± 14.3**
Isolated systolic hypertension (group 2, n = 506)
Clinic
174.0 ± 13.8
Daytime average
152.8 ± 16.1
Difference (clinic minus daytime)
21.2 ± 16.0**
Values are expressed as means ± SD. *P < 0.05, **P < 0.01.
Diastolic
blood pressure
(mmHg)
Heart
rate
(beats/min)
103.3 ± 4.9
94.1 ± 9.5
9.1 ± 8.6**
75.3 ± 8.6
77.3 ± 8.8
1.9 ± 9.2*
85.8 ± 7.9
84.5 ± 9.8
1.3 ± 10.2*
73.9 ± 10.6
74.0 ± 9.6
0.0 ± 9.9
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Reproducibility of clinic and ambulatory blood pressure and heart rate values for 108 subjects with systolic and diastolic
hypertension (group 1) and 128 subjects with isolated systolic hypertension (group 2)
Table 2
Systolic and diastolic hypertension (group 1, n = 108)
Clinic
Daytime average
Difference (clinic minus daytime)
Isolated systolic hypertension (group 2, n = 128)
Clinic
Daytime average
Difference (clinic minus daytime)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Heart rate
(beats/min)
Change
(mmHg)
Repeatability
(mmHg)/(%)
Change
(mmHg)
Repeatability
(mmHg)/(%)
Change
(beats/min)
Repeatability
(beats/min)/(%)
−1.7
0.7
−2.4
27.6/49.3
19.6/36.3
34.2/62.0
−0.8
0.5
−1.3
19.9/63.8
13.4/36.0
23.4/61.6
−0.6
1.3
−2.0
14.4/45.0
12.8/43.8
17.6/54.3
−0.9
−2.5**
+1.6
30.2/46.6
19.2/28.8
32.3/49.0
−1.0
−1.3*
+0.3
15.0/40.8
13.2/30.0
18.2/43.9
0.5
−0.8
+1.3
17.7/42.5
11.3/29.8
19.4/58.0
Values are expressed as mean ± SD. ‘Change’ indicates the mean difference between two recordings, at 4 week intervals, taking into account the sign of the
difference (a decrease indicated by ‘–’ and an increase by ‘+’). *P < 0.05; **P < 0.01.
Fig. 1
Relationship between clinic and daytime blood
pressures for 783 patients with mild or moderate
essential hypertension (group 1, upper panels) and
506 elderly patients with isolated systolic hypertension (group 2, lower panels). Individual data for
systolic blood pressure (SBP) and diastolic blood
pressure (DBP) are shown separately. Continuous
lines represent the identity and the discontinuous
lines the regression lines for relationships between
clinic and daytime blood pressure.
daytime blood pressure by definition exhibits an opposite
(and expected) dependence on these blood pressure
values. Namely, it increases with an increase in clinic
blood pressure, but it decreases with an increase in
daytime blood pressure.
Discussion
Our results show that the surrogate measure of the whitecoat effect that is commonly used in the clinical setting
(i.e. the difference between clinic and daytime average
blood pressures) has a limited reproducibility. Moreover,
our data provide evidence that it is characterized by other
limitations. First, confirming previous data from a large
population survey [25] both for the essential (group 1)
and for the isolated systolic hypertensive patients (group
2) of the present study, clinic and daytime average blood
pressures were positively related to each other. Namely,
these two blood pressures exhibited a mutual interdependence, which means that their difference (i.e. the
surrogate white-coat effect) cannot be measured in an
entirely independent fashion. Second, whereas for group
1 patients the clinic–daytime difference was similar for
Clinic-daytime blood pressure difference and white-coat effect Parati et al. 27
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Fig. 2
Magnitude of the clinic–daytime difference in
blood pressure plotted versus clinic blood pressure
values. Individual data are shown separately for
systolic blood pressure (SBP) and diastolic blood
pressure (DBP) and for the groups with mild or
moderate essential hypertension (group 1, upper
panel) and isolated systolic hypertension
(group 2, lower panels).
Fig. 3
Magnitude of the clinic–daytime difference in blood
pressure plotted versus average daytime blood
pressure values. Individual data are shown
separately for systolic blood pressure (SBP) and
diastolic blood pressure (DBP) and for the groups
with mild or moderate essential hypertension (group
1, upper panels) and isolated systolic hypertension
(group 2, lower panels).
J HYPERTENSION 16/1: Paper ID: 188
PARATI
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systolic and diastolic blood pressures, for group 2 patients
it was exceedingly large for systolic but virtually nonexistent for diastolic blood pressure. Furthermore, with both
groups we consistently observed no difference between
clinic and daytime heart rate values. Thus, the white-coat
effect reflected by this surrogate measure varies enormously according to the haemodynamic variable considered. This is in striking disagreement with the results
obtained by direct measurement of this phenomenon
through ambulatory intra-arterial blood pressure monitoring, which showed it to be characterized by increases
in systolic blood pressure, diastolic blood pressure and
heart rate at all baseline blood pressures and ages [1,2].
Were they to reflect the white-coat effect precisely, differences between clinic and daytime data should thus always
be detectable in all these variables.
stimuli, exercise and, for the elderly, also blood-pressurelowering events such as maintaining an upright posture
and digestion. The interpretation of the clinic–daytime
blood pressure difference as a specific reflection of the
white-coat effect is thus simplistic [13,31]. One might
speculate that a closer correspondence between the true
white-coat effect and the clinic–daytime blood pressure
difference could be achieved by only using the daytime
values occurring at the time around the clinic blood
pressure measurements, which could make this difference
more specific. This suggestion, however, which might
make the clinic–daytime blood pressure differences even
less reproducible, needs to be suitably tested in future
studies.
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Third, confirming and expanding on previous observations [25–30], for our essential and isolated systolic hypertensive patients the difference between clinic and
daytime average blood pressures increased with the
increase in clinic blood pressure. However, this difference
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pressure the less the surrogate measure of the white-coat
effect based on the clinic–daytime blood pressure difference). Because daytime blood pressure values are by definition not affected by the alerting reaction to the doctor’s
visit, this is another argument against the utility of
clinic–daytime blood pressure differences as an exclusive
expression of the white-coat effect.
An additional finding that should contribute to discouraging one from using the clinic–daytime blood pressure
difference as a precise quantification of the white-coat
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