Several studies have reported that blood pressure (BP) measurement values taken at home predict cerebrovascular and cardiovascular disease events better than office BP measurements.^1-3 This superiority is thought to be related to the fact that home BP measurements are taken over a long observation period under relatively controlled conditions.^2,4 In contrast, white-coat hypertension is defined as elevated BP values in a medical setting but normal values in nonmedical, or home, settings. If home BP values are truly superior for predicting cardiovascular and cerebrovascular disease, then white-coat hypertension should be innocuous compared with sustained hypertension, which is defined as elevated BP regardless of setting or circumstance.

Results from prospective studies regarding the clinical relevance of white-coat hypertension are contradictory. Four prospective studies have investigated cardiovascular risk for patients with white-coat hypertension and compared the risk with that of subjects having sustained normal BP values in office and in nonmedical settings.^3,5-7 Three of these studies had short follow-up periods (mean, < 5 years) and results showed similar cardiovascular risk for both groups.^3,5,6 The fourth study, with a 10-year follow-up, demonstrated higher risk for subjects with white-coat hypertension.⁷

Table 2. Risk factors for developing home hypertension.*
	Odds ratio (95% Cl)
Age (per 10 years)	1.32 (1.0-1.60)	P < .01
Male	1.78 (1.12-2.82)	P = .01
Smoker	0.90 (0.53-1.52)
Obesity†	1.76 (1.14-2.72)	P = .01
Family history of hypertension	0.80 (0.54-1.19)
Diabetes	0.67 (0.37-1.20)
Hypercholesterolemia	1.35 (0.70-2.63)
White-coat hypertension	2.86 (1.90-4.31)	P < .001
*Results according to multiple logistic regression analysis. †Body mass index >= 25 kg/m2.

A more recent study with a total median follow-up period of 5.4 years showed that the occurrence of stroke was virtually the same between the groups with and without white-coat hypertension.⁸ An increased rate of stroke in the group with white-coat hypertension was observed beyond the sixth year of follow-up. This disparity suggests that white-coat hypertension predicts sustained hypertension. Whether this condition represents a transient state in the development of hypertension outside medical settings is not known. One small short-term study reported that the transition rate to ambulatory hypertension (high BP values during ambulatory readings) in subjects with sustained normal BP is similar to that in subjects with white-coat hypertension.⁹ Although comparisons with normotensive controls were not done, some studies demonstrated that the progression rate for ambulatory hypertension in subjects with white-coat hypertension is high.^10,11 Based on these conflicting data, we sought to determine the risk of transition to hypertension outside medical settings, specifically at home, in subjects with and without white-coat hypertension. We have observed home BP measurements in a general population sample in Japan since 1987.¹²

Subjects and methods
Based on several guidelines,^4,13,14 subjects with home systolic BP values of 135 mm Hg or above, home diastolic BP values of 85 mm Hg or above, or both, were defined as having high home BP. Lower values were considered normal home BP values. High office BP values were defined as 140/90 mm Hg or above. White-coat hypertension was defined as high BP values in the office but normal values at home. Sustained normotension was defined as normal BP values in both office and home settings. The definition of home hypertension was based on (1) normal home BP measurements that progressed to high home BP values, or (2) the clinician’s decision to treat the subject with antihypertensive drugs. We observed 972 participants who had measured and recorded their home BP values for at least 3 days, had recorded office BP measurements, were not taking antihypertensive drugs at baseline, and were normotensive at the baseline examination.

Details of home BP measurement technique have been described previously.² The mean number of baseline home BP measurements was 23.2 (mean SD, 6.8; range, 3-60). The same procedure was used for follow-up BP measurements. Home BP was measured with an automated device at baseline, and the same device plus an additional device was used for measurements at follow-up.

All Japanese citizens 40 years or older are eligible for annual health checkups, which includes BP measurements. A nurse or technician takes 2 consecutive BP measurements after the subject has been seated at rest for at least 2 minutes. The office screening BP was the average of 2 readings obtained in the same year as the initiation of home BP measurements. The screening BP was measured with a fully automatic device based on Korotkoff sound technique.

All data are shown in means ± SDs. We used multiple logistic regression models to investigate the association between the baseline BP and the likelihood of progression to home hypertension. Age, sex, smoking status, obesity (body mass index >= 25 kg/m2), family history of hypertension, and history of hypercholesterolemia or diabetes mellitus were used as covariates. In all analyses, we considered the subjects with sustained normal BP values as the reference group. Variables were compared using a t test, chi-square test, or analysis of variance. Differences of P < .05 were considered statistically significant.

Results
Among the 972 subjects with or without white-coat hypertension who did not take antihypertensive drugs at the time of the baseline survey, 60 died or had moved away before follow-up. Of the remaining 912 subjects, 777 (85%) took part in the follow-up home BP measurements. Mean duration of the period between the baseline and the follow-up home BP measurements was 8.2 ± 2.0 years.

The mean age of the 777 subjects was 56.0 ± 8.7 years and the pro-portion of men was 34.0% (Table 1). Of this total, 83.5% (649) were classified as having sustained normal BP, and the remaining 128 were classified as having white-coat hyper-tension. Mean office and home BP values were significantly higher in sub­­jects with than without white-coat hypertension.

Development of home hypertension was defined as either progression to high home BP values or the start of antihypertensive drug treatment. At the time of follow-up measurements, 144 subjects with normal BP values (22.2%) and 60 with white-coat hy­pertension (46.9%) developed home hypertension. The rate of progression to home hypertension was significantly higher in subjects with white-coat hypertension and was observed for both definitions: hypertension defined by progression to higher BP levels (home BP >=135/85 mm Hg in 71 of 649 [10.9%] with normal BP values and in 31 of 128 [24.2%] with white-coat hypertension; P < .01) and hypertension defined by the start of antihypertensive drugs in 73 of 649 (11.2%) with normal BP values and in 29 of 128 (22.6%) with white-coat hypertension (P < .001). Dif­ferences be­tween follow-up home BP and baseline home BP in subjects with white-coat hypertension were 6.0 mm Hg for systolic and 3.1 mm Hg for diastolic. The corresponding values in subjects with normal BP were 4.9 mm Hg for systolic and 3.6 mm Hg for diastolic.

Compared with subjects with normal BP measurements, rates of development of home hypertension were higher in most subjects with white-coat hypertension despite similar baseline home BP values. Similar trends were observed regarding the rate for those who developed home hypertension defined by the start of antihypertensive drug treatment (data not shown).

The odds ratio (OR) for progression to home hypertension after we adjusted for other factors was significantly higher in subjects with white-coat hypertension than in those with normal BP values (OR = 2.86; P < .001; Table 2). The significant odds ratio for progression to home hypertension in the group with white-coat hypertension was similarly observed for both definitions (home BP 135/85 mm Hg: OR = 3.09; 95% confidence interval [CI], 1.83-5.23; P < .001; definition by start of antihypertensive drugs: OR = 2.71; 95% CI, 1.61-4.56; P < .001). These results remained statistically significant even when we adjusted for home systolic and diastolic BP values separately (adjusted home systolic BP: OR = 1.81; 95% CI, 1.16-2.82; P < .01; adjusted home diastolic BP: OR = 2.36; 95% CI, 1.55-3.61; P < .001). Our subgroup analysis of home BP levels at baseline showed similar re­sults (home BP < 125/80 mm Hg: OR in white-coat hy­pertension = 2.24; 95% CI, 1.25-4.01; P < .01; in subjects with home BP 125/80 mm Hg and < 135/85 mm Hg: OR in white-coat hy­pertension = 1.84; 95% CI, 0.94-3.60).

Discussion
This 8-year follow-up study de­m­onstrated that white-coat hypertension predicted the development of home hypertension independently of other confounding factors and baseline home BP levels. Only 1 study has compared the risk of developing hy­pertension outside medical settings in subjects with and without white-coat hypertension.¹⁰ The investigators found that the rate for developing ambulatory hypertension was similar in subjects with and without white-coat hypertension. Those results were inconsistent with our findings; how-ever, the follow-up period of that study was shorter (3.5 years) and the sample size was smaller than ours (36 subjects with and 56 without white-coat hypertension).

Development of home hypertension was defined as either progression to high BP measurements taken at home or by the start of antihypertensive drug treatment at follow-up. Our subjects with white-coat hypertension had higher BP values in the office; thus, it is possible that the higher risk of developing hypertension might be explained because they re­ceived antihypertensive drug treatment based on these levels. White-coat hypertension conferred a significant risk for progression to home hypertension not only according to the definition of home BP levels but also by the definition of the start of antihypertensive drugs. Fur­th­er­more, the rate of developing home hypertension, when it was defined as starting antihypertensive drug treatment, was consistently higher in subjects with than without white-coat hypertension irrespective of baseline home BP levels. This finding indicates that white-coat hypertension might be a transitional condition leading to home hypertension irrespective of high office BP levels.

Conclusion
The prognostic significance of white-coat hypertension cannot be de­termined by these results, but they suggest it is not a totally benign condition. Follow-up studies that target cardiovascular outcomes are needed for further clarification. Until such study results are available, we recommend that patients with white-coat hypertension be carefully monitored.

Acknowledgments
This work was supported by Grants for Scientific Research 12877163, 13470085, 13671095, 15790293, and 14010301 from the Ministry of Ed­ucation, Culture, Sports, Science and Technology, and by Health Science Research Grants on Health Services 13170201, 13072101, H12-Medical Care-002, and H15-Gan Yobou-039 from the Ministry of Health, Labor and Welfare, Japan. Research grants were also provided from Junkanki-byo Itaku Kenkyu 11C-5 (1999 and 2000), the Japan Atherosclerosis Prevention Fund (2000 to 2003), the Uehara Memorial Foundation (2002), the Japan Car­dio­vascular Research Foundation (2002), and the Takeda Medical Re­search Foundation (2003).

References
1. Ohkubo T, Imai Y, Tsuji I, et al. Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens. 1998;16(7):971-975.

2. Ohkubo T, Asayama K, Kikuya M, et al. How many times should blood pressure be measured at home for better prediction of stroke risk? Ten-year follow-up results from the Ohasama study. J Hypertens. 2004;22(6):1099-1104.

3. Bobrie G, Chatellier G, Genes N, et al. Cardiovascular prognosis of “masked hy­pertension” detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA. 2004;291(11):1342-1349.

4. Imai Y, Otsuka K, Kawano Y, et al. Japanese Society of Hypertension (JSH) guidelines for self-monitoring of blood pressure at home. Hypertens Res. 2003;26(10):771-782.

5. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension [published correction appears in Hypertension 1995;25(3):462]. Hyper-t­ension. 1994;24(6):793-801.

6. Kario K, Shimada K, Schwartz JE, et al. Silent and clinically overt stroke in older Japanese subjects with white-coat and sustained hypertension. J Am Coll Cardiol. 2001;38(1):238-245.

7. Gustavsen PH, Hoegholm A, Bang LE, et al. White-coat hypertension is a cardiovascular risk factor: a 10-year follow-up study. J Hum Hypertens. 2003;17(12):811-817.

8. Verdecchia P, Reboldi GP, Angeli F, et al. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005;45(2):203-208.

9. Celis H, Staessen JA, Thijs L, et al. Cardiovascular risk in white-coat and sustained hypertensive patients. Blood Press. 2002;11(6):352-356.

10. Polonia JJ, Santos AR, Gama GM, et al. Follow-up clinic and ambulatory blood pressure in untreated white-coat hy-pertensive patients (evaluation after 2-5 years). Blood Press Monit. 1997;2(6):289-295.

11. Bidlingmeyer I, Burnier M, Bidlingmeyer M, et al. Isolated office hypertension: a prehypertensive state? J Hypertens. 1996;14(3): 327-332.

12. Imai Y, Satoh H, Nagai K, et al. Char­acteristics of a community-based distribution of home blood pressure in Ohasama in northern Japan. J Hypertens. 1993;11(12): 1441-1449.

13. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.

14. O’Brien E, Asmar R, Beilin L, et al. Practice guidelines of the European Society of Hy­pertension for clinic, ambulatory and self blood pressure measurement. J Hypertens. 2005;23(4):697-701.

A more detailed discussion of this topic can be found in Ugajin T, Hozawa A, Ohkubo T, et al. White-coat hypertension as a risk factor for development of home hypertension: the Ohasama study. Arch Intern Med. 2005;165:1541-1546. (Tables adapted with permission.)