Few years ago Verdecchia et al. [18] reported the results of a meta-analysis of several studies in which a comparison was made between the incidence of stroke in truly normotensive subjects, white coat hypertensives, and individuals with an elevation of ambulatory blood pressure . Compared to truly normotensives, the incidence of stroke was from the beginning much greater in subjects with ambulatory hypertension. In contrast, the incidence of stroke did not differ between truly normotensives and white coat hypertensives over the first 4–6 years, after which the latter group exhibited a steep rise that made the stroke cumulative incidence superimposable to that of ambulatory hypertension over the remaining observation time (Fig. 7.5) [18]. The implication was that white coat hypertension is associated with an increased risk of cardiovascular events which takes time to become manifest and therefore can mainly be seen in studies with an adequate duration of the follow-up.

A long follow-up of subjects with white coat hypertension has been made available by a few studies only [19, 20]. In the PAMELA study , cardiovascular morbid and fatal events were assessed from the initial examination in 1991–1992 to 2004 with an average observation period longer than 11 years [19]. As shown in Fig. 7.6, the cumulative incidence of cardiovascular morbid and fatal events increased progressively from true normotension to white coat and true hypertension, identification of the three conditions being based on office versus ambulatory blood pressure. In the white coat hypertensive group, the age- and gender-adjusted risk of morbid plus fatal or only fatal cardiovascular events amounted to 76 and 65 %, respectively, an increase that was less than that seen in true hypertension (+116 and 129 %) but that nevertheless differed significantly and substantially from what was seen in the true normotensive group. White coat hypertensives additionally showed a 46 % increase in age- and gender-adjusted risk of all-cause mortality that was of borderline statistical significance.

More recently, the follow-up of the white coat hypertensive subjects from the PAMELA population has been extended to an average of 16 years [21]. As shown in Fig. 7.7, over this long follow-up white coat hypertensives (diagnosed as done in clinical practice, i.e., by an elevation of office with a normal ambulatory or home blood pressure) continued to show an incidence of cardiovascular mortality that was intermediate between true normotensive and true hypertensive individuals. Compared to the normotensive group, the age- and gender-adjusted cardiovascular mortality risk was substantially greater, and the significance extended to fully adjusted data, i.e., to baseline variables reflecting metabolic factors and other clinical conditions, to indicate an independent contribution to prognosis of the elevated blood pressure values.

The different results of studies on the prognostic value of white coat hypertension justify the hypothesis that this condition may have a high prognostic heterogeneity. Namely, that depending on its more or less frequent coexistence with metabolic risk factors, subclinical organ damage, and other features involved in cardiovascular risk, its relationship with an increased incidence of morbid or fatal cerebrovascular or cardiac events may turn out to vary within a range that has at one extreme a similarity with true normotension and at another extreme a similarity with true hypertension. Analysis of the PAMELA data has detected two possibilities to differentiate the cardiovascular risk level within the white coat hypertension category. One, because in all individuals of the PAMELA study measurements included both ambulatory and home blood pressure, white coat hypertensives were subdivided into those in whom both out-of-office blood pressure values were normal and those in whom one blood pressure was normal, while the other was elevated or vice versa [21]. As shown in Fig. 7.8, the incidence of cardiovascular events was markedly greater in the latter as compared to the former group in which the risk was only slightly and nonsignificantly increased compared to that seen in true normotensive subjects. Thus, the information provided by ambulatory and home blood pressure is by no means redundant. Indeed, the combined use of these two diagnostic approaches may serve the important purpose to identify white coat hypertensives in whom a substantial increase of cardiovascular risk may justify not only a close follow-up but perhaps also initiation of antihypertensive drug treatment.

The second possibility is offered by repetition of office blood pressure measurements. Because in the PAMELA study office blood pressure was measured three times at a visit performed before and three times at a visit performed after completion of 24 h blood pressure monitoring , white coat hypertensive subjects could be subdivided into four groups according to whether this condition was found twice or in only one of the office visits. As shown in Fig. 7.9, patients with “stable” white coat hypertension had an incidence of cardiovascular fatal events that was greater than that of individuals in whom the office BP elevation was seen one time only. This was the case also for all-cause mortality which in subjects with stable white coat hypertension was only slightly less than that of patients with true hypertension.