Traditionally, identification and management of hypertension has been based on office blood pressure (BP) measurements. However, after the introduction of methods to assess BP values under everyday life conditions, through either 24-hour ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM), there has been growing awareness about the substantial discrepancies between information on BP provided by these “out-of-office BP” methodologies and conventional office BP (OBP) measurements. This has led to identification of four specific hypertension phenotypes, characterized by variable agreement or disagreement between OBP and out-of-office BP: (1) “true” or “sustained” normotension (SN) when both office and out-of-office BP are within currently defined normal limits; (2) “sustained” hypertension (SH), when both office and out-of-office BP are above normal limits; (3) “white-coat” hypertension (WCH), also defined as “isolated office hypertension,” when office BP is elevated but out-of-office BP levels are within normal limits; and (4) “masked” hypertension (MH), when office is normal, but out-of-office BP levels are elevated. WCH and MH have for years been matter of debate, regarding their actual clinical significance. However, recent observational studies and metaanalyses have indicated that both these BP phenotypes, compared with true or sustained normotension, are associated with some negative impact on cardiovascular prognosis, which in the case of MH may indeed be very similar to that of SH. However, in clinical practice these conditions have been often treated rather simplistically, ignoring important problems associated with their identification and management.
In its first part, this chapter will address the clinical significance and the initial diagnostic and therapeutic approach to white-coat and masked hypertension in untreated subjects. Because these discrepancies between office and out-of-office BP may continue to be present even after initiation of antihypertensive treatment, the second part of this chapter will address the persistence of an elevated OBP combined with normal out-of-office BP during treatment (so called “white-coat resistant” hypertension), as well as the condition characterized by the persistence of elevated out-of-office BP combined with normal OBP (defined as “masked uncontrolled” hypertension) in treated hypertensive patients.
White-Coat Hypertension and Masked Hypertension in Untreated Individuals
Definition
White-Coat Hypertension
The BP rise associated with the alerting reaction during the medical visit, the so called “white-coat effect” (WCE) represents a major problem associated with conventional BP measurement because it may lead to overestimation of initial BP levels. As a consequence of this, there will be a significant number of subjects with elevated BP values in the office but with persistently normal out-of-office BP levels (a condition defined as “white-coat” hypertension, WCH, or “isolated office” hypertension). Traditionally, WCH has been defined as BP levels measured in the office persistently equal to or higher than 140 mm Hg for systolic and/or 90 mm Hg for diastolic, associated with persistently normal out-of-office BP values either on ambulatory or on home BP monitoring. Because BP levels are different during the day and night, and BP may be elevated during either of these periods or throughout the 24-hours, definition of normality in out-of-office BP levels must take into consideration the whole BP recording period. In recognition of this, as well as of the prevailing prognostic relevance of nighttime blood pressure levels over other components of ABPM, current European Society of Hypertension/European Society of Cardiology (ESH/ESC) hypertension guidelines and ABPM guidelines have expanded the definition of WCH, requiring normality in ambulatory BP values during either daytime (i.e., <135/85 mm Hg); 24-hours (i.e., <130/80 mm Hg) and nighttime (i.e., <120/70 mm Hg) and also normality in average home BP levels (i.e., <135/85 mm Hg) when this methodology is used ( Fig. 12.1 and Table 12.1 ).
| White-coat (or isolated office) hypertension | Untreated patients with elevated office blood pressure ≥140/90 mm Hg a and 24-hour ambulatory blood pressure measurement <130/80 mm Hg and awake ambulatory blood pressure measurement <135/85 mm Hg and sleep measurement <120/70 mm Hg or home blood pressure <135/85 mm Hg |
| Masked hypertension | Untreated individuals with office BP <140/90 mm Hg and 24-hour ABP ≥130/80 mm Hg and/or awake ABP ≥135/85 mm Hg and/or sleep ABP ≥120/70 mm Hg b or home BP ≥135/85 mm Hg |
| Masked uncontrolled hypertension | Treated individuals with office BP <140/90 mm Hg and 24-hour ABP ≥130/80 mm Hg and/or awake ABP ≥135/85 mm Hg and/or sleep ABP ≥120/70 mm Hg b or home BP ≥135/85 mm Hg |
a Ambulatory blood pressure values obtained in the clinic during the first or last hour of a 24-h recording may also partly reflect the white-coat effect.
b Patients with office BP<140/90 mm Hg, 24-h BP<130/80 mm Hg, awake BP <135/85 mm Hg but sleep BP ≥120/70 mm Hg should be defined as having ‘Isolated Nocturnal Hypertension,’ to be considered as a form of masked hypertension.
Masked Hypertension
The condition characterized by normal in-office but elevated out-of-office BP levels has been defined as masked hypertension. For its diagnosis, conventional BP in the office is considered to be normal if it is less than 140/90 mm Hg. However, when defining elevation in out-of-office BP, according to recent guidelines, it is now considered inappropriate to exclude nocturnal BP and to focus on daytime BP levels only, as done in the past. Indeed, masked hypertension might be attributed not only to elevated daytime BP levels, but also to isolated nocturnal hypertension, which characterizes 7% of hypertensive individuals and can at present only be diagnosed with 24h ABPM. The definition of masked hypertension, has thus been extended to include elevation in ambulatory BP levels during either daytime (i.e., ≥135/85 mm Hg), and/or 24-hours (i.e., ≥130/80 mm Hg) and/or nighttime (i.e., ≥120/70 mm Hg); and/or elevation in average home BP levels (i.e., 135/85 mm Hg) (see Fig. 12.1 and Table 12.1 ).
Although, ABPM is currently considered the standard method for estimating out-of-office BP, and for assessing daily life BP control in treated hypertensive patients, it is not easily available everywhere and requires trained clinic staff and specialized equipment and software for its analysis. Conversely, HBPM could be easily used on a routine basis, as recommended by recent ESH guidelines. Indeed, when performed on a regular basis and following standardized protocols, repeated BP measures obtained by patients at home offer the possibility to accurately and frequently assess out-of-office BP not only during a single day, but also over several days, weeks, or months in a usual life setting, thus providing a reliable assessment not only of the degree but also of the consistency of BP control over time.
Besides, recent studies have indicated that HBPM is almost as reliable as ABPM in identifying WCH and MH although it provides complementary rather than superimposable information on out-of-office BP as compared with ABPM. Based on its undeniable advantages, as well as on the predictive value of HBP values over and above the information provided by OBP, current hypertension guidelines recommend the extensive use of HBPM not only for the initial diagnostic approach to hypertension, but also and more specifically, for the long-term follow-up of treated hypertensive patients as well as an additional useful method for assessment of WCH and MH. The currently proposed threshold values for definition of WCH and MH based on this methodology, are shown in Table 12.1 . Of note, the cutoff BP values of 135/85 mm Hg or higher for diagnosing hypertension pertain to both daytime ABPM and to average self measured BP values obtained through HBPM.
In particular, a report of the Pressioni Arteriose Monitorate e Loro Associazioni study, (PAMELA study) in which the initial diagnosis of WCH (identified as office BP ≥140/90 mm Hg with 24-hour BP mean <125/79 mm Hg or home BP <132/82 associated mm Hg) was reassessed 10 years later, showed similar results in the ability of HBPM and ABPM to identify WCH, sustained hypertension, true normotension and masked hypertension, even if a substantial percentage of subjects, changed from one category to another, including progression from normotension, WCH or MH to sustained hypertension (true hypertension) ( Fig. 12.2 ).
However, as mentioned previously, although HBPM shares many of the advantages of ABPM, resulting more cost-effective for the diagnosis of WCH and MH, it cannot be considered as a substitute but rather a complement to ABPM, as these methods are likely to pick up different moments of BP behavior in a subject’s daily life.
Prevalence
White-Coat Hypertension
WCH or isolated office hypertension (IOH) has been shown to be a rather common phenomenon, reasonably reproducible when properly studied with OBP measurements along with real-life ABPM or HBPM. The prevalence reported in literature for WCH is quite variable across different studies, ranging from less than 10% to more than 60% with several intermediate values. After the evidence from several population studies and their metaanalyses supporting a threshold value equal or higher than 135/85 mm Hg to define hypertension with average daytime ambulatory BP, the frequency of WCH has been reported to range from 9% to 16% in the general population (average 13%) and from 25% to 46% (average about 32%) among hypertensive subjects defined only based on OBP. The frequency of WCH has been shown to increase in the presence of certain clinical characteristics, such as office systolic (S)BP in the range of 140 to 159 mmHg or diastolic (D)BP in the range of 90 to 99 mm Hg ; female sex; increasing age ; nonsmoking status; hypertension of recent diagnosis; limited number of BP measurements in the doctor’s office; and normal left ventricular mass at echocardiography. It should be emphasized that despite having home and ambulatory BP within “normal” limits, subjects with WCH have nevertheless slightly higher out-of-office BP levels than normotensive controls ( Fig. 12.3 ).
Masked Hypertension
Overall, the prevalence of masked hypertension in the general population ranges from 8.5% to 16.6%, and may increase up to 30.4% in populations with high normal clinic BP. The variability in prevalence estimates is attributed to the heterogeneous definition of masked hypertension, and to differences in the characteristics of the populations being investigated across studies. In the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (IDACO) study, the prevalence of MH was 44.5% among middle-aged and elderly patients (mean age, 64 years). A subsequent report of the IDACO showed a prevalence for MH of 18.8% among subjects from a nondiabetic population, and of 29.3% among normotensive diabetic patients. Masked hypertension is more likely to occur in elderly male patients with increased BP variability, in whom a marked reduction in OBP immediately after a large meal may contribute to a diagnosis of MH ; in subjects who experience mental stress at work or at home (i.e., BP rise to hypertensive levels during working hours with normal BP at the time of conventional office measurements) ; in smokers, further supporting a previous observation from our group that smoking one cigarette may increase ambulatory BP over 15 minutes ; in case of excessive alcohol consumption ; in sedentary obese individuals who are characterized by poor exercise tolerance throughout the daytime activities, whereas they often display normal BP values while at rest in the physician’s office ; the presence of metabolic risk factors or diabetes mellitus ; in chronic kidney disease ; in association with shortened sleep time, or obstructive sleep apnea and with other conditions characterized by isolated nocturnal hypertension, nondipping or rising nocturnal BP patterns whenever these patterns are associated with normal conventional office BP values.
Clinical Significance
White-Coat Hypertension
Population studies have indicated that compared with true normotension, WCH may increase the risk of developing sustained hypertension leading to consider this condition as a prehypertensive state ( Fig. 12.4 ).
Moreover, compared with sustained normotension, patients with WCH have been shown to exhibit a greater prevalence/severity of alterations in glucose and lipid metabolism (blood glucose, serum cholesterol, impaired fasting glucose or diabetes mellitus, etc.), albeit less than in patients with true hypertension that make the overall cardiovascular risk profile of this condition unfavorable when compared with the true normotensive fraction of the population ( Fig. 12.5 ).
Evidence has also been provided that compared with sustained normotension, WCH is associated with an increased risk of development and progression of renal, cerebral, vascular and cardiac organ damage (i.e., increased left ventricular [LV] mass index and carotid intima-media thickness). Besides, most population studies (although not all) and their metaanalyses have also indicated that WCH is associated with an increased risk of cardiovascular morbidity and mortality compared with true normotension, although such a risk remains lower than that of MH and sustained hypertension ( Fig. 12.6 ). Thus, on the background of the evidence summarized above, the idea that WCH is a clinically innocent condition that should be regarded as not being substantially different from true normotension, cannot be supported.
Masked Hypertension
Evidence from large cohort studies has demonstrated that MH is associated with an increased risk of new-onset sustained hypertension (see Fig. 12.4 , lower panel) and with an increased prevalence of metabolic alterations and cardiovascular risk factors (see Fig. 12.5 ). Consistent evidence from large population studies and their metaanalyses have also indicated that compared with their true normotensive counterparts, subjects with MH have a higher risk of development and progression of cardiac (i.e., LV structural alterations) and vascular subclinical organ damage (i.e., early carotid atherosclerosis) and an increased incidence of cardiovascular events and mortality. Although in some reports only sustained hypertension and not MH was significantly associated with cardiovascular outcomes, the metaanalyses of available studies including subjects from the general population and from primary care and specialty clinics have provided more consistent evidence in this regard. In one of such metaanalyses, after a mean follow-up of 8 years, compared with sustained normotension, the adjusted hazard ratios for cardiovascular disease events were 1.12 (95% confidence interval [CI] 0.84 to 1.50) for white-coat hypertension, 2.00 (95% CI 1.58 to 2.52) for masked hypertension, and 2.28 (95% CI 1.87 to 2.78) for sustained hypertension. The results did not differ significantly across the studies ( p = 0.89). Of note, other metaanalyses have found an increased risk of cardiovascular events for subjects with masked hypertension (HR 1.62, 95% CI 1.35 to 1.96) which not only was higher than that of WCH (hazard ratio [HR] 1.22, 95% CI 0.96 to 1.53) but was also not significantly different from that of sustained hypertension (HR 1.80, 95% CI 1.59 to 2.03) ( Fig. 12.7 ).
Management
White-Coat Hypertension
In recognition of the prognostic relevance and frequent occurrence of this condition in clinical practice, current hypertension guidelines have included suspicion of WCH in untreated individuals among the compelling clinical indications for out-of-office BP monitoring. They recommend confirming the diagnosis of WCH within 3 to 6 months, along with follow-up visits at yearly intervals accompanied by out-of-office BP measurements (i.e., ABPM, or home BP monitoring), so as to detect whether and when sustained hypertension may develop. There is still uncertainty regarding the question on whether patients with WCH should or should not be given antihypertensive treatment, with some experts suggesting that because it does not differ from normotension, WCH needs no therapeutic intervention. Along this line of thinking, identification of WCH would thus avoid administering “unnecessary” treatment to subjects who have otherwise normal BP levels in daily life conditions, thus preserving them from the possible adverse effects associated with inappropriate long-term drug administration, improving their quality of life, and reducing the health care costs. This could be particularly true in elderly subjects or in presence of severe atherosclerotic disease, where unnecessary BP lowering treatment, might compromise renal and/or cardiac perfusion leading to episodes of acute kidney injury or coronary ischemia. On the other hand, on the background of the more recent evidence that patients with WCH are at greater risk of developing sustained hypertension, metabolic alterations and cardiovascular complications compared with truly normotensive individuals (although still remaining at a lower risk than in true hypertension), it has been suggested that WCH subjects could benefit from an active therapeutic intervention. Because no evidence is yet available that antihypertensive drugs are beneficial in WCH, this intervention has in most cases to be limited, however, to close follow-up and lifestyle changes, aimed at improving the adverse risk profile of these subjects. In line with the 2013 ESH/ESC Guidelines on hypertension management, drug treatment could be considered in presence of organ damage and with a history of cardiovascular disease.
Masked Hypertension
Although the evidence on the adverse cardiovascular consequences associated with MH strongly suggests a potential benefit from BP lowering, no clinical trial up to date has specifically addressed whether or not treatment of MH may translate into improved cardiovascular prognosis. Despite this lack of evidence, the 2013 ESH/ESC guidelines have suggested that in patients with MH, drug treatment could also be considered because in these subjects the risk of hypertensive subclinical organ damage and adverse cardiovascular outcomes is very close to that of subjects with sustained hypertension. A first step in the management of patients with MH should thus include a careful diagnostic work up to assess the presence of additional risk factors including a deranged metabolic profile and search for the presence of target organ involvement. Initially, nonpharmacologic strategies such as lifestyle changes should be implemented to decrease out-of-office BP levels and to ameliorate metabolic alterations. If nonpharmacologic measures are insufficient to normalize BP levels, pharmacologic treatment could be initiated, although evidence from randomized control trials is still lacking in this regard. The ongoing MASTER trial (MASked-unconTrolled hypERtension management based on office BP or on out-of-office [ambulatory] BP measurement [NCT028047074]), a research project of the European Society of Hypertension and the ARTEMIS Consortium, is aimed at filling this gap in the next few years.
When ambulatory blood pressure is measured, pharmacologic treatment may be modulated according to whether blood pressure is elevated either during daytime or during nighttime hours.
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