Hypertension is a common medical disorder, affecting. Is Resistant Hypertension Really Resistant? Mark A. Brown, Megan L. Buddle, and Allison Martin

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1 AJH 2001; 14: Is Resistant Hypertension Really Resistant? Mark A. Brown, Megan L. Buddle, and Allison Martin Background: Managing resistant hypertension is difficult and mostly involves expensive testing seeking an underlying secondary cause. This study was undertaken to determine 1) the extent of the white-coat phenomenon in patients with resistant hypertension, and 2) whether 24-h ambulatory blood pressure (BP) monitoring (ABPM) or having BP recorded by a nurse instead of the referring doctor could clarify how many apparently resistant hypertensives actually have controlled BP. Methods: This study involved 611 patients with BP 140/90 mm Hg who were referred for 24-h ABPM by their specialist or general practitioner, including 277 patients who were taking no antihypertensives (group 1), 216 taking one or two antihypertensive drugs (group 2), and 118 taking at least three antihypertensives in combination (group 3). Each had BP recorded by one of two nurses before 24-h ABPM. Controlled BP was defined as awake ambulatory BP 135/85 mm Hg and the white-coat effect was the difference between the BP recorded by the referring doctor or nurse and the average awake ambulatory BP. Results: Those with resistant hypertension (group 3) were older (61 years (12) v group 1: 46 years (14) and group 2: 56 (14) years; P.001), but were of similar weight, height, and arm circumference to the other groups. Hypertension is a common medical disorder, affecting as many as 30% of the population by the age of 60 years. Some 10% of hypertensive patients appear resistant to combinations of antihypertensive drugs, 1 prompting referral for specialist care. In most cases this includes expensive investigations for secondary causes of hypertension in conjunction with an increase in antihypertensive drug therapy and further attention to nondrug therapy. However, even in this highly selected group of resistant hypertensives only about 10% are found to have a treatable secondary cause, 2 leaving the other 90% of patients requiring considerable adjustments to drug therapy, often with disappointing results. With the advent of automated home blood pressure (BP) recording and particularly 24-h ambulatory blood Referral systolic, but not diastolic BP was higher in resistant hypertensives (mean 171/95 v 154/95 mm Hg and 164/94 mm Hg, respectively, P.001 for systolic BP only). Twenty-eight percent of resistant hypertensives and 32% of those taking no antihypertensive drugs had normal awake ambulatory BP and the white-coat effect attributable to the referring doctor was always greater than that due to the nurse (range 16 to 26/12 to 14 mm Hg v 9to 17/4 mm Hg, P.001). Nurse recorded BP was highly sensitive (97%) in identifying awake hypertension but lacked specificity (57%) to replace ABPM. Conclusion: Our results show that approximately one in four patients with apparent resistant hypertension referred for ABPM have controlled BP and one-third of patients referred for initial evaluation of office or clinic hypertension have normal BP using ABPM, ie, white-coat hypertension. Twenty-four-hour ABPM appears an appropriate initial step before further investigating or treating patients with apparently resistant hypertension. Am J Hypertens 2001;14: American Journal of Hypertension, Ltd. Key Words: Resistant hypertension, refractory hypertension, white-coat hypertension, white-coat effect, ambulatory blood pressure monitoring. pressure monitoring (ABPM), the phenomena of white coat hypertension and white coat effect have been described. 3 The former refers to apparent office or clinic hypertension (and therefore, is sometimes called isolated office or clinic hypertension, although debate continues on this issue 4 ), but normal BP when assessed in the patient s usual environment. The latter refers to the difference between BP obtained in the office or clinic and those recorded in the patient s usual environment. Thus, a patient can be truly hypertensive but still demonstrate a significant white coat effect. Despite recognition of this phenomenon only limited studies so far have sought to determine how commonly this occurs in patients with apparent resistant hypertension. Clearly defining patients with truly resistant hypertension, by excluding those with controlled BP in Received December 13, Accepted May 4, From the Departments of Renal Medicine and Medicine, St. George Hospital and University of NSW Kogarah, Sydney, Australia. Address correspondence and reprint requests to Professor Mark Brown, Dept. of Renal Medicine, St. George Hospital, Kogarah NSW 2217 Australia; mbrown@unsw.edu.au 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc /01/$20.00 PII S (01)

2 1264 RESISTANT HYPERTENSION AJH December 2001 VOL. 14, NO. 12 Table 1. Demographic and blood pressure (BP) data for patients having 24-h ABPM Group A Group B Group C N Age (y) 52(17) 47 (16) 52(15) Height (cm) 167 (10) 168 (10) 167 (10) Weight (kg) 73 (15) 73 (15) 75 (16) Arm circumference (cm) 30 (4) 29 (3) 30 (4) Males (%) 42* Successful ABPM (%) Controlled awake BP (%) Controlled awake and 24-h ABPM (%) ABPM ambulatory blood pressure monitoring; Group A neither referring doctor s or nurse s blood pressure available; group B only referring doctor s BP available; group C both referring doctor s and nurse s BP available. Data are mean (SD) or percentages. * P.01; P.0001 v group C. their usual environment, would reduce the considerable expense and inconvenience of investigations and adjustments to therapy for these patients. The aims of this study were to determine in subjects with apparent resistant hypertension 1) the prevalence of a white coat effect large enough to result in controlled BP in the patient s usual environment, 2) whether this occurred more commonly than did the phenomenon of white coat hypertension (in subjects taking no antihypertensives), and 3) the accuracy of nurse recorded BP as a possible alternative to home BP monitoring. Methods Study Population One thousand six hundred eighty-six patients referred by specialists or general practitioners to our ABPM service between 1993 and 1999 were entered into a database recording their age, height, weight, number of different antihypertensive drugs being taken at the time of ABPM, and ambulatory BP results. The referring doctor s BPwas noted and from late 1996 BP was also recorded systematically by the unit s hypertension nurse just before beginning the 24-h ABPM. Both nurses were formally trained in BP measurement and initially had to successfully complete the British Hypertension Society video test on methodology of BP recording. This was also used as later quality control testing. This BP was recorded in the sitting position using mercury sphygmomanometry and an appropriate size cuff, a large cuff being used if the mid-upper arm circumference was 32 cm. This was followed by 24-h ambulatory BP recording using either a Spacelabs (Spacelabs Medical Products, Sydney, Australia) or Accutracker II (Cardiometrics Pty Ltd, Victoria, Australia) device with BP recorded half hourly throughout awake and sleep periods, these being determined from the accompanying patient diary. Acceptable BP monitoring had to include more than 80% successful recordings and at least 18 awake readings and nine sleep readings. Subjects were selected for referral at the discretion of their general practitioner or specialist and were categorized as follows according to the number of antihypertensive drugs they were taking: no drugs, one or two different antihypertensives, at least three antihypertensives in combination. The main outcome measures of this study were 1) the white coat effect, ie, the difference between the referring doctor s BP and awake ABPM; 2) the white coat effect, as measured by the difference between the nurse s BP and the awake ABPM; 3) the prevalence of controlled hypertension, ie, awake ambulatory BP 135 mm Hg systolic and 85 mm Hg diastolic. 5 A second analysis was undertaken that defined controlled BP as above but also required 24-h BP 125/80 mm Hg, according to World Health Organization International Society of Hypertension (WHO ISH) guidelines. 6 The antihypertensives taken during the 24-h monitoring were also recorded by the patients in their diary. Continuous data were analyzed by analysis of variance across groups and Student s t tests between groups. Multiple linear regression analysis was used to relate the white coat effect to other BP and demographic parameters. Categorical data were compared by 2 testing. The study was approved by the South Eastern Sydney Area Health Service Ethics Committee. Results Seven hundred fifty-eight (45%) patients had both nurses and referring doctor s BP available for analysis, 363 (22%) had the referring doctor s BP only, and 565 (34%) had neither referring doctor or nurse s BP to accompany the ABPM recordings. These groups did not differ substantially in their demographic data (age, height, weight, upper arm circumference), their number of successful 24-h ABPM recordings, or the prevalence of controlled awake and 24-h BP (Table 1). Ninety-five percent with only the referring doctor s BP and 92% with both referring doctor and nurse s BP were referred because of a doctor s BP 140/90 mm Hg. As these groups were similar (Table 1)

3 AJH December 2001 VOL. 14, NO. 12 RESISTANT HYPERTENSION 1265 Table 2. Demographic and BP data for 611 patients with referring doctor s BP 140/90 mm Hg No Antihypertensive Drugs the remainder of the analysis was confined to those who had successful ABPM, had a referring doctor s BP 140/90 mm Hg, and for whom both referring doctor and nurse s BP were available (n 611). These 611 patients were divided according to the number of antihypertensive drugs they were taking during the 24-h ABPM (Table 2). Those with resistant hypertension were older and had a greater proportion of men than the other two groups. They also had significantly higher referring doctor and nurse s systolic BP (P.01), but not diastolic BP. Similarly awake, sleep, and 24-h systolic BP were higher (P.001) in those with resistant hypertension. 1 2 Drugs White Coat Effect Resistant Hypertension >3 Drugs N Age (y) 46 (14) 56 (14) 61 (12) Height (cm) 167 (4) 166 (10) 168 (9) Weight (kg) 75 (16) 72(15) 76 (18) Arm circumference (cm) 30 (4) 29 (4) 30 (4) Males (%) 35* 34* 48 Referring doctor SBP (mm Hg) 154 (16) 164 (20) 171 (21) Referring doctor DBP (mm Hg) 95 (8) 94 (11) 95 (16) Nurse s SBP (mm Hg) 147 (19) 153 (22) 161 (26) Nurse s DBP (mm Hg) 87 (10) 83 (12) 85 (17) ABPM BPs Awake SBP (mm Hg) 138 (12) 138 (15) 145 (18) Awake DBP (mm Hg) 84 (8) 79 (9) 81 (15) Sleep SBP (mm Hg) 117 (15) 120 (20) 131 (20) Sleep DBP (mm Hg) 67 (9) 65 (11) 71 (15) 24-h SBP (mm Hg) 132 (12) 133 (15) 141 (20) 24-h DBP (mm Hg) 80 (8) 76 (9) 79 (15) SBP systolic blood pressure; DBP diastolic blood pressure; other abbreviation as in Table 1. Data are mean (SD) or percentages. * P.05; P.01; P.001 v resistant hypertension. The average systolic white coat effect ranged from 16 to 26 mm Hg across groups, with those taking antihypertensive drugs having the greatest difference between routine doctor or nurse recorded systolic BP and awake ABPM systolic BP (Fig. 1). The magnitude of this effect was significantly lower (P.001) when BP was recorded by a nurse. Diastolic white coat effect was similar across groups, whether referring doctor or nurse s BP was used, but as with systolic BP the magnitude of this effect was always lower (P.001) when BP was recorded by a nurse (Fig. 2). FIG. 1. Average systolic blood pressure (BP) differences (white-coat effect) between referring doctor (open bars) and nurse s (closed bars) BP and awake ambulatory systolic BP. *** P.001 v nurse recorded BPs.

4 1266 RESISTANT HYPERTENSION AJH December 2001 VOL. 14, NO. 12 FIG. 2. Average diastolic blood pressure (BP) differences (white-coat effect) between referring doctor (open bars) and nurse s (closed bars) BP and awake ambulatory diastolic BP. *** P.001 v nurse recorded BPs. Abbreviation as in Fig. 1. The white coat systolic effect, ie, the systolic BP difference between referral doctor BP and awake ABPM recorded BP, was significantly inversely related to age and positively with referral systolic BP and female sex (P.001 for all). The diastolic white coat effect was positively related to referral doctor systolic and diastolic BP and female sex (P.01). Prevalence of Controlled BP Using a definition of awake ambulatory BP 135/85 mm Hg, 28% of resistant hypertensives had controlled BP and 32% of apparent hypertensives (taking no antihypertensive drugs) had normal BP, ie, had white coat hypertension. Using a more stringent definition of controlled BP as both awake ambulatory BP 135/85 mm Hg and 24-h BP 125/80 mm Hg, the corresponding figures were again similar, 19% and 23%, respectively (Fig. 3). The nurse s BP correctly identified awake hypertension in 97% of cases (sensitivity) and awake normotension in 57% (specificity) with positive and negative predictive values for nurse s BP identifying ambulatory hypertension of 88% and 83%, respectively. FIG. 3. Prevalence of controlled BP as defined by awake ABPM BP 135/85 mm Hg (closed bars) or as both awake ABPM 135/85 mm Hg and 24-h BP 125/80 mm Hg (open bars). Abbreviations as in Figs. 1 and 2.

5 AJH December 2001 VOL. 14, NO. 12 RESISTANT HYPERTENSION 1267 Table 3. Characteristics of apparent resistant hypertensives and true resistant hypertensives, white-coat hypertensives and true hypertensives Characteristics of Patients With Apparent Resistant Hypertension But Controlled Awake BP The 33 patients with controlled awake BP in this clinically important group were compared with the 85 who had proven resistant hypertension (Table 3). They were of similar age, weight, arm size, and sex, but had lower referral systolic BP and nurse recorded BP than did true resistant hypertensives. A similar pattern was seen comparing white coat and true hypertensives who were taking no antihypertensive drugs (Table 3). In both groups, those with true hypertension had higher sleep (as well as awake) BP as determined by the ABPM device. Discussion Apparent Resistant (Controlled BP) >3 Drugs This study shows that 2 to 3 of every 10 patients with apparent resistant hypertension have controlled BP when this is assessed by 24-h ABPM. There is considerable white coat effect both in patients taking and not taking antihypertensive drugs and the white coat effect induced by doctors is greater than that induced by nurses. The first observation from this large study is that of more than 1600 patients referred for ABPM, approximately 20% to 30% had normal ambulatory BP, the rates varying according to the stringency of criteria used. This implies a high rate of significant white coat effect in the community studied and this was borne out in our substudy of 611 patients who had differences between the BP recorded by their doctor and awake average BP of 16 26/ mm Hg (Figs. 1 and 2). The corresponding values using nurse-recorded BP were significantly lower, 9 17/4 mm Hg. This suggests that nursing staff working in a BP True Resistant (Ambulatory Hypertension) White-Coat Hypertensives No Drugs True Hypertensives N Age (y) 59 (12) 62 (12) 43 (12)* 48 (15) Height (cm) 166 (10) 169 (12) 168 (9) 167 (10) Weight (kg) 74 (15) 77 (18) 75 (15) 75 (17) Arm circumference (cm) 30 (3) 30 (4) 30 (4) 30 (4) Males (%) Referring doctor SBP (mm Hg) 161 (16) 175 (21) 149 (13) 157 (16) Referring doctor DBP (mm Hg) 92(11) 96 (18) 94 (7)* 96 (8) Nurse s SBP (mm Hg) 140 (14) 169 (26) 137 (14) 152(19) Nurse s DBP (mm Hg) 78 (10) 87 (19) 82(8) 89 (11) Awake SBP (mm Hg) 125 (6) 152(15) 126 (7) 147 (13) Awake DBP (mm Hg) 72(7) 84 (16) 77 (5) 87 (8) Sleep SBP (mm Hg) 114 (11) 138 (19) 106 (9) 121 (14) Sleep DBP (mm Hg) 62(7) 74 (16) 61 (7) 70 (9) Abbreviations as in Tables 1 and 2. * P.05; P.01; P.001. unit induce less anxiety or less alerting reaction than does a doctor recording BP in the medical setting. One caveat to this interpretation of the data, however, is that the BP recorded by the nurses were taken a median of 20 days after the referring doctor s BP, which may have permitted any changes in treatment or increased compliance in the interim to have an effect. This possibility seems unlikely as we found that the white coat effect induced by nurses was significantly lower than that induced by doctors even in patients taking no antihypertensive drugs (Figs. 1 and 2). This is also in accord with the study of Meyers et al 7 who found a white coat effect of at least 20/10 mm Hg in 62% of patients when their ambulatory BP was compared with their referring family physician s BP, but in only 20% when compared with readings taken by a research nurse. In that study less than 20% of the 147 patients were taking three or more antihypertensive drugs and it is hard to be certain whether that finding also applied to their patients with resistant hypertension. It is clear from our data that both doctors and nurses commonly generate a white coat effect in patients with resistant hypertension and in less severe hypertensives. A critical point is that the results of this study depend on the definitions of resistant hypertension and normal ambulatory BP. Although we used a definition of resistant hypertension similar to that of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) group, 5 we do not know whether the antihypertensive drugs were used in these patients at an appropriate maximum dose or whether nonpharmacologic treatments were being used, ie, some resistant hypertensives may have been poorly compliant or undertreated. A study such as this also requires

6 1268 RESISTANT HYPERTENSION AJH December 2001 VOL. 14, NO. 12 careful definition of ambulatory normotension and we have used both the JNC VI (awake) value of 135/85 mm Hg and the WHO ISH 24-h value of 125/80 mm Hg as discriminant values acknowledging that choice of other cutoff values would produce different results. There have been surprisingly few data published using ambulatory monitoring to define the prevalence of controlled BP in patients with apparent resistant hypertension, despite a report that at least 40% of ambulatory monitoring was undertaken for the purposes of assessing BP control or drug-resistant hypertension. 8 Mezzetti et al 9 used ambulatory monitoring in a cohort of 250 treated hypertensive subjects. Only 27 (11%) of this group had resistant hypertension, defined as clinic BP 140/90 mm Hg despite taking at least three antihypertensive drugs. Half to threequarters of this small group had ambulatory BP in the normal range, depending on the criteria used to define normal ABPM-derived BP. An important point in this small study was that increasing the number of antihypertensive drugs in those with apparent resistant hypertension (but controlled BP using ABPM) did not influence the magnitude of the white coat effect. This highlights the clinical difficulties in treating such patients as their clinic or office BPs remain elevated despite increasing their antihypertensive drugs. Redon et al 10 studied 86 patients who had diastolic hypertension ( 100 mm Hg) despite taking three or more antihypertensive drugs. One-third of this group had an average ambulatory diastolic BP below 88 mm Hg; a discriminant value generally considered higher than that which defines normal diastolic BP when using ABPM. 5 This group had a very similar office ambulatory BP difference of 29/15 mm Hg (the white coat effect) as did our resistant hypertensives, averaging 26/17 mm Hg. Hernandez-del Ray et al 11 studied 60 patients with resistant hypertension, a prevalence of 5% in their hypertensive cohort, and found that 32% of this small group had ambulatory awake BP 135/85 mm Hg, close to that observed in this study. We acknowledge that our study was limited to a convenience rather than population sample and as such our observations cannot immediately be extended to the general hypertensive population. Nevertheless, this is a large study that reflects clinician s patterns of use of 24-h ABPM to assess their patients with persistent or resistant hypertension. We found that as a group resistant hypertensives were older, more likely to be male, and had greater referral systolic, but not diastolic hypertension than those with persistent hypertension taking no or fewer antihypertensive drugs. Furthermore, these patients had higher sleep BP (Table 2). When examined in greater detail, the subset of this group who had proven resistant hypertension had higher BP both at referral and also during sleep (Table 3), but were neither heavier nor had greater arm circumferences, which might have led to inaccurate (higher) office BP measurements in the first instance if an incorrect cuff size was chosen. Thus, these patients with true resistant hypertension are not identified by readily obtainable characteristics and require ABPM (or perhaps other home BP measures 12 ) to establish their diagnosis. It is possible they could be identified by other markers such as heart rate, alcohol intake, smoking history, lipids, creatinine, left ventricular hypertrophy, or microalbuminuria, but we have not examined this. Although nurse recorded BP was lower than that recorded by doctors and highly sensitive overall, the specificity was inadequate to replace ABPM with nurse-recorded BP. Our observation that 20% to 30% of the cohort taking no antihypertensive drugs also had normal BP by ABPM defines a group with white coat hypertension. This prevalence is in accord with data from previous studies, 13 but are higher than some more recently quoted figures of 16% 14 or 11%, 15 probably due to the selected nature of patients referred for ABPM. As these figures in our study were so similar to the prevalence of controlled BP in those taking drug therapy it is possible that some of those taking drug therapy may have the whole phenomenon of white coat hypertension, not just a white coat effect, and could come off drug therapy altogether. Further studies would be required to determine what clinical or laboratory parameters might define such a group and as our study did not measure factors such as renal impairment, microalbuminuria, left ventricular hypertrophy, abnormal glucose tolerance, or other cardiovascular risk factors, studies will be needed to help define such a group who might cease taking antihypertensive drugs after such a finding using ABPM. Moreover, there is emerging evidence that white coat hypertension defined at one study does not necessarily remain consistent over time. Polonia et al 16 found that over a 2- to 6-year follow-up of 36 patients some 10% to 20% of those with white coat hypertension (taking no antihypertensive drugs) developed true hypertension as defined by 24-h ABPM. Similar results have been found by Palatini et al 14 in a slightly larger study. Whether the same applies to those resistant hypertensives with a large white coat effect and normal ambulatory BP is yet to be studied. A further point is the potential of the variability surrounding repeated ABPM measurements to affect the prevalence of controlled or truly resistant hypertension. It is likely that any 24-h ABPM test incorporates some regression to the mean as BP during the first2hisusually higher than subsequent readings. 17 However, mean awake and sleep BP averages do not differ significantly over a 48-h ABPM study and it would appear unlikely that variance around ABPM mean values would be significant to alter these findings. These issues notwithstanding, there are potential cost implications of these findings. For example, if 100 resistant hypertensives underwent ambulatory BP monitoring at an approximate cost of $80 per study (costs will vary according to institutions), this would equate to an expenditure of $8000 (Australian $). For the approximately 30% with controlled BP there would be savings for each patient

7 AJH December 2001 VOL. 14, NO. 12 RESISTANT HYPERTENSION 1269 in our unit of the following: repeat plasma urea, electrolytes, creatinine ($17), 24-h urinary catecholamines ($34), plasma renin ($27), and aldosterone ($27) measurement, renal ultrasound ($100), and in most cases renal angiography ($600). We would estimate an additional four specialist visits per year without ABPM diagnosis, approximately $240 per patient, additional drug costs of estimated $50 per month (ie, $600 per year), and an additional two measurements of urea, electrolytes, creatinine ($34) to monitor for biochemical side effects of drugs, usually angiotensin converting enzymes inhibitors or angiotensin II receptor blockers. Thus, additional costs for the 30 controlled hypertensives would each be $1680 (or about $1000 without angiography) per year. Approximate overall savings per year per 100 resistant hypertensives would be between $22,000 and $42,500 by undertaking 24-h ABPM before further investigations in apparently resistant hypertensives. These figures are obviously only an estimate and will vary greatly among countries, even among hypertension units. In summary, this study confirms earlier studies that the prevalence of white coat hypertension is approximately 20% to 30% in patients with isolated office or clinic hypertension taking no antihypertensive drugs. For those taking antihypertensive medications, particularly those with apparent resistant hypertension, 20% to 30% of patients referred for ABPM in fact have normal BP. On the assumption that this group has a better clinical outcome than those with true resistant hypertension, an hypothesis yet to be tested formally, and considering the high cost of investigations and treatments for secondary causes of hypertension, ABPM would seem a sensible initial investigation in patients with apparent resistant hypertension. Acknowledgments We thank Jodie Hendley and Sharon Dickson for their assistance in preparation of this manuscript. References 1. Setaro JF, Black HR: Refractory hypertension. New Engl J Med 1992;327: Anderson GH, Blakeman N, Streeten DHP: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994;12: Pickering TG: Blood pressure measurement and detection of hypertension. Lancet 1994;344: Mancia G, Zanchetti A: Editor s corner: White coat hypertension: misnomers, misconceptions and misunderstandings. What should we do next? J Hypertens 1996;14: The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157: World Health Organization International Society of Hypertension: Guidelines for the management of hypertension. J Hypertens 1999;17: Myers M, Oh P, Reeves R, Joyner C: Prevalence of white coat effect in treated hypertensive patients in the community. Am J Hypertens 1995;8: Grin J, McCabe EJ, White WB: Management of hypertension after ambulatory blood pressure monitoring. Ann Intern Med 1993;118: Mezzetti A, Pierdomenico SD, Costantini F, Romano F, Bucci A, Di Gioacchino MD, Cuccurullo F: White-coat resistant hypertension. Am J Hypertens 1997;10: Redon J, Campos C, Narciso ML, Rodicio JL, Pasculal JM, Ruilope LM: Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: A prospective study. Hypertension 1998; 31: Hernandez-del Ray R, Armario P, Martin-Baranera M, Sanchez P, Cardenas G, Pardell H: Target-organ damage and cardiovascular risk profile in resistant hypertension: Influence of the white-coat effect. Blood Pressure Monit 1998;3: Padfield PL, Stewart MJ, Gough K: The role of self-measurement of blood pressure in the management of hypertension. Blood Pressure Monit 1996;1: Kouame N, Cleroux J, Lefebvre J, Ellison R, Lacourciere Y: Incidence of overestimation and underestimation of hypertension in a large sample of Canadians with mild to moderate hypertension. Blood Pressure Monit 1996;1: Palatini P, Dorigatti F, Roman E, Giovinazzo P, Piccolo D, De Venuto G, Mattarei M, Cozzutti E, Gregori S, Mormino P, Pessina AC: White-coat hypertension: a selection bias? J Hypertens 1998; 16: Owens P, Lyons S, O Brien E: Ambulatory blood pressure in the hypertensive population: patterns and prevalence of hypertensive subforms. J Hypertens 1998;16: Polonia JJ, Santos AR, Gama GM, Basto F, Bettencourt PM, Martins LR: Follow-up clinic and ambulatory blood pressure in untreated white-coat hypertensive patients (evaluation after 2 5 years). Blood Pressure Monit 1997;2: Prasad N, MacFadyen RJ, Ogston SA, MacDonald TM: Elevated blood pressure during the first two hours of ambulatory blood pressure monitoring: a study comparing consecutive twenty-four hour monitoring periods. J Hypertens 1995;13: