Extending the Reach of Ambulatory Blood Pressure MonitoringMasked and Resistant Hypertension

Ambulatory blood pressure (BP) monitoring is very gradually finding its way into everyday clinical practice. However, the only clinical indication approved for reimbursement in the United States so far is suspected white coat hypertension, defined by the Centers for Medicare and Medicaid Services (CMMS) in 2001 as the combination of elevated clinic blood pressure (BP) and at least two readings taken outside the clinic that are in the normal range.1 In addition there must be no evidence of target organ damage. Another indication considered was the evaluation of patients with apparently resistant hypertension. At that time there was only one study, by Redon et al,2 that had used ABP to evaluate prognosis in this group; that study had found that about one third of those patients whose clinic BP remained obdurately high despite taking three or more antihypertensive drugs were at low risk of morbid events during a 3-year follow-up period. These patients were identified by low ambulatory BP. The CMMS committee decided to reject this indication on the grounds that it rested on the findings of a single study. The initial prognostic studies using ABPM have largely focused on the identification of patients who are at lower cardiovascular risk than would be suspected from their clinic BP,3 particularly those with white coat hypertension. Whether these patients should be given antihypertensive medications remains controversial, but there is no evidence that this would benefit them. The CMMS decision was based on the assumption that most patients with white coat hypertension would not be started on drugs. More recent studies, of which the study by Pierdomenico et al4 in this issue of the Journal is a good example, have extended the scope of ABPM in two directions: first, by applying it to patients in whom hypertension is already diagnosed and treated; and second, by identifying another group of patients in whom a normal clinic BP significantly underestimates the risk. This group has been variously labeled with the terms “reverse white coat hypertension” and “white coat normotension”; but we preferred to call it “masked hypertension” on the grounds that such patients looked like truly hypertensive patients except for their normal clinic BP—that is, they had elevated BP during the day and evidence of target organ damage.5 The Pierdomenico study is of particular interest because it investigated a group of treated patients who were being followed in a hypertension clinic, some of whom appeared to have good BP control whereas others did not. Each of these two groups could be subdivided into two subgroups according to whether the ambulatory BP was controlled or not controlled. The first disturbing finding was that of the total 742 patients, only 470 (63%) were classified as having controlled or uncontrolled BP by both criteria. Thus if it is accepted that ABP predicts risk better than clinic BP, approximately one third of the patients attending this clinic were misclassified by their clinic BP. Of the patients who had normal clinic BP, about one quarter were found to have high ABP (masked hypertension), and their event rate during follow-up was nearly three times higher (2.42 v 0.87) than in the “true responders.” As it is not practical to perform ABPM on every patient attending a hypertension clinic, this finding raises the question as to how these patients can be identified. Their clinic BP (134/82 mm Hg) were only minimally higher than the BP in the true responders (127/79 mm Hg), but the former were more likely to show left ventricular hypertrophy on their echocardiograms (23% versus 13.5%). It has been suggested that the superiority of ABPM over clinic pressure is diminished if multiple clinic readings are taken,6 and unfortunately the paper does not specify whether more than one visit was used to characterize the clinic readings. One might suspect that if multiple visits had been used there would have been greater separation between the two groups. The study also did not investigate the use of home monitoring, a technique that is being more widely used than before. There is now increasing evidence that home BP predicts risk better than clinic BP in treated hypertensive patients,7–9 and it is certainly practical to screen most, if not all, patients using the technique. It seems quite likely that these patients with masked hypertension might have been identified if home BP monitoring had been used. The study by Bobrie et al used home monitoring to identify masked hypertension and also found it to be associated with increased cardiovascular risk.8 It may come as a surprise that so many patients have BP that is higher away from the clinic than in it. If only one set of clinic readings is used, this could occur just from the spontaneous variability of BP, which may result in differences between one visit and the next by as much as 25 mm Hg, even in normal healthy individuals.10 However, there are other factors that need to be considered. There may be factors that elevate the BP during the day that are not operative in the clinic setting. An obvious one is smoking. In the Pierdominco study the proportion of smokers was only marginally higher in the masked hypertension group; but the proportion of coffee drinkers was higher (77.8% v 63.8%), so this could be another factor. Others might include increased levels of physical activity and stressful jobs, but these were not evaluated. Resistant hypertension is usually diagnosed as a persistently high BP despite taking multiple medications (typically at least three), and in the Pierdomenico study nearly 90% of the apparently resistant patients were taking three or more drugs. The only other study to investigate systematically the role of ABPM was the study by Redon et al, cited above.2 It is of particular interest that in that study the low risk group, which was equivalent to the “false resistant” hypertension group of the Pierdomencio study, showed the same changes in clinic BP throughout the 4 years of the study as did the other two groups who were at higher risk for morbid events. The Redon et al study also did not use home BP monitoring, but again it is reasonable to suppose that the low risk group might have been identified by using it. One study that is relevant here is the Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation (SAMPLE) study,11 which recruited hypertensive patients with left ventricular hypertrophy and treated them with lisinopril and a diuretic. The outcome variable in this case was the regression of left ventricular hypertrophy, and the changes in BP during treatment were evaluated using clinic, ambulatory, and home BP. It was found that the change in clinic BP showed no correlation with the change in left ventricular mass, whereas both the ambulatory and the home BP did (although the correlations were weak with the home BP values). There is still uncertainty as to the exact role of the different modalities of BP measurement; but one thing is increasingly clear, and that is that we should no longer rely exclusively on measurements made by a doctor in a clinical setting. There are two important reasons for this: 1) the small number of readings that can be obtained, and 2) the white coat effect. The study by Armitage and Rose cited above concluded that multiple readings were needed to define an individual's true BP, but it is not practical for patients to make multiple clinic visits just to have their BP checked, and neither is it practical for physicians or nurses to take multiple readings during a single visit as proposed by Smirk et al many years ago.12> A possible solution is to take readings with an automatic device that can take multiple readings in the absence of a physician, which may give readings that are closer to the ambulatory BP level, but the utility of this remains to be defined. Both ABP and home BP monitoring offer the opportunity to increase the number of readings, but there is a limit to the number of times that a patient can wear a 24-h monitor. In contrast, the number of home readings that can be obtained is virtually limitless. The white coat effect is usually defined as the difference between the clinic BP and the daytime ambulatory or home BP, and in one recent study in which the clinic BP was measured by the patient's own physician was found to average 19/11 mm Hg.13 So far it has not been shown to have any prognostic significance,14 and it is not a reliable marker of generalized hyper-reactivity to stress.15 It can be positive (as in patients with white coat hypertension or the false group with false resistant hypertension in the Pierdomenico study) or negative (as in masked hypertension), and can be regarded as “noise” that interferes with the estimate of the true BP. The measurement of BP is too important an issue to be left to doctors.