The Masked Hypertension Conundrum: Risk Is Increased, but What Should Be Done About It?

Masked hypertension (MH) is an entity first described by Pickering in 2002 to describe individuals with normal in-office but elevated out-of-office blood pressure (BP).1 In contemporary practice, the broader term “masked phenomenon” is now preferred, with MH reserved for individuals that are not treated with antihypertensive drugs and masked uncontrolled hypertension (MUCH) applied to those under treatment. Masked phenomenon is a clinical conundrum. On the one hand, substantial observational data describing its prevalence, predictors, and associated risks have accumulated. Conversely, very little direct evidence is available informing a preferred management strategy. In this issue of the Journal, Yano et al. describe an analysis of 161 adults aged 25–45 years in which they assessed the dose of phenylephrine, an alpha-1 adrenergic receptor agonist, required to increase BP by 25 mm Hg.2 In the 21 subjects with MH, as determined by performing 24-hour ambulatory blood pressure monitoring (ABPM), the dose required was 222 µg, similar to the 254 µg required in 28 subjects with sustained hypertension (P = 0.1) and significantly lower than the 329 µg required in 106 normotensive subjects (P = 0.01). Potential limitations of this work include the relatively small sample size, the unknown relationship between phenylephrine-based BP stimulation and cardiovascular outcomes, and its post hoc nature. Nevertheless, this is a useful analysis and a worthy addition to the literature on masked phenomenon, demonstrating that such individuals exhibit increased vascular reactivity in response to pharmacological stimulation of the sympathetic nervous system. This article refocuses attention on masked phenomenon, which, in a recent meta-analysis of 257 studies and 103,802 subjects, was found in 11% of individuals (10% had MH and 13% had MUCH). Additional, important recent learnings about MH and/or MUCH include: The etiology of masked phenomenon is likely multifactorial. The enhanced vascular reactivity found by Yano et al. and corroborated in other studies reporting increased sympathetic nervous system activity and autonomic dysregulation likely plays a role.3,4 Job strain, smoking, and increased alcohol intake may also contribute.5 The possibility that greater medication adherence around clinic visits may play a role in causing MUCH seems logical, but empiric evidence is lacking.6 A higher prevalence in subjects with diabetes, sleep apnea, and chronic kidney disease exists.5,7,8 Greater associations with higher left ventricular mass index, left ventricular hypertrophy, carotid atherosclerosis, and renal target organ damage have been demonstrated.5,7,9 A risk of cardiovascular events and death that is higher than normotension and sometimes similar to sustained hypertension.10–13 The 5-year risk of progression to sustained hypertension is approximately 40%.14 The reproducibility of MH on serial assessments is about 70%.15 MH has relatively low concordance, when it is defined according to ABPM vs. home blood pressure monitoring (HBPM). In a combined cohort of 1,971 subjects, 48% exhibited MH using ABPM and HBPM, 30% on ABPM only, and 22% on HBPM only. Younger subjects were more likely to have isolated ABPM-defined MH and older ones more likely to have isolated HBPM-defined MH.16 This introduces uncertainty with respect to the best method to assess for and monitor MH and also indicates that there are different age-related phenotypes of MH, whose characteristics and prognosis require further investigation. A major question is whether MH in younger individuals, potentially related to increased activity, is equivalent to MH in more sedentary older persons. Overall, the accumulated evidence indicates that masked phenomenon is an important prognostic indicator and a likely contributor to cardiovascular disease and death. What is missing is definitive evidence that treatment of masked phenomenon reduces these outcomes. Indeed, because the recruitment of subjects in foundational hypertension treatment trials was necessarily focused on those with initially elevated BP, subjects with MH would have been excluded. Finding a funding source for outcome studies of MH and MUCH is also challenging. The Practice Versus Ambulatory Blood Pressure Measurement Under treatment with ramipril (PLUR) study provides some supportive data for initiating treatment in MUCH, but is limited by a complex design, high dropout rate, and a small number of events.17 This study compared an ABPM-based treatment strategy (n = 651) vs. an office-based strategy (n = 647) in patients with initially BP levels of >165/95 mm Hg after drug washout. In the office-based strategy study arm, but not in the ABPM-based study arm, subjects with white coat hypertension were excluded. Cardiovascular events occurred in 3.1% of the ABPM arm vs. 5.4% of the office-based arm (P = 0.04). Limitations notwithstanding, the observed relative reduction in events was presumably due to the more aggressive treatment of MUCH in the ABPM study arm. The ongoing Masked-Uncontrolled Hypertension Management Based on Office BP or on Ambulatory Blood Pressure Measurement (MASTER) trial will provide more data with respect to the benefits of treating MUCH. MASTER is a 4-year multicenter clinical trial in 1,240 treated hypertensive patients utilizing a prospective, randomized, open-label, with blinded endpoint (PROBE) design that is comparing an office BP-based management strategy to an ABPM-based strategy.18 The coprimary outcomes include left ventricular mass and microabuminuria at 1 year. Cardiovascular events, a predefined secondary endpoint, will be examined at 4 years. Estimated completion date is January 2023. Until more treatment data are available, what should be done regarding the management of patients with MH and MUCH? Like many practicing clinicians, I am uncomfortable with leaving MH and MUCH patients untreated given the aforementioned, accumulated data demonstrating that their risk is substantially increased. Conversely, evidence-based purists would argue that, in the absence of definitive data, treatment should be withheld and this viewpoint is certainly defensible. Because I routinely use home BP telemonitoring to guide treatment decisions in my patients, I will automatically treat MH and MUCH. Although most national and international hypertension clinical practice guideline panels have avoided direct recommendations, the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Task Force has taken a stand and outlined an approach to MH and MUCH.19 Detection and treatment of MH and/or MUCH using out-of-office monitoring is recommended, as follows: Patients with BP levels between 120–129/75–79 mm Hg and suspected MH should, after a 3-month trial of lifestyle modification, undergo ABPM or HBPM. If out-of-office BP is 130 mm Hg or greater, initiation of antihypertensive drug therapy is recommended. Patients at increased risk of cardiovascular disease or with target organ damage who have achieved office BP targets should be screened for MUCH using HBPM and, if present, confirmed with ABPM. If present, intensification of antihypertensive drug therapy is recommended. The masked phenomenon conundrum, characterized by the availability of substantial prognostic data yet limited evidence for treatment, is quite possibly the most compelling question left in the field of hypertension but it unfortunately may not be definitively answered for some time. Accordingly, personal preference and shared decision-making remain the most important principles to use when guiding clinical decision-making in patients with the masked phenomenon. None declared. RP is co-founder and CEO of mmHg Inc., a digital health company specializing in blood pressure measurement and monitoring.