Should White Coat Hypertension Be Treated?

When the Centers for Medicare & Medicaid Services (CMS) approved the limited use of ambulatory blood pressure monitoring (ABPM) for reimbursement in 2001, the only indication was to detect white coat hypertension (WCH), on the grounds that patients whose ambulatory blood pressure (ABP) was normal despite a high clinic pressure (and who had no evidence of target organ damage) were at low risk of cardiovascular morbidity and, therefore, did not need drug treatment. The recommendation reads as follows:

At this point in time, ABPM will be covered for those patients with suspected WCH. Suspected WCH will be defined as an office blood pressure (BP) >140/90 mm Hg on at least three separate office/clinic visits with two separate measurements made at each visit. In addition, there should be at least two BP measurements taken outside the office which are <140/90 mm Hg. There should be no evidence of end‐organ damage. The information obtained by ABPM is necessary in order to determine the appropriate management of the patient.

We encourage physicians to study the guidelines on the management of WCH. For those patients who undergo ABPM, and have an ABP <135/85 mm Hg with no evidence of end‐organ damage, it is likely that their cardiovascular risk is similar to normotensives. They should be followed over time. For those patients for which ABPM demonstrates BP >135/85 mm Hg, they may be at increased cardiovascular risk, and a physician may wish to consider antihypertensive therapies.

The basis for this statement was a series of prospective studies showing that WCH was associated with a relatively low risk of morbid events. These were reviewed by a Task Force of the Eighth International Consensus Conference on Blood Pressure Monitoring. ¹ No specific recommendations about treatment were made. Since then, a number of studies relating to the prognosis of WCH have appeared, some of which have confirmed that the risk is low, while others have called this into question. A recent statement on WCH by the European Society of Hypertension ² stated: “Overall, evidence to date, however, does not allow us to make firm recommendations regarding drug treatment in patients with WCH. Antihypertensive drug treatment would seem to be unnecessary in most patients with WCH.”

There are three important questions that need to be answered before we can make a definite recommendation one way or the other. They include: 1) is the risk sufficiently low to warrant withholding antihypertensive treatment? 2) does treatment lower the 24‐hour BP level? and 3) does treatment lower the risk?

WHAT IS THE RISK OF WCH?

The risk associated with WCH has been assessed in two ways: by relating it to target organ damage in cross‐sectional studies and, more directly, in prospective studies in which the outcome is cardiovascular events. Studies of target organ damage have given a mixed picture. Early studies focused on cardiac changes (principally echocardiographically determined left ventricular hypertrophy), ³ , ⁴ but, more recently, other markers of risk such as carotid atherosclerosis, ⁵ , ⁶ endothelial dysfunction, ⁷ , ⁸ and homocysteine ⁹ have been considered. There is disagreement among these studies as to whether the risk in WCH patients is closer to that of true normotensives or true hypertensives, so the best conclusion would be that it is intermediate. The findings of the prognostic studies have been much more clear, ¹⁰ including some recent findings ¹¹ , ¹² , ¹³ that indicate that the risk may be less than that of true hypertension but more than that of true normotension. One study, however, found the risk in WCH to be the same as that in true hypertension. ¹⁴ Although these studies differed widely in their design, ranging from a population study to one of refractory hypertensives, the results all point in the same direction: ambulatory pressures give a better prediction of prognosis after controlling for clinic pressure and, therefore, patients with WCH have a more benign prognosis than those with sustained hypertension. While these studies have provided general support for the wider use of ABPM in official guidelines, ¹⁵ , ¹⁶ there have been no formal statements about treatment.

One of the reasons for expressing doubt on the view that WCH is benign comes from a recent analysis of an international database that pools prospective data from four individual studies in the United States, Italy, and Japan (two). ¹⁷ We analyzed the incidence of stroke during a 10‐year follow‐up period, which is longer than previous studies. The main finding was that WCH was associated with low risk, similar to the true normotensives, for the first 5 years of follow‐up. After that, however, the risk increased and became the same as that in the true hypertensives. Since ABPM was performed only once in this study, we do not know whether these patients would still have been classified as having WCH during the follow‐up period. It has been suggested that WCH may be a precursor for sustained hypertension, and this is almost certainly true for some patients. This may be the result of misclassification rather than any true evolutionary change. Some of the earlier studies that attempted to look at the natural history of WCH were difficult to interpret because of the lack of adequate control groups. ¹⁸ , ¹⁹ A more recent analysis by Polonia et al. ²⁰ followed 39 normotensive and 76 WCH subjects for an average of 7.6 years with repeated ABP recordings. Some patients in the WCH group were given treatment during the follow‐up period. The main finding was that there was a trend for the ABP level to increase slightly in all groups during the follow‐up, but this was no greater in the WCH than in the normotensives. Thus, the concept that WCH evolves into true hypertension remains unproven.

DOES ANTIHYPERTENSIVE TREATMENT LOWER BP?

If any type of antihypertensive treatment is to be beneficial, it has to lower BP. While this statement may seem obvious, it is highly relevant in the case of WCH, because the issue is whether it lowers both the clinic and the ambulatory pressure. The majority of drug treatment studies are consistent with the view that such treatment is unlikely to be beneficial in patients with WCH. Several studies have shown that the main effect of antihypertensive drugs in patients with WCH is to lower the clinic pressure, without having significant effect on the ambulatory pressure, which by definition is normal to begin with. There is suggestive evidence, however, that there may be differences in the drug classes used. Skeptics might argue that a decrease in clinic pressure is all that is needed, but the goal of any antihypertensive drug treatment is to produce a sustained reduction in BP throughout the 24 hours, and merely reducing the clinic pressure is generally regarded as a placebo effect. In addition, the largest study of the effects of drug treatment on the regression of left ventricular hypertrophy, the Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation (SAMPLE), ²¹ found that while there was a close correlation between the changes of left ventricular mass and BP, they were highly significant for ambulatory pressure, but not for clinic pressures.

Three studies have compared the effects of angiotensin‐converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs), in all cases as a retrospective analysis in which the study participants were separated according to whether their ABP was high or low. In the first study, by Herpin et al., ²² a number of different drugs were used in both classes, while in the second, by Ashida et al., ²³ the drugs used were enalapril and nifedipine SR, and in the third, by Kristensen et al., ²⁴ benazepril and felodipine were used. In all three cases, the effects of the ACE inhibitors and CCBs were similar when the baseline ABP was high, but when it was low (equivalent to WCH), the ACE inhibitor had a much bigger effect. Other studies have confirmed that CCBs do not lower ABP in patients with WCH, ²⁵ , ²⁶ and the same may be true of a blockers. ²⁷ At least two studies have described the regression lines between the resting daytime pressure and the change with treatment, which enables the calculation of the threshold below which the drugs in question would not lower BP. In the first, by Fagard et al., ²⁸ both an ACE inhibitor (lisinopril) and a CCB (isradipine) were used, and the estimated threshold was 128/88 mm Hg for daytime and 106/73 mm Hg for nighttime pressure. These results remained stable when estimated on three separate occasions over a period of 9 months. The second made the same calculation for four drugs—for two CCBs (nilvadipine and amlodipine), the thresholds were 127 mm Hg for both; for a β blocker (bisoprolol), it was 124 mm Hg; and for an ACE inhibitor (lisinopril), it was 97 mm Hg. The implication of this study is that, as with the three studies noted above, ACE inhibitors may have a greater effect on normal ABP than CCBs.

DOES ANTIHYPERTENSIVE TREATMENT LOWER RISK?

Ultimately, what we really need to know is whether treating WCH will significantly lower the risk of morbid events. At the present time, there are no prospective studies that have examined this question and none in progress. So far, the only study that has examined the consequences of treating WCH is a substudy of the Systolic Hypertension in Europe (Syst‐Eur) study, ²⁹ in which patients with isolated systolic hypertension were randomized to be treated with a nitrendipine‐based treatment regimen compared with a program that did not include this dihydropyridine CCB. ABPM was performed in 695 patients who were divided into three subgroups according to their daytime systolic ABP: moderate sustained hypertension (ABP ≥160 mm Hg), mild sustained hypertension (ABP 140–159 mm Hg), or nonsustained (white coat) hypertension (ABP <140 mm Hg). The main finding was that drug treatment lowered clinic pressure in all patients but had little effect on the ambulatory pressure in the white coat hypertensives. The rate of strokes (the main end point in this study of elderly patients) was reduced in the patients with moderate sustained hypertension (from 12 to three events per 1000 patient‐years; p<0.03), but was not in the WCH group (from two to zero events per 1000 patient‐years), in whom the stroke rate (whether or not they were treated) was lower than the treated patients with moderate or mild hypertension. This can be interpreted in different ways, depending on one's point of view: on one hand, treatment had no significant effect on outcome, but on the other, the actual number of strokes was lower in the treated group.

SHOULD THERE BE A CLINICAL TRIAL ON TREATMENT OF WCH?

If it is accepted that the risk in patients with WCH is intermediate between true normotension and sustained hypertension, a logical strategy would be to try to identify those patients within the WCH group who are at highest risk. This could be done in two ways: more intense measurement of BP, and assessment of target organ damage. Most of the studies that have shown WCH to be associated with low risk have not used home BP recording, but this is now becoming standard clinical practice. Thus, one option would be to recommend a clinical trial of patients who are classified as having WCH by either home or ambulatory readings, but as having sustained hypertension by the other method. Another would be to look for target organ damage, such as increased left ventricular mass or microalbuminuria, on the assumption that patients diagnosed with WCH who have target organ damage may be regarded as having increased risk. An unresolved issue is which type of medication should be used. An ACE inhibitor might lower ABP more than a CCB, but this would need to be tested prospectively. Any such placebo‐controlled study would need to be large (and expensive), because it would deal with a relatively low‐risk group of patients; however, the pressure may be increasing to undertake one.