Ambulatory Blood Pressure Monitoring (ABPM) as the reference standard for diagnosis of hypertension and assessment of vascular risk in adults

Abstract

New information has become available since the ISC, AAMCC, and SECAC released their first extensive guidedelines to improve the diagnosis and treatment of adult arterial hypertension. A critical assessment of evidence and a comparison of what international guidelines now propose are the basis for the following statements, which update the recommendations first issued in 2013. Office blood pressure (BP) measurements should no longer be considered to be the “gold standard” for the diagnosis of hypertension and assessment of cardiovascular risk. Relying on office BP, even when supplemented with at-home wake-time self-measurements, to identify high-risk individuals, disregarding circadian BP patterning and asleep BP level, leads to potential misclassification of 50% of all evaluated persons. Accordingly, ambulatory BP monitoring is the recommended reference standard for the diagnosis of true hypertension and accurate assessment of cardiovascular risk in all adults ≥18 yrs of age, regardless of whether office BP is normal or elevated. Asleep systolic BP mean is the most significant independent predictor of cardiovascular events. The sleep-time relative SBP decline adds prognostic value to the statistical model that already includes the asleep systolic BP mean and corrected for relevant confounding variables. Accordingly, the asleep systolic BP mean is the recommended protocol to diagnose hypertension, assess cardiovascular risk, and predict cardiovascular event-free interval. In men, and in the absence of compelling clinical conditions, reference thresholds for diagnosing hypertension are 120/70 mmHg for the asleep systolic/diastolic BP means derived from ambulatory BP monitoring. However, in women, in the absence of complicating co-morbidities, the same thresholds are lower by 10/5 mmHg, i.e., 110/65 mmHg for the asleep means. In high-risk patients, including those diagnosed with diabetes or chronic kidney disease, and/or those having experienced past cardiovascular events, the thresholds are even lower by 15/10 mmHg, i.e., 105/60 mmHg. Bedtime treatment with the full daily dose of ≥1 hypertension medications is recommended as a cost-effective means to improve the management of hypertension and reduce hypertension-associated risk. Bedtime treatment entailing the full daily dose of ≥1 conventional hypertension medications must be the therapeutic regimen of choice for the elderly and those with diabetes, resistant and secondary hypertension, chronic kidney disease, obstructive sleep apnea, and medical history of past cardiovascular events, among others, given their documented high prevalence of sleep-time hypertension.

• Clinical guidelines for the application of ambulatory blood pressure monitoring
• ambulatory blood pressure monitoring
• cardiovascular risk
• sleep-time blood pressure
• masked normotension
• masked hypertension
• true hypertension
• hypertension chronotherapy

INTRODUCTION

Hypertension, a common chronic condition that affects up to 40% of human adults (Hermida et al., 2013; Mancia et al., 2013; Piper et al., 2015), is a major risk factor for stroke, heart attack, and other vascular as well as renal and metabolic (type 2 diabetes) diseases. Pharmacologic treatment of high blood pressure (BP) reduces to some extent the incidence of these complications and prolongs life (Mancia et al., 2013). Accordingly, there is strong incentive, from the point of view of primary prevention, to identify individuals who have high BP and to provide them appropriate treatment. The diagnosis of hypertension and all clinical decisions regarding its treatment today are still mainly based only on a limited number of daytime office BP measurements (OBPM) obtained at the clinic, occasionally supplemented by wake-time patient self-assessments at home and work (Mancia et al., 2013). Those casual time-unspecified OBPM, and even home BP measurements (HBPM), disregard the mostly predictable nyctohemeral variation in BP that results from the interrelationship of many 24 h cyclic physiologic, neuroendocrine, and environmental determinants: (i) rest-activity associated changes in behavior (including activity routine and level, stimulant [e.g. caffeine] consumption, meal timings and content, emotional and mental stress, and posture); (ii) the external day-night divergence in ambient light intensity and spectrum, temperature, humidity, and noise; and (iii) endogenous circadian (∼24 h) variation in neuroendocrine, endothelial, vasoactive peptides and opiods, and hemodynamic parameters (e.g., plasma noradrenaline and adrenaline [autonomic nervous system], atrial natriuretic and calcitonin gene-related peptides, and renin, angiotensin, and aldosterone [renin-angiotensin-aldosterone system]) (Fabbian et al., 2013; Hermida et al., 2007c, 2011a; Portaluppi & Smolensky, 2007; Portaluppi et al., 2012; Smolensky et al., 2015c). Most importantly, correlation between BP level and risk of target organ damage as well as cardiovascular disease (CVD) events is higher for parameters derived from around-the-clock ambulatory BP monitoring (ABPM) (Clement et al., 2003; Dolan et al., 2005; Eguchi et al., 2008; Hermida et al., 2011b, 2012a, b, 2013l; Minutolo et al., 2011; Salles et al., 2008; The ABC-H Investigators et al., 2014; Verdecchia et al., 1994), a diagnostic tool that allows thorough description and quantification of all aspects of the 24 h BP variation.

On the basis of the substantial and indisputable evidence of the significantly better prognostic value of ABPM compared to OBPM, several international guidelines now propose ambulatory measurements as a requirement to confirm the office diagnosis of hypertension (National Institute for Health and Clinical Excellence, 2011; Piper et al., 2015). The latest update of the guidelines for the clinical management of adult primary hypertension from the National Institute for Health and Clinical Excellence (NICE) recommends ABPM be conducted to corroborate the diagnosis of hypertension in all adults with elevated clinic BP (NICE, 2011). However, the NICE guidelines specify “use the average of at least 14 measurements taken during the person’s usual waking hours to confirm a diagnosis of hypertension”, thereby explicitly recommending such diagnosis be based solely upon the ABPM-derived daytime systolic BP (SBP) and diastolic BP (DBP) means ≥135/85 mmHg, the established thresholds for these parameters (Hermida et al., 2013l; Mancia et al., 2013). This recommendation totally disregards findings of the substantial number of investigations (Ayala et al., 2013a; Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagard et al., 2008; Fan et al., 2010; Hermida et al., 2011b, 2012a, b, 2013b; Kikuya et al., 2005; Minutolo et al., 2011; The ABC-H Investigators et al., 2014) that document sleep-time BP more strongly predicts future CVD events than does wake-time BP. In addition, it precludes determination of the most relevant information provided by around-the-clock ABPM of the asleep SBP/DBP means. Thus, the 2011 NICE guidelines fail to recognize the high prevalence of sleep-time hypertension and its associated markedly elevated CVD risk (Hermida et al., 2011b, 2012b, 2013b, 2014a), as well as the considerable prevalence and clinical implications of masked hypertension, i.e. normal office BP but elevated ambulatory BP (Hermida et al., 2012a), and “non-dipping normotension”, i.e., the absence of sleep-time relative decline from daytime BP mean level by ≥10% in individuals with otherwise normal ambulatory BP levels (Hermida et al., 2013e).

The most recently issued guidelines for the management of arterial hypertension from the European Society of Hypertension (ESH) and European Society of Cardiology (ESC) state “it is now generally accepted that out-of-office BP is an important adjunct to conventional office BP measurement, but the latter currently remains the ‘gold standard’ for screening, diagnosis and management of hypertension” (Mancia et al., 2013). These ESH/ESC guidelines provide just a limited list of conditions “considered as clinical indications for out-of-office BP measurement for diagnostic purposes”, specifically, suspected isolated-office and/or masked hypertension; considerable variability of office BP over the same or different visits; autonomic, postural, post-prandial, siesta- and drug-induced hypotension; elevated office BP or suspected preeclampsia in pregnant women; identification of true and false resistant hypertension; suspicion of nocturnal hypertension or absence of dipping; and assessment of BP variability (Mancia et al., 2013). As emphatically expressed in the ESH/ESC guidelines, the out-of-office methods of ABPM and HBPM do not assess BP status equivalently: “since the two methods provide somehow different information on the subject’s BP status and risk, they should thus be regarded as complementary, rather than competitive or alternative” (Mancia et al., 2013).

The most recent 2015 U.S. Preventive Services Task Force (USPSTF) report (Piper et al., 2015) constitutes an important update that recommends significant changes in primary care practice. The most important conclusions of this report are (Piper et al., 2015): (i) ABPM predicts long-term CVD outcomes independently of OBPM, and (ii) ABPM, rather than traditional and long-honored OBPM, now be considered the reference standard in primary care medicine to diagnose hypertension in adults ≥18 yrs of age, i.e., corroborate or contradict OBPM-determined elevated BP based on single or repeated-interval in-office measurements, to avoid misdiagnosis and over-treatment of persons displaying elevated OBPM yet proven normotensive by ABPM, i.e., commonly termed isolated office hypertension although the more accurate preferred term is masked normotension (Hermida et al., 2013l; Smolensky et al., 2015a). On the basis of the questionable finding (Smolensky et al., 2015a) of an exploratory meta-analysis of no apparent difference in hazard ratio (HR) for vascular risk per 10 mmHg increase between ABPM-derived nighttime, daytime, and 24 h SBP means, the USPSTF report concludes that anyone of those means might be used to corroborate the diagnosis of hypertension in adults (Piper et al., 2015).

As summarized above, there are multiple differences between the recommendations of the USPSTF and the various international practice guidelines. They include recommended: (i) continuous reliance solely on OBPM in some guidelines (Mancia et al., 2013) versus ABPM in others (NICE, 2011; Piper et al., 2015) as the reference standard for diagnosis of hypertension; and (ii) among the later, emphasis upon reliance of the daytime ABPM-derived mean alone (NICE, 2011) versus either the daytime, nighttime, or 24 h ABPM-derived means to confirm such diagnosis (Piper et al., 2015). Beyond the above outlined discrepancies, most current hypertension guidelines have either ignored or only partially addressed, without binding recommendations, several highly relevant critical questions (Hermida et al., 2013l). While many of these questions have previously been addressed in the published 2013 ABPM mutual recommendations of the International Society of Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM) (Hermida et al., 2013l), we here present an updated position statement on ABPM as the reference standard for the diagnosis of hypertension in adults by providing the evidence-based responses to each.

What should be the recommended diagnostic ABPM protocol?

Specific features of the 24 h BP pattern determined by ABPM have been explored as biomarkers or mediators of target tissue injury and triggers of and risk factors for CVD events – angina pectoris, myocardial infarction, cardiac arrest, sudden cardiac death, pulmonary embolism – and cerebrovascular events – ischemic and hemorrhagic stroke (Hermida et al., 2011b, 2013b, 2014a; Portaluppi et al., 2012). The fall of BP during sleep from its daytime level is commonly quantified by the sleep-time relative BP decline (percent decrease in mean BP during night-time sleep relative to the mean BP during daytime activity). Although individuals are broadly designated as dippers when the sleep–time-relative SBP decline is ≥10% or non-dippers when <10%, they should be more precisely categorized as extreme-dippers (decline ≥ 20%), dippers (decline ≥ 10%), non-dippers (decline < 10%), and risers (decline < 0%, asleep SBP mean > awake SBP mean) (Hermida et al., 2013l; Mancia et al., 2013). Numerous studies consistently substantiate a strong association between the atypical and abnormal physiologic feature of blunted sleep-time relative BP decline (non-dipper/riser BP pattern) and increased incidence of fatal and non-fatal CVD events, not only in hypertensive patients (Ayala et al., 2013a; Boggia et al., 2007; Brotman et al., 2008; Dolan et al., 2005; Eguchi et al., 2008; Hermida et al., 2011b, 2013b; Ingelsson et al., 2006; Kario et al., 2001; Nakano et al., 1998; Ohkubo et al., 2002; Salles et al., 2008; Sturrock et al., 2000; Verdecchia et al., 1994) but also in normotensive individuals (Hermida et al., 2013e). Furthermore, various independent prospective studies demonstrate CVD events are better predicted by the asleep than awake or 24 h BP means (Ayala et al., 2013a; Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagard et al., 2008; Fan et al., 2010; Hermida et al., 2011b, 2012a, b, 2013b; Kikuya et al., 2005; Minutolo et al., 2011; The ABC-H Investigators et al., 2014).

Overall, these studies demonstrate that elevated sleep-time BP constitutes a significant CVD risk factor, independent of daytime clinic BP or the ambulatory awake and 24 h BP means. Nonetheless, the findings and conclusions of most previous ABPM studies may be imprecise because of inherent limitations of their investigative methods (Smolensky et al., 2015a), leading to profound inaccuracies and inconsistencies between studies on the prognostic value of multiple ABPM-derived variables, mainly the awake and asleep SBP/DBP means that, in turn, led to the surely biased statement from the USPSTF report concluding similar prognostic value of the 24 h, awake, and asleep SBP/DBP means (Piper et al., 2015). All previous studies addressing the merit of ABPM for predicting CVD risk, except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study (MAPEC, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) discussed below (Ayala et al., 2013a; Hermida, 2007; Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, e, g, h, 2015a, b) relied upon only a single, low-reproducible (Hermida et al., 2007b, 2013d) 24 h ABPM assessment per participant conducted at study inclusion. Such a study design is unsound because it presumes all features of the baseline-determined ambulatory BP pattern are maintained without alteration during the many years of follow-up, despite institution of BP-lowering therapy, aging, and/or development of target organ damage and concomitant morbidity (Hermida et al., 2013a). Additional limitations of most previous ABPM studies are: (i) frequent use of arbitrarily fixed clock hours to define morning awakening and evening bedtime, resulting in daytime and nighttime BP means that do not accurately represent the true awake and asleep BP ones, because they are calculated without assessing and taking into account the actual rest and activity spans of each participant; and (ii) analysis of the prognostic value of dipping status and nighttime BP mean without proper adjustment for the daytime BP mean. Moreover, lack of systematic and multiple ABPM evaluations of patients over time in all previously reported long-term follow-up studies precluded the opportunity to explore the potential reduction in CVD risk associated with modification of prognostic parameters by hypertension therapy, i.e., either increase of sleep-time relative BP decline towards the more normal dipper pattern or, more specifically, reduction of asleep BP mean. Incorporation of periodic (at least annual) ABPM patient studies during follow-up, as in the MAPEC study, clearly establishes that: (i) features of the 24 h BP pattern change over time; and (ii) therapeutic reduction of the asleep BP mean and increase of the sleep-time relative BP decline towards normal dipping lessen not only CVD risk (Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, 2014a, b, d) but also progression towards new-onset type 2 diabetes (Hermida et al., 2015a, b).

Potential reduction in CVD risk through modification of prognostic ABPM parameters by a time-specified hypertension-treatment strategy has so far been investigated only in the MAPEC study, a prospective, randomized, open-label, blinded endpoint trial designed to test the hypothesis that bedtime hypertension chronotherapy entailing conventional hypertension medications exerts better ambulatory BP control and CVD risk reduction than standard therapy, i.e., all such prescribed hypertension medications ingested in the morning. Complete details of the rationale and design of the MAPEC study are reported elsewhere (Ayala et al., 2013a; Hermida, 2007; Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, e, g, h, 2015a, b). Briefly, 3344 subjects (1718 male/1626 female) with baseline ABPM ranging from normotension to sustained hypertension were prospectively followed for a median duration of 5.6 yrs. Hypertensive participants at baseline were randomized to two treatment strategies: (i) all prescribed conventional hypertension medications ingested upon awakening or (ii) the complete daily dose of ≥1 of them ingested at bedtime. At baseline and thereafter at yearly intervals (more frequently if hypertension treatment required adjustment based on ABPM criteria), ambulatory BP and physical activity (wrist actigraphy to accurately derive the awake and asleep BP means on an individual basis) (Crespo C et al., 2013) were simultaneously monitored for 48 consecutive hours. Registered events included: all-cause mortality, myocardial infarction, angina pectoris, coronary revascularization, heart failure, lower-extremity acute arterial occlusion, retinal artery thrombotic occlusion, hemorrhagic and ischemic stroke, and transient ischemic attack.

In the MAPEC study, the best Cox’s regression model (fully adjusted for the significant influential characteristics of sex, age, diabetes, anemia, and chronic kidney disease [CKD]) includes only the asleep SBP mean (HR = 1.23, [1.16–1.32], p < 0.001) and the sleep-time relative SBP decline (HR = 0.98 [0.97–0.99], p = 0.019). Most important, when the asleep SBP mean is adjusted for the awake SBP mean, only the former significantly predicts CVD outcomes (HR = 1.63 [1.44–1.85], p < 0.001, per SD elevation in asleep SBP mean; HR = 0.94 [0.81–1.08], p = 0.348, per SD elevation in awake SBP mean). To further investigate the clinical relevance of the asleep, but not the awake, BP mean on CVD risk, the studied population of the MAPEC study was divided into four groups according to BP level at the final ABPM evaluation of the respective patients, i.e., normal or elevated, using the established ABPM thresholds of 135/85 mmHg for the awake SBP/DBP means and of 120/70 mmHg for the asleep SBP/DBP means (Hermida et al., 2013l; Mancia et al., 2013), independent of clinic BP. The results shown in Figure 1 indicate: (i) equivalent adjusted HR of total CVD events among participants with normal asleep BP mean whether the awake BP mean is normal or elevated (p = 0.489); (ii) equivalent HR in hypertensive patients with elevated asleep BP mean, independent of awake BP mean (p = 0.385); and (iii) significantly higher adjusted HR of CVD events in hypertensive patients with elevated compared to those with normal asleep BP mean, whether the awake BP mean is below or above 135/85 mmHg (Hermida et al., 2011b, 2012a, 2013b, 2014a). In summary, the asleep, but not the awake, BP mean constitutes a highly significant independent prognostic indicator of CVD morbidity and mortality (Hermida et al., 2011b, 2013b).

FIGURE 1. Adjusted HR of total CVD events in the MAPEC study. Participants were categorized into groups according to the level (normal or high) of the ABPM-derived awake and asleep SBP and DBP means. The awake SBP/DBP means were considered normal if <135/85 mmHg and high otherwise. The asleep SBP/DBP means were considered normal if <120/70 mmHg and high otherwise. Adjustments were applied for sex, age, diabetes, CKD, sleep duration, and hypertension treatment-time – all medications upon awakening versus the entire daily dose of ≥1 medications at bedtime. Updated from Hermida et al. (2012a, 2013b).

Exploration of the combined contribution to CVD risk of multiple BP parameters further revealed clinic BP does not independently predict CVD events when the outcomes model is adjusted for the asleep BP mean, the strongest predictor of CVD events among all potential contributing BP parameters (HR = 1.50, 95%CI [1.37–1.63], p < 0.001 per SD elevation in asleep SBP mean; HR = 1.09 [0.98–1.22], p = 0.089 per SD elevation in clinic SBP). Indeed, when each of the four groups of participants categorized by awake and asleep SBP/DBP means (Figure 1) were further categorized according to either normal or elevated clinic BP (using the currently accepted 140/90 mmHg thresholds), CVD risk was significantly higher in all of the four groups classified by elevated asleep BP mean, regardless of whether the daytime clinic BP or ABPM-derived awake BP mean was normal or elevated, than in all of the other four groups of patients classified by normal sleep-time BP mean (Figure 2).

FIGURE 2. Adjusted HR of total CVD events in the MAPEC study. Participants were categorized into groups, both according to OBPM level (normal or high) and ABPM-derived awake and asleep SBP and DBP means. OBPM-obtained SBP/DBP values were considered normal if <140/90 mmHg and high otherwise. The ABPM-derived awake SBP/DBP means were considered normal if <135/85 mmHg and high otherwise, and the asleep SBP/DBP means were considered normal if <120/70 mmHg and high otherwise. Adjustments were applied for sex, age, diabetes, CKD, sleep duration, and hypertension treatment-time – all medications upon awakening versus the entire daily dose of ≥1 medications at bedtime. Updated from Hermida et al. (2013l).

Beyond the information derived from the MAPEC study summarized in Figures 1 and 2, several other prospective studies and meta-analyses have also documented the absence of prognostic value of both the OBPM and ABPM-derived awake BP mean when corrected by the most significant asleep BP mean (Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagard et al., 2008; Fan et al., 2010; Kikuya et al., 2005; Minutolo et al., 2011; The ABC-H Investigators et al., 2014). For instance, a recent meta-analysis of nine cohorts, a total of 13 844 hypertensive patients, concluded that individually, increases in clinic SBP as well as in awake and asleep SBP means are all significantly associated with elevated CVD risk. However, simultaneous inclusion of all three SBP measurements into the statistical model indicates that only the asleep SBP mean is an independent predictor of CVD events, while clinic SBP and awake SBP mean are not (The ABC-H Investigators et al., 2014).

Data from the MAPEC study, in which participants were repeatedly assessed by periodic 48 h ABPM, also allowed prospective evaluation of the impact of changes in clinic and ambulatory BP during follow-up on CVD risk. Progressive treatment-induced lowering of the awake, asleep, and 48 h BP means, but not clinic BP, is associated with significantly increased CVD event-free survival. Results also revealed that reduction from baseline in the asleep SBP/DBP means is the most significant predictor of survival among all the tested ambulatory and clinic BP parameters (Hermida et al., 2011b, 2013b). Most important, when the treatment-induced changes during follow-up in the asleep and awake BP means are entered jointly in the same time-dependent Cox’s regression model, progressive attenuation of the asleep SBP mean is significantly associated with increased event-free survival (adjusted HR = 0.65 [0.55–0.77], p < 0.001, per SD reduction in asleep SBP mean), while progressive attenuation in the awake SBP mean is not (adjusted HR = 0.99 [0.86–1.14], p = 0.849, per SD decrease in awake SBP mean during follow-up). Thus, a diminished asleep, but not awake, BP mean is a highly significant independent prognostic marker of reduced CVD morbidity and mortality risk; it, therefore, constitutes a novel therapeutic target for increased event-free survival (Hermida et al., 2011b, 2013b).

What should be the recommended treatment regimen for reducing asleep BP?

Many published clinical trials document reduction of asleep BP and the corresponding effects on the 24 h BP pattern, i.e., increase of sleep-time relative BP decline towards the normal dipper profile, by BP-lowering medications of six different classes are greatly improved when consistently ingested at bedtime than upon awakening (Hermida et al., 2007a, 2011a, 2013c, j,k, 2014c, d, 2015b; Smolensky et al., 2010, 2012, 2015b). Table 1 reports changes from baseline in the awake and asleep BP means plus sleep-time relative BP decline when angiotensin converting enzyme inhibitors [ACEIs], angiotensin-II receptor blockers [ARBs], calcium-channel blockers [CCBs], α-blockers, β-blockers, diuretics, and their combinations are ingested either upon awakening or at bedtime by hypertensive patients. The reported findings are derived from randomized, open label, blinded endpoint trials, totaling 2306 investigated hypertensive patients, simultaneously assessed by 48 h ABPM at 20–30 min intervals and wrist actigraphy (activity level) at 1 min intervals to accurately derive the awake and asleep SBP/DBP means (Crespo et al., 2013) and dipper BP patterning on an individual basis before and after timed treatment. As summarized in Table 1, bedtime, compared to upon-awakening, ingestion of most tested BP-lowering medications results in statistically significant enhanced asleep BP mean reduction without loss of efficacy for reducing the awake BP mean, thereby enhancing the sleep-time relative BP decline.

TABLE 1. Comparison of changes (mmHg) from baseline in awake and asleep SBP/DBP means and sleep-time relative SBP/DBP decline by hypertension medications and their combinations when ingested upon awakening versus bedtime by hypertensive patients adhering to a normal routine of daytime activity and nighttime rest.

			Effect on awake SBP/DBP mean		Effect on asleep SBP/DBP mean		Effect on sleep-time relative SBP/DBP decline
Medication	Dose, mg	Patients	Awakening Rx	Bedtime Rx	Awakening Rx	Bedtime Rx	Awakening Rx	Bedtime Rx
ACEIs Ramipril	5	115	−10.1/−6.9	−10.5/−9.0	−4.5/−4.1	−13.5/−11.5*	−3.3/−1.8	3.4/4.9*
Spirapril	6	165	−9.9/−8.0	−8.5/−5.7	−5.7/−4.6	−12.8/−8.6*	−2.5/−2.7	4.1/4.5*
ARBs Valsartan	160	90	−17.0/−11.1	−12.0/−9.8	−15.9/−10.8	−17.9/−13.3	0.2/1.3	5.4/6.3*
Valsartan	160	100^a	−12.8/−6.6	−13.0/−8.5	−10.9/−5.5	−20.5/−11.1*	−1.0/−0.3	6.6/5.4*
Valsartan	160	200^b	−13.1/−8.3	−12.6/−9.3	−12.9/−8.1	−21.1/−13.9*	0.4/0.9	7.2/7.1*
Olmesartan	20	133	−14.5/−12.1	−13.3/−9.6	−11.2/−8.7	−15.2/-11.5‡	−1.3/−1.4	2.9/4.6*
Olmesartan	40	72	−17.1/−10.1	−16.3/−11.5	−12.6/−8.2	−17.9/-12.5‡	−1.6/−0.2	3.0/3.8*
Telmisartan	80	215	−11.7/−8.8	−11.3/−8.2	−8.3/−6.4	−13.8/−9.7*	−1.6/−1.0	3.1/3.9*
CCBs Amlodipine	5	194	− 10.2/−7.7	−11.8/−7.2	−9.6/−5.5	−11.2/−6.7	0.1/−1.6	0.2/0.7‡
Nifedipine GITS	30	238	−9.4/−6.3	−12.8/−7.7‡	−7.5/−5.1	−12.8/−7.8*	−0.7/−0.2	1.0/1.5‡
β-blocker Nebivolol	5	173	−14.7/−12.4	−13.4/−10.9	−7.9/−7.4	−10.2/−8.1	−3.6/−3.0	−1.2/−1.4‡
Diuretic Torasemide	5	113	−7.3/−3.7	−15.6/−9.9*	−4.3/−2.5	−12.5/−8.0*	−1.6/−0.7	−1.3/−0.2
α-blocker Doxazosin GITS	4	39^c	−2.9/−3.7	−6.0/−5.4	0.7/−1.3	−8.2/−6.5 †	−2.3/−2.4	1.9/1.9‡
Doxazosin GITS	4	52^d	−3.4/−2.9	−5.9/−4.4	0.1/−0.5	−4.9/−5.3‡	−2.3/−2.4	1.7/1.5‡
Combination Rx Valsartan/amlodipine	160/5	203	−18.3/−14.5	−22.6/−12.7	−14.4/−10.1	−28.1/−14.7*	−1.3/−2.1	5.5/5.2*
Valsartan/hydrochlorothiazide	160/12.5	204	−17.4/−11.5	−16.7/−11.4	−16.0/−12.0	−20.1/−13.6‡	0.5/2.4	3.9/4.7*

All cited studies were conducted by some of the authors and followed a prospective, randomized, open label, blinded endpoint design. Participants (2306 patients in total) of all studies were grade 1 or 2 essential hypertension individuals, evaluated simultaneously by 48 h ambulatory BP monitoring and wrist actigraphy before and after timed treatment to accurately derive the awake and asleep SBP/DBP means and sleep-time relative BP decline (calculated as ([awake BP mean − asleep BP mean]/awake BP mean) × 100), i.e., the percent decline in mean BP during nighttime sleep relative to mean BP during daytime activity.

Statistical significance of the comparison of effects on BP between treatment-times: *p < .001; †p < .01; ‡p < .05.

^aStudy on elderly patients (≥60 yrs of age).

^bStudy on non-dipper patients, i.e., sleep-time relative SBP decline <10%.

^cPatients treated with doxazosin monotherapy.

^dPatients treated with doxazosin in combination with other hypertension medications (polytherapy).

The results of the MAPEC study – the first prospective trial specifically designed and conducted to test the hypothesis bedtime hypertension chronotherapy that focuses specifically on normalization of the asleep BP mean and sleep-time relative BP decline better reduces CVD and stroke risk than conventional upon-awakening timing – substantiate the implications of the ingestion-time dependent differences in effects of the various hypertension medications shown in Table 1 (Ayala et al., 2013a; Hermida, 2007; Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, e, g, h, 2015a, b). After a median follow-up of 5.6 yrs, hypertensive patients randomized to ingest the full daily dose of ≥1 BP-lowering medications at bedtime, in comparison to those randomized to ingest all prescribed hypertension medications upon awakening, displayed as expected (Table 1) significantly lower asleep BP mean, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34 versus 62%; p < 0.001), and higher prevalence of controlled ambulatory BP (62 versus 53%, p < 0.001). Most important, the bedtime therapy regimen, compared to the upon-awakening one, resulted in significantly lower adjusted HR of total CVD events (HR = 0.39 95%CI [0.29–0.51]; p < 0.001) and major CVD events – composite of CVD death, myocardial infarction, and ischemic and hemorrhagic stroke – (HR = 0.33 [0.19–0.55]; p < 0.001) (Hermida et al., 2010). CVD risk was higher in patients randomized to treatment upon awakening, no matter the classes of BP-lowering medications ingested. Greater benefits were observed for bedtime than awakening treatment with ARBs (HR = 0.29 [0.17–0.51]; p < 0.001) and CCBs (HR = 0.46 [0.31–0.69]; p < 0.001) (Hermida et al., 2013g). Additionally, patients randomized to ingest at bedtime an ARB, in comparison to any other class of medication, with or without additional hypertension drugs, evidenced significantly lowest HR of CVD events (p < 0.017) (Hermida et al., 2013g).

Thus, the MAPEC study not only substantiates the asleep SBP mean is the most significant and only independent BP prognostic marker of CVD morbidity and mortality (Hermida et al., 2011b, 2012a, b, 2013b), as earlier discussed, a finding corroborated by numerous other prospective ABPM studies (Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagard et al., 2008; Fan et al., 2010; Kikuya et al., 2005; Minutolo et al., 2011; The ABC-H Investigators et al., 2014), but it further substantiates reduction of the asleep SBP mean by a hypertension treatment strategy defined by ingestion of the full daily dose of ≥1 conventional BP-lowering medications at bedtime significantly and cost-effectively decreases CVD risk, both for patients of the general hypertension population (Hermida et al., 2010) and those of greater vulnerability and enhanced CVD risk, i.e., those diagnosed with CKD (Hermida et al., 2011d), type 2 diabetes (Hermida et al., 2011c, 2012a), and resistant hypertension (Ayala et al., 2013a). In this regard it is noteworthy that several international medical and scientific societies (American Diabetes Association, 2012; Chiang et al., 2015; Hermida et al., 2013l; Shimamoto et al., 2014; The Task Force on diabetes, 2013) now acknowledge the clinical relevance of this specific concept of hypertension chronotherapy by recommending physicians advise their hypertensive patients ingest one or more of their prescribed BP-lowering medications at bedtime.

Future prospective long-term outcomes trials that incorporate periodic, annually or more frequent, ABPM assessments and simultaneous diary recording of bed and wake times – to accurately and reliably ascertain asleep and awake BP level and dipping status – as done in the completed MAPEC study (Ayala et al., 2013a; Hermida, 2007; Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, e, g, h, 2015a, b) and currently ongoing Hygia Project (Ayala et al., 2013b; Crespo JJ et al., 2013; Hermida et al., 2013k; Mojón et al., 2013; Moyá et al., 2013; Ríos et al., 2013) are needed to confirm the beneficial effects (reduced risk of CVD events and target tissue and organ injury) and safety of enhanced asleep BP reduction by bedtime hypertension chronotherapy with conventional medications. In the interim, we recommend this bedtime treatment strategy be adopted for management of every person with predominant sleep-time hypertension or non-dipper BP patterning; this includes the elderly and those diagnosed with elevated asleep BP due to diabetes, CKD, obstructive sleep apnea, or resistance to pharmacotherapy intervention when timed upon awakening (Hermida et al., 2013l).

What should be the recommended reference ABPM thresholds for diagnosis of hypertension?

For the most part, diagnostic ABPM thresholds are either based on the distribution of ambulatory BP in reference normotensive populations (Hansen et al., 2008) or regression of ambulatory BP values on clinic BP measurements (Bur et al., 2002; Head et al., 2010). A few investigative teams (Kikuya et al., 2007; Ohkubo et al., 1998) have previously proposed ABPM diagnostic threshold criteria based on CVD outcomes, but without differentiating patients according to factors known to significantly affect BP regulation, such as patient’s sex and significant morbidities, e.g., diabetes and CKD (Ayala et al., 2013b; Fabbian et al., 2013; Hermida et al., 2007c; Mojón et al., 2013; Portaluppi & Smolensky, 2007; Portaluppi et al., 2012; Ríos et al., 2013).

ABPM reference thresholds according to sex.

Epidemiologic studies report sex differences in BP and heart rate (Ben-Dov et al., 2008; Hermida et al., 2002a, b, 2004, 2013i; Kagan et al., 2007; Meininger et al., 2004; Pimenta, 2012; Roger et al., 2011; The ABC-H Investigators et al., 2015; Vriz et al., 1997; Wang et al., 2006). Typically, men have a slower heart rate and higher BP than women, the differences being larger for SBP than DBP (Hermida et al., 2002a). These differences become apparent during adolescence and remain significant until 55–60 yrs of age (Meininger et al., 2004; Pimenta, 2012; Wang et al., 2006). A recent U.S. National Health and Nutrition Examination Survey confirms SBP increases progressively with age in both men and women, and that SBP is higher in men compared to women commencing in early adulthood (Roger et al., 2011). The survey also found the age-related rate of rise in BP is steeper for women, such that SBP in women is higher than in men during and after the seventh decade of life. In the overall population, DBP increases progressively in both men and women until approximately the sixth decade of life, after which it decreases progressively, men having a slightly higher DBP than women at all ages. Previous OBPM-based investigations show the prevalence and severity of hypertension increase markedly with advancing age in women, such that a higher proportion of women than men have elevated BP after 65 yrs of age (Ong et al., 2008; Roger et al., 2011). Proposed explanations for the observed male-female disparity in BP level and trend with aging are sex-related differences in the biological and pathophysiological mechanisms of hypertension, response to medication, vulnerability to target organ damage, and CVD risk (Manfredini et al., 2011; Ong et al., 2008; Pimenta, 2012; Roger et al., 2011; The ABC-H Investigators et al., 2015; Vriz et al., 1997).

Hermida et al. (2013i) examined the adjusted HR of CVD events of the MAPEC study participants categorized by sex and the ABPM-derived awake and asleep SBP/DBP means. The analyses: (i) documented the expected increase in the adjusted HR of CVD events associated with progressively elevated ambulatory awake and asleep SBP/DBP means; (ii) revealed significantly greater slope of CVD and stroke risk with progressively elevated SBP/DBP in women compared to men; and (iii) showed progressively and significantly greater differences in the adjusted HR of total CVD events between men and women for awake SBP/DBP means ≥125/75 mmHg and asleep SBP/DBP means ≥110/70 mmHg. Furthermore, Cox’s regression analyses disclosed significant interaction between patient sex and both the awake and asleep SBP means (p always < 0.009 [Hermida et al., 2013i]). Using the baseline ABPM values of CVD event and non-event male participants of the MAPEC study, the maximum combined sensitivity and specificity for the diagnosis of hypertension corresponded to the previously proposed outcome (CVD event)-based threshold values of 135/85 mmHg for the awake and 120/70 for the asleep SBP/DBP means (Hermida et al., 2013i). These findings, based on documented CVD events of the study, are in agreement with the currently recommended ABPM reference values for the diagnosis of hypertension in uncomplicated persons of both sexes (Chiang et al., 2015; Mancia et al., 2013; Shimamoto et al., 2014). In contrast, Cox’s proportional-hazard regression analyses of the baseline ABPM values of CVD event and non-event female participants disclosed that women attained an equivalent HR of total CVD events at much lower BP levels than men, specifically 11.2/6.4 mmHg lower for their awake SBP/DBP means and 10.8/6.0 mmHg lower for their asleep SBP/DBP means. Thus, the proposed CVD outcome-based ABPM reference thresholds in women equivalent to the cutoff values provided above for men, rounded to the closest integer value ending in 0 or 5, are 125/80 mmHg for the awake and 110/65 for the asleep SBP/DBP means (Hermida et al., 2013i, 2013l). Figure 3 illustrates the difference between men and women in the risk for CVD events according to the ABPM-determined asleep SBP mean; it shows the CVD risk of men associated with an asleep SBP mean of 120 mmHg is equivalent to the CVD risk of women with much lower asleep SBP mean, i.e., 109 mmHg. Thus, an additional plausible explanation of the increased CVD and stroke morbidity and mortality of women >65 yrs of age (Roger et al., 2011) may well entail failure to diagnose hypertension and initiate appropriate BP-lowering interventions early in life due to reliance upon population and male threshold criteria, rather than sex-specific ones.

FIGURE 3. Relative risk of total CVD events in MAPEC study male and female participants as a function of the ABPM-derived asleep SBP mean. Shaded area represents patient diagnosed hypertension according to the current recommended ABPM criterion for the general population, i.e. asleep SBP mean ≥120 mmHg (Hermida et al., 2013l). The specified diagnostic threshold value for women corresponds to the asleep SBP mean level associated with the same relative risk as men. Updated from Hermida et al. (2013i).

ABPM reference thresholds in high-risk patients.

Apart from our previous 2013 ABPM recommendation that the diagnosis of adult hypertension should distinguish between uncomplicated lower-risk versus high-risk patients, e.g., those with type 2 diabetes, CKD and/or past CVD events (Hermida et al., 2013l), no other guidelines yet recommend separate ABPM thresholds for these respective patient groups. Diabetes significantly affects BP regulation and CVD risk (Ayala et al., 2013b; Equiluz-Bruck et al., 1996; Fogari et al., 1993; Hermida et al., 2007c; Portaluppi & Smolensky, 2007; Portaluppi et al., 2012). Ayala et al. (2103b) compared the features of the ambulatory 24 h BP pattern of 2954 hypertensive patients with type 2 diabetes and 9811 hypertensives without diabetes enrolled in the Hygia Project. The authors documented that, independent of whether the patients are or not treated with hypertension medications, ambulatory SBP is significantly higher in patients with than without diabetes, particularly during night-time sleep and following morning awakening; ambulatory DBP, however, is significantly lower in patients with type 2 diabetes, particularly during daytime activity (Ayala et al., 2013b). Most important, according to this cross-sectional report, the sleep-time relative BP decline is significantly attenuated in patients with diabetes and, thus, the prevalence of non-dipping is significantly higher in patients with than without diabetes (62.1 versus 45.9%; p < 0.001). Additionally, 89.2% of uncontrolled hypertensive patients with type 2 diabetes in this cohort evidenced sleep-time hypertension (Ayala et al., 2013b).

Hermida et al. (2015a) recently investigated, using the prospective data of the MAPEC study, the prognostic value of clinic and ambulatory BP to predict new-onset type 2 diabetes and whether risk reduction is related to the progressive decrease of OBPM values or ABPM-derived awake or asleep BP means. The asleep SBP mean was the most significant predictor of new-onset diabetes in a Cox’s proportional-hazard model adjusted for age, waist circumference, glucose, CKD, and hypertension treatment-time. Neither daytime OBPM values nor awake nor 48 h ambulatory BP means were predictive of diabetes risk when corrected by the asleep BP mean. Analyses of BP changes during follow-up revealed a 30% reduction in the risk of new-onset diabetes per SD decrease in asleep SBP mean, independent of changes in OBPM values or awake or 48 h ambulatory BP means. These novel findings indicate altered sleep-time BP regulation precedes, rather than follows, the development of type 2 diabetes. Most important, lowering asleep BP, a novel therapeutic target requiring ABPM evaluation, could be a significant and cost-effective method of reducing the risk of new-onset diabetes (Hermida et al., 2015a).

On the other hand, the prevalence of elevated asleep BP (sleep-time hypertension) and non-dipper BP patterning is also very high in CKD (Agarwal & Andersen, 2005; Agarwal et al., 2009; Crespo JJ et al., 2013; Davidson et al., 2006; Hermida et al., 2011d, 2013j, 2014d; Mojón et al., 2013; Pogue et al., 2009; Portaluppi et al., 1990). Mojón et al. (2013) assessed by 48 h ABPM a large cohort of 10 271 hypertensive participants enrolled in the Hygia Project, including 3227 patients with CKD, finding the prevalence of non-dipper BP patterning significantly higher in those with (60.6%) than without CKD (43.2%; p < 0.001 between groups). The prevalence of riser BP patterning (sleep-time relative SBP decline <0), associated with highest CVD risk, constituted the greatest difference between cohorts (17.6% vs. 7.1% in patients with and without CKD, respectively; p < 0.001). The proportion of patients with riser BP patterning significantly and progressively increased from 8.1% for stage-1 CKD to a very high 34.9% for stage-5 CKD. Moreover, 90.7% of uncontrolled hypertensive participants with CKD evidenced sleep-time hypertension (Mojón et al., 2013).

As an example of the impact of enhanced risk of ABPM diagnostic thresholds, Hermida et al. (2013f) further examined the adjusted HR of CVD events of the MAPEC study participants categorized by the presence or absence of type 2 diabetes and the ABPM-derived awake and asleep SBP/DBP means. The analyses revealed a significantly greater slope of increasing risk with progressively elevated SBP and DBP in patients with than without diabetes, and they also showed progressively and significantly greater differences in the adjusted HR of total CVD events between patients with and without diabetes for awake SBP/DBP means ≥130/75 mmHg and asleep SBP/DBP means ≥110/65 mmHg. Furthermore, Cox’s regression analyses revealed significant interaction between type 2 diabetes and both the awake and asleep SBP/DBP means for patients displaying values above these thresholds (p always < 0.023), thus documenting the synergistic relationship regarding CVD risk between type 2 diabetes and increasing BP above these thresholds (Hermida et al., 2013f) (Figure 4). Cox’s proportional-hazard regression analyses additionally showed that patients with type 2 diabetes had an equivalent HR of total CVD events at a much lower BP level than those without diabetes, i.e., when the awake SBP/DBP mean was lower by 14.4/11.3 mmHg, and the asleep SBP/DBP mean was lower by 14.0/7.9 mmHg (Hermida et al., 2013f). Thus, after rounding these values to the nearest integer ending in 0 or 5, the outcome-based ABPM reference thresholds for the diagnosis of hypertension in patients with type 2 diabetes – equivalent to the cutoff values of 135/85 mmHg for the awake and 120/70 for the asleep SBP/DBP means for patients without diabetes – are 120/75 mmHg for the awake and 105/60 for the asleep SBP/DBP means, which also may be applied to other high-risk groups including patients with CKD or previous CVD events (Hermida et al., 2013l).

FIGURE 4. Relative risk of total CVD events in MAPEC study participants with and without type 2 diabetes as a function of asleep SBP mean. Shaded area represents patient diagnosed hypertension according to the current recommended ABPM criteria for the general population, i.e., asleep SBP mean ≥120 mmHg (Hermida et al., 2013l). The specified diagnostic threshold value for participants with diabetes corresponds to the asleep SBP mean level associated with the same relative risk as those without diabetes. Updated from Hermida et al. (2013f).

CONCLUSIONS AND POSITION STATEMENT

The goal of all hypertension treatment strategies is reduction of SBP and DBP as a method to prevent end-organ injury and decrease risk of CVD, stroke, renal disease, and other life-threatening outcomes. The beneficial effect of BP lowering in terms of preventing CVD events is consistent and, to a certain extent, independent of the class of medications prescribed to achieve it, although this conclusion has been mainly derived from outcome trials targeting the correction of only daytime OBPM level as opposed to correction of those features of the 24 h BP pattern known to be more strongly associated with CVD risk, mainly the asleep SBP mean and sleep-time relative SBP decline. Current hypertension therapy strategies, almost exclusively focused upon attenuating daytime OBPM level (Mancia et al., 2013), unfortunately have not effectively eliminated the CVD hazards associated with elevated BP; indeed, they have only succeeded in moderating them by a markedly suboptimal ∼33% (Gradman, 2011). The treatment strategies of all but a few previous outcome trials, and also those incorporated into the clinical practice of medicine, disregard the facts the: (i) correlation between BP and CVD risk is far stronger for ambulatory than OBPM values (Clement et al., 2003; Dolan et al., 2005; Eguchi et al., 2008; Hermida et al., 2011b, 2012a, b, 2013l; Minutolo et al., 2011; Salles et al., 2008; The ABC-H Investigators et al., 2014; Verdecchia et al., 1994); (ii) ABPM-determined asleep SBP mean is an independent and superior predictor of CVD events compared to either the awake or 24 h BP means (Ayala et al., 2013a; Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagard et al., 2008; Fan et al., 2010; Hermida et al., 2011b, 2012a, b, 2013b; Kikuya et al., 2005; Minutolo et al., 2011; The ABC-H Investigators et al., 2014); and (iii) BP-lowering efficacy and other beneficial effects upon features of the 24 h BP pattern by six different classes of hypertension medications and their combinations exhibit statistically and clinically significant circadian rhythm-dependent, i.e., awakening versus bedtime, treatment-time differences (Hermida et al., 2007a, 2011a, 2013c, j, k, 2014c, d, 2015b; Smolensky et al., 2010, 2012). The findings of the MAPEC study, based upon periodic systematic 48 h ABPM evaluation of all participants throughout a median follow-up of 5.6 yrs, constitute the first proof-of-concept evidence the progressive reduction of the asleep SBP mean and correction of the sleep-time relative SBP decline towards the normal dipper BP profile, most efficiently accomplished by a bedtime hypertension treatment strategy, best attenuates the risk of CVD, stroke, and new-onset diabetes (Ayala et al., 2013a; Hermida, 2007; Hermida et al., 2010, 2011b, c, d, 2012a, b, 2013b, e, g, h, 2015a, b). These results document 24 h BP control and pattern normalization plus multiple risk reduction are best achieved when hypertension medications are optimally timed in step with the circadian staging of key physiologic, neuroendocrine and other biological determinants.

Taking into consideration the new information summarized in the previous sections of this article, the ISC, AAMCC, and SECAC through the following statements update the recommendations of their previous extensive guidelines (Hermida et al., 2013l) to improve the diagnosis and treatment of adult arterial hypertension:

1. There are several major disadvantages of conventional OBPM; they are: (i) indicative of the BP status of only a very brief and small fraction of the entire 24 h BP pattern; (ii) affected by several potential sources of error, including a rather large “white-coat” effect; and (iii), most importantly, unable to provide independent prognostic value to assess CVD morbidity and mortality risk when corrected by ABPM measurement. Accordingly, OBPM values should no longer be considered to be the “gold standard” for the diagnosis of hypertension and assessment of CVD risk.

2. The joint prevalence of masked normotension and masked hypertension is >35% in the adult population. Moreover, >20% of “normotensive” adults exhibit a non-dipper BP profile and, thus, are at high CVD risk (Hermida et al., 2013e, 2013l). Therefore, relying on OBPM, even when supplemented with at-home wake-time self-measurements, to identify high-risk individuals, disregarding the vital information pertaining to circadian BP patterning and asleep BP level, leads to potential misclassification of 50% of all evaluated persons. Accordingly, ABPM is the recommended reference standard for the diagnosis of true hypertension and accurate assessment of CVD risk in all adults ≥18 yrs of age, regardless of whether OBPM is normal or elevated.

3. Among the different individual parameters derived from ABPM, the asleep SBP mean is the most significant independent predictor of CVD events, both individually and jointly when combined with other ABPM-derived potential prognostic markers. The sleep-time relative SBP decline adds prognostic value to the statistical model that already includes the asleep SBP mean and corrected for relevant confounding variables. Accordingly, the asleep SBP mean derived from around-the-clock ABPM is the recommended protocol to diagnose hypertension and assess CVD risk. Most importantly, the progressive decrease in the asleep BP mean, a novel therapeutic target that requires accurate evaluation by ABPM, is a highly significant predictor of CVD event-free interval.

4. Reference thresholds for the diagnosis of hypertension should be established taking into consideration documented factors that significantly affect BP regulation and CVD risk. The reference thresholds listed in Table 2 to establish the diagnosis of hypertension, i.e., high CVD risk, should also be used as the therapeutic goals for treated patients. These proposed thresholds are as follows: (i) outcome-based ABPM reference thresholds for men, in the absence of compelling clinical conditions, are 120/70 mmHg for the asleep SBP/DBP means; (ii) outcome-based reference thresholds for the diagnosis of hypertension are lower by 10/5 mmHg for ambulatory SBP/DBP in women in the absence of complicating co-morbidities, i.e., 110/65 mmHg for the asleep SBP/DBP means; (iii) outcome-based reference thresholds for the diagnosis of hypertension are lower by 15/10 mmHg for ambulatory SBP/DBP in high-risk patients, including those diagnosed with diabetes or CKD, and/or those having experienced past CVD events, i.e., 105/60 mmHg for the asleep SBP/DBP means.

5. Bedtime treatment with the full daily dose of ≥1 hypertension medications is recommended as a cost-effective means to improve the management of hypertension and reduce CVD and other hypertension-associated risks. Bedtime treatment must be the therapeutic regimen of choice for the elderly and those with diabetes, resistant and secondary hypertension, CKD, obstructive sleep apnea, and medical history of past CVD events, among others, given their documented high prevalence of sleep-time hypertension.

TABLE 2. Diagnostic threshold values for ABPM-derived asleep BP mean (mmHg) based on CVD outcomes.

ABPM characteristic	Low-risk men	Low-risk women	High-risk patients^a
Asleep SBP mean	120	110	105
Asleep DBP mean	70	65	60

^aHigh-risk patients include: Type 2 diabetes, CKD, and previous CVD event.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.