Prognostic Significance of the White Coat Effect
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Abstract
Abstract The difference between clinic and ambulatory blood pressure (BP) has been used to quantify the pressure reactivity to the doctor’s visit (white coat effect). We investigated the prognostic significance of the clinic-ambulatory BP difference in the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study. A total of 1522 subjects contributed 6371 person-years of observation. All subjects had an initial off-therapy diagnostic workup including 24-hour noninvasive ambulatory BP monitoring. The predicted values of ambulatory BP progressively diverged from the identity line (white coat effect of 0 mm Hg) with increasing clinic BP, but the predicted values of clinic BP tended toward the identity line with increasing ambulatory BP. Hence, the clinic-ambulatory BP difference showed a direct association with clinic BP and an inverse association with ambulatory BP. Consequently, a high clinic-ambulatory BP difference predicted both a high clinic and a low ambulatory BP, whereas a low clinic-ambulatory BP difference predicted both a low clinic and a high ambulatory BP. The clinic-ambulatory BP difference showed also a direct association with age. During up to 9 years of follow-up (mean, 4.2 years), there were 157 major cardiovascular morbid events (125 nonfatal and 32 fatal). The rate of total cardiovascular morbid events did not differ (log-rank test) among the four quartiles of the distribution of the clinic-ambulatory BP difference (2.13, 2.92, 2.10, and 2.83 events per 100 patient-years for systolic BP and 2.94, 2.14, 2.58, and 2.16 events per 100 patient-years for diastolic BP). Also, the rate of fatal cardiovascular events did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference. The clinic-ambulatory BP difference, taken as a measure of the white coat effect, does not predict cardiovascular morbidity and mortality in subjects with essential hypertension.
Measurement of blood pressure (BP) by the doctor in the clinic environment may trigger an alerting reaction, leading to a transient pressor rise in the patient.1 2 The BP rise is maximal during the first 4 minutes of the visit and persists over about 10 minutes.3 4 A reliable measurement of the transient pressor rise during the visit, usually referred to as the white coat effect or phenomenon, is possible through intra-arterial or noninvasive techniques that allow a beat-by-beat estimate of the BP rise from immediately before to during the visit. The white coat effect has also been estimated by the difference between clinic BP and average daytime ambulatory BP,5 6 on the assumption that average daytime ambulatory BP reflects the BP immediately before the visit. However, Parati et al7 recently demonstrated that there is no association between the BP rise from before to during the visit, determined beat-to-beat with the Finapres method, and the difference between clinic and daytime ambulatory BPs. The prognostic significance of the white coat effect is still unsettled, while recent prospective data suggest that isolated clinic hypertension, also referred to as white coat hypertension,8 9 appears to be a condition of low cardiovascular morbidity.10 11 12
In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study,10 13 all subjects underwent baseline off-therapy clinic BP determination and 24-hour noninvasive ambulatory BP monitoring, and all were subsequently followed for up to 9 years for assessment of cardiovascular morbidity and mortality. Thus, we analyzed the PIUMA database to investigate correlates and the prognostic significance of the difference between clinic and ambulatory BPs before treatment, taken as a surrogate measure of the white coat effect.
Methods
Subjects
The study group was composed of 1522 hypertensive subjects (51% men; mean age, 52 years [SD 12]) enrolled in the PIUMA study, a registry of morbidity and mortality in subjects with essential hypertension whose off-therapy initial diagnostic work included 24-hour noninvasive ambulatory BP monitoring according to a standardized protocol.10 13 All subjects had clinic systolic BP of 140 mm Hg or higher and/or diastolic BP of 90 mm Hg or higher on at least three visits at 1-week intervals and fulfilled all the following inclusion criteria: (1) no previous treatment for hypertension or withdrawal from antihypertensive drugs at least 4 weeks before the study; (2) no clinic or laboratory evidence of heart failure, coronary heart disease, valvular defects, or secondary causes of hypertension; and (3) at least one valid BP measurement per hour over the 24 hours. The initial evaluation in the PIUMA study has been described elsewhere.10 13
BP Measurement
Clinic BP was measured by a mercury sphygmomanometer with the subject sitting for at least 10 minutes. Heart rate was determined immediately thereafter. No caffeine ingestion or cigarette smoking was permitted during the previous 2 hours. Ambulatory BP was recorded with ambulatory BP monitors (SpaceLabs 90202 and 90207) set to take a reading every 15 minutes throughout the 24 hours. Normal daily activities were allowed, and subjects were told to keep their nondominant arm still and relaxed to the side during measurements. Daytime and nighttime BP averages were calculated by the so-called narrow fixed-clock intervals (daytime period from 10 am to 8 pm, nighttime period from midnight to 6 am) to avoid the transitional periods (from 6 to 10 am and from 8 pm to midnight) during which a variable number of subjects may be awake or asleep. It has been previously shown that the narrow fixed-clock intervals method is appropriate for estimation of daytime and nighttime BPs14 ; also, in our and others’15 experience, the periods of wakefulness and sleep resulting from subjects’ diaries may not always be accurate. The spontaneous day-to-day variations of 24-hour, daytime, and nighttime ambulatory BPs were previously assessed in some of these subjects.16
Echocardiography
M-mode echocardiographic study of the left ventricle was performed under cross-sectional control with commercially available machines according to standard laboratory procedures described previously.10 13 Only tracings with optimal visualization of interfaces and showing simultaneous visualization of the septum, left ventricular (LV) internal diameter, and posterior wall were considered adequate for determination of LV mass. Echocardiographic examinations were performed by two physicians and tracings read by two other investigators. The mean value from at least five measurements of the left ventricle per observer was computed. At the time of the echocardiographic examination, all involved investigators were unaware of subjects’ casual and ambulatory BP values. LV mass (grams) was determined with the formula of Devereux et al17 —LV Mass=0.80×{1.04×[(Septal Thickness+LV Internal Diame-ter+Posterior Wall Thickness)3−(LV Internal Diameter)3]}+0.6 g—and normalized by body surface area. LV mass was also corrected by height elevated at a power of 2.7, as suggested by de Simone et al.18
Electrocardiography
Standard 12-lead electrocardiograms were recorded on all subjects at 25 mm/s and 1 mV/cm calibration. Tracings were coded and interpreted by two investigators without knowledge of other subject data. Interobserver differences occurred for less than 5% of readings and were resolved by consensus. Subjects with complete bundle branch block, previous myocardial infarction, Wolff-Parkinson-White syndrome, or atrial fibrillation were excluded from the analysis. None of the subjects was being treated with digitalis. LV hypertrophy was diagnosed with the sex-specific Cornell voltage (sum of the amplitudes of S wave in V3 and R wave in aVL >2.0 mV in women and >2.8 mV in men).19
Follow-up
All subjects were followed by their family doctors in cooperation with the out-patient clinic of the referring hospital and treated with the aim of reducing clinic BP below 140/90 mm Hg using standard lifestyle and pharmacological measures. By protocol, therapeutic strategies were based on clinic BP, although ambulatory BP reports remained accessible to subjects and their doctors. Diuretics, β-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and α1-blockers, alone or in various combinations, were the antihypertensive drugs most frequently used. Since no more than 30% of the subjects had the opportunity to repeat 24-hour ambulatory BP monitoring during therapy at a distance of months or years from the initial evaluation, telephone interviews were conducted with most of the subjects to ascertain the incidence of major complications of hypertension. All interviews were conducted directly with the subjects without knowledge of the results of ambulatory BP monitoring.
Hospital record forms and other available original source documents were reviewed in conference by the authors of this study for the subjects who died from any cause or developed a major fatal or nonfatal cardiovascular event. Cardiovascular events included myocardial infarction, stroke, sudden death, angina pectoris, coronary revascularization, transient cerebral ischemic attack, aortoiliac occlusive disease verified at angiography, documented thrombotic occlusion of a retinal artery, progressive heart failure requiring hospitalization, or renal failure requiring dialysis. Transient ischemic attack was defined by the diagnosis, made by a physician, of any sudden focal neurological deficit that cleared completely in less than 24 hours. Heart failure was defined by the simultaneous presence of at least two major criteria or one major plus two minor criteria as suggested in the Framingham Study.20 The international standard criteria used to diagnose cardiovascular events in the PIUMA study have been described elsewhere.10 13
Data Analysis
Parametric data are reported as mean±SD. Standard descriptive and comparative statistical analyses were undertaken. The outcome events studied were fatal plus nonfatal cardiovascular morbid events. Event rate is presented as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure. Survival curves in the four quartiles of the distribution of the difference between clinic and average daytime ambulatory BPs were estimated with the Kaplan-Meier product-limit method21 and compared by the Mantel (log-rank) test.22 In two-tailed tests, values of P<.05 were considered statistically significant. SAS statistical software (version 6.08, SAS Institute) was used to perform the analysis.
Results
Table 1⇓ shows the main descriptive data in the overall population. Overall, 40% of the subjects were grouped in stage I as defined by the Fifth Joint National Committee report on the detection, evaluation, and treatment of high BP (JNC-V) (clinic systolic BP 140 to 159 mm Hg and diastolic BP 90 to 99 mm Hg).23 The prevalence of echocardiographic LV hypertrophy was 25.3% using the threshold value of 125 g/m2 and was 41.3% using the division line of 51 g/height2.7. The prevalence of LV hypertrophy at electrocardiography was 8.9% using the Cornell score.19 The difference between clinic and daytime ambulatory BPs averaged 13.5 mm Hg (SD 15) for systolic pressure and 4.8 mm Hg (SD 9) for diastolic pressure. The limits for definition of the four quartiles of the distribution of the clinic-ambulatory BP difference were 3, 13, and 23 mm Hg for systolic BP and −1, 5, and 11 mm Hg for diastolic BP.
Descriptive Data in the Study Population (n=1522)
Table 2⇓ shows the main descriptive data in the four quartiles of the distribution of the clinic-ambulatory BP difference. Age, clinic systolic BP, and the proportion of women progressively increased from the lowest to the highest quartile of the distribution for systolic BP (all comparisons between quartiles, P<.01) but not for diastolic BP. LV mass, the prevalence of LV hypertrophy at electrocardiography, and the prevalence of diabetes did not differ among the four quartiles of the distribution for both systolic and diastolic BPs. The prevalence of smokers progressively decreased from the bottom to the top quartile of the distribution of the clinic-ambulatory BP difference for both systolic and diastolic BPs (all comparisons between quartiles, P<.01).
Descriptive Data in the Four Quartiles of the Distribution of Clinic-Ambulatory Blood Pressure Difference
As shown in Fig 1⇓, there was a direct association between clinic BP and average daytime ambulatory systolic (r=.61, P<.001) and diastolic (r=.60, P<.001) BPs. The predicted values of ambulatory systolic and diastolic BPs progressively diverged from the identity line (white coat effect of 0 mm Hg), with the increase in clinic BP over most of its distribution (Average Daytime Systolic BP=62.7+0.52×Clinic Systolic BP; Average Daytime Diastolic BP=30.7+0.63×Clinic Systolic BP). However, the predicted values of clinic systolic and diastolic BPs tended toward the identity line, with the increase in ambulatory BP over most of its distribution (Clinic Systolic BP=53.3+0.73×Average Daytime Systolic BP; Clinic Diastolic BP=44.8+0.57×Average Daytime Diastolic BP). Consequently, as shown in Table 3⇓ and Fig 2⇓, the clinic-ambulatory BP difference showed a direct association with clinic BP and an inverse association with ambulatory BP. The clinic-ambulatory systolic BP difference showed also a direct association with age (r=.32, P<.01). Table 4⇓ shows that antihypertensive treatment during follow-up did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference.
Association between clinic and average daytime ambulatory blood pressures (BPs). Predicted values of ambulatory BP progressively diverged from the identity line (white coat effect of 0 mm Hg) with the increase in clinic BP (left), but after reversion of the association, the predicted values of clinic BP tended toward the identity line with the increase in ambulatory BP (right).
Clinic-ambulatory blood pressure (BP) difference displays a direct association with clinic BP (r=.59 for systolic and r=.40 for diastolic BP) and inverse association with ambulatory BP (r=−.28 for systolic and r=−.50 for diastolic BP).
Relation of the Difference Between Clinic and Average Daytime Blood Pressures to Age and Blood Pressure (White Coat Effect)
Distribution of Antihypertensive Treatment
Cardiovascular Morbidity
During follow-up, there were 157 major cardiovascular morbid events (32 fatal and 125 nonfatal), and the 1522 study subjects contributed 6371 person-years of observation. There were 12 subjects with fatal stroke, 5 with fatal myocardial infarction, 15 with sudden cardiac death, 37 with nonfatal stroke, 12 with transient ischemic attack, 17 with nonfatal myocardial infarction, 20 with new-onset angina, 4 who underwent coronary surgery, 11 with severe heart failure requiring hospitalization, 15 with new-onset aortoiliac occlusive disease, 2 with occlusion of the retinal artery, and 5 with renal failure requiring dialysis. The rate of events in each quartile of the distribution of the clinic-ambulatory BP difference is reported in Fig 3⇓. The rate of total cardiovascular morbid events did not differ (log-rank test) among the four quartiles of the distribution of the clinic-ambulatory BP difference (2.13, 2.92, 2.10, and 2.83 events per 100 patient-years for systolic BP and 2.94, 2.14, 2.58, and 2.16 events per 100 patient-years for diastolic BP). Also, the rate of fatal cardiovascular events did not differ among the four quartiles of the distribution of the clinic-ambulatory BP difference (0.38, 0.69, 0.67, and 0.31 events per 100 patient-years for systolic BP and 0.69, 0.36, 0.61, and 0.30 events per 100 patient-years for diastolic BP).
Rate of total (top) and fatal (bottom) cardiovascular morbid events over a follow-up period of 0 to 9.7 years in 1522 subjects with essential hypertension. Cardiovascular morbidity and mortality rates did not differ among the four quartiles of the distribution of the difference between clinic blood pressure and average daytime ambulatory blood pressure.
Discussion
The white coat effect and white coat hypertension differ in their definitions, pathophysiological mechanisms, and clinical significance. The former is a measure of BP change from before to during the visit,3 4 which increases with clinic BP6 24 and age.25 The latter is an attempt to define a low-risk stratum of clinically hypertensive subjects with normal BP levels out of the medical setting,8 26 regardless of their rise in BP from before to during the visit. The white coat effect has been estimated beat-to-beat using invasive3 4 or noninvasive7 techniques, as well as from the difference between clinic BP and average ambulatory BP during the awake period.6 25 27 The definition of white coat hypertension is not yet unanimously settled, requiring consensus on what are “normal” and “abnormal” BP values out of the doctor’s office.5
It is tempting to consider the white coat effect and white coat hypertension as nearly synonymous because a marked rise in BP from before to during the visit suggests an increased likelihood of clinic hypertension associated with normal BP levels outside the medical setting. However, such practice is incorrect for several reasons. First, the white coat effect does not necessarily show an inverse association with the severity of hypertension. In fact, although the magnitude of the white coat effect is greater, on average, in subjects with white coat hypertension than it is in those with higher levels of ambulatory BP (“ambulatory hypertension”),24 it also increases with the severity of clinic hypertension according to JNC-V stage. In contrast, the prevalence of white coat hypertension decreases with increasing JNC-V stage.24 In other words, a small white coat effect may lead to white coat hypertension in subjects with mild hypertension and mildly increased ambulatory BP, whereas a large white coat effect may still be associated with increased ambulatory BP levels in subjects with moderate or severe hypertension and high levels of ambulatory BP. Second, there is less target-organ damage in subjects with white coat hypertension than in those with ambulatory hypertension, although it is unrelated to the magnitude of the white coat effect. In some studies,24 27 28 but not in all,29 no association has been found between the magnitude of the white coat effect and a widely used measure of target-organ damage, such as LV mass, which in most studies,9 24 30 31 32 but not in all,33 34 35 was normal in individuals with white coat hypertension. Third, the estimate of the white coat effect from the difference between clinic and awake ambulatory BPs may not reflect the true increase in BP elicited by the clinic visit. Parati et al7 did not detect any association between the white coat effect determined beat-to-beat from before to during the visit and the difference between clinic and daytime ambulatory BPs.
The present study is the first to address the prognostic significance of the clinic-ambulatory BP difference in a large cohort of subjects with essential hypertension, who contributed 6371 person-years of observation. The rate of total and fatal cardiovascular events over an observation period of up to 9 years did not show any association with the white coat effect. Since cardiovascular morbidity and mortality are directly associated with clinic BP and initial prospective data show that this seems to the case for ambulatory BP,5 10 12 36 the opposite sign of the relation of the clinic-ambulatory BP difference to clinic BP versus ambulatory BP may provide a potential explanation for the lack of prognostic significance of this surrogate measure of the white coat effect. Such an opposite relation appears to be a mathematical consequence of the fact that the predicted values of daytime ambulatory BP diverged from the identity line with the rise in clinic BP, whereas the predicted values of clinic BP tended toward the identity line with the increase of ambulatory BP (Fig 1⇑). Consequently, a high clinic-ambulatory BP difference was associated not only with high values of clinic BP, which would imply a detrimental prognostic effect, but also with low values of ambulatory BP, which would imply a favorable prognostic effect (Fig 2⇑). On the other hand, a low difference between clinic and ambulatory BPs was associated with both a low clinic BP and a high ambulatory BP.
In this study, we found an inverse association between the white coat effect and cigarette smoking since the prevalence of smokers progressively decreased from the bottom to the top quartile of the distribution of the white coat effect. Cigarette smoking evokes a persistent rise in ambulatory BP in hypertensive subjects,37 38 39 and through this mechanism, it may be associated with a lesser clinic-ambulatory BP difference for any given value of clinic BP.
The prevalence of women progressively increased from the bottom to the top quartile of the clinic-ambulatory BP difference, and this finding may reflect a higher BP reactivity to clinic visits in women. Female sex is an established independent predictor of white coat hypertension.8
In conclusion, our prospective findings show that the clinic-ambulatory BP difference, taken as a measure of the white coat effect, does not predict cardiovascular morbidity and mortality in subjects with essential hypertension.
Acknowledgments
This work was supported in part by grants from Associatione Umbria Cuore e Ipertensione, Perugia, Italy.
Footnotes
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Reprint requests to Dr Paolo Verdecchia, Ospedale Generale Regionale “R. Silvestrini,” Area Omogenea di Cardiologia e Medicina, Località San Sisto, 06156 Perugia PG, Italy.
- Received October 28, 1996.
- Revision received November 14, 1996.
- Accepted December 13, 1996.
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- Prognostic Significance of the White Coat EffectPaolo Verdecchia, Giuseppe Schillaci, Claudia Borgioni, Antonella Ciucci and Carlo PorcellatiHypertension. 1997;29:1218-1224, originally published June 1, 1997https://doi.org/10.1161/01.HYP.29.6.1218
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