What should we know about white coat hypertension

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 3 3 e3 7

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Review Article

What should we know about white coat hypertension Prerna Kapoor a, Aditya Kapoor b,* a

Medicine Specialist, General Hospital, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, UP, India b Professor of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, UP, India

article info

abstract

Article history:

White coat hypertension (WCH) is fairly common and may be seen in upto 20e40% of

Received 24 October 2012

hypertensive patients, and is increasingly common in aging populations. Despite being

Accepted 23 January 2013

known for over a hundred years, awareness about the adverse effects of WCH is limited

Available online 4 February 2013

and there is still ongoing debate about the long term prognosis and appropriate management of WCH. The term is used for individuals who have BP readings that are consistently

Keywords:

higher than normal only in the clinical setting, while the readings recorded outside, either

White coat hypertension

by ambulatory monitoring or self measurement at home, are normal. Recognition of WCH

Cardiovascular risk

is especially important to avoid over-diagnosis of hypertension or resistant hypertension

Blood pressure

as well as injudicious treatment escalation based on isolated office BP readings. The following review shall attempt to focus on these issues related to white coat hypertension. Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.

1.

Introduction

Office (or clinic) blood pressure (BP) measurement remains the standard method for assessment and diagnosis of hypertension. The advent of home monitoring or ambulatory BP measurement monitoring, have made it possible for the clinician to detect white coat hypertension and Masked hypertension, which remain unrecognized if only clinic BP recordings are preformed. White coat hypertension (WCH) is the term used for individuals who have BP readings that are consistently higher than normal only in the clinical setting, while the readings recorded outside, either by ambulatory monitoring or self measurement at home, are normal. The difference between the two BP measurements is labeled as the white coat effect (WCE), induced due to a positive pressor reaction induced by the clinical visit. The term “white coat” originates from the white coats traditionally worn by doctors;

interestingly WCE is more commonly observed when office BP is measured by physicians as compared to that measured by nurses. The terms “Office hypertension” or “isolated clinical hypertension” are also used synonymously with WCH.1,2 Masked HT (MHT) is the term used for patients with elevated BP recordings only in the out-of-office blood pressure (BP) recordings, while the clinic recordings are within normal range. It is also known as reverse white-coat hypertension, white-coat normotension, or isolated ambulatory hypertension. Normotensive individuals have both in-office and outof-office BP readings within the normal range. Patients with sustained hypertension have elevated BP readings regardless of setting or circumstance. Despite being known for over a hundred years, after its first description by Riva-Rocci3 awareness about the adverse effects of WCH is limited and there is still ongoing debate about the long term prognosis and appropriate management of WCH.

* Corresponding author. E-mail address: [email protected] (A. Kapoor). 2211-9477/$ e see front matter Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cqn.2013.01.002

34 1.1.

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 3 3 e3 7

Prevalence

The prevalence of WCH is estimated to be 20e40% amongst hypertensive patients, and approximately one in six adults attending hypertension clinics exhibit the WCE.4,5 An additional one in 10 people exhibit the phenomenon of “masked” hypertension with sporadically high BP values in out of office settings. Data from the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) revealed that of more than 7000 subjects, 25% had sustained HT, while 10% and 15% respectively had WCH and masked HT.6,7 The phenomenon of WCH appears to be more common in females, pregnancy, non-smokers, elderly and those with mild hypertension. Age specific trends indicate a 30e50% prevalence of WCH in 2nde4th decades of life, which reaches up to nearly 75% in the eighth decade of life. Recognition of WCH is especially important to avoid overdiagnosis of hypertension or resistant hypertension as well as injudicious treatment escalation based on isolated office BP readings. Recent data from the Spanish Ambulatory Blood Pressure Monitoring Registry revealed that of more than 8000 resistant hypertensive patients, 38% actually had WCH as detected by ambulatory BP monitoring, and therefore did not require anti-HT therapy intensification.8

1.2.

Definition

It is important to precisely define what constitutes as a normal BP (outside the medical environment) to be able to correctly identify an individual with WCH. To accurately define WCH, it is necessary to use BP readings obtained outside clinic settings (either ambulatory BP monitoring or home BP measurements). Amongst 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, (PAMELA), WCH was defined as office BP > 140/90 mmHg and mean 24-hour ambulatory BP < 125/ 79 mmHg or home BP < 132/82 mmHg; MHT was defined as office BP < 140/90 mmHg while the 24-hour ambulatory BP was > 125/79 mmHg, and home BP > 132/82 mmHg. Sustained HT was identified in office as well as ambulatory BP (or home BP) values were above the given thresholds.9 Other studies have used ambulatory average daytime cut offs of <135 mmHg systolic and <90 mmHg diastolic as criteria to diagnose WCH.10 According to recent consensus, 135/85 mmHg should be used as cut-off for daytime ambulatory BP.11 Although ambulatory BP monitoring provides a wide range of BP information and may offer a more reliable definition of WCH, it is neither widely available nor a very practical method. Home BP measurements make it possible to obtain multiple measurements over long observation periods under relatively uniform conditions and are now widely recommended. Hence WCH has also been defined as office BP > 140/ 90 mmHg and home BP readings < 135/85 mmHg.12,13 According to the 2007 ESH and ESC guidelines, diagnosis of WCH should include office BP measurements (>140/90 mmHg, determined during at least 3 clinic visits) with two separate measurements made at each visit. In addition, at least 2 measurements made outside the office should have BP < 130e135/85 mmHg or average BP values recorded in the 24-h monitoring with cut-offs for 12 h as <130e135/85 mmHg and for 24 h as <125e130/80 mmHg.14

Recent United Kingdom Hypertension Guidelines defines a discrepancy 20 mmHg systolic BP or 10 mmHg diastolic BP between office BP, and ABPM, or HBPM as fulfilling the criteria for WC-HTN, wherein ABPM/HBPM are lower than office BP.

1.3.

Pathophysiology of target organ damage in WCH

The role of stress in the genesis of WCH is important; these patients have higher office BP readings presumably because they react to stress with an exaggerated rise in blood pressure. Therefore higher office BP readings identify individuals who are more likely to have higher BP readings even during normal daily stressors. An existent hyper-adrenergic state also contributes to abnormal variation of diurnal BP and pulse pressure, leading to target organ damage. In observational studies of patients with WCH wherein a high progression to sustained HT was noted at follow up, the rise in BP was greater for systolic as compared to diastolic BP, leading to more pronounced increase in pulse pressure, suggesting that the rate of progression to sustained HT depends at least in part to a more pronounced stiffening of the large arteries. Individuals with WCH are also more likely to be obese and have a higher prevalence of insulin resistance as compared to those with normotension. Oxidative stress and endothelial dysfunction may also play a role in accelerated target organ damage and cardiovascular abnormalities in these patients.

1.4. Is WCH associated with CV risk and progression to sustained HT? Since many of these patients have average normal daytime blood pressure readings outside the medical setting, WCH was thought to be a benign condition that identified individuals with low overall long term cardiovascular risk. Initial studies revealed that patients with WCH had significantly fewer cardiovascular events compared to patients with sustained hypertension and the event rate in WCH and normotensive subjects were almost similar.15,16 Cardiovascular outcomes in the Ambulatory Blood Pressure Monitoring and Treatment of Hypertension (APTH) trial, also demonstrated that patients with WCH were less likely to receive anti-HT drugs during follow-up, and had a better prognosis than patients with sustained hypertension.17 This is further supported by the fact that target organ damage in hypertension more closely correlates with the range of BP over the entire day rather than with clinic BP levels. The risk associated with WCH may be quantified either by looking for target organ damage or prospective assessment of cardiovascular outcomes. Studies have demonstrated that subtle functional cardiovascular abnormalities and target organ damage are common in patients with WCH, just as in patients with sustained HT. Patients with WCH are known to have abnormal left ventricular mass, left ventricular function, arterial compliance, elasticity and stiffness as well as higher incidence of retinopathy and microalbuminuria, suggesting that long term CV outcomes in WCH are intermediate between normotensive subjects and sustained hypertensive subjects.18,19 Studies have demonstrated that patients with WCH have higher carotid intima-media thickness at baseline, with greater increase during follow up as compared to

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normotensive subjects, with final end-points being no different in WCHs and those with sustained hypertension.20 Although patients with WCH are noted to have lesser echocardiographic structural abnormalities and lower prevalence of microalbuminuria than subjects with sustained hypertension, the indices are significantly greater than normotensive patients.21 Left ventricular hypertrophy detected by echocardiography was seen in 25%, 15% and 4% of patients with sustained HT, WCH and normotension respectively, demonstrating that the risk profile of WCH was intermediate between the other two conditions.22 In hypertension, myocyte hypertrophy and myocardial fibrosis cause structural changes in the left ventricle much before left ventricular hypertrophy is clinically apparent. Serum levels of transforming growth factor (TGF) b1 and procollagen type I propeptide (PIP) are early markers of myocardial fibrosis and have been found to be elevated in patients with WCH as compared to normotensive subjects, while levels were found to be comparable between those with WCH and sustained HT.23 Of 955 cases (53% normotensives, 33% WCH and 14% sustained HT), there was a gradually increasing prevalence of obesity, impaired glucose tolerance, diabetes, and coronary heart disease HD from the normotensive group toward the WCH and sustained HT groups; the prevalence of dyslipidemia was highest amongst those with WCH.24 Over a 3.5 year follow up in 1048 patients, Pierdomenico et al reported a 4 time higher rate of occurrence of renal impairment and cardiovascular events in subjects with WCH.25 Although initial follow up studies of patients with WCH, revealed that transition to sustained HT was not different as compared to those normotensive subjects, most of these studies comprised of small number of patients with only intermediate term follow up.15,16,26 Subsequent studies with more number of patients and longer follow up have confirmed that the percentage of subjects who develop sustained hypertension over 5e10 years is greater in individuals with baseline WCH or MHT as compared to normotensive individuals. During an 8-year follow-up of 128 subjects with WCH, 47% progressed to sustained HT; these individuals had a 2.8 time higher risk of developing sustained HT as compared to those with normotension.12 Amongst 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, (PAMELA), 18%, 42% and 47% of those who had baseline normotension, WCH and MHT respectively, went on to develop sustained HT after 10 years.9 Subjects with WCH and MHT had respectively, a 2.5 and 1.8 time risk of developing sustained HT over follow up. This could be related to the fact that, with higher initial BP, there is a greater chance to reach the cutoff value separating normotension from sustained HT over long term follow up. Hence WCH may truly be a prehypertensive state explaining the observation that some individuals progress to develop established hypertension. The incidence of fatal and non-fatal cardiovascular events is also known to increase progressively from normotension to white-coat and masked hypertension, with highest risk being noted, in those with sustained hypertension. Although at baseline, CV risk associated with WCH is closer to normotension than to masked or sustained hypertension, over long term follow up, the risk conferred by WCH exceeds that of normotension, but still remains lesser than that associated

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with sustained hypertension. Amongst 420 patients (18% of whom had WCH), longitudinal follow up over 10 years demonstrated increased cardiovascular risk in WCH compared to normotensive controls, with an event rate similar to those with established HT.10 In a 10-year follow up of the Ohasama cohort, the composite risk of CV mortality and stroke was reported to be higher in patients with sustained and masked HT, as compared to those with WCH and normotension.27 However the investigators concluded that given the wide CI reported (0.76e2.14), subjects with WCH could potentially have small to moderate increase in risk as compared to those with normotension. Recent pooled data from four international prospective studies analyzed the cumulative hazard for stroke in subjects with WCH over a period of 10 years.28 Interestingly, the initial risk for stroke was low (comparable to normotensives for the first 5e6 years) and then tended to rise, becoming similar to that of established HT after 10 years of follow up. In a primary care cohort of more than 5000 patients (of whom 25% had WCH), the rate of all-cause mortality in patients with WCH, though high (4.4 deaths per 1000 years of follow-up) was lower than that in patients with sustained hypertension (10.2 deaths per 1000 years of follow-up), over a 7-year follow up.29 Recent data from the Finn-Home study also show that prevalence of baseline risk factors, the incidence of CV events and all-cause deaths increased across the spectrum from, normotensive subjects to those with white-coat, masked and sustained hypertension.30 Therefore sufficient evidence exists to indicate that WCH is a form of hypertension which is intermediate between normotension and sustained hypertension as far as the implications regarding CV risk are concerned. There is a definite increase in the risk of developing sustained HT, target organ damage (at least in some patients), with resultant long term deleterious consequences, and hence it should no longer be regarded as a clinical innocent state. Therefore, similar to patients with essential hypertension, appropriate risk stratification of these individuals is mandatory. Assessment of target organ damage, evaluation of risk of future cardiovascular events and consideration of therapeutic intervention in patients with WCH form the cornerstone of management of these patients.

2.

Treatment

Initial guidelines on the management of WCH stated that patients with BP < 135/85 mmHg outside the office and with no evidence of end-organ damage, had a low cardiovascular risk. Such patients did not warrant medical therapy and could be followed over time. For those patients with BP > 135/ 85 mmHg outside the office (documented by ambulatory or home monitoring), are at an increased cardiovascular risk, and may be considered for antihypertensive therapy. However the premise that it may be safe to withhold therapy in white-coat hypertension remains untested. Withholding therapy has the advantages of avoiding (a) unnecessary labeling of patients as hypertensives, (b) the cost of therapy, and (c) possible adverse effects of antihypertensive drugs. However it is important to remember that most evidence

36

c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 3 3 e3 7

linking hypertension with adverse CV risk and effectiveness of anti-HT therapy in reducing this risk is based on office BP readings. Since ideally the goal of anti-HT drug treatment is to produce a sustained reduction in BP throughout the 24 h, the main issue in patients with WCH would be whether therapy lowers both clinic and ambulatory BP readings. Studies have shown that the main effect of antihypertensive drugs in patients with WCH is to lower the clinic BP, without having significant effect on the ambulatory BP, which by definition is normal to begin with. Retrospective analysis of effectiveness of anti-HT drugs in patients classified according to high or low ambulatory BP recordings (i.e. sustained HT vs true WCH, respectively) reveal interesting trends.31e33 Angiotensin converting enzyme inhibitors (ACEI) were much more effective than calcium channel blockers (CCB) in those with lower ambulatory BP (i.e. patients with WCH), while in those with sustained HT, both classes of drugs were equally effective. Inability to effectively lower ambulatory BP has also been reported in other studies using alpha blockers and CCB’s.34,35 In a substudy of the Systolic Hypertension in Europe (Syst-Eur) study, it was demonstrated that although CCB based regimes, lowered clinic pressure in all patients, they had little effect on ambulatory pressure in subjects with WCH.36 Although drug therapy reduced the rate of strokes in patients with sustained hypertension, there was no evidence of any reduction in stroke rate in those with WCH (who had a very low stroke rate whether or not they were treated). Since WCH is especially common in patients with chronic kidney diseases, intensive anti-HT therapy of this subgroup of patients (based only on office BP readings) may actually be harmful. As these patients often exhibit display daytime and especially nighttime systolic BP values at the threshold limit of hypoperfusion (100 mmHg), intensive therapy driven solely by office systolic BP > 130 mmHg may predispose patients to ischemia-induced adverse renal and cardiovascular outcomes. The phenomenon of WCH is also important to recognize in patients with resistant HT (BP > 140/90 on treatment with optimized doses of at least 3 anti-HT drugs, including a diuretic). Studies have shown that more than 1/3rd of patients, initially classified by clinic BP readings as having resistant HT were determined to have WCH after ambulatory BP monitoring.8 Hence it is recommended that ambulatory or home BP monitoring be used for all patients with resistant HT before making radical changes in treatment regimens. Randomized, controlled trials need to be performed in subjects with WCH wherein they are assigned to have their BP treated on the basis of both office BP and different thresholds of ambulatory BP measurements. Until that is done, the prudent course is to treat high blood pressures measured in the office. Moreover more data are also needed to assess whether treating patients with WCH will significantly lower the risk of CV events.

3.

Conclusion

White coat hypertension is fairly common and may be seen in upto 20e40% of hypertensive patients, and is increasingly common in aging populations. Since studies have shown that the risk in patients with WCH is intermediate between

normotension and sustained hypertension, one should make an effort to identify patients with WCH who are at high global cardiovascular risk. Clinicians should be aware that WCH represents a continuum across the hypertension spectrum. Antihypertensive medication may be required in patients with high-risk WCH including those with target organ damage and associated multiple CV risk factors like diabetes mellitus or metabolic syndrome. It is reasonable to state that in absence of other CV risk factors and signs of target organ damage, treatment of patients with WCH can be limited to lifestyle measures and regular measurement of clinic BP (every 6 months) and ambulatory BP (every 1 or 2 years). Close follow up is essential because of a definite risk of WCH developing into sustained hypertension and leading to cardiovascular events. These risks are higher in individuals in whom the out-of-clinic pressures are in the high normal range and those with associated cardiovascular risk factors.

Conflicts of interest All authors have none to declare.

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