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A P B M 2 0 1 3 G U I D E L I N E S

2013 Ambulatory Blood Pressure Monitoring Recommendations for the


Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other
Hypertension-associated Risk, and Attainment of Therapeutic Goals
Joint Recommendations from the International Society for 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)
Writing Committee: Ramn C. Hermida,
1
Michael H. Smolensky,
2
Diana E. Ayala,
1
and
Francesco Portaluppi
3
Reviewing Committee: Juan J. Crespo,
4
Fabio Fabbian,
3
Erhard Haus,
5
Roberto Manfredini,
3
Artemio Mojn,
1
Ana Moy,
1,6
Luis Pieiro,
1,7
Mara T. Ros,
1,8
Alfonso Otero,
9
Horia Balan
10
and
Jos R. Fernndez
1
1
Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain,
2
Cockrell School of
Engineering, Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA,
3
Hypertension
Center, University Hospital S. Anna and Department of Medical Sciences, University of Ferrara, Ferrara, Italy,
4
CS Bembrive,
Gerencia de Atencin Primaria de Vigo, Servicio Galego de Sade (SERGAS), Vigo, Spain,
5
Department of Pathology and
Laboratory Medicine, University of Minnesota, HealthPartners Institute for Education and Research, Regions Hospital, St. Paul,
Minnesota, USA,
6
CS Lrez, Gerencia Unica Integrada Pontevedra-Salns, Servicio Galego de Sade (SERGAS), Pontevedra,
Spain,
7
Internal Medicine Department, Hospital Provincial de Pontevedra, Servicio Galego de Sade (SERGAS), Pontevedra,
Spain,
8
CS A Doblada, Gerencia de Atencin Primaria de Vigo, Servicio Galego de Sade (SERGAS), Vigo, Spain,
9
Nephrology
Department, Complejo Hospitalario Universitario, Servicio Galego de Sade (SERGAS), Ourense, Spain,
10
University of Medicine
and Pharmacy, Bucharest, Romania.
Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular
disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office
measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a
substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant
predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers.
Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive
decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The
24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information
pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h
BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of
individuals by comparing office with either the 24-h or awake BP mean as masked normotensives (elevated clinic BP but
normal ABPM), which should replace the terms of isolated office or white-coat hypertension, and masked
hypertensives (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical
significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of
compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower
by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and
female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population,
Address Correspondence to Prof. Ramn C. Hermida, Ph.D., Bioengineering and Chronobiology Labs, University of Vigo; Campus Univer-
sitario Vigo, 36310 Spain. Ph.: 34-986-812148; Fax: 34-986-812116; E-mail: rhermida@uvigo.es
Prof. Francesco Portaluppi, M.D., Ph.D. Hypertension Center, S. Anna Hospital, University of Ferrara; via Savonarola 9, I-44121 Ferrara,
Italy. Ph.: 39-0532-236631; Fax: 39-0532-236622; E-mail: prf@unife.it
Reprint Address: Same as above.
Submitted August 23, 2012, Returned for revision September 24, 2012, Accepted October 1, 2012
Chronobiology International, 30(3): 355410, (2013)
Copyright Informa Healthcare USA, Inc.
ISSN 0742-0528 print/1525-6073 online
DOI: 10.3109/07420528.2013.750490

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the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of normotensive
adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented
with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential
misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true
hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension
chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk,
i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes,
CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).
Keywords: 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
OUTLINE
1. Introduction.
2. 24-h BP patterns determined by ABPM: Diagnostic
implications.
3. Analyses and interpretation of ABPM data: Role of
rest-activity cycle.
4. Prognostic value of ABPM-derived characteristics.
4.1. Prognostic value of ABPM: Findings and limit-
ations of available studies.
4.2. Comparative prognostic value of different
ABPM-derived characteristics.
4.3. Changes in ABPM during follow-up as
predictors of CVD risk.
5. Masked normotension and masked hypertension.
6. The normotensive non-dipper paradox.
7. J-shaped relationship between BP and CVD risk.
8. Reference ABPM thresholds for the diagnosis of
hypertension.
8.1. Sex differences in ABPM reference thresholds.
8.2. Reference ABPM thresholds in high-risk patients.
8.3. Reference ABPM thresholds in pregnancy.
9. Clinical applications of ABPM.
9.1. Secondary hypertension.
9.2. Resistant hypertension: Diagnostic and
treatment issues.
9.3. Elderly patients.
9.4. Diabetes.
9.5. Obesity and metabolic syndrome.
9.6. Chronic kidney disease (CKD).
9.7. Obstructive sleep apnea and other
sleep disorders.
9.8. Pregnancy.
9.9. Evaluation of treatment efficacy.
10. ABPM: Practical considerations.
10.1. Sampling rate and duration of ABPM.
10.2. Time interval between repeated ABPM
evaluations
10.3. Editing and validation of ABPM.
10.4. Requirements for healthcare personnel in
charge of ABPM.
10.5. Maintenance and utilization of ABPMdevices.
10.6. Patient instructions.
10.7. Schedulingof patient appointments for ABPM.
11. Conclusions.
12. ABPM: Summary of recommendations.
1. INTRODUCTION
Blood pressure (BP) exhibits 24-h variation as a conse-
quence of both cyclic day-night, or rather rest-activity,
alterations in behavior (e.g., daily routine of activities and
diet, mental stress, and posture), environmental phenom-
ena (e.g., ambient temperature, noise, etc.), and endogen-
ous circadian (24-h) rhythms in neural, endocrine,
endothelial, and hemodynamic variables (e.g., plasma
noradrenaline and adrenaline [autonomic nervous
system] and renin, angiotensin, and aldosterone
[renin-angiotensin-aldosterone system]) (Baumgart, 1991;
Fabbian et al., 2013; Hermida et al., 2007d; Pinotti et al.,
2005; Portaluppi & Smolensky, 2007; Portaluppi et al.,
1992b, 1994b, 1996, 2012; Sica & Wilson, 2000; Smolensky
et al., 2007, 2012; Trasforini et al., 1991; Varani et al., 1999).
Moreover, circadian rhythms in BPand other phenomena,
e.g., those affecting blood coagulation, result in prominent
24-h patterns of acute cardiovascular disease (CVD)
events, such as myocardial infarction, cardiac arrest,
sudden cardiac death, plus ischemic and hemorrhagic
stroke (Casetta et al., 2002; Cohen et al., 1997; Elliot et al.,
1998; Gallerani et al., 1997; Manfredini et al., 1996a,
1996b, 1999a, 1999b, 2004, 2013; Muller et al., 1989; Porta-
luppi & Hermida, 2007; Portaluppi et al., 1999). BP is
measured for clinical purposes because the damage
causedtothe arterial walls is directlyandcontinuously pro-
portional to the BP levels maintained over time. Therefore,
BP must be maintained as low as possible for as long as
possible, to the extent that it remains compatible with a
good quality of life and does not cause undesired side
effects or complications, to avert target tissue and organ
damage and heightened CVD risk. Time awareness is
implicit in any definition of risk, and the CVD risk due to
elevated BP is no exception. Hence, to successfully
prevent such risk, one needs to be aware of all significant
BP variations over time, from those occurring during the
24 h, particularly ones relating to daytime activity and
nighttime sleep, to those derived from lifestyle changes
and therapeutic intervention.
In spite of the knowledge on 24-h BP variability, con-
ventional, typically daytime, clinic BP measurements
made in the physicians office continue to be used as the
basis to diagnose hypertension as well as to evaluate treat-
ment efficacy and clinical outcome (Chobanian et al.,
{, R. C. Hermida et al.
Chronobiology International
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2003; Mancia et al., 2007a; Pickering et al., 2005). However,
these conventional time-unspecified single measure-
ments have major disadvantages. They are indicative of
the BP status of only a very brief and small fraction of
the entire 24-h BP pattern; moreover, such measurements
are often affected by circumstances in the clinic that exert
significant pressor effect (white-coat effect [Pickering,
1995; Pickering et al., 1988]), resulting in higher than
actual BP values. Additionally, clinical BP measurements
can be affected by several potential sources of error
(Halberg et al., 1990); these include defects in instrumen-
tation (lack of proper validation and periodic calibration of
the measurement devices plus use of inappropriate sized
BP cuffs, e.g., in slim and overweight subjects) and impro-
per technique and procedures of measurement by inade-
quately trained healthcare personnel, including digit
preference that leads to observer round-off of an arbitrary
last digit, usually to 0 or 5 (Patterson, 1984; Sassano et al.,
1987; Wilcox, 1961). Moreover, the within-day variability
of BP, even among healthy individuals, can be so great
that the identificationof hypertensionandits proper categ-
orization in terms of severity are highly ambiguous when
based solely on unspecified single time-of-day measure-
ments (Hermida, 1999). Finally, unusually high or low
values may occur only at certain times during the 24-h
span that may not be covered by casual clinic BPsampling,
as in the case of nighttime hypertension.
The use of automatic instrumentation for non-inva-
sive ambulatory BP monitoring (ABPM) makes it possible
today to followthe time course of BP variation around the
clock on an individual basis. ABPM constitutes a method
of BP assessment that compensates for most, if not all, of
the limitations of office BP measurements (Hermida,
1999; Parati et al., 1990). ABPM-derived data allow
better characterization of BP during everyday activities
and sleep and, most importantly, the findings correlate
more strongly than clinic BP with target organ damage,
CVD risk, and long-term patient prognosis (Ayala &
Hermida, 2013; Clement et al., 2003; Dolan et al., 2005;
Eguchi et al., 2008; Hansen et al., 2007; Hermida &
Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,
2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;
Salles et al., 2008; Staessen et al., 1999; Verdecchia
et al., 1994). Moreover, ABPM is particularly useful not
only for defining in clinical trials the efficacy of hyperten-
sion medications (Coats et al., 1996), but also clinically
for evaluating individual patients (Waeber & Brunner,
1999), especially according to the administration-time
(morning versus evening) treatment regimen as a cost-
effective means of better preventing CVD events
(Hermida, 2007; Hermida & Smolensky, 2004; Hermida
et al., 2005a, 2007a, 2008a, 2010b, 2011a, 2011b, 2011d,
2013c; Portaluppi & Hermida, 2007; Portaluppi & Smo-
lensky, 2010; Portaluppi et al., 2012; Smolensky et al.,
2010, 2012). However, apart from the relatively, partially
unjustified, higher cost of the currently marketed ABPM
instruments than conventional cuff assessment, patient
tolerability to around-the-clock ABPM has been
discussed as a possible limitation, mostly because it
may induce modest disturbance of nighttime sleep
(Degaute et al., 1992). Furthermore, concern has been
raised by some (Mochizuki et al., 1998; Musso et al.,
1997) about the low individual reproducibility of the cir-
cadian BP profile found between repeated 24-h ABPMs
performed on the same patients. Nonetheless, in terms
of reproducibility ABPM is markedly superior to clinic
BP measurements (Hermida et al., 2000b, 2004a; James
et al., 1988).
Based on the above considerations, ABPM provides
the needed essential time-aware and sensitive infor-
mation for state-of-the-art individualized diagnostic
categorization, treatment efficacy evaluation, and CVD
outcome prediction. The 2013 recommendations pre-
sented herein are based upon detailed analyses of the
diagnostic, therapeutic, and prognostic applications of
ABPM that should be of common usage, with its intrinsic
temporal information, as it is for various other clinical
tests, for instance, the well established examples of glo-
merular filtration rate (National Kidney Foundation,
2002) and oral glucose tolerance test (American Diabetes
Association, 2012).
2. 24-H BP PATTERNS DETERMINED BY ABPM:
DIAGNOSTIC IMPLICATIONS
Predictable changes during the 24 h in environmental
and biological variables give rise to the circadian
pattern in systolic BP (SBP), diastolic BP (DBP), and
heart rate. In many, but not all, persons with normal BP
or uncomplicated essential hypertension, SBP and DBP
decline to lowest levels during nighttime sleep, rise
with morning awakening, and attain peak values during
the initial hours of daytime activity. In so-called normal
dippers, the asleep BP mean is lower by 10-20% relative
to the daytime (awake) BP mean. In addition to this pro-
found, sleep-related nighttime decline, the typical circa-
dian BP pattern exhibits two daytime peaks, the first one
approximately 3 h after awakening and the second one
around 12 h after awakening, with a small nadir in
between, in the afternoon (Hermida et al., 2002a). The
extent of the nighttime BP attenuation has been mainly
quantified through the so-called sleep-time relative BP
decline, which is defined as the percent decrease in
mean BP during nighttime sleep relative to the mean
BP during daytime activity, and calculated as
(100[awake BP mean asleep BP mean]/awake BP
mean). Using this percent ratio, subjects have been arbi-
trarily classified as dippers or non-dippers (sleep-time
relative BP decline or <10%, respectively [OBrien
et al., 1988]). More recently, the classification has been
extended by dividing individuals into four groups:
extreme-dippers (sleep-time relative BP decline 20%),
dippers (sleep-time relative BP decline 10% but
<20%), non-dippers (sleep-time relative BP decline
<10%), and inverse-dippers or risers (sleep-time relative
BP decline <0%, indicating asleep BP > awake BP mean).
Guidelines for ambulatory blood pressure monitoring {,;
Informa Healthcare USA, Inc.
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Advantages of identifying the rather simple pattern
that describes the circadian BP variation come from the
fact that departure from the normal dipper profile may
be indicative of overt pathology (Fabbian et al., 2013;
Hermida et al., 2007d; Portaluppi & Smolensky, 2007;
Portaluppi et al., 2012; Smolensky et al., 2007, 2012).
Attenuation of the normal 10% sleep-time BP decline
towards the non-dipper or riser BP patterns is, indeed,
associated with elevated risk of end-organ injury, particu-
larly to the heart (left ventricular hypertrophy, congestive
heart failure, and myocardial infarct), brain (stroke), and
kidney (albuminuria and progression to end-stage renal
failure) (Bianchi et al., 1994; Davidson et al., 2006;
Hermida et al., 2003e; Shimada & Kario, 1997; Timio
et al., 1995). Numerous studies have consistently shown
elevated risk of end-organ injury and increased incidence
of fatal and non-fatal CVD events is significantly associ-
ated with blunted sleep-time relative BP decline in the
general population (Boggia et al., 2007; Brotman et al.,
2008; Burr et al., 2008; Dolan et al., 2005; Hermida
et al., 2011c, 2013b; Ingelsson et al., 2006; Kario et al.,
2001; Ohkubo et al., 2002; Verdecchia et al., 1994) and,
in particular, in high-risk individuals, such as those
with diabetes (Astrup et al., 2007; Bouhanick et al.,
2008; Eguchi et al., 2008; Hermida et al., 2011b, 2012b;
Nakano et al., 1998; Sturrock et al., 2000), chronic
kidney disease (CKD) (Agarwal & Andersen, 2006a,
2006b; Hermida et al., 2011d; Liu et al., 2003; Minutolo
et al., 2011; Tripepi et al., 2005), and resistant hyperten-
sion (Ayala et al., 2013a; Salles et al., 2008).
The static threshold values for conventional clinic
SBP/DBP measurements of 140/90 mmHg currently
used to diagnose hypertension (Chobanian et al., 2003;
Mancia et al., 2007a; Pickering et al., 2005) do not take
into account the predictable circadian pattern in SBP
and DBP, and nor do they take into account the markedly
increased CVD risk associated with blunted nighttime BP
decline (non-dipping). When relying on ABPM, all
current recommendations for the diagnosis of hyperten-
sion continue to focus on earlier published guidelines
that propose the threshold values of 130/80 mmHg for
the 24-h SBP/DBP means, but which totally disregard
the valuable information relating to the 24-h BP variabil-
ity and other endpoints one obtains by performing ABPM
(Chobanian et al., 2003; Head et al., 2012; JCS Joint
Working Group, 2012; Mallion et al., 2006; Mancia
et al., 2007a; Myers et al., 2005; OBrien et al., 2003;
Ogihara et al., 2009; Pickering et al., 2005); some,
although not all (Myers et al., 2005), of these guidelines
also provide separate reference thresholds for the
daytime and nighttime spans, usually 135/85 mmHg for
the awake SBP/DBP means and 120/70 for the asleep
SBP/DBP means. Alternatively, it has also been suggested
these static diagnostic thresholds might be replaced by a
time-qualified reference limit reflecting the mostly pre-
dictable BP variability during the 24 h (Hermida, 1999;
Hermida et al., 2001b, 2004d). Time-specified reference
limits can be constructed in different ways; they can be
model-dependent (Fernndez & Hermida, 2000) or
model-independent (Hermida, 1999; Hermida &Fernn-
dez, 1996), and they can be computed as prediction
(Hermida et al., 1993; Nelson et al., 1983) or tolerance in-
tervals (Hermida & Fernndez, 1996; Hermida et al.,
1997b). When samples froma reference group of subjects
are available, one may construct a prediction interval that
is expected to include any single future observation from
the reference population with a specified confidence
(Hermida et al., 1993; Nelson et al., 1983). Alternatively,
the reference interval may consist of a somewhat
broader tolerance interval that will include at least a
specified proportion of the population with a stated con-
fidence (Hermida & Fernndez, 1996; Hermida et al.,
2001b, 2004d). The latter kind of reference interval,
which is commonly used in industry, has been rec-
ommended for application to clinical measurements
(Hermida, 1999; Hermida & Fernndez, 1996).
Once the time-varying threshold, given for instance by
the upper limit of a tolerance interval (Hermida et al.,
2004d), is available, the hyperbaric index (HBI), as a
determinant of BP excess (Halberg et al., 1984; Hermida
et al., 1996, 1998, 2000b, 2002d, 2003a, 2004a), can be cal-
culated as the total area of any givensubjects BPabove the
threshold during the entire 24-h period (Figure 1). The
HBI, as well as the duration of BP excess (% time of
excess, defined as the percentage time during the 24 h
when the BP of the test subject exceeds the upper limit of
the tolerance interval), can then be used as nonparametric
FIGURE 1. The concept of the hyperbaric index (HBI), defined as
total area during the entire 24-h period of any given subjects BP
(dashed line) above a time-varying threshold (derived from
ABPM assessment of a non-hypertensive reference population)
shown in the figure as a tolerance interval, i.e., upper and lower
limits depicted by the two continuous lines. The percentage
time of BP excess (t
excess
) is defined as the percent time during
the 24 h when the BP of the test subject exceeds the upper limit
of the tolerance interval of the reference population.
{,8 R. C. Hermida et al.
Chronobiology International
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endpoints for the diagnosis of hypertension. This so-called
tolerance-hyperbaric test, whereby the diagnosis of hyper-
tension is based on the HBI calculated with reference to a
time-specified tolerance limit, has been shown to provide
high reproducibility in the diagnosis of hypertension
(Hermida et al., 2000b). Because the conventional assess-
ment of hypertension relies on clinic BP values 140/90
mmHg for SBP/DBP (Chobanian et al., 2003; Mancia
et al., 2007a; Pickering et al., 2005), results based on the
determination of BP excess usually have been expressed
as a function of the maximum HBI, defined as the
maximum of the three values of HBI determined for SBP,
mean arterial BP, and DBP, respectively, for any given indi-
vidual (Hermida et al., 1996, 2000b, 2002d, 2003a, 2004a).
A HBI 15 mmHg h indicates suspected hypertension
and a HBI 50 mmHg h indicates hypertension. Simi-
larly, the hypobaric index (HBO), defined as total area of
any given subjects BP below the lower limit of the toler-
ance interval during the entire 24-h period, can be
readily used as a sensitive endpoint for suspicion of poten-
tially too-lowBP, especially intreatedhypertensivepatients
(Hermida et al., 1996, 2000b).
Advantages of the tolerance-hyperbaric test for
the diagnosis of hypertension include: (i) easy visual
interpretation of the 24-h BP pattern for the tested indi-
vidual (Figure 1); (ii) quantitative evaluation of hyperten-
sion severity through the value of the HBI; (iii) analysis of
any subjects BP in terms of his/her rest-activity cycle
instead of meaningless clock time (Section 3); and (iv)
diagnosis of hypertension based on time-specified toler-
ance limits calculated taking into account factors of
potential prognostic value in terms of target organ
injury and CVD risk assessment, including patients age
and sex, and/or concomitant clinical conditions, e.g., dia-
betes, CKD, and/or previous CVD events. The available
software containing the tolerance-hyperbaric test,
described in detail elsewhere (Hermida et al., 2002d),
allows ABPM evaluation in <1 s and it has already
proven to be an effective analytical tool when ABPM is
used to evaluate therapeutic interventions for CVD risk
reduction (Hermida et al., 2010b, 2011b, 2011c, 2011d,
2012b, 2013b, 2013g). As such, it is currently used in pro-
spective population outcome studies as the standard
approach for CVD risk assessment plus guide to individ-
ualizing hypertension therapy based on ABPM findings
(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermida
et al., 2013j; Mojn et al., 2013; Moy et al., 2013; Ros
et al., 2013), and we recommend it be utilized as a
future standard procedure in the clinic setting.
Limitations of the 24-h BP mean as a diagnostic
parameter are illustrated in Figures 2 and 3. The graph
on the left of Figure 2 represents the 24-h SBP pattern
(dashed thick line) of a normotensive man plotted with
respect to circadian time-specified tolerance limits (con-
tinuous thin lines) calculated from the data of a reference
population of normotensive individuals (Hermida et al.,
2004d), as a function of sex and rest-activity cycle (time
expressed relative to hours after awakening from night-
time sleep). The dark bar on the lower horizontal axis
indicates the nighttime sleep span for this man, as deter-
mined by wrist actigraphy (Section 3). The graph shows
SBP is within the normotensive range as visible in relation
to the upper and lower tolerance limits throughout the 24
h, corroborating the diagnosis of normotension, as also
one might infer by using the current guidelines with the
24-h SBP mean being 124.5 mmHg. The sleep-time rela-
tive SBP decline of 17% indicates he has a normal dipper
BP pattern. The graph on the right of Figure 2 represents
the SBP (dashed line) of a different man with an extreme-
dipper BP pattern (sleep-time relative SBP decline of
24.3%), daytime HBI of 67.5 mmHg X h, quite above the
diagnostic threshold for hypertension (Hermida et al.,
2000b, 2002d), and too-low nighttime SBP, all documen-
ted markers of increased CVD risk. The 24-h SBP mean of
this hypertensive patient, however, is also 124.5 mmHg.
The graph on the left of Figure 3 shows the 24-h SBP
pattern of a third man with a sleep-time relative BP
decline of 5.4% (non-dipper), nighttime HBI of
FIGURE 2. 24-h SBP pattern (dashed thick lines) of a normotensive dipper subject (left) and a hypertensive extreme-dipper patient (right),
plotted with respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference population of normo-
tensive individuals as a function of their rest-activity cycle and sex.
Guidelines for ambulatory blood pressure monitoring {,
Informa Healthcare USA, Inc.
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39.5 mmHg X h, and asleep SBP mean of 122.1 mmHg,
thus corroborating the diagnosis of hypertension and
elevated CVD risk, even though his 24-h SBP mean is
also 124.5 mmHg, below the currently accepted diagnos-
tic threshold of hypertension. Finally, the graph on the
right of Figure 3 presents the SBP of a fourth man with
a riser BP pattern (sleep-time relative SBP decline of
-2.4%), associated with the highest CVD risk among all
the possible BP patterns, and nighttime HBI of 77.2
mmHg X h. Despite his elevated CVD risk, that is mark-
edly greater than all of the other individuals represented
in Figures 2 and 3, the 24-h SBP mean is again 124.5
mmHg. These illustrative examples indicate the same
24-h normal BP mean might be associated with totally
different circadian BP patterns and, thus, markedly differ-
ent CVD risk. Accordingly, the 24-h BP mean is insuffi-
cient and therefore not recommended for use in making
the diagnosis of hypertension and assessing CVD risk.
The mathematical calculation of mean BP values is an
additional relevant issue that is typically omitted in the
current guidelines (Chobanian et al., 2003; Head et al.,
2012; Mancia et al., 2007; Pickering et al., 2005). This is
crucial, as many diagnostic parameters derived from
ABPM, i.e., the awake, asleep, and 24-h mean, and the
sleep-time relative BP decline values, are based on esti-
mation of mean BP levels, frequently calculated just as
the simple arithmetic average of all the BP values deter-
mined by ABPM. However, the arithmetic mean is
highly dependent on sampling rate. Typically, ABPM is
performed by measuring BP at a higher rate during
daytime activity than nighttime sleep. This leads to
marked overestimation of the true 24-h BP mean in
normal dippers (because of the greater number of
measurements performed when BP is highest, i.e.,
during the awake/activity span) and its potential under-
estimation in non-dippers/risers (because BP is
measured less frequently during the sleep period, even
though the asleep BP values are atypically high in these
types of patients). An easy alternative is to calculate 24
individual means, one for each hourly class, and then
derive the 24-h BP mean as the average of the resulting
24 hourly means (Frank et al., 2010; Octavio et al.,
2010). This procedure, however, might not be fully valid
for calculation of the awake and asleep BP means, as the
awake and asleep spans might not necessarily be an
integer numbers of hours. The best alternative is to
divide each of the awake and asleep spans into an
integer number of classes of identical time length, calcu-
late the mean BP in each class, and average these result-
ing means to obtain proper estimation of the awake and
asleep BP means. Comparison of these more accurate
mean values between individuals or populations would
additionally require an estimator of BP variance that
can be easily obtained following the approach described
by Dixon & Massey (1983).
3. ANALYSES AND INTERPRETATION OF ABPM DATA:
ROLE OF REST-ACTIVITY CYCLE
The mechanisms underlying the loss of the normal
decline in BP during sleep that characterizes non-
dipping are as yet unclear (Fabbian et al., 2013;
Hermida et al., 2007d; Kanbay et al., 2008; Pickering,
1990; Portaluppi & Smolensky, 2007; Portaluppi et al.,
2012; Smolensky et al., 2007, 2012). The non-dipping
pattern has been reported to be frequent in secondary hy-
pertensive patients with endocrine abnormalities and
autonomic nervous system dysfunction (Hermida et al.,
2007d). Some results indicate the abnormal 24-h BP pat-
terns are related to circadian dysfunction of the auto-
nomic nervous system (Kario et al., 1997; Ragot et al.,
1999). Also, enhanced sodium sensitivity has been
shown to be an independent determinant of the dimin-
ished nighttime fall of BP in essential hypertension (Uzu
et al., 1996), which explains why sodium restriction can
restore the asleep BP decline, especially in those with en-
hanced sodium sensitivity (Uzu et al., 1999). It is impor-
tant to recognize that non-dipping is highly prevalent in
FIGURE 3. 24-h SBP pattern (dashed thick lines) of a hypertensive non-dipper (left) and a hypertensive riser patient (right), plotted with
respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference population of normotensive indi-
viduals as a function of their rest-activity cycle and sex.
{o R. C. Hermida et al.
Chronobiology International
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adults (Ayala et al., 2013b; Hermida et al., 2013j; Mojn
et al., 2013; Ros et al., 2013) in spite of the fact its sus-
pected causes cannot be clinically documented in most
subjects. Thus, like the well-established concept of essen-
tial hypertension used to categorize patients with primary
BP elevation, one might consider that, under the
unknown clinical causes of the blunted asleep BP
decline, a patient with attenuated sleep-time relative BP
decline should be classified and termed as essential
non-dipper.
The availability of noninvasive devices, i.e., actigraphs,
to monitor physical activity around the clock has made it
possible to study the effects of changes in daily activity on
BP variability. Using this approach, several authors have
related non-dipping status to increased nocturnal activity
and/or abnormalities of sleep (Agarwal & Light, 2010;
Blazquez et al., 2012; Huang et al., 2011; Kario et al.,
1999; Leary et al., 2000; Mansoor et al., 2000). These
results, however, have been mostly based on correlations
between mean values of activity and BP calculated for the
daytime and nighttime spans of normotensive (Kario
et al., 1999) or untreated hypertensive patients
(Mansoor et al., 2000), without proper evaluation of the
possible relationship between the circadian patterns of
variation of activity on the one hand and BP on the
other hand. Extending previous findings (Hermida
et al., 2002c), the graph on the left of Figure 4 represents
the circadian SBP pattern of 800 hypertensive patients,
categorized according to dipping status, who underwent
simultaneous ABPM (cuff on the non-dominant arm)
and wrist activity (actigraph on the dominant wrist)
for 48 consecutive hours. Asterisks above the lower hori-
zontal time axis denote statistically significant differences
between the hourly mean SBP values obtained for
dippers and non-dippers as documented by t-tests ad-
justed for multiple testing. The information shown in
this figure documents the absence of differences
between groups in the awake SBP mean. Despite the
expected differences in the asleep SBP mean derived
from the a priori categorization of patients as dipper vs.
non-dipper types, the graph on the right of Figure 4 indi-
cates similarity of the circadian pattern in wrist activity a
well documented surrogate measure of physical activity.
Figure 4 thus indicates the amount of nighttime physical
activity, alone, does not explain the increase in the asleep
BP mean that characterizes non-dipper hypertensive
patients (Hermida et al., 2002c).
Despite the findings documented in Figure 4, one needs
to be aware that the 24-h BP pattern is markedly synchro-
nized with the nighttime rest-daytime activity cycle (Baum-
gart, 1991; Fabbian et al., 2013; Hermida et al., 2007d;
Portaluppi &Smolensky, 2007; Portaluppi et al., 2012; Smo-
lensky et al., 2007, 2012). Thus, the presentation of ABPM
findings interms of clocktime, as sofar customary, is mean-
ingless and should be avoided. To illustrate this point,
Figure 5 presents the circadian SBP pattern (dashed thick
line) of an apparently healthy man, with the values
plotted with respect to circadian time-specified tolerance
limits (continuous thin lines) calculated from the data of a
reference population of normotensive men (Hermida
et al., 2004d), who on average slept 8.9 h and who on
average went to sleep at 23:58 h. The test subject slept for
9 h, from 21:00 to 06:00 h, as corroborated by wrist actigra-
phy. In keeping with the most common current approach
for ABPM analysis, the graph on the left of Figure 5 shows
the SBP data of the test subject expressed in reference to
FIGURE 4. 24-h pattern of SBP (left) and wrist activity (right) in dipper and non-dipper patients with grade 1-2 hypertension sampled by
48-h ABPM. Each graph shows the hourly means and standard errors of data collected from dippers (continuous line) and non-dippers
(dashed line). Dark shading along the lower horizontal axis of graphs denotes the average hours of nighttime sleep across the sample. Non-
sinusoidal shaped curves (thick lines) correspond to the best-fitted waveform models determined by population multiple-component
analysis (Fernndez & Hermida, 1998). MESOR (midline estimating statistic of rhythm) is the 24-h average value of the rhythmic function
fitted to the time series data. Amplitude is one-half the difference between the maximum and minimum values of the best-fitted curve.
MESOR and amplitude were compared between groups using a specially developed nonparametric statistical test (Fernndez et al., 2004).
Guidelines for ambulatory blood pressure monitoring {+
Informa Healthcare USA, Inc.
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the clock time of each of the measurements. Results from
this improper analysis of the BP data erroneously indicate
(bottom table of Figure 5) the test subject is hypertensive
(asleepSBP>120 mmHg; HBI 39.7 mmHg Xh) anda non-
dipper (sleep-timerelativeSBPdeclineof 3.5%). Thegraph
on the right of Figure 5 shows the exact same BP data of the
same test subject after being re-expressed in terms of hours
from bedtime; the reference tolerance limits did not
change, as the zero time (bedtime) was coincident with
midnight, as indicated above. Analysis of the re-ex-
pressed/synchronized data correctly indicates the test
subject is normotensive and a normal dipper. In
summary, analysis of ABPM data in terms of the actual
clock time of BPsampling canbe misleading, bothinpopu-
lation studies and in individual patient evaluations.
This example demonstrates why proper synchroniza-
tion of BP data to the patients specific rest-activity
cycle, such as hours from bedtime or hours after awaken-
ing, is preferable. This means that accurate information
on the rest-activity cycle must be properly collected
from patients. Thus, as a minimum requirement, all indi-
viduals undergoing ABPM must maintain a diary listing
the time of retiring to bed at night, awakening in the
morning, consumption of meals, participation in exercise,
and episodes of unusual physical activity, mood/emotional
states, and other atypical events that might affect BP. This
individualized information can be utilized to determine
thecommencement andterminationof thedaytimeactivity
and nighttime sleep spans to enable accurate derivation of
the awake and asleep BP means of each subject, after refer-
ring each individuals clock time BP values to, e.g., hours
after awakening from nighttime sleep; plus, it can be
utilized to edit the ABPM data, if required.
Alternatively, subjects evaluated by ABPM might also
simultaneously wear an actigraph on the dominant
wrist to record the level of physical activity during BP
measurement. This compact (about half the size of a
wristwatch) device works as an accelerometer. Although
wrist actigraphy provides just a limited estimation of the
total activity level of the patient at any given time during
the 24 h, the procedure has been shown to accurately
identify the onset, offset, and duration of the sleep and
awake periods (Cole et al., 1992; Crespo et al., 2012,
2013), with results highly correlated with those obtained
from polysomnography, even estimation of the number
of apneas in patients with obstructive sleep apnea
(Sadeh et al., 1989). When using actigraphs with ABPM,
one must take care to ensure that the internal clocks of
the two devices are synchronized in terms of actual
clock time, e.g., through their respective interfaces
using the same computer. In so doing, one needs first
to confirm the internal clock of the computer is correctly
set to the actual clock time. Actigraphy data also can be
used to verify the absence/presence of daytime napping
and nighttime awakenings due to nocturia, apneas,
sleep disturbances associated with ABPM, etc. and to
precisely define the commencement and termination of
the daytime wake and nighttime sleep spans of each indi-
vidual facilitated by the use of dedicated software (Crespo
et al., 2012, 2013), so as to accurately calculate the
respective SBP and DBP means and other ABPM-
derived variables of clinical interest.
4. PROGNOSTIC VALUE OF ABPM-DERIVED
CHARACTERISTICS
4.1. Prognostic Value of ABPM: Findings and Limitations of
Available Studies
During the past two decades, specific features of the
ABPM-determined 24-h BP pattern have been assessed
as mediators of injury to target tissues and triggers of
and risk factors for CVD events, such as angina pectoris,
FIGURE 5. 24-h SBP pattern (dashed thick lines) of a normotensive dipper man plotted with respect to circadian time-specified tolerance
limits (continuous thin lines) calculated froma reference population of normotensive individuals as a function of rest-activity cycle and sex.
The same BP data are represented as a function of clock time (left) and hours from bedtime (right).
{: R. C. Hermida et al.
Chronobiology International
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myocardial infarction, cardiac arrest, sudden cardiac
death, plus ischemic and hemorrhagic stroke. For
instance, the extent of the BP surge upon awakening
has been associated with increased CVD morbidity and
mortality in some, but not all, studies (Gosse et al.,
2004; Israel et al., 2011; Kario et al., 2003; Metoki et al.,
2006; Verdecchia et al., 2012). The morning BP surge is
usually calculated as the difference between the average
BP during the initial 2 h after wake-up time (i.e., the so-
called morning BP) and the hourly BP average centered
on the lowest BP reading recorded during nighttime
sleep (i.e., so-called lowest sleep BP).
The findings of prospective studies that investigated
the prognostic significance of the morning BP surge are
inconsistent. In the recently reported MAPEC (Monitori-
zacin Ambulatoria para Prediccin de Eventos Cardio-
vasculares, i.e., Ambulatory Blood Pressure Monitoring
for Prediction of Cardiovascular Events) Study (Hermida
et al., 2011c), the authors found a larger morning BP
surge was associated with a significantly lower CVD
risk, in line with the lower risk associated with increased
dipping of the circadian BP pattern (see Section 4.2.). The
highest risk was, indeed, found in subjects with the riser
pattern (asleep BP mean > awake BP mean) and, thus,
characterized by a negative morning BP surge, i.e., a BP
reduction after awakening from nighttime sleep. Verdec-
chia et al. (2012) also reported lowest CVD risk in hyper-
tensive patients of the first quartile of the morning BP
surge, fully corroborating the novel conclusions from
the MAPEC Study (Hermida et al., 2011c). Contrasting
findings have been reported by others: a morning BP
surge within the top decile was associated with higher
risk of stroke in the Jichii Medical School ABPM study
(Kario et al., 2003) and of total CVD events in the Bor-
deaux hypertensive cohort study (Gosse et al., 2004).
These results, however, might be misleading, as analyses
of the prognostic value of the morning BP surge were not
properly adjusted by other significant confounders, in
particular, the asleep BP mean. Moreover, results of the
Japanese study conducted by Kario et al. (2003) seem
to be inconsistent with their reported higher prevalence
of events among patients in the same database with the
riser BP pattern (Kario et al., 2001). Finally, the
morning BP surge is poorly reproducible, irrespective of
whether it is analyzed as a continuous or categorical vari-
able (Wang et al., 2007; Wizner et al., 2008). In con-
clusion, the morning BP surge does not seem to be an
independent marker of CVD risk; an increased morning
BP surge might indeed be associated with lower risk of
CVD events (Hermida et al., 2011c; Verdecchia et al,
2012), contrary to the most common current belief.
As indicatedabove, numerous studies have consistently
shown an association between blunted sleep-time relative
BP decline (non-dipper BP pattern) and increased inci-
dence of fatal and non-fatal CVD events (Astrup et al.,
2007; Ayala et al., 2013a; Boggia et al., 2007; Brotman
et al., 2008; Burr et al., 2008; Dolan et al., 2005; Eguchi
et al., 2008; Hermida et al., 2011b, 2011c, 2011d, 2012b,
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). Independent prospec-
tive studies have also reported the asleep BP mean is a
better predictor of CVD events than the awake or 24-h
BP means (Agarwal & Andersen, 2006a, 2006b; Amar
et al., 2000; 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.,
2011c, 2012b, 2013b, 2013e; Kikuya et al., 2005; Minutolo
et al., 2011). Limitations of most of these previous
studies are: (i) frequent use of fixed clock hours to define
morning awakening and bedtime at night, such that the
daytime and nighttime BP means were calculated
without assessing and taking into account the actual rest
and activity spans of the individual patients; and (ii) analy-
sis of the prognostic value of dipping status and nighttime
BP mean without proper adjustment for the daytime
BP mean.
A major additional limitation of all previous ABPM-
based prognostic studies is reliance on only a single base-
line profile from each participant at the time of inclusion,
without accounting for potential changes in the level and
circadian pattern of ambulatory BP thereafter during the
subsequent years of follow-up, as a consequence of BP-
lowering therapy, aging, and/or development of target
organ damage and concomitant diseases. Thus, results
of studies so far reported pertaining to the prognostic
value of ABPM for CVD risk are based on the assumption
that the features of the 24-h ABPM pattern do not change
over time, i.e., during the years of follow-up. In other
words, it is assumed that event-subjects with an elevated
sleep-time BP mean at the time of baseline evaluation,
many years before the occurrence of the event, continued
to have an elevated sleep-time BP mean during the entire
follow-up span. Furthermore, due to the lack of periodic
multiple evaluations with ABPM in all previously
reported studies, except the MAPEC one described
below (Hermida, 2007; Hermida et al., 2010b, 2011b,
2011c, 2011d, 2012a, 2012b, 2013b, 2013e, 2013g), the
potential reduction in CVD risk associated with modifi-
cation of the prognostic ABPM parameters, i.e., either
increase of the sleep-time relative BP decline towards a
more normal dipping pattern or reduction of the asleep
BP mean, was not evaluated. Finally, most studies
reported results derived from investigating mainly one
unique ABPM characteristic, e.g., either a BP mean
value, or BP dipping status, or BP variability, or
morning BP surge, without comparison or appropriate
adjustment for the prognostic value of additional
ABPM-derived characteristics. Thus, whether or not the
prognostic value of ABPM in predicting CVD events
may be improved by the combined use of novel sensitive
parameters, such as the sleep-time relative BP decline,
morning BP surge (Kario et al., 2003), or the recently pro-
posed ambulatory arterial stiffness index (AASI, calcu-
lated as 1 minus the regression slope of DBP on SBP
from ABPM [Dolan et al., 2006]), in conjunction with
Guidelines for ambulatory blood pressure monitoring {{
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the more traditional mean BP values and/or determi-
nants of BP variability, has only recently been elucidated
(Hermida et al., 2011c).
4.2. Comparative Prognostic Value of Different ABPM-
Derived Characteristics
The MAPEC Study was specifically designed to prospec-
tively investigate whether specific changes in the circa-
dian BP profile alter, i.e., reduce CVD risk (Hermida,
2007; Hermida et al., 2010b, 2011b, 2011c, 2011d,
2012a, 2012b, 2013b, 2013e, 2013g). Complete details of
the rationale and design of the study are described in pre-
vious publications (Hermida, 2007; Hermida et al.,
2010b). In summary, the authors prospectively studied
3344 subjects (1718 men/1626 women), 52.6 14.5
(mean standard deviation [SD]) yrs of age, with the
baseline BP ranging from normotension to sustained
hypertension according to ABPM criteria, during a
median follow-up of 5.6 yrs. Those with hypertension at
baseline were randomized to ingest all their prescribed
hypertension medications upon awakening or 1 of
them at bedtime. At baseline, BP was measured at 20-
min intervals from 07:00 to 23:00 h and at 30-min inter-
vals during the night for 48 h, and physical activity was
simultaneously monitored every minute by wrist actigra-
phy to accurately derive the awake and asleep BP means.
Identical ABPM assessment was scheduled annually and
more frequently (quarterly) if hypertension treatment
was adjusted. Just before commencing each 48-h ABPM
session, the same investigator obtained six consecutive
clinic cuff BP measurements after the subject had
rested in a seated position for 10 min. Investigators
blinded to the timed-treatment scheme of the random-
ized hypertensive patients reviewed the complete clinical
records of all enrolled participants at least annually as
well as the year following their last ABPM for assessment
of CVD morbidity and mortality. Registered events
included: death from all causes, myocardial infarction,
angina pectoris, coronary revascularization, heart
failure, acute arterial occlusion of the lower extremities,
thrombotic occlusion of the retinal artery, hemorrhagic
stroke, ischemic stroke, and transient ischemic attack.
During the median follow-up period of 5.6 yrs (range
.5 to 8.6 yrs) in the MAPEC Study, the authors documen-
ted 331 events (58 deaths, 45 myocardial infarctions, 51
cases of severe angina pectoris, 35 coronary revasculari-
zations, 44 cerebrovascular events, 46 heart failures, 21
cases of aortoiliac occlusive disease, and 31 thrombotic
occlusions of the retinal artery). Table 1 (left column)
reports the hazard ratio (HR) of total CVD events esti-
mated by the Cox proportional-hazard model, calculated
on the basis of the baseline ABPM profile of each partici-
pant, and adjusted for patients sex and age, and diagno-
sis of diabetes, anemia, and CKD. Table 1 (left column)
indicates the HR of CVD events, as expected, was
greater with progressively higher clinic as well as ambu-
latory BP (Hermida et al., 2011c, 2013b). For each of
the three clinical criteria of SBP, DBP, and pulse pressure
(PP, difference between SBP and DBP) derived by the
around-the-clock ABPM, the asleep BP mean was the
most significant predictor of CVD outcome among all
the tested BP parameters (Table 1). Interestingly, a
greater either morning or pre-awakening BP surge calcu-
lated as previously defined by Kario et al. (2003) was sig-
nificantly associated with lower, not higher, CVD risk
(Table 1, left column). This finding is in agreement with
the highly significant association between increased
sleep-time relative SBP and DBP decline and reduced
CVD risk (Table 1); indeed, a significant relationship
between normal dipping of the circadian BP pattern
and event-free survival was verified. The morning BP
and the lowest sleep BP, calculated as BP averages
within short (2- or 1-h) time intervals immediately
upon awakening or during sleep, respectively, provided
poorer prognostic value than the awake and asleep BP
means, respectively (Table 1). The adjusted Cox
regression model with the asleep SBP mean had the
lowest Akaike Information Criterion (AIC) (Akaike,
1974) among all the other parameters tested in Table 1.
Difference in the AIC with respect to the asleep SBP
mean was 21 for every other tested parameter, indicat-
ing a considerably poorer prognostic model for all the
ABPM-derived characteristics listed in Table 1 according
to the rules proposed by Burnham & Anderson (2004).
The findings of the analyses based on data of the last
ABPM obtained from each participant at his/her final
evaluation were similar, namely, the asleep SBP mean
was the most significant predictor of both total and
major CVD events a composite of CVD death, myocar-
dial infarction, and stroke (Hermida et al., 2013b).
The authors further evaluated the potential combined
contribution of the multiple BP parameters listed in
Table 1 to CVD risk (Hermida et al., 2011c). Cox
regression analyses using the corresponding asleep
SBP, DBP, or PP mean as an additional confounder
(Table 1, center column) indicated clinic BP was not a
significant predictor of outcome in the models that
already included the ABPM-derived asleep BP mean. In-
terestingly, when the analyses were corrected for the
asleep BP mean, an attenuated awake BP mean (for the
same asleep BP mean, an attenuated awake mean indi-
cates enhanced non-dipping) was found to be associated
with higher, not lower, CVD. Since the asleep SBP mean
was the single most significant predictor of CVD risk, the
authors further evaluated the potential contribution to
CVD risk by all the clinic and ambulatory BP character-
istics when adjusted for the asleep SBP mean (Table 1,
right column). The analysis indicated the best joint fully
adjusted model for predicting CVD events included
only the asleep SBP mean (HR = 1.23, 95% CI [1.16 -
1.32], p < .001) and the sleep-time relative SBP decline
(HR = .98 [.97 - .99], p = .019). Other variables, including
the awake and 48-h SBP means, morning surge, SD of
the awake, asleep, and 48-h time spans, AASI, and all
parameters derived from DBP and PP, provided signifi-
cantly less prognostic value or were not statistically
{| R. C. Hermida et al.
Chronobiology International
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significant at all when the asleep SBP mean was simul-
taneously included in the Cox regression models.
To further investigate the clinical impact of the awake
and asleep BP on the risk of CVD events, the authors
divided the studied population into four groups accord-
ing to BP level at the final evaluation, i.e., normal or
elevated, using the thresholds of 135/85 mmHg for the
awake SBP/DBP means and of 120/70 mmHg for the
asleep SBP/DBP means (Mancia et al., 2007a), indepen-
dent of clinic BP (Hermida et al., 2012a, 2013b). The
results, as depicted in Figure 6, indicate the: (i) adjusted
HRs were equivalent in subjects with normal asleep BP,
TABLE 1. Adjusted HR of total CVD events associated with baseline clinic and ambulatory BP
Parameter Adjusted HR
Further adjusted for corresponding
asleep mean
Further adjusted for asleep
SBP mean
SBP
Clinic 1.15 (1.09 - 1.21) * 1.04 ( .98 - 1.10) 1.04 ( .98 - 1.10)
Awake mean 1.19 (1.12 - 1.27) * .93 ( .84 - 1.03) .93 ( .84 - 1.03)
Asleep mean 1.25 (1.19 - 1.32) *
48-h mean 1.23 (1.16 - 1.32) * .87 ( .75 - 1.01) .87 ( .75 - 1.01)
Sleep-time relative decline .96 ( .95 - .97) * .98 ( .97 - .99) .98 ( .97 - .99)
SD, awake 1.07 (1.05 - 1.10) * 1.03 ( .97 - 1.09) 1.03 ( .97 - 1.09)
SD, asleep 1.05 (1.02 - 1.08) * 1.01 ( .98 - 1.04) 1.01 ( .98 - 1.04)
SD, 48-h 1.06 (1.03 - 1.09) * 1.02 ( .99 - 1.05) 1.02 ( .99 - 1.05)
Morning surge .98 ( .97 - .99) * .99 ( .98 - 1.00) .99 ( .98 - 1.00)
Pre-awakening surge .98 ( .97 - .99) * .99 ( .98 - 1.00) .99 ( .98 - 1.00)
Nighttime fall .99 ( .98 - .99) 1.00 ( .99 - 1.01) 1.00 ( .99 - 1.01)
Morning BP 1.11 (1.06 - 1.18) * .93 ( .88 - .98) .93 ( .88 - .98)
Lowest sleep BP 1.22 (1.16 - 1.28) * .90 ( .76 - 1.08) .90 ( .76 - 1.08)
DBP
Clinic 1.06 (1.01 - 1.11) 1.00 ( .95 - 1.06) .99 ( .95 - 1.05)
Awake mean 1.03 ( .98 - 1.09) .87 ( .80 - .94) .93 ( .85 - 1.01)
Asleep mean 1.12 (1.06 - 1.18) * .96 ( .90 - 1.02)
48-h mean 1.06 (1.01 - 1.12) .79 ( .70 - .90) * .94 ( .88 - 1.00)
Sleep-time relative decline .96 ( .95 - .97) * .97 ( .96 - .98) * .99 ( .98 - .1.00)
SD, awake 1.08 (1.03 - 1.13) 1.06 (1.02 - 1.22) 1.04 ( .99 - 1.10)
SD, asleep 1.02 ( .98 - 1.06) 1.01 ( .98 - 1.06) .99 ( .95 - 1.03)
SD, 48-h 1.03 ( .98 - 1.08) 1.03 ( .98 - 1.08) 1.02 ( .98 - 1.07)
Morning surge .97 ( .96 - .98) * .97 ( .96 - .99) * .98 ( .97 - .99)
Pre-awakening surge .97 ( .96 - .98) * .98 ( .96 - .88) * .98 ( .97 - .99)
Nighttime fall .98 ( .97 - .99) .98 ( .97 - .99) .99 ( .98 - 1.01)
Morning BP 1.01 ( .97 - 1.05) .91 ( .87 - .95) * .94 ( .90 - .98)
Lowest sleep BP 1.11 (1.06 - 1.17) * 1.11 ( .99 - 1.24) .98 ( .92 - 1.05)
PP
Clinic 1.10 (1.06 - 1.13) * 1.01 ( .96 - 1.06) 1.03 ( .99 - 1.07)
Awake mean 1.13 (1.09 - 1.18) * .95 ( .87 - 1.04) 1.02 ( .96 - 1.08)
Asleep mean 1.14 (1.11 - 1.18) * 1.05 ( .98 - 1.12)
48-h mean 1.15 (1.10 - 1.19) * .92 ( .82 - 1.05) 1.02 ( .96 - 1.09)
Sleep-time relative decline .98 ( .97 - .99) * .99 ( .98 - 1.00) .99 ( .98 - 1.00)
SD, awake 1.11 (1.07 - 1.16) * 1.02 ( .97 - 1.08) 1.03 ( .98 - 1.09)
SD, asleep 1.10 (1.06 - 1.15) * 1.04 ( .99 - 1.09) 1.03 ( .98 - 1.08)
SD, 48-h 1.13 (1.09 - 1.18) * 1.04 ( .99 - 1.10) 1.05 ( .99 - 1.10)
Morning surge .99 ( .98 - 1.00) .99 ( .98 - 1.01) .99 ( .98 - 1.01)
Pre-awakening surge .97 ( .96 - .99) * .99 ( .98 - 1.01) .99 ( .98 - 1.00)
Nighttime fall .99 ( .98 - 1.01) 1.01 ( .99 - 1.02) 1.00 ( .99 - 1.01)
Morning BP 1.09 (1.06 - 1.13) * .95 ( .87 - 1.03) .99 ( .95 - 1.04)
Lowest sleep BP 1.11 (1.08 - 1.15) * .93 ( .86 - 1.02) .99 ( .94 - 1.05)
AASI 1.02 (1.01 - 1.03) * 1.01 ( .99 - 1.02) 1.01 ( .99 - 1.02)
HRs (95% CI) per each 10 mmHg elevation in SBP, 5 mmHg elevation in DBP and PP, 1% absolute elevation in sleep-time relative BP
decline, 1 mmHg elevation in morning surge, or .01 elevation in ambulatory arterial stiffness index (AASI). Adjustments were applied for
significant influential characteristics of patient age and sex, and diagnosis of diabetes, anemia, and CKD (left column), with further
adjustment for the corresponding asleep SBP, DBP, or PP means (center column), or the asleep SBP mean (right column). The sleep-
time relative BP decline, index of BP dipping, is defined as the percent decline in BP during nighttime sleep relative to the mean BP during
daytime activity, and calculated as: (100[awake BP mean asleep BP mean]/awake BP mean). SD: standard deviation of BP values.
Morning BP surge was calculated as the difference between the average BP during the initial 2 h after wake-up time (i.e., morning BP) and
the hourly BP average centered on the lowest BP reading recorded during nighttime sleep (i.e., lowest sleep BP). Pre-awakening BP surge
was calculated as the difference between the average BP during the initial 2 h after wake-up time and the average BP during the 2 h just
before wake-up time. Nighttime fall was calculated as the difference between the average BP during the 2 h just before going to bed and the
hourly average centered on the lowest BP reading recorded during nighttime sleep. *p < .001, p < .01, p < .05.
Guidelines for ambulatory blood pressure monitoring {,
Informa Healthcare USA, Inc.
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independent of the awake BP mean; (ii) HRs were equiv-
alent between subjects with elevated asleep BP, independ-
ent of the awake BP mean; and (iii) subjects with elevated
asleep BP had a significantly higher adjusted HR of CVD
events than those with normal asleep BP, independent of
the awake BP mean. Results were identical both for total
CVD events (Figure 6, top), and major and more severe
CVD events (Figure 6, bottom).
In conclusion, the results of the Cox regression and
other statistical analyses corroborate the higher prognos-
tic value of CVDevents for ABPMthan clinic BP measure-
ments. Among the different individual parameters
derived from ABPM (Table 1), the asleep SBP mean
was the most significant predictor of CVDevents, both in-
dividually and jointly when combined with other ABPM-
derived potential prognostic markers in the best possible
Cox proportional-hazard model. In fact, only the sleep-
time relative SBP decline added significant prognostic
value to the model that already included the asleep SBP
mean and which was corrected for all relevant confound-
ing variables. Moreover, when the asleep SBP mean was
adjusted for the awake SBP mean, only the former proved
to be a significant predictor of outcome. CVD risk signifi-
cantly increased exponentially when the sleep-time rela-
tive SBP decline was <6% and decreased more slightly for
sleep-time relative SBP decline values above this
threshold (Hermida et al., 2013b). These results indicate
the sleep-time relative SBP decline, as a continuous vari-
able, and not the dipping classification usually based on
an arbitrary 10% threshold value, should be used for
appropriate CVD risk assessment.
4.3. Changes in ABPM during Follow-up as Predictors of CVD
Risk
Results of the time-dependent Cox regression analysis
(adjusted for patients age and sex, diagnosis of diabetes,
anemia, and CKD, baseline BP, and number of hyperten-
sion medications) for total CVD events from the MAPEC
Study indicated the progressive decrease in the awake,
asleep, and 48-h means of SBP, DBP, and PP was associ-
ated with significantly increased event-free survival
(Hermida et al., 2011c, 2013b). Changes in the BP SD,
morning BP surge, and AASI during follow-up were
less, or not at all, significantly associated with reduced/
increased CVD risk. Progressive decrease in the asleep
BP mean during follow-up was also a significant predic-
tor of survival from major CVD events (HR = .81 [.73 -
.91] for SBP; HR = .68 [.56 - .82] for DBP; p < .001).
When the changes during follow-up in the asleep and
awake BP means were entered jointly in the same Cox
regression model, decrease in the asleep SBP mean was
significantly associated with increase in event-free survi-
val (adjusted HR per 5 mmHg reduction in the asleep
SBP mean being .85 [.79 - .91], p < .001), while the
decrease in the awake SBP was not (HR = 1.00 [.94 -
1.05], p = .849). Interestingly, the reduced HR associated
with each 5 mmHg decrease in the asleep SBP mean
during follow-up was significant for subjects with both
normal (HR = .81 [.68 - .95]; p = .005) or elevated BP at
baseline (HR = .84 [.79 - .89]; p < .001) (Hermida et al.,
2011c).
Considered together, these results not only corrobo-
rate that the asleep SBP mean is the most significant
prognostic marker of CVD morbidity and mortality, as
previously suggested by numerous investigators
(Agarwal & Andersen, 2006a, 2006b; Amar et al., 2000;
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), but they also document for the first time that
decreasing the asleep SBP mean by properly timed
hypertension medications significantly reduces CVD
risk. These findings have been fully corroborated in
separate analyses of data derived from the MAPEC
Study for patients with diabetes (Hermida et al.,
2011b, 2012b), CKD (Hermida et al., 2011d), and resist-
ant hypertension (Ayala et al., 2013a). However,
changes in clinic SBP and DBP during follow-up were
not significantly associated with either increased or de-
creased CVD risk, even when corrected for the
Figure 6. Adjusted HR of total CVD events (top) and major CVD
events (bottom) in the MAPEC Study. Major events included CVD
death, myocardial infarction, and stroke. Participants were cate-
gorized into groups according to the level (normal or elevated)
of the ABPM-derived awake and asleep SBP and DBP means.
The awake SBP/DBP means were considered normal if <135/85
mmHg and elevated otherwise. The asleep SBP/DBP means
were considered normal if <120/70 mmHg and elevated other-
wise. Adjustments were applied for patient sex and age, diagnosis
of diabetes or CKD, sleep duration, and hypertension treatment
time (all medications upon awakening vs. 1 medications at
bedtime). Updated from Hermida et al. (2012a, 2013b).
{ R. C. Hermida et al.
Chronobiology International
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progressive decrease during the 5.6 yrs median follow-
up in the asleep SBP mean (Hermida et al., 2011c). Of
relevance to this finding, Keenan et al. (2009) found
changes in clinic BP along the course of the Perindopril
Against Recurrent Stroke Study (PROGRESS) have low
probability of yielding reliable information about the
true changes in BP in response to hypertension medi-
cations. Their results prompted the authors to advocate
the urgent need for evidence-based guidelines to
monitor treatment-response and guide clinical practice.
Results of the MAPEC Study, awaiting corroboration
from the ongoing prospective Hygia Project in which
participants are also evaluated by periodic 48-h ABPM
(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermida
et al., 2013j; Mojn et al., 2013; Moy et al., 2013;
Ros et al., 2013), indicate ABPM should be considered
a requirement to evaluate changes in asleep BP as a
prognostic indicator of CVD risk and also its modifi-
cation by treatment.
5. MASKED NORMOTENSION AND MASKED
HYPERTENSION
Current guidelines (Chobanian et al., 2003; Mancia et al.,
2007a; Pickering et al., 2005) define normotension as a
consistently normal BP and sustained hypertension
as a consistently elevated BP based upon both clinic
and ambulatory measurements. Discrepancies between
the two methods of measurements have been defined
as isolated-office or white-coat hypertension, i.e., ele-
vated clinic BP but normal ambulatory BP, and masked
hypertension, i.e., normal clinic BP but elevated ambula-
tory BP (Mancia et al., 2007a). The same guidelines rec-
ommend the use of separate threshold values for
daytime and nighttime BP means for the diagnosis of hy-
pertension based on ABPM (Chobanian et al., 2003;
Mancia et al., 2007a; Pickering et al., 2005). However,
classification of subjects into isolated-office and
masked hypertension has most frequently relied, as erro-
neously suggested in the guidelines themselves (Mancia
et al., 2007a), on the comparison only of daytime clinic
and awake-time mean BP values (Angeli et al., 2010;
Bobrie et al., 2008; Fagard & Cornelissen, 2007; Gustav-
sen et al., 2003; Ohkubo et al., 2005; Pierdomenico &
Cuccurullo, 2011; Verdecchia et al., 2005), disregarding
entirely the asleep BP mean otherwise used to
define hypertension.
Previous studies have mostly, but not consistently
(Gustavsen et al., 2003; Mancia et al., 2006; Verdecchia
et al., 2005), suggested that CVD risk does not differ sig-
nificantly between patients who exhibit isolated-office
hypertension and those who are normotensive, but it is
significantly higher in masked and sustained hyperten-
sion than in normotension (Angeli et al., 2010; Fagard
& Cornelissen, 2007; Ohkubo et al., 2005; Pierdomenico
& Cuccurullo, 2011). A major limitation of everyone of
these previous studies is that by classifying subjects
from the comparison of clinic and ambulatory awake or
even 24-h BP means (Baguet et al., 2008; Mancia et al.,
2006) each of the four resulting categories would
include individuals with either a normal or elevated
asleep BP mean, and thus having a markedly different
CVD risk (Figure 6).
Data from the MAPEC Study allowed prospective
examination of the impact of sleep-time BP on the defi-
nition of ambulatory hypertension and the associated
prognostic value of isolated-office and masked hyperten-
sion, points of disagreement between clinic and ambula-
tory BP measurements in the diagnosis of hypertension,
i.e., identification of individuals at higher CVD risk
(Hermida et al., 2012a). Participants were divided into
four categories normal BP, isolated-office hypertension,
masked hypertension, and sustained hypertension
according to the agreement/disagreement between the
diagnosis of hypertension based on clinic and ambula-
tory BP measurements using as threshold values 135/85
for the awake SBP/DBP means, 120/70 for the asleep
SBP/DBP means, and 140/90 for clinic SBP/DBP; the
authors then compared CVD risk between the four cat-
egories obtained by defining ambulatory hypertension
on the basis of either the awake BP mean alone, the
asleep BP mean alone, or both the awake and asleep
BP combined.
Based upon comparison of clinic BP with the awake
BP mean, as done in most previously published studies,
there was a non-significant tendency of increasing
adjusted HR of total CVD events across the categories
(Figure 7, top). The adjusted HR did not differ signifi-
cantly between subjects with normal BP, isolated-office,
and masked hypertension. Patients with sustained hyper-
tension had a higher HR than those with normal BP
(p < .001), but an equivalent HR as those who had
masked hypertension (p = .545; Figure 7, top). The
results and conclusions indicating increased HR of CVD
events only in sustained hypertension also were similar
when analyses were restricted to major CVD events and
when the 48-h mean in comparison with clinic BP was
used instead of the awake mean for classification
(Hermida et al., 2012a).
Participants in the MAPEC Study were also divided
into the same four categories based upon comparison
of clinic BP with both the ABPM-derived awake and
asleep BP means, as a joint unique criterion for defining
hypertension versus normotension (Figure 7, bottom).
The results indicated: (i) an equivalent adjusted HR of
CVD events (p = .549) between normal BP and isolated-
office hypertension; (ii) a non-significantly different
adjusted HR between masked and sustained hyperten-
sion (p < .252); and (ii) a highly significant greater HR
in masked and sustained hypertension compared to
either normal BP or isolated-office hypertension
(p < .001). These differences between groups in the HR
of CVD events were slightly greater when classification
was based on the asleep BP mean alone (Hermida
et al., 2012a).
Guidelines for ambulatory blood pressure monitoring {;
Informa Healthcare USA, Inc.
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The authors further evaluated the risk of CVD events
in the eight resulting categories of subjects, as shown in
Table 2, according to the clinic BP and the ABPM-
derived awake and asleep BP means as three different di-
agnostic variables. Subjects were classified first into the
categories of normal BP, isolated-office hypertension,
masked hypertension, and sustained hypertension by
comparing clinic BP with the awake BP mean alone
(columns 1 and 2 in Table 2); then, subjects in each of
these four categories were further divided in two
classes according to the agreement/disagreement
between the awake and asleep BP mean for the diagnosis
of hypertension (comparison of columns 2 and 3 in
Table 2). The adjusted HR of each group was calculated
in comparison with the reference subjects with normal
clinic BP and normal awake and asleep BP means
(Group 1). The results can be summarized as follows:
A. Subjects with elevated asleep BP but normal awake
and clinic BP (Group 2) had a significantly greater
adjusted HR (HR = 1.68; p = .034) than subjects with
normal BP in all three BP characteristics (Group 1),
but an equivalent HR as those with normal clinic BP
with elevated awake and asleep BP (Group 4; HR =
1.77; p = .039 compared to Group 1).
B. Subjects with normal asleep BP, elevated awake BP,
and normal clinic BP (commonly classified as
masked hypertension; Group 3) had a comparable
HR as the reference group (Group 1) of normotensive
subjects (HR = .71; p = .629).
C. Subjects with elevated asleep BP, normal awake BP,
and elevated clinic BP (usually classified as isolated-
office hypertension; Group 6) had a significantly
greater HR than the reference group of normotensive
subjects (HR = 2.08; p < .001), but an equivalent HR as
those with elevated BP in all three characteristics
(Group 8; HR = 2.36; p < .001 compared to Group 1).
D. Subjects with normal asleep BP but elevated awake
and clinic BP (usually classified as sustained hyper-
tension; Group 7) had a HR not significantly different
than that of Group 1, i.e., the reference group of
normotensive subjects (HR = .61; p = .348), and fully
equivalent to that of subjects of Group 5 (HR = .87;
p = .501), those with elevated clinic BP but normal
awake and asleep BP.
Figure 8 presents the adjusted HR of CVD events for
the eight categories described in Table 2. In agreement
with the findings depicted in Figure 5, Figure 8 shows,
in terms of CVD risk, that there are mainly two groups
of subjects: (i) a relatively low-risk group composed of
those with normal asleep SBP/DBP means, and (ii) a sig-
nificantly elevated-risk group composed of those with
elevated asleep SBP/DBP means, independent of either
clinic or awake mean BP values.
Apart from the marked difference in CVD risk assess-
ment when the asleep BP mean is omitted for classifi-
cation in comparison with clinic BP, the findings shown
in Table 2 indicate the so far thus reported prevalence
of the four considered categories of patients, i.e.,
normal BP, isolated-office hypertension, masked hyper-
tension, and sustained hypertension, and thus the real
clinical dimension of isolated-office and masked hyper-
tension, is surely incorrect. According to the results pre-
sented in Table 2: (i) 58.2% of subjects who should be
label masked hypertension based on their elevated
asleep BP (Group 2) were in the past classified as normo-
tensive (based on their normal office and ambulatory
awake BP) and thus mistakenly included in the reference
group to calculate CVD risk of the other categories; (ii)
38.2% of subjects with normal office, elevated ambula-
tory awake, but normal asleep BP, and thus at low CVD
risk (Group 3), have always been labeled masked hyper-
tension; (iii) 12.6% of subjects with elevated office, ele-
vated ambulatory awake, but normal asleep BP, in the
past labeled sustained hypertension, should be labeled
isolated-office hypertension (Group 7); and (iv) 26.3%
of subjects with elevated clinic, normal awake, and
FIGURE 7. Adjusted HRof total CVD events in the MAPEC Study.
Adjustments were applied for patient sex and age, diagnosis of
diabetes or CKD, sleep duration, and hypertension treatment
time (all medications upon awakening vs. 1 medications at
bedtime). Subjects were classified into the categories of normal
BP, isolated-office hypertension (HT), masked HT, and sustained
HT by comparing clinic BP with either the awake BP mean only
(top) or with the awake and asleep BP means used jointly
(bottom). Clinic SBP/DBP measurements were considered
normal if <140/90 mmHg and elevated otherwise. The ABPM-
derived awake SBP/DBP means were considered normal if <135/
85 mmHg and elevated otherwise. The ABPM-derived asleep
SBP/DBP means were considered normal if <120/70 mmHg and
elevated otherwise. Updated from Hermida et al. (2012a).
{8 R. C. Hermida et al.
Chronobiology International
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elevated asleep BP (Group 6), in the past labeled iso-
lated-office hypertension, should be labeled sustained
hypertension. In conclusion, the asleep BP determined
by ABPM must be used to properly identify out-of-
office hypertension and cannot be omitted in the defi-
nition of isolated-office and masked hypertension.
Accordingly, these two conditions cannot be defined by
comparing clinic BP with at-home self-measurements,
which are not feasible during sleep, as frequently re-
ported in the literature and misleadingly recommended
as an alternative to ABPM (Nasothimiou et al., 2012;
Parati et al., 2008).
The results presented in Figures 7 and 8 indicate CVD
risk is equivalent in normotension and isolated-office hy-
pertension when the asleep SBP/DBP means are prop-
erly used for classification, while individuals in these
two categories have significantly reduced risk compared
to those with masked and sustained hypertension.
Taking these results into consideration, hypertension,
conceptually connotating a high-risk condition, should
not be used when ABPM is normal, regardless of clinic
BP values. Accordingly, we recommend the term iso-
lated-office hypertension be avoided and replaced by
the more appropriate term masked normotension.
The recent update of the guidelines for the clinical
management of adult primary hypertension fromthe Na-
tional Institute for Health and Clinical Excellence pro-
poses for the very first time the requirement for ABPM
to corroborate the diagnosis of hypertension in all
adults with elevated clinic BP (National Institute for
Health and Clinical Excellence, 2011). This recommen-
dation is mainly based on the potential cost-effectiveness
of identifying people with masked normotension so as to
avoid unnecessary long-term costly treatment based on
clinic BP measurement only (Lovibond et al., 2011).
The results summarized in Figures 7 and 8 indicate
masked hypertension represents a relevant and more sig-
nificant clinical burden in terms of increased CVD risk
than masked normotension. Moreover, when properly
taking into account the asleep BP mean for classification,
FIGURE 8. Adjusted HR of total CVD events in the MAPEC Study
(Hermida et al., 2012a). Adjustments were applied for patient sex
and age, diagnosis of diabetes or CKD, sleep duration, and hyper-
tension treatment time (all medications upon awakening vs. 1
medications at bedtime). Subjects were classified first into the cat-
egories of normal BP, isolated-office hypertension (HT), masked
HT, and sustained HT by comparing clinic BP with awake BP
mean alone (columns 1 and 2 in Table 2); subjects in each of
these four categories were further divided in two classes according
to agreement/disagreement between the awake and asleep BP
mean for the diagnosis of hypertension (comparison of columns
2 and 3 in Table 2). Clinic SBP/DBP measurements were con-
sidered normal if <140/90 mmHg and elevated otherwise. The
ABPM-derived awake SBP/DBP means were considered normal
if <135/85 mmHg and elevated otherwise. The ABPM-derived
asleep SBP/DBP means were considered normal if <120/70
mmHg and elevated otherwise.
TABLE 2. Adjusted HR of total CVD events in subjects classified by comparison of the diagnosis of hypertension based on clinic BP and
ABPM-derived awake BP mean, asleep BP mean, or both.
Clinic
BP
Awake
BP
Asleep
BP
Classification by
awake BP
Classification by
asleep BP
Classification by
awake & asleep BP
Group
#
Event-
rate in %
Adjusted HR [95% CI];
p value
Normal Normal Normal N-BP N-BP N-BP 1 4.7 1.00
Elevated N-BP M-HT M-HT 2 16.5 1.68 [1.04-2.72]; .034
Elevated Normal M-HT N-BP M-HT 3 2.7 .71 [ .17-2.91]; .629
Elevated M-HT M-HT M-HT 4 16.1 1.77 [1.03-3.05]; .039
Elevated Normal Normal ISO-HT ISO-HT ISO-HT 5 5.9 .87 [ .59-1.29]; .501
Elevated ISO-HT S-HT S-HT 6 17.6 2.08 [1.33-3.24]; < .001
Elevated Normal S-HT ISO-HT S-HT 7 3.0 .61 [ .22-1.71]; .348
Elevated S-HT S-HT S-HT 8 21.0 2.36 [1.68-3.31]; < .001
HR (adjusted by the significant confounding variables of patient sex and age, diagnosis of diabetes and CKD, time of hypertension
treatment [all medications upon awakening vs. 1 at bedtime], and duration of nighttime sleep) was obtained by Cox regression
analysis using as reference the group of subjects with normal BP according to all three different BP measurements clinic BP, awake
BP, and asleep BP (Group 1, see text). Clinic SBP/DBP measurements were considered normal if <140/90 mmHg and elevated
otherwise. The ABPM-derived awake SBP/DBP means were considered normal if <135/85 mmHg and elevated otherwise. The ABPM-
derived asleep SBP/DBP means were considered normal if <120/70 mmHg and elevated otherwise. In columns 4-6, normal (N-BP) and
sustained hypertension (S-HT) are defined as consistently normal BP or elevated BP, respectively, according to both the clinic BP and
considered ABPM parameter; isolated-office hypertension (ISO-HT) is defined as elevated clinic BP but normal ABPM; masked
hypertension (M-HT) is defined as normal clinic BP but elevated ABPM. Column 8 (event-rate) indicates the percentage of subjects
with a documented event in each of the resulting 8 categories. Updated from Hermida et al. (2012a).
Guidelines for ambulatory blood pressure monitoring {
Informa Healthcare USA, Inc.
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previous reports have indicated attenuation by about 50%
in the prevalence of masked normotension and a signifi-
cant two-fold increase in the prevalence of masked
hypertension, mainly in high-risk populations character-
ized by a large proportion of patients with the non-
dipper/riser BP pattern, i.e., elderly, diabetic, CKD, and
resistant hypertension patients (Ayala et al., 2013b;
Crespo JJ et al., 2013; Hermida et al., 2013a, 2013j;
Mojn et al., 2013; Moy et al., 2013; Ros et al., 2013).
Accordingly, ABPM must be a requirement for proper
CVD risk assessment of all individuals, independent of
clinic BP measurements, taking into account the prog-
nostic value of the asleep BP mean and sleep-time rela-
tive BP decline, two prognostic markers and validated
novel therapeutic targets that can be assessed only by
around-the-clock ABPM.
The differing CVD liability of patients categorized in
terms of clinic versus ambulatory BP measurements indi-
cates, from the point of view of the clinical value of ABPM
and its applicability to accurately stratify CVD risk, this
diagnostic technique should not be used for the first-
time evaluation of patients already treated with 1 or 2
BP-lowering medications. In the absence of a baseline
ABPM performed before the initiation of treatment,
therapy was undoubtedly prescribed in keeping with a di-
agnosis based only upon clinic BP measurements. As
such, ABPM performed for the very first time in treated
patients is unable to distinguish who, indeed, is hyper-
tensive but properly controlled by therapy from those
prescribed unnecessary therapy because of masked nor-
motension. These limitations must be taken into con-
sideration when performing first-time ABPM in patients
treated with 2 medications who cannot be washed-
out, e.g., for about 2 wks before ABPM. In conclusion,
in principle first-time evaluation by ABPM should be re-
stricted to untreated subjects and patients treated with 3
BP-lowering medications, those who might thus be truly
resistant to treatment if the awake and/or asleep BP
means are inadequately controlled (Ayala et al., 2013a;
Hermida et al., 2005b, 2008a, 2010c, 2011c, 2013b,
2013g, 2013j; Ros et al., 2013).
6. THE NORMOTENSIVE NON-DIPPER PARADOX
As previously discussed, a blunted decline of nighttime
BP (non-dipping) has been associated with poor progno-
sis, primarily in patients with sustained hypertension.
Nevertheless, studies have shown that normotensive
individuals with a non-dipper BP pattern may have: (i)
increased left ventricular mass and relative wall thickness
and reduced myocardial diastolic function (Hoshide
et al., 2003; Soylu et al., 2009); (ii) elevated myocardial
repolarization lability and impaired baroreflex function,
suggesting autonomic nervous system dysfunction
(Myredal et al., 2010); (iii) increased urinary albumin
excretion (Soylu et al., 2009); (iv) increased prevalence
of diabetic retinopathy (Rodrigues et al., 2010); and (v)
impaired glucose tolerance (Li et al., 2008). However, it
is unknown as yet whether the non-dipper BP pattern
or just elevated BP, alone, is the most important predictor
of advanced target organ damage and elevated risk of
future CVD events (Ohkubo et al., 2002).
Hermida et al. (2013e) prospectively investigated the
role of dipping status and ambulatory BP level as poten-
tial contributing factors to CVD morbidity and mortality
in a recent evaluation of the data obtained from the
MAPEC Study. Participants were divided into four
groups on the basis of the two criteria of dipping status
and ambulatory BP level: (i) dipper versus non-dipper,
and (ii) normal ambulatory BP (awake SBP/DBP means
<135/85 mmHg and asleep SBP/DBP means <120/70
mmHg) versus elevated ambulatory BP. Cox survival
analyses, adjusted for significant confounding variables,
documented that non-dippers experienced significantly
higher CVD risk than dippers, whether they had normal
(p = .017) or elevated ambulatory BP (p < .001). Non-
dippers with normal awake and asleep SBP and DBP
means, who accounted for 21%of the studied population,
had a similar HR of CVD events (HR = 1.61 [1.09 - 2.37])
as dippers with elevated ambulatory BP (HR = 1.54
[1.01 - 2.36]; p = .912 between groups). The results and
conclusions were fully equivalent when the authors eval-
uated the HR of major CVD events, i.e., a composite of
CVD death, myocardial infarction, and stroke, as well as
for treated and untreated patients analyzed separately
(Hermida et al., 2013e).
These novel findings document the risk of CVD events
is influenced not only by ambulatory BP elevation, but
also by blunted nighttime BP decline, even within the
normotensive range, thus supporting ABPM as a require-
ment for appropriate assessment of CVD risk in the
general population, as recently advocated (Giles et al.,
2012). The elevated CVD risk in normotensive individ-
uals having a non-dipper BP profile, who might account
for >20% of the adult population, represents a clear
paradox, as those persons have neither normal BP
nor low CVD risk. This, in turn, indicates the need to re-
define the concepts of normotension and hypertension,
which have been established on the unique basis of BP
level, mainly if not exclusively, measured in the clinic
during the daytime and in the absence of knowledge of
the entire 24-h BP pattern.
7. J-SHAPED RELATIONSHIP BETWEEN BP AND CVD
RISK
Several studies have found too great a reduction in clinic
BP by hypertension treatment results in increase of CVD
risk, whereas moderate reduction in clinic BP results in
decrease of risk (Messerli et al., 2007). Thus, it has
been suggested that the relationship between treat-
ment-achieved BP and CVD events is J-shaped, decreas-
ing as BP is lowered but rising again as BP is further
decreased (Boutitie et al., 2002; Irie et al., 1993;
Okumura et al., 2005; Voko et al., 1999). This concept
has generated extensive discussion and concern,
{;o R. C. Hermida et al.
Chronobiology International
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leading to recommendations to lower BP only to a certain
level (140/90 mmHg for clinic SBP/DBP), even in
patients at high CVD risk, such as those with diabetes
(Cushman et al., 2010) or CKD (Appel et al., 2010). As
an example, the Action to Control Cardiovascular Risk
in Diabetes (ACCORD) trial failed to demonstrate a differ-
ence in the occurrence of CVD events between intensive
and non-intensive treatment goals defined, respectively,
in terms of the clinical-cuff SBP targets of <120 and
<140 mmHg (Cushman et al., 2010). These results have
lead to the question if the currently recommended
target goal of clinic SBP/DBP <130/80 mmHg for patients
with diabetes (Mancia et al., 2007a) should be revised
(Bangalore et al., 2011; Kendall, 2011). Unfortunately,
the ACCORD study did not provide information on
ABPM, and the time of day of hypertension treatment
was neither standardized nor reported.
Commonly, the therapeutic strategies used to improve
BP control in a hypertensive patient include increase of
therapeutic dose, sequential change of hypertension
medications, or application of a combination of medi-
cations that exert synergic effects (Mancia et al., 2007a).
In practice, all such therapeutic strategies typically
involve a common element: the administration of hyper-
tension medication(s) in the morning either at the com-
mencement of the diurnal activity span or, more
commonly, with breakfast. It is important to realize
that: (i) most marketed medications do not provide
homogeneous long-lasting efficacy throughout the
entire 24 h, and (ii) no marketed hypertension medi-
cation induces greater reduction of the asleep than
awake BP when administered in the morning (Hermida
& Smolensky, 2004; Hermida et al., 2005a, 2007a,
2011a, 2013c; Portaluppi & Smolensky, 2010; Portaluppi
et al., 2012; Smolensky & Portaluppi, 1999; Smolensky
et al., 2010, 2012). Typically, progressive increase in the
number of BP-lowering medications administered in
the morning results in greater reduction of the awake
than the asleep SBP and DBP means, the result being de-
crease in the sleep-time relative BP decline. This is unde-
sirable since it is known that progressive reduction of
sleep-time relative BP decline towards a more non-
dipper BP pattern (Hermida et al., 2008a) leads to pro-
gressively increased CVD risk (Ayala et al., 2013a;
Hermida et al., 2010b, 2011c, 2012b, 2013b).
Hermida et al. (2013h) examined, using the data from
the prospective MAPEC Study, the questions of whether
the documented J-shaped relationship between clinic
BP and CVD risk also applies to ambulatory BP and
whether such a relationship is dependent on the time-
of-day regimen of hypertension treatment. Participants
of each of the two randomized treatment-time groups,
i.e., all BP-lowering medications scheduled upon awak-
ening or 1 medications scheduled at bedtime, were
further divided into quintiles of achieved BP, with the
class having the lowest rate of events used as reference
for each tested BP characteristic, namely clinic BP,
awake BP, and asleep BP. The relationship between
achieved clinic SBP and adjusted CVD risk was
U-shaped for the patients randomized to the morning-
treatment group; CVD risk was significantly higher
(p always < .008) in the first two and the last two quintiles
compared with the third quintile (achieved clinic SBP
ranging between 140 and 150 mmHg). The shape of the
relationship between clinic SBP and CVD risk, however,
was markedly different for the patients randomized to
the bedtimetreatment group; CVD risk was significantly
higher (HR = 3.09 [1.33 - 7.18]; p < .001) in the last (i.e.,
highest clinic SBP) compared to the first quintile, and
the adjusted HR of CVD events was progressively, but
not significantly, diminished with decreased achieved
clinic SBP <160 mmHg. These results on the influence
of time-of-day (i.e., circadian time) of treatment regard-
ing the relationship between achieved BP and CVD risk
were similar for clinic DBP and also for the ABPM-
derived awake SBP and DBP means (Hermida et al.,
2013h).
The relationship between CVD risk and the achieved
asleep SBP mean assessed by around-the-clock ABPM
differed markedly from that described for office BP,
being exponential independent of the treatment-time
regimen; CVD risk was lowest in the first quintile
(achieved asleep SBP <103 mmHg), and significantly
higher when the asleep SBP was >115 mmHg. Con-
clusions were similar for the achieved DBP mean; CVD
risk was significantly higher when the asleep DBP mean
was >73 mmHg, again independent of treatment-time
regimen. There was no single registered major CVD
event in patients of either treatment-time group with an
achieved asleep BP mean <103 mmHg, which rep-
resented 22% of the studied population. The absence of
a J-shaped relationship between CVD risk and progress-
ive reduction in the asleep SBP mean was also document-
ed in separate analyses of data from patients with either
untreated hypertension or resistant hypertension at base-
line (Hermida et al., 2013h).
In conclusion, the proposed J-shaped relationship
between achieved BP level and CVD risk, described so
far only on the basis of clinic cuff BP values in patients
presumably treated with hypertension medications in
the morning (Appel et al., 2010; Bangalore et al., 2010;
Cushman et al., 2010; Okumura et al., 2005; TRANSCEND
Investigators, 2008; Voko et al., 1999; Yusuf et al., 2008),
does not apply to the ABPM-determined asleep BP
mean, a more significant and sensitive predictor of
CVD morbidity and mortality than either the daytime
clinic BP or ambulatory awake BP mean (Agarwal &
Andersen, 2006a, 2006b; Amar et al., 2000; Ayala et al.,
2013a; Ben-Dov et al., 2007; Boggia et al., 2007; Bouha-
nick et al., 2008; Dolan et al., 2005; Fagard et al., 2008;
Fan et al., 2010; Hermida et al., 2003e, 2011c, 2012b,
2013b, 2013e; Kikuya et al., 2005; Minutolo et al., 2011).
Accordingly, the J-curve seems to be a manifestation of
the over-treatment in the morning of elevated BP to
achieve the misleading therapeutic goal of progressive
reduction in the daytime clinic BP level and disregard
Guidelines for ambulatory blood pressure monitoring {;+
Informa Healthcare USA, Inc.
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entirely of the control of asleep BP. The decreased CVD
risk associated with progressive reduction in the asleep
SBP mean, more feasible by a bedtime than morning
hypertensiontreatment regimen (Hermida & Ayala,
2009; Hermida & Smolensky, 2004; Hermida et al.,
2003d, 2004c, 2005a, 2007a, 2007b, 2007e, 2008b,
2009a, 2010a, 2011a, 2013c; Portaluppi & Smolensky,
2010; Portaluppi et al., 2012; Smolensky & Portaluppi,
1999; Smolensky et al., 2010, 2012), indicates the impor-
tance of the proper timing during the 24 h of hyperten-
sion medications, in conjunction with the application
of ABPM for the appropriate assessment of awake and
asleep BP control, as an improved and cost-effective
means of reducing CVD morbidity and mortality.
8. REFERENCE ABPM THRESHOLDS FOR THE
DIAGNOSIS OF HYPERTENSION
Despite the knowledge of the progressive relationship
between increase of BP and escalation of CVD risk that
makes the diagnosis of hypertension based on fixed BP
cutoff values rather arbitrary, international guidelines
recommend the diagnostic threshold of 140/90 mmHg
for clinic SBP/DBP in the absence of compelling clinical
conditions (uncomplicated persons), and the lower
threshold of 130/80 mmHg as a therapeutic goal when
present, i.e., diabetes, CKD, or past CVD events (Choba-
nian et al., 2003; Mancia et al., 2007a; Pickering et al.,
2005). Since ambulatory BP values are usually several
mmHg lower than clinic ones, the same guidelines
provide different thresholds for the diagnosis of hyper-
tension based on ABPM, namely an awake SBP/DBP
mean 135/85 mmHg, or an asleep SBP/DBP mean
120/70 mmHg (Mancia et al., 2007a). However, differ-
ent ABPM thresholds have not yet been recommended
for uncomplicated lower-risk versus higher-risk persons,
as some guidelines indirectly recommend on the basis
of clinic BP.
Most published reports have proposed ABPM diag-
nostic limits based on either the distribution of ambula-
tory BP in reference normotensive populations (Hansen
et al., 2008) or the regression of ambulatory BP values
on clinic BP measurements (Bur et al., 2002; Head
et al., 2010). A few studies have proposed ABPM diagnos-
tic cutoff threshold values based on actual associated
CVD outcomes (Kikuya et al., 2007; Ohkubo et al.,
1998), but without differentiating patients according to
documented factors that significantly affect BP regu-
lation, such as patients sex, and diagnosis of diabetes
and CKD, among others (Fabbian et al., 2013; Hermida
et al., 2002a, 2007d; Portaluppi &Smolensky, 2007; Porta-
luppi et al., 1990, 2012)
8.1. Sex Differences in ABPM Reference Thresholds
Epidemiologic studies have reported sex differences in
BP and heart rate (Ben-Dov et al., 2008; Burt et al.,
1995; Hermida, 1999; Hermida et al., 2002a, 2002d,
2004d; Kagan et al., 2007; Pimenta, 2012; Reckelhoff,
2001; Roger et al., 2011; Vriz et al., 1997). As shown in
Figure 9, typically, men exhibit lower heart rate and
higher BP than women, the differences being larger for
SBP than DBP (Hermida et al., 2002a). These differences
first become apparent during adolescence and remain
significant until 55-60 yrs of age (Meininger et al., 2004;
Palatini et al., 2001; Pimenta, 2012; Wang et al., 2006).
The most recent U.S. National Health and Nutrition
Examination Survey involving daytime cuff measure-
ments confirmed SBP increases progressively with age
in both men and women, and also that SBP is higher in
men commencing in early adulthood (Roger et al.,
2011). In contrast, the survey found the age-related rate
of rise in SBP is steeper for women, such that SBP in
women is higher than in men during and after the 7
th
decade of life. In the overall population, DBP increases
progressively in both men and women until approxi-
mately the 6
th
decade of life, after which it decreases pro-
gressively, men having a slightly higher DBP than women
at all ages. The prevalence and severity of hypertension in
women increase markedly with advancing age, such that
a higher percentage of women than men experience high
BP after 65 yrs of age (Ong et al., 2008; Roger et al., 2011).
Furthermore, BP control is more difficult to achieve in
older women (Lloyd-Jones et al., 2005). Sex-related
differences in BP regulation may play a role in the docu-
mented male-female dissimilarities in the pathophysiol-
ogy of hypertension, treatment responses to medications,
tissue and organ damage, and CVD risk (Atalar et al.,
2010; Ayala & Hermida, 2010; Burt et al., 1995; Gu
et al., 2008; Keyhani et al., 2008; Klungel et al., 1998; Li
et al., 2006; Manfredini et al., 2011; Ong et al., 2008;
Pimenta, 2012; Roger et al., 2011; Safar et al., 2002; Vriz
et al., 1997; White et al., 2001; Yoshida et al., 2010).
Hermida et al. (2013i) evaluated the adjusted HR of
CVD events for the participants of the MAPEC Study
categorized by sex and their 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 a signifi-
cantly greater slope of increasing risk in women com-
pared to men with progressively elevated SBP/DBP; and
(iii) showed progressively and significantly greater differ-
ences 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. Fur-
thermore, Cox regression analyses indicated significant
interaction between sex of patient and both the awake
and asleep SBP means (p always < .009 [Hermida et al.,
2013i]).
Using the baseline ABPM values of CVD event and
non-event male participants of the MAPEC Study
revealed the maximum combined sensitivity and speci-
ficity for the diagnosis of hypertension corresponded to
the proposed outcome (CVD event)-based threshold
values shown in Table 3, i.e., 135/85 mmHg for the
awake and 120/70 for the asleep SBP/DBP means
{;: R. C. Hermida et al.
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(Hermida et al., 2013i). These findings, based on docu-
mented CVD events of the study, are in agreement with
the currently recommended ABPM reference values for
the diagnosis of hypertension in uncomplicated
persons (Mancia et al., 2007a). However, Cox pro-
portional-hazard regression analyses indicated 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 CVD outcome-based ABPM reference
thresholds in women, equivalent to the cutoff values pro-
vided in Table 3 for men, are 123.8/78.6 mmHg for the
awake and 109.2/64.0 mmHg for the asleep SBP/DBP
means. Rounding these point estimates to the nearest
integer value ending in 0 or 5 provides the newly pro-
posed outcome-based threshold values for women, i.e.,
125/80 mmHg for the awake and 110/65 for the asleep
SBP/DBP means (Hermida et al., 2013i).
Alternatively, the diagnosis of hypertension might be
based on the tolerance-hyperbaric test, as extensively de-
scribed in Section 2. Figure 10 shows the tolerance inter-
vals for SBP (top) and DBP (bottom) derived to include
90% of the reference population of normotensive individ-
uals with 90% confidence (Hermida et al., 2004d). Toler-
ance intervals for SBP and DBP were obtained from data
sampled by 48-h ABPM in a reference population of 743
clinically healthy individuals (400 men and 343 women)
and calculated using the mathematical non-parametric
method described in detail elsewhere (Hermida &
Fernndez, 1996). These time-specified reference
thresholds, expressed in hours after awakening from
nighttime sleep, reflect the circadian BP variability and
the documented sex differences in BP regulation. In
keeping with previous findings (Hermida et al., 2000b,
2002d), hypertension is defined as a HBI 50 mmHg X
h, while a HBI 15 mmHg X h is indicative of suspected
hypertension that will require repeated subject
FIGURE 9. 24-h pattern of SBP (left) and heart rate (right) of normotensive men (continuous line) and women (dashed line) sampled by
48-h ABPM. Each graph shows the hourly means and standard errors of data derived from subjects of each group. Dark shading along the
lower horizontal axis of graphs denotes the average hours of nighttime sleep across the sample. Nonsinusoidal shaped curves correspond to
the best-fitted waveform models derived by population-multiple-component analysis (Fernndez & Hermida, 1998). MESOR (midline es-
timating statistic of rhythm) is the 24-h average value of the rhythmic function fitted to the time series data. Amplitude is one-half the differ-
ence between the maximum and minimum values of the best-fitted curve. MESOR and amplitude were compared between groups using a
specially developed nonparametric statistical test (Fernndez et al., 2004). Updated from Hermida et al. (2002a).
TABLE 3. Diagnostic threshold values for ABPM in mmHg based on CVD outcome.
ABPM characteristic Men Women High-risk patients
Awake mean
SBP 135 125 120
DBP 85 80 75
Asleep mean
SBP 120 110 105
DBP 70 65 60
High-risk patients include those diagnosed with diabetes, CKD, and having experienced a previous CVD event.
Alternatively, hypertension might be defined as a hyperbaric index (HBI) 50 mmHg X h. The HBI is defined as the total area during the
entire 24-h period of any given subjects BP being above a time-varying threshold defined by a tolerance interval calculated as a function of
patient sex and CVD risk. A HBI 15 mmHg X h indicates suspected hypertension that will require repeated subject evaluation by ABPM to
confirm/refute the diagnosis of hypertension.
Guidelines for ambulatory blood pressure monitoring {;{
Informa Healthcare USA, Inc.
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evaluation by ABPM to confirm/refute the diagnosis of
hypertension. Similarly, a HBO (area of BP deficit
below the lower tolerance limit) 50 mmHg X h has
been previously utilized to down-titrate therapy in
treated hypertensive patients (Hermida et al., 2010b).
8.2. Reference ABPM Thresholds in High-Risk Patients
As indicated above, different ABPM thresholds have not
been yet recommended for uncomplicated lower-risk
versus higher-risk persons, e.g., patients with diabetes,
CKD, and/or past CVD events. Diabetes is among the
documented factors that significantly affects BP regu-
lation and CVD risk (Ayala et al., 2013b; Equiluz-Bruck
et al., 1996; Fogari et al., 1993; Hermida et al., 2007d; Por-
taluppi & Smolensky, 2007; Portaluppi et al., 2012; Rutter
et al., 2000). The blunted sleep-time BP decline that is
characteristic of the non-dipping pattern is also very
common in patients with CKD (Agarwal & Andersen,
2005; Agarwal et al., 2009; Crespo JJ et al., 2013; Davidson
et al., 2006; Mojn et al., 2013; Pogue et al., 2009; Porta-
luppi et al., 1990).
Hermida et al. (2013f ) evaluated the adjusted HR of
CVD events for the participants of the MAPEC Study
categorized by the presence/absence of diabetes and
their ABPM-derived awake and asleep SBP/DBP means.
The analyses revealed a significantly greater slope of in-
creasing risk with progressively elevated SBP and DBP
in patients with than without diabetes, and 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 regression analyses indicated signifi-
cant interaction between diabetes and both the awake
and asleep SBP/DBP means for patients displaying
values above these thresholds (p always < .023). Accord-
ingly, contrary to the conclusions of a recent report by
Sehestedt et al. (2011), these data document the synergic
relationship with CVDrisk between diabetes and increas-
ing BP above these thresholds (Hermida et al., 2013f).
Cox proportional-hazard regression analyses further
indicated that patients with diabetes reached an equiva-
lent HR of total CVD events at a 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 the values to the
nearest integer ending in 0 or 5, the outcome-based
ABPM reference thresholds in patients with 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, as
indicated in Table 3.
These ABPM thresholds are slightly lower than those
of a recent report by Cardoso et al. (2012) stating 125/
75 mmHg for the daytime and 110/65 mmHg for the
nighttime SBP/DBP means as optimal for patients with
diabetes. These later thresholds, however, derived from
patients with diabetes under hypertension treatment,
were calculated in relation to the likelihood of developing
microvascular complications, rather than upon actual
CVD events; in addition, these thresholds were offered
without comparison to corresponding ones for patients
without diabetes. Head et al. (2012) also proposed
lower ABPM-threshold values for patients with diabetes,
CKD, proteinuria, or previous CVD events, than for un-
complicated persons. The ABPM thresholds provided in
Table 3 are slightly lower than those suggested by Head
et al. (2012) for patients with diabetes, but similar to
those proposed by these authors for hypertensive
patients with proteinuria, although their cutoff values
are based on regression analyses of ambulatory on
clinic BP measurements as opposed to actual CVD out-
comes. In conclusion, outcome-based reference
thresholds for the diagnosis of hypertension are
reduced by 15/10 mmHg for ambulatory SBP/DBP in
high-risk patients, mainly those with diabetes and CKD.
8.3. Reference ABPM Thresholds in Pregnancy
Conventional clinic BP readings are neither diagnostic
nor sufficiently predictive of the development of
FIGURE 10. Sex- and time-specified 24-h 90%tolerance intervals
for SBP (top) and DBP (bottom) derived from a reference popu-
lation of normotensive men and women who were assessed by
48-h ABPM, for use in making the diagnosis of hypertension (BP
above the upper tolerance limit) and/or hypotension (BP below
the lower tolerance limit). Updated from Hermida et al. (2004d).
{;| R. C. Hermida et al.
Chronobiology International
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hypertension in pregnancy (Hermida & Ayala, 1997,
2002, 2004; Hermida et al., 1998, 2003a, 2004c; Peek
et al., 1996). The reported sensitivity and specificity of
clinic BP measurements vary greatly between studies,
with the sensitivity being as low as 9% (Ayala et al.,
1997a) and the positive predictive value being as low as
8% (Page & Christianson, 1976). Nonetheless, the diag-
nosis of gestational hypertension still relies on conven-
tional clinic BP measurements and constant threshold
values, i.e., 140/90 mmHg for SBP/DBP after 20 wks of
gestation in a previously normotensive woman (Brown
et al., 2001c; Davey & MacGillivray, 1988; Lindheimer
et al., 2008).
Many previous studies that have evaluated ABPM for
the diagnosis of hypertension in pregnancy (Bellomo
et al., 1999; Brown et al., 1998, 2001a, 2001b; Ferguson
et al., 1994; Halligan et al., 1993; Hermida & Ayala,
1997, 2005a; Higgins et al., 1997; Kyle et al., 1993; Margu-
lies et al., 1987; Penny et al., 1998; for an extensive review
see Ayala & Hermida, 2013) have found different
threshold reference values that only occasionally have
been tested prospectively (Bellomo et al., 1999;
Hermida & Ayala, 2005a). Moreover, there is still con-
siderable controversy regarding the comparative prog-
nostic value of the awake and asleep BP means for
prediction of complications in pregnancy (Brown et al.,
2001a, 2001b; Halligan et al., 1993; Kyle et al., 1993).
Hermida & Ayala (1997) performed a study on 113
pregnant women sampled for 48 h every 4 wks from the
first obstetric examination until delivery, thus providing
759 ABPM profiles in total. The purpose of this investi-
gation was to assess the sensitivity and specificity of the
48-h BP mean per trimester of pregnancy in identifying
hypertensive complications in pregnancy. This was
accomplished by comparing distributions of the 48-h
BP mean values of both healthy and complicated preg-
nancies, without assuming an a priori threshold for the
diagnosis of gestational hypertension based on mean
BP. Sensitivity ranged from32%for DBP in the second tri-
mester to 84% for SBP in the third trimester. Specificity,
however, was as low as 7% for DBP in the first trimester.
Results of this study revealed the threshold values that
would eventually provide the highest combined sensi-
tivity and specificity for the diagnosis of hypertension
in pregnancy are: 111/66 mmHg for the 48-h SBP/DBP
means during the first trimester of pregnancy, 110/65
mmHg during the second trimester, and 114/69 mmHg
during the third trimester. The corresponding threshold
values for each of the three trimesters of pregnancy
were 115/70, 115/69, and 118/72 mmHg for the awake
SBP/DBP means; and 99/58, 98/56, and 104/60 mmHg
for the asleep SBP/DBP means (Table 4 [Hermida &
Ayala, 1997]). These apparently low values, reflecting
the predictable changes in BP during gestation in normo-
tensive pregnant women (Ayala & Hermida, 1997b;
Hermida et al., 2001a) plus the expected diminished BP
in pregnant as compared to non-pregnant women
(Ayala & Hermida, 2013; Hermida & Ayala, 2004;
Hermida et al., 2001b, 2003a, 2004a), are fully equivalent
to those proposed by other independent investigators
(Halligan et al., 1993; OBrien et al., 2003) to define
normal ABPM values in pregnancy.
In the attempt to validate prospectively these
threshold reference limits, Hermida & Ayala (2005a) cal-
culated the sensitivity and specificity of the 48-h, awake,
and asleep BP means for the early identification of hyper-
tension in pregnancy in a study involving 403 (207 nulli-
parous) untreated pregnant women. Among them, 235
remained normotensive, 128 developed gestational
hypertension, and 40 developed preeclampsia. The
women were evaluated by 48-h ABPM at the time of
recruitment (usually within the first trimester of preg-
nancy), and then every 4 wks thereafter until delivery,
representing in total 2430 ABPM profiles. The use of
established thresholds tested prospectively revealed rela-
tively small overlap between healthy and complicated
pregnant women. Only 40 out of the 546 (7.3%) BP pro-
files representative of normotensive pregnant women in
the second trimester of gestation showed a 48-h SBP
mean >110 mmHg, while 362 out of the 412 (87.9%) pro-
files representative of those who later developed gesta-
tional hypertension or preeclampsia showed a 48-h SBP
mean above this threshold. Results were similar for the
awake SBP mean, although the overlap between the dis-
tributions of values of normotensive and hypertensive
women was slightly greater for the asleep SBP mean.
The results further indicated a slightly larger overlap of
BP mean values between these two groups during the
TABLE 4. Diagnostic threshold values for ABPM in mmHg for pregnant women as a function of gestational age
ABPM characteristic 1
st
trimester (<14 wks gestation) 2
nd
trimester (14-27 wks gestation) 3
rd
trimester (27 wks gestation)
Awake mean
SBP 115 115 118
DBP 70 69 72
Asleep mean
SBP 99 98 104
DBP 58 56 60
Alternatively, hypertension in pregnancy might be defined as a hyperbaric index (HBI) 15 mmHg X h independent of pregnancy stage.
The HBI is defined as the total area during the entire 24-h period of any given pregnant womans BP above a time-varying threshold defined
by a tolerance interval calculated as a function of gestational age and derived from a reference population of normotensive pregnant
women.
Guidelines for ambulatory blood pressure monitoring {;,
Informa Healthcare USA, Inc.
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first trimester, and a slightly smaller overlap of the data
sampled during the third trimester. Thus, the sensitivity
and specificity in the diagnosis of hypertension in preg-
nancy based on mean SBP values increased with gesta-
tional age. For the threshold values provided above
(Table 4), at all stages of pregnancy the sensitivity and
specificity of the DBP means were consistently lower
than they were for the SBP means (Hermida & Ayala,
2005a).
Some studies based solely on conventional office BP
measurements concluded that both maternal age and
parity exert significant effects on BP during pregnancy
(Christianson, 1976; Ness et al., 1993). These findings,
however, are controversial due to the lack of correlation
between parity and BP shown in other investigations
(Lee-Feldstein et al., 1980; Moutquin et al., 1982; Okono-
fua et al., 1992). Most important, data obtained from sys-
tematic ABPM studies of normotensive pregnant women
have indicated lack of differences in BP according to
parity (Ayala & Hermida, 2001; Hermida & Ayala,
2005b; Hermida et al., 2004b). Accordingly, the ABPM
threshold values proposed in Table 4 can be used for
the early identification of hypertension in pregnancy,
independent of maternal age and parity.
The sensitivity andspecificity of meanBPvalues for the
early identification of hypertension in pregnancy can be
improved by the use of other indexes also derived from
ABPM. In particular, the tolerance-hyperbaric test rep-
resents a reproducible, noninvasive, and highly sensitive
test for the early identification of subsequent hyperten-
sion in pregnancy, including preeclampsia (Hermida &
Ayala, 2002; Hermida et al., 1998, 2003a, 2004a).
Figure 11 shows the tolerance intervals for SBP (top)
and DBP (bottom) derived to include 90%of the reference
population of normotensive individuals with 90% confi-
dence. These tolerance intervals were obtained, first,
from data sampled by 48-h ABPM during the second tri-
mester of pregnancy in the reference group of 235 normo-
tensive pregnant women referred to above and, second,
froma reference population of 504 non-pregnant normo-
tensive women matched by age and, to the greatest extent
possible, other clinical characteristics (Ayala & Hermida,
2013). For both groups of pregnant and non-pregnant
normotensive women, the graphs in Figure 11 represent
the upper and lower limits of the tolerance interval with
reference to time during the 24 h, defined in terms of
hours after awakening from nighttime sleep. The upper
limit of the tolerance interval for both groups of women
is not only markedly <140/90 mmHg with reference to
office values, but also below the ABPM thresholds of
135/85 mmHg currently recommended for the diagnosis
of essential hypertension in both women and men based
on the awake SBP/DBP means (Chobanian et al., 2003;
Mancia et al., 2007a; Pickering et al., 2005). Moreover,
the values for the upper and lower limits of the tolerance
intervals represented in Figure 11 for pregnant women
sampled in their second trimester of gestation are mark-
edly lower than those obtained for clinically healthy
normotensive non-pregnant women also studied by
48-h ABPM. These time-specified threshold values
reflect the expected lower SBP and DBP in normotensive
pregnant women compared to non-pregnant women
(Ayala & Hermida, 2013; Hermida & Ayala, 2004;
Hermida et al., 2001b, 2003a, 2004a) as well as the circa-
dian pattern of BP variability previously demonstrated
in normotensive pregnant women during each trimester
of gestation (Ayala et al., 1997a; Benedetto et al., 1996;
Hermida et al., 2000a, 2003c; Miyamoto et al., 1998).
9. CLINICAL APPLICATIONS OF ABPM
Hypertension is a common chronic condition assumingly
affecting up to 40% of all adults. The actual prevalence of
individuals with hypertension, i.e., those at high CVD
risk, is unknown, as all current statistics are based on
unreliable clinic BP measurements. One needs to be
aware that the joint prevalence of masked normotension
and masked hypertension in the adult population as
defined here, i.e., by incorporating the asleep and not
only the awake SBP/DBP means for classification, is
>35% (Hermida et al., 2012a; Ros et al., 2013). Moreover,
with an estimated 30% prevalence of non-dipping within
the normotensive BP range (Hermida et al., 2002a), >20%
FIGURE 11. Circadian 90% tolerance intervals for SBP (top) and
DBP (bottom) derived from a reference population of 504 normo-
tensive non-pregnant women and an additional 235 normotensive
pregnant women assessed by 48-h ABPM in their second trimester
of pregnancy (14 to 27 wks gestation). Updated from Ayala &
Hermida (2013).
{; R. C. Hermida et al.
Chronobiology International
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of the population might be normotensive non-dippers
(Hermida et al., 2013e). Therefore, relying on clinic BP
measurements, or even at-home self-measurements, for
the identification of high-risk subjects as currently rec-
ommended (Chobanian et al., 2003; Mancia et al.,
2007a; Pickering et al., 2005), disregarding the vital infor-
mation pertaining to circadian BP patterning and the
asleep BP level, leads to potential misclassification of
up to 50% of all evaluated individuals. With these con-
siderations in mind, ABPM must be considered the
gold standard for the diagnosis of true hypertension
and the accurate assessment of CVD risk in the general
population. Nevertheless, due to the documented high
prevalence of blunted nighttime BP decline and associ-
ated elevated CVD risk, individuals with specific clinical
conditions must be given priority for ABPM evaluation.
These include, among others, those with secondary and
resistant hypertension, those who are elderly and
obese, and those diagnosed with diabetes, CKD, meta-
bolic syndrome (MS), or obstructive sleep apnea and
other sleep disorders.
9.1. Secondary Hypertension
One of the major advantages of identifying by ABPM the
rather simple pattern that describes the 24-h BP variation
is that departure from the normal dipper profile could
signify overt pathology. Alteration of the circadian
rhythm of the neurohumoral factors that affect the auto-
nomic nervous and cardiovascular systems, secondary to
various pathological conditions, results in persistent
change of the 24-h BP pattern (Fabbian et al., 2013;
Hermida et al., 2002a, 2007d; Portaluppi & Smolensky,
2007; Portaluppi et al., 1996, 2012; Smolensky et al.,
2007, 2012). A high prevalence of nocturnal hypertension
and/or reduced sleep-time relative BP decline (non-
dipping) or even asleep BP above the awake BP mean
(riser BP pattern) has been reported, apart from other
conditions described more extensively in the following
sections, in patients with orthostatic autonomic failure
(Mann et al., 1983), Shy-Drager syndrome (Martinelli
et al., 1981), vascular dementia (Tohgi et al., 1991), Alz-
heimer-type dementia (Otsuka et al., 1990), cerebral
atrophy (Tominaga et al., 1995), phaeochromocytoma
(Littler & Honour, 1979), autonomic neuropathy
(Cabezas-Cerrato et al., 2009; Cardoso et al., 2008;
Hornung et al., 1989; Ikeda et al., 1993; Monteagudo
et al., 1996; Schalekamp et al., 1985; Spallone et al.,
1993, 2001, 2007), cerebrovascular disease (Matsumura
et al., 1993; Sander & Klingelhfer, 1994; Shimada
et al., 1990, 1992; Stoica & Enulescu, 1983), ischemic ar-
terial disease after carotid endarterectomy (Asmar et al.,
1994), neurogenic hypertension (Franklin et al., 1986),
fatal familial insomnia (Portaluppi et al., 1994a, 1994b),
catecholamine-producing tumors (Dabrowska et al.,
1990; Imai et al., 1988a; Isshiki et al., 1986; Oishi et al.,
1988; Statius van Eps et al., 1994), Cushings syndrome
(Imai et al., 1988b), exogenous glucocorticoid adminis-
tration (Imai et al., 1989; van de Borne et al., 1993),
mineralocorticoid excess syndromes (Imai et al., 1992;
Veglio et al., 1993; White & Malchoff, 1992), Addisons
disease (Fallo et al., 1994), pseudohypoparathyroidism
(Brickman et al., 1990), normotensive and hypertensive
asthma (Franz et al., 1992), chronic renal failure
(Cottone et al., 1995; Del Rosso et al., 1994; Hayashi
et al., 1993; Heber et al., 1989; Imai et al., 1992;
Middeke et al., 1989, 1991; Portaluppi et al., 1990, 1991;
Rosansky, 1991; Timio et al., 1993, 1995; Torffvit &
Agardh, 1993), salt-sensitive essential hypertension (de
la Sierra et al., 1995; Uzu et al., 1996, 1999), essential hy-
pertension with left ventricular hypertrophy (Kuwajima
et al., 1992; Verdecchia et al., 1990) or albuminuria
(Opsahl et al., 1988), and with renal (Soergel et al.,
1992), liver (Taler et al., 1995; van de Borne et al.,
1993), and cardiac transplantation related to immuno-
suppressive treatment (Dart et al., 1992; Idema et al.,
1994a, 1994b; Reeves et al., 1986; Sehested et al., 1992;
van de Borne et al., 1992b), congestive heart failure
(Caruana et al., 1988; Portaluppi et al., 1992a; Suzuki
et al., 1992; van de Borne et al., 1992a), and recombinant
human erythropoietin therapy (van de Borne, 1992c). A
circadian profile characterized by daytime hypertension
and nighttime hypotension has been described in hemo-
dynamic brain infarction associated with prolonged dis-
turbance of the blood-brain barrier (Sander &
Klingelhofer, 1993). In these patients, the range of vari-
ation in BP between the awake and asleep BP means
was significantly increased from expected. The highly
prevalent altered 24-h BP variation in all these clinical
conditions indicates ABPM is the recommended gold
standard for the diagnosis and CVD risk assessment in
patients with suspected secondary hypertension.
9.2. Resistant Hypertension: Diagnostic and Treatment
Issues
Hypertension is currently defined as resistant to treat-
ment when a therapeutic plan that includes attention to
lifestyle measures and prescription of 3 hypertension
medications (ideally including a diuretic unless contrain-
dicated) in therapeutic doses fails to sufficiently lower
SBP and DBP (Calhoun et al., 2008; Chobanian et al.,
2003; Fagard, 2012; Mancia et al., 2007a). As defined,
resistant hypertension includes also patients with con-
trolled BP when treated with >3 medications, i.e., all
patients treated with 4 BP-lowering medications
should be considered resistant to treatment, irrespec-
tively of their BP. This definition, based on unreliable
clinic BP determinations, lacks relevant information
for the proper identification of patients truly resistant to
treatment. Therefore, below we propose a more appro-
priate and complete definition of resistant hypertension.
Patients with resistant hypertension are at a greater
risk for stroke, renal insufficiency, and CVD events than
are those for whom BP is responsive to and well con-
trolled by therapeutic interventions (Ayala et al., 2013a;
Calhoun et al., 2008; Cuspidi et al., 2001). The currently
accepted definition of resistant hypertension, presented
Guidelines for ambulatory blood pressure monitoring {;;
Informa Healthcare USA, Inc.
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above, relies solely on conventional daytime clinic BP
measurements. However, published reports document
the correlation between BP level and target organ
damage, CVD risk, and long-term prognosis is far
greater for ABPM than clinical BP measurements (Ayala
& Hermida, 2013; Clement et al., 2003; Dolan et al.,
2005; Eguchi et al., 2008; Hansen et al., 2007; Hermida
& Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,
2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;
Salles et al., 2008; Staessen et al., 1999; Verdecchia
et al., 1994). Additionally, recent findings (Ros et al.,
2013) reveal the classification of patients as isolated-
office, masked, and true resistant hypertension cannot
be based on the comparison of clinic and home BP
measurements or the awake BP mean derived from
ABPM, as is often the case in the available literature
that, based on misleading current guidelines, totally dis-
regards the highly significant prognostic value of the
nighttime BP (see Section 5).
Therapeutic strategies for resistant hypertension
currently include prescription of additional medications
or exchanging one medication for a new one in the
search for a potentially better synergistic combination
(Calhoun et al., 2008; Mancia et al., 2007a). Based on
the published literature, it is common for a large pro-
portion of hypertensive patients, including those with
resistant hypertension, to ingest all their hypertension
medications in the morning (de la Sierra et al., 2009,
2011; Hermida et al., 2002c, 2005b, 2008a, 2010c; Mux-
feldt et al., 2003; Salles et al., 2008). In resistant hyperten-
sion, however, shifting the ingestion of the complete daily
dose of one or more hypertension medications to
bedtime, as compared to the ingestion of all medications
upon-waking, has been prospectively shown by ABPM to
significantly improve BP control, in particular, to de-
crease the sleep-time BP and prevalence of non-
dipping (Hermida et al., 2008). Most important, recently
reported results pertaining to resistant hypertension
patients who participated in the MAPEC Study document
both significantly better ambulatory BP control and CVD
risk reduction in patients randomized to ingest the com-
plete daily dose of 1 hypertension medications at
bedtime than in those randomized to ingest all such
medications upon awakening (Ayala et al., 2013a;
Hermida et al., 2010b, 2013g).
Using 24-h ABPM, Muxfeldt et al. (2003) reported a
69% prevalence of non-dipping in resistant hypertension
patients who presumably ingested all medications in the
morning. In another much larger cross-sectional study,
Hermida et al. (2010c) assessed the impact of BP-lower-
ing treatment-time on 1794 resistant hypertension
patients evaluated by 48-h ABPM. The proportion of con-
trolled patients was significantly higher (31.9 vs. 23.1%;
p < .001) and the prevalence of non-dipping significantly
lower (40 vs. 83%; p < .001) among those who routinely
ingested the full daily dose of 1 hypertension medi-
cations at bedtime than in those who always ingested
all their medications upon awakening. More recently,
Hermida et al. (2013j) evaluated 2899 resistant hyperten-
sion patients enrolled in the on-going Hygia Project
(Ayala et al., 2013b; Crespo JJ et al., 2013; Mojn et al.,
2013; Moy et al., 2013; Ros et al., 2013); 1084 of them
were ingesting all their hypertension medications upon
awakening (awakening-regimen), 1436 were ingesting
the full daily dose of 1 of their medications at bedtime
(bedtime-regimen), and 379 were ingesting split equal
doses of 1 medications twice-daily, upon awakening
and at bedtime (BID-regimen). The sleep-time relative
SBP and DBP decline was significantly attenuated by
the awakening- and BID-therapy regimens (p < .001),
resulting in significantly higher prevalence of non-
dipping in these two treatment groups (80.5 and 77.3%,
respectively) than in the bedtime-regimen group
(54.4%; p < .001 between groups). Additionally, the
prevalence of the riser BP pattern, associated with
highest CVD risk, was much greater, 31.0 and 29.8%,
respectively, among patients of the upon-awakening
and BID-treatment regimens, compared to the
bedtime-treatment regimen (17.6%; p < .001 between
groups). Thus, in resistant hypertension, ingestion of
the same medications BID neither improves ambulatory
BP control nor reduces the prevalence of non-dipping;
thus, the BID-treatment regimen should be avoided.
Moreover, this treatment strategy cannot in anyway be
considered hypertension chronotherapy, i.e., the timing
of medications according to circadian rhythms to opti-
mize their desire effects and minimize or avoid comple-
tely their adverse effects.
Collectively, the findings of the above cited studies
indicate a bedtime hypertension medication regimen,
in conjunction with proper patient evaluation by ABPM
to corroborate the diagnosis of true resistant hyperten-
sion, should be the therapeutic scheme of choice for
patients who, by conventional cuff methods (and in the
absence of the application of ABPM) and an inappropri-
ate morning-treatment regimen, may have been mistak-
enly judged to be resistant to therapy. Finally, these
findings also indicate the definition of resistant hyper-
tension must be modified by taking treatment-time into
consideration; accordingly, a patient should be categor-
ized as resistant to treatment if the ABPM-determined
awake and/or asleep SBP or DBP means are greater
than the reference diagnostic thresholds (Table 3) when
ingesting 3 hypertension medications of different
classes (ideally including a diuretic unless contraindi-
cated), with at least one of them ingested as a full
daily dose at bedtime; patients with properly controlled
awake and asleep SBP/DBP means when treated with 4
medications are also resistant to treatment.
9.3 Elderly Patients
Several reports document the prognostic value of ABPM
in the elderly (Burr et al., 2008; Palmas et al., 2006,
2009; Staessen et al., 1999). Additionally, some studies
report a reduction in sleep-time relative BP decline
towards a more non-dipping pattern in elderly
{;8 R. C. Hermida et al.
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hypertensive patients, assumingly associated with the di-
minished production of vasoactive peptides, altered
endothelial function, sleep disturbances, and athero-
sclerosis, among other causes (Di Iorio et al., 1999; Man-
fredini et al., 1996a; OSullivan et al., 2003; Portaluppi
et al., 1992b, 1994b, 1996; Smolensky et al., 2007, 2012;
Trasforini et al., 1991). In fact, increasing age is an inde-
pendent marker of non-dipping, even after correction
for other significant confounders of reduced estimated
glomerular filtration rate, diabetes, reduced HDL-choles-
terol, and elevated urinary albumin excretion (Ayala et al.,
2013b). This correction is necessary because, compared
to younger hypertensives, elderly patients more fre-
quently have diagnoses of albuminuria, CKD, obstructive
sleepapnea, MS, anemia, and/or obesity, all conditions in
which non-dipping is more frequently observed
(Hermida et al., 2013a; Portaluppi et al., 1990; Smolensky
& Portaluppi, 1999; Smolensky et al., 2007, 2012). None-
theless, among the published studies the prevalence of
non-dipping in older patients is highly variable; thus, its
exact prevalence is uncertain.
Arecent cross-sectional study involved 6147 hyperten-
sive patients of diverse age evaluated by 48-h ABPM, with
2137 being 60 yrs of age (Hermida et al., 2013a). At the
time of ABPM, 1809 patients were newly diagnosed as
being hypertensive and were not yet under treatment,
2641 were diagnosed as being hypertensive and ingested
all their prescribed BP-lowering medications upon awa-
kening, and another 1697 such patients ingested the
full daily dose of 1 hypertension medications at
bedtime. The prevalence of non-dipping was signifi-
cantly higher in older than younger patients (63.1 vs.
41.1%; p < .001). However, the largest difference
between the age groups was in the prevalence of the
riser BP pattern, 19.9 vs. 4.9% in older and younger
patients, respectively (p < .001). The sleep-time relative
SBP decline was mainly unchanged until 40 yrs of
age, and then significantly and progressively decreased
with increasing age at the rate of .28%/yr (p < .001),
reaching a minimum SBP decline of 4.38 .47% (mean
SD) in patients 75 yrs of age. Treated compared to
untreated patients showed lower awake and asleep SBP
means, although the predictable changes of SBP and
DBP with age were equivalent in both groups. As a con-
sequence, there were no significant differences between
untreated and treated patients regarding changes with
age of the sleep-time relative SBP and DBP declines.
However, the asleep SBP and DBP means were signifi-
cantly lower (p < .001) and the sleep-time relative SBP
and DBP decline significantly greater (p < .001) at all
ages in patients ingesting 1 BP-lowering medications
at bedtime as compared to those ingesting all medi-
cations upon awakening (Hermida et al., 2013a).
In conclusion, this large cross-sectional study of
hypertensive patients evaluated by 48-h ABPM demon-
strated significantly increased prevalence of a blunted
nighttime BP decline with increasing age 40 yrs. The
prevalence of the riser BP pattern, associated with the
highest CVD risk among all other possible circadian BP
patterns, was four-fold more prevalent in patients 60
yrs of age than in ones <60 yrs. Indeed, an elevated
asleep BP mean was the major basis for making the diag-
nosis of hypertension and/or lack of adequate ambula-
tory BP control among older patients. Moreover,
patients of all ages who ingested 1 hypertension medi-
cations at bedtime in comparison to patients who
ingested all of them upon awakening had an attenuated
prevalence of blunted nighttime BP decline. Hence, the
proper therapeutic approach for elderly hypertensives
should not neglect differences in their treatment require-
ments, which includes the optimal time-of-day schedul-
ing of medications, as dictated by the specific features of
the individual 24-h BP pattern (Hermida et al., 2013c).
Collectively, these findings indicate elderly subjects, at
a threshold age even <60 yrs, should be evaluated by
ABPM to corroborate the diagnosis of hypertension,
ensure proper evaluation of CVD risk associated with
alterations of the 24-h BP pattern, and establish the
most appropriate timed therapeutic scheme to increase
CVD event-free survival (Hermida et al., 2010b, 2011b,
2011c, 2011d, 2013g).
9.4. Diabetes
There is strong association between diabetes and risk of
end-organ damage, stroke, and CVD morbidity and mor-
tality (American Diabetes Association, 2012). Blunted
sleep-time BP decline, characteristic of the non-dipping
pattern, is thought to be more common in patients with
than without diabetes (Afsar et al., 2007; Ayala et al.,
2013b; Chau et al., 1994; Cuspidi et al., 2006; Equiluz-
Bruck et al., 1996; Fogari et al., 1993; Ikeda et al., 1993;
Palmas et al., 2008; Pistrosch et al., 2007; Rutter et al.,
2000; Wiegman et al., 1990), and this, in turn, might
also be associated with the elevated CVD risk in diabetes.
Nonetheless, the prevalence of non-dipping in diabetes
is highly variable among the reported studies; thus, its
exact prevalence is uncertain. Among other factors, this
might be due to differences in the studied populations
(normotensive subjects, untreated hypertensives,
treated hypertensives), relatively small sample sizes, defi-
nition of daytime and nighttime periods by arbitrary fixed
clock-hour spans, and frequent reliance only on a single,
low-reproducible, 24-h ABPM evaluation per participant.
A recent cross-sectional study of 12 765 hypertensive
patients, including 2954 with type 2 diabetes, evaluated
by 48-h ABPM documented ambulatory SBP was signifi-
cantly higher in patients with than without diabetes,
mainly during the hours of nighttime sleep and initial
hours after morning awakening; ambulatory DBP,
however, was significantly lower in patients with dia-
betes, mainly during the hours of daytime activity
(Ayala et al., 2013b). Differing trends for SBP and DBP
between groups resulted in large differences in ambula-
tory PP, it being significantly greater (p < .001) through-
out the entire 24 h in patients with diabetes, even after
correcting for age. Age-independent elevated clinic and
Guidelines for ambulatory blood pressure monitoring {;
Informa Healthcare USA, Inc.
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ambulatory PP in patients with diabetes has been re-
ported in several previous studies, also documenting a
close relationship in diabetes between elevated PP and
increased CVD risk (Cockcroft et al., 2005; Foucan
et al., 2005; Nakano et al., 2005; Palmas et al., 2006;
Schram et al., 2002). Elevated PP, indicative of the stiff-
ness of the large arteries, has been identified as an inde-
pendent marker of CVD risk, mainly for myocardial
infarction, congestive heart failure, and CVD deaths
(Benetos et al., 1997; Blacher et al., 2000; Franklin et al.,
1999; Verdecchia et al., 1998, 2001). Furthermore, Ayala
et al. (2013b) found the prevalence of non-dipping to
be significantly higher in patients with than without dia-
betes (62.1 vs. 45.9%; p < .001). Largest difference
between groups was in the prevalence of the riser BP
pattern, 19.9 vs. 8.1% in patients with and without dia-
betes, respectively (p < .001). Elevated asleep SBP mean
was the major basis for the diagnosis of hypertension
and/or inadequate BP control among patients
with diabetes; thus, among the uncontrolled hyperten-
sive patients with diabetes, 89.2% exhibited
nocturnal hypertension.
Further evaluation of patients of the same study with
diabetes who were under treatment for their hyperten-
sion at the time when 48-h ABPM was performed
revealed, in addition, that those ingesting 1 medications
at bedtime versus those ingesting all medications upon
awakening had lower likelihood of CKD; had significantly
lower albumin/creatinine ratio, glucose, total cholesterol,
and LDL-cholesterol; plus had higher estimated glomer-
ular filtration rate and HDL-cholesterol (Moy et al.,
2013). Ingestion of 1 medications at bedtime was also
significantly associated with lower asleep SBP and DBP
means than treatment with all medications upon awak-
ening; thus, the sleep-time relative SBP and DBP
decline was significantly attenuated in patients ingesting
all BP-lowering medications upon awakening (p < .001).
As a result, the prevalence of non-dipping was signifi-
cantly higher when all hypertension medications were
ingested upon awakening (68.6%) than when 1 of
them were ingested at bedtime (55.8%; p < .001
between groups), and even further attenuated (49.7%)
when all of them were ingested at bedtime (p < .001).
Additionally, prevalence of the riser BP pattern was
much greater (23.6%) among patients ingesting all such
medications upon awakening, compared to those ingest-
ing some (20.0%) or all of them at bedtime (12.2%;
p < .001 between groups). The latter group also showed
significantly higher prevalence of properly controlled
ambulatory BP (p < .001) that was achieved by a signifi-
cantly lower number of hypertension medications
(p < .001) compared to patients ingesting all such medi-
cations upon awakening (Moy et al., 2013).
These findings are clinically relevant since non-
dipping is related to an increase in end-organ injury
and CVD events in patients with diabetes (Astrup et al.,
2007; Bouhanick et al., 2008; Eguchi et al., 2008;
Hermida et al., 2011b, 2012b; Nakano et al., 1998;
Sturrock et al., 2000). Furthermore, it has been recently
documented that the progressive reduction of the
asleep BP mean, a novel therapeutic target best achieved
by a bedtime hypertension therapeutic strategy (Hermida
& Smolensky, 2004; Hermida et al., 2005a, 2007a, 2010b,
2011a, 2013c; Portaluppi & Smolensky, 2010; Portaluppi
et al., 2012; Smolensky et al., 2010, 2012), is the most sig-
nificant predictor of CVD event-free survival (Ayala et al.,
2013a; Hermida et al., 2010b, 2011b, 2011c, 2011d,
2013b), particularly in patients with type 2 diabetes
(Hermida et al., 2012b). Thus, it is noteworthy that the
recent 2012 update of the standards of medical care in
diabetes and clinical practice recommendations from
the American Diabetes Association indicates the need
to administer one or more antihypertensive medications
at bedtime (level of evidence A) when treating hyperten-
sive patients with diabetes (American Diabetes Associ-
ation, 2012).
In summary, the asleep SBP mean is significantly
lower and the prevalence of a blunted nighttime BP
decline highly attenuated, i.e., lower prevalence of
markers of CVD risk, plus the metabolic profile is mark-
edly improved in patients with type 2 diabetes
managed by a therapeutic strategy that entails the inges-
tion of 1 of their hypertension medications at bedtime
than those managed by one that entails the ingestion of
all of them upon awakening. These collective findings
indicate bedtime hypertension treatment, in conjunction
with proper patient evaluation by ABPM to corroborate
the diagnosis of hypertension, should be the strategy of
choice for patients with type 2 diabetes.
9.5. Obesity and Metabolic Syndrome
The Third Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (ATP-III)
(Grundy et al., 2005) proposed a working definition of
MS based on the presence of at least three of the five fol-
lowing factors: elevated waist circumference (102 cm
men/ 88 cm women), elevated triglycerides (150 mg/
dl, or drug treatment for elevated triglycerides),
reduced HDL-cholesterol (<40 mg/dl men/ < 50 mg/dl
women, or drug treatment for HDL-cholesterol), elevated
clinic BP (SBP 130 mmHg and/or DBP 85 mmHg, or
BP-lowering treatment), and elevated fasting glucose
(100 mg/dl, or treatment for diabetes). These factors
have recently been adopted as a harmonizing definition
of MS in response to earlier discrepancies between
various international societies and organizations
(Alberti et al., 2009). Independent of the definition used
for MS, there is strong association between this condition
and increased risk of coronary heart disease, stroke, and
CVD morbidity and mortality (Isomaa et al., 2001; Nino-
miya et al., 2004; Ridker et al., 2003; Sattar et al., 2003;
Schillaci et al., 2004). Moreover, the individual attributes
of MS listed above are associated with markers of organ
damage, including left ventricular hypertrophy, diastolic
dysfunction, and albuminuria (Cuspidi et al., 2004a; Lind
{8o R. C. Hermida et al.
Chronobiology International
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et al., 1995; Masugata et al., 2006; Palaniappan et al.,
2003; Schillaci et al., 2006).
Although a blunted sleep-time BP decline is highly
prevalent in diabetes (Ayala et al., 2013b), the association
between MS and non-dipper BP patterning seems con-
troversial (Ayala et al., 2009; Bastos et al., 2007; Cuspidi
et al., 2004b, 2005; Foss et al., 2000; Hermida et al.,
2009b, 2011e; Mancia et al., 2007b; Tartan et al., 2006;
Vyssoulis et al., 2007). For instance, Cuspidi et al.
(2004b, 2005) found no significant difference in noctur-
nal BP, assessed by two consecutive 24-h ABPM sessions,
in untreated hypertensive MS patients compared to those
without MS. In contrast, Tartan et al. (2006) documented
significant elevation in nighttime SBP in hypertensive
patients with high MS score, based on numeric grading
of the different factors comprising the ATP-III definition
given above; this score was also an independent predictor
of the non-dipper BP pattern. Corroborating previous
findings on the impact of obesity on impaired circadian
BP regulation (Kotsis et al., 2005), abdominal obesity
was also a significant influential factor for the progressive
decrease in sleep-time relative SBP decline (Tartan et al.,
2006). Vyssoulis et al. (2007) also found elevated preva-
lence of non-dipping in a large group of untreated hyper-
tensive MS patients, the prevalence being directly related
to the number of the defining components of MS ident-
ified per patient. However, the relative influence of each
single component upon the absence of proper nocturnal
BP decline was not explored. Ayala et al. (2009) investi-
gated the circadian BP pattern of 2045 non-diabetic
untreated patients with uncomplicated essential hyperten-
sion simultaneously evaluated by 48-h ABPMand wrist act-
igraphy. Those with MS, 40.7% of the patients, were
characterized by a significantly higher 48-h SBP mean and
a lower DBPmeanas comparedtopatients without MS. Ac-
cordingly, in the MS versus the non-MS patients, ambula-
tory PP was significantly elevated during the entire 24 h.
The prevalence of an altered non-dipper BP profile was
also significantly higher in MS than non-MS patients (48.4
vs. 36.1%, p < .001). MS patients were also characterized by
significantly higher concentrations of uric acid, fibrinogen,
and hemoglobin as well as leukocyte count and erythrocyte
sedimentation rate, and by a lower estimated glomerular fil-
tration rate, all relevant markers of increased CVD risk.
A recent cross-sectional study of 3352 non-diabetic
hypertensive patients evaluated by 48-h ABPM and
wrist actigraphy (Hermida et al., 2011e) investigated the
relationship between MS, circadian time of hypertension
treatment, and impaired nighttime BP decline. MS was
present in 52.6% of the treated hypertensives. The preva-
lence of an altered non-dipper BP profile was signifi-
cantly higher among patients with than without MS
(52.0 vs. 39.5%; p < .001). Of particular relevance was
the finding that non-dipping was significantly more
prevalent among patients ingesting all BP-lowering
medications upon awakening (56.8%) than among
those ingesting 1 of their medications at bedtime
(29.1%; p < .001). Finally, non-dipping was found to
be significantly associated with the presence of MS and
treatment upon awakening in a multiple logistic
regression model adjusted by significant confounding
factors, including age, creatinine, erythrocyte sedimen-
tation rate, and cigarette smoking (Hermida et al., 2011e).
In summary, the results of recent large studies indicate
significantly increased prevalence of non-dipping and
additional markers of CVD risk in patients with MS
and/or abdominal obesity. Bedtime treatment with 1
hypertension medications is significantly associated
with an attenuated prevalence of the high-risk non-
dipper BP profile, both in patients with and without
MS. These collective findings indicate MS and abdominal
obesity must be included among the medical conditions
for which ABPM is recommended to make the diagnosis
of hypertension, accurately evaluate CVD risk, and deter-
mine the most advantageous therapeutic scheme, the
preference being a bedtime dosing strategy.
9.6. Chronic Kidney Disease (CKD)
Hypertension is very common in patients with CKD; its
prevalence increases with diminished glomerular fil-
tration rate (GFR), reaching an estimated 86% in patients
with end-stage renal disease (Agarwal et al., 2003). On the
other hand, hypertension leads to kidney and other
target-organ damage through mechanical and oxidative
stress on the vascular wall (Portaluppi et al., 2004). The
diagnosis of hypertension in CKD as well as clinical
decisions regarding treatment of this modifiable con-
dition has been made so far using daytime clinic BP
measurements obtained in the physicians office. Even
in the most recent guidelines on hypertension in CKD,
no proper attention is given to the diagnostic and prog-
nostic relevance of ABPM (Kidney Disease, 2012).
However, as in the general population, in patients with
CKD the correlation between BP level and target organ
damage, CVD risk, and long-term prognosis is greater
for ABPM than clinic BP (Agarwal & Andersen, 2006a,
2006b; Hermida et al., 2011d; Minutolo et al., 2011;
Tripepi et al., 2005). In addition, there is a strong associ-
ation between blunted sleep-time relative BP decline and
increased incidence of fatal and non-fatal CVD events in
patients with CKD (Agarwal & Andersen, 2006a, 2006b;
Amar et al., 2000; Hermida et al., 2011d; Liu et al.,
2003; Minutolo et al., 2011; Tripepi et al., 2005). Most
important, from a therapeutic point of view, are the find-
ings of the recent evaluation of a cohort of patients with
CKD (Hermida et al., 2011d) from the MAPEC Study
(Ayala et al., 2013a; Hermida, 2007; Hermida et al.,
2010b, 2011b, 2011c, 2012a, 2012b, 2013b, 2013e,
2013g) that enabled investigation of whether CVD risk
reduction is more related to the progressive decrease
during follow-up of the awake or asleep BP mean. Anal-
yses of changes in BP during the median 5.4 yrs follow-
up revealed 14% CVD risk reduction per 5 mmHg
decrease in the asleep SBP mean (p < .001), independent
of changes in clinic BP or any other ambulatory BP
parameter (Hermida et al., 2011d).
Guidelines for ambulatory blood pressure monitoring {8+
Informa Healthcare USA, Inc.
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Non-dipping is highly prevalent in patients with CKD
(Agarwal & Andersen, 2005; Agarwal et al., 2009; Crespo
JJ et al., 2013; Davidson et al., 2006; Mojn et al., 2013;
Pogue et al., 2009; Portaluppi et al., 1990), although the
reported prevalence of non-dipping in CKD is highly
variable. Such variability is probably due to relatively
small sample sizes; differences in the diagnosis of CKD
based in some studies on reduced GFR, only, without
accounting for elevated urinary albumin excretion; differ-
ences in the studied populations according to stage
(severity) of CKD; reliance only on a single, low-
reproducible, 24-h ABPM evaluation per participant;
and definition of daytime and nighttime periods by
arbitrary fixed clock-hour spans. Davidson et al. (2006)
reported 57.5% prevalence of non-dipping in a retrospec-
tive cohort study of 322 patients but without specification
of the exact prevalence of non-dipping among those with
CKD. Pogue et al. (2009) conducted a cross-sectional
24-h ABPM study of 617 participants with CKD,
only defined on the basis of reduced GFR, in the
African American Study of Kidney Disease Cohort
Study (AASK), finding very high 80.7% prevalence of
non-dipping. Agarwal & Andersen (2005) evaluated
232 elderly patients with CKD, determining the
prevalence of non-dipping increased from 60.0% in
patients with stage 2 CKD, to 80.3%, 71.9%, and 71.4%
in patients with stage 3, 4, and 5 CKD, respectively
(p = .046).
Mojn et al. (2013) recently assessed by 48-h ABPM
the circadian BP pattern of 10 271 hypertensive patients
enrolled in the Hygia Project. Among the participants,
3227 had CKD, defined as an estimated GFR <60 ml/
min/1.73 m
2
, albuminuria (urinary albumin excretion
30 mg/24-h urine, or albumin/creatinine ratio 30
mg/gCr), or both, at least twice within 3 mo (Levey
et al., 2005, 2009; National Kidney Foundation, 2002).
In patients with CKD, ambulatory SBP was significantly
elevated (p < .001), mainly during the hours of nighttime
sleep, independent of the presence/absence of BP-lower-
ing treatment; ambulatory DBP, however, was signifi-
cantly higher (p < .001), mainly during the daytime.
Differing trends for SBP and DBP between groups re-
sulted in large differences in ambulatory PP, it being sig-
nificantly greater (p < .001) throughout the entire 24 h in
patients with CKD. The prevalence of non-dipping was
significantly higher in patients with than without CKD
(60.6 vs. 43.2%; p < .001), but the largest difference
between groups was in the prevalence of the riser BP
pattern, 17.6 versus 7.1% in patients with and without
CKD, respectively (p < .001). The riser BP pattern signifi-
cantly and progressively increased from 8.1% among
patients with stage 1 CKD to a very high 34.9% for those
with stage 5 CKD. An elevated asleep SBP mean was
the major basis for the diagnosis of hypertension and/
or inadequate BP control among patients with CKD;
thus, among the uncontrolled hypertensive patients
with CKD, 90.7% exhibited nocturnal hypertension
(Mojn et al., 2013).
Furthermore, analyses of treated hypertensive patients
with CKD revealed ingestion of 1 medications at
bedtime was significantly associated with lower asleep
SBP/DBP means than treatment with all medications
upon awakening (Crespo JJ et al., 2013). The sleep-time
relative SBP decline was significantly attenuated in
patients who ingested all their hypertension medications
upon awakening (p < .001). Thus, the prevalence of non-
dipping was significantly greater when all medications
were ingested upon awakening (68.3%) than when the
entire daily dose of 1 of them was ingested at bedtime
(54.2%; p < .001 between groups), and even further atten-
uated (47.9%) when all of them were ingested at bedtime
(p < .001). Additionally, the prevalence of the riser BP
pattern was much greater (21.5%) among patients ingest-
ing all their BP-lowering medications upon awakening,
compared to those ingesting some (15.7%) or all of
them at bedtime (10.6%; p < .001 between groups), inde-
pendent of CKD severity. Patients of the latter treatment-
regimen group also showed a significantly higher preva-
lence of properly controlled ambulatory BP (p < .001)
that was achieved by a significantly lower number of
hypertension medications (p < .001) compared to those
ingesting all of their hypertension medications upon
awakening (Crespo JJ et al., 2013).
In conclusion, patients with CKD show a significantly
elevated prevalence of blunted nocturnal BP decline.
Most important, the riser BP pattern is 2.5-fold more
prevalent in CKD, and up to 5-fold more prevalent in
end-stage renal disease. Patients with CKD also show sig-
nificantly elevated ambulatory PP, reflecting increased
arterial stiffness and, thus, enhanced CVD risk. Further-
more, patients with CKD who ingest 1 hypertension
medications at bedtime, as compared to those who
ingest all of them upon awakening, show significantly
lower asleep SBP/DBP means and attenuated prevalence
of non-dipping, i.e., lower prevalence of these markers of
CVD risk. Collectively, these findings indicate CKD must
be included among the clinical conditions for which
ABPM is recommended for the accurate diagnosis of hy-
pertension and assessment of CVD risk, as well as the
means to establish the optimal therapeutic scheme to in-
crease CVD event-free survival. In keeping with the
current available information, bedtime hypertension
treatment should be the preferred therapeutic scheme
for hypertensive patients with CKD.
9.7. Obstructive Sleep Apnea and Other Sleep Disorders
Obstructive sleep apnea is a common condition that fre-
quently goes undiagnosed (Lugaresi et al., 1983; Pack,
1994), either because patients are asymptomatic during
the daytime (only severe, symptomatic, sleep apnea is
easily detected during clinical visits) or because they
simply do not present themselves to a physician.
Apneic snoring through frequent arousals and enhanced
sympathetic hyperactivity disrupts sleep architecture and
also induces a non-dipper BP pattern (Pedulla et al.,
1995; Portaluppi et al., 1997); thus, undiagnosed sleep-
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disordered breathing might play a role in the genesis of
the altered BP pattern of some non-dipper hypertensives.
This is especially true for male patients, since snoring and
apnea are much more prevalent among men than
women (Lugaresi et al., 1994; Young et al., 1993). Essen-
tial hypertension is also a very frequent condition in
patients with sleep apnea. Therefore, ABPM is rec-
ommended for the accurate diagnosis of hypertension
and assessment of CVD risk in all individuals with sus-
pected or confirmed sleep disorders.
The non-dipper BP pattern appears to be associated
strictly with sleep-disordered breathing that is character-
ized by apneic snoring, whereas nonapneic snoring is
associated with only minor increase in BP variability
(Portaluppi et al., 1997). Unfortunately, a blunted noctur-
nal BP fall is a highly unspecific finding (see Section 4.1);
accordingly, ABPM is of limited value for making the di-
agnosis of obstructive sleep apnea even when
accompanied by measurement of activity level by wrist
actigraphy during nighttime sleep, which can provide
an estimate (albeit a non-specific one since an altered
nighttime activity level might possibly be indicative of
other sleep disturbances) of the number of apneas with
fairly good approximation (Sadeh et al., 1989). Thus,
the gold standard to achieve the diagnosis of apneic
snoring and assess its severity remains polysomnogra-
phy, during which incorporated continuous measure-
ments of BP with a fully automated instrument is
preferred to discontinuous ABPM. In fact, only polysom-
nography can derive complete and simultaneous infor-
mation about breathing events, BP changes, and sleep
architecture, thus permitting differentiation of non-
dippers with actual abnormalities in sleep-related BP
changes from subjects whose non-dipper condition
may be related to other anomalies of entirely different
pathophysiologic origin, e.g., restless leg syndrome, per-
iodic limb movements, or even simple insomnia, some-
times induced by the monitoring procedure, itself
(Portaluppi et al., 2009). Moreover, snoring and non-
severe sleep apnea constitute phenomena that vary not
only from minute to minute but also from night to
night, depending on the lifestyle of the patient and
body position during sleep. Hence, discontinuous
ABPM measurements might not be fully representative
of all the transient changes in BP occurring during the
night in these patients. Instead, a single session of poly-
somnography with continuous BP recording detects
even transient anomalies of breathing and BP that are
present even in mild cases. Thus, in addition to clearly
differentiating sleep apnea from other sleep-related dis-
eases, polysomnography also reveals which patients are
at risk of developing more severe sleep-disordered
breathing and sustained nocturnal hypertension. In any
case, in view of the expected higher target-organ
damage and increased CVD risk in non-dippers and the
high prevalence in the adult population of undiagnosed
disordered breathing during sleep, we recommend as-
sessment of the subjects sleep history as part of the
routine diagnostic screening of hypertension, especially
when non-dipping is found by ABPM evaluation. When
the patients sleep history suggests significant sleep dis-
turbance, polysomnography is the appropriate sub-
sequent diagnostic step.
9.8. Pregnancy
Predictable differences in the 24-h BP pattern throughout
gestation have been identified by means of ABPM in both
clinically healthy and hypertensive pregnant women
(Ayala & Hermida, 2013). In normotensive pregnancies,
BP steadily decreases up to the middle of gestation and
then increases up to the day of delivery. In contrast,
women who develop gestational hypertension or pre-
eclampsia show a stable BP during the first half of preg-
nancy and thereafter a continuous linear BP increase
until delivery (Ayala & Hermida, 1997b; Hermida et al.,
2001a). Epidemiologic studies have also consistently re-
ported sex differences in the 24-h pattern of ambulatory
BP and heart rate (Ben-Dov et al., 2008; Burt et al.,
1995; Hermida, 1999; Hermida et al., 2002a, 2002d,
2004d; Kagan et al., 2007; Pimenta, 2012; Reckelhoff,
2001; Roger et al., 2011; Vriz et al., 1997). Typically,
men exhibit a lower heart rate and higher BP than
women, the differences being larger for SBP than DBP
(Figure 9). Additionally, as early as in the first trimester
of gestation, statistically significant increased 24-h,
awake, and asleep SBP and DBP means characterize
women who during their pregnancy will be complicated
with gestational hypertension or preeclampsia compared
to those with normal and uncomplicated pregnancies
(Ayala et al., 1997a; Benedetto et al., 1996; Hermida
et al., 2000a, 2003c). However, the normally lower BP in
non-gravid women as compared to men, additional de-
crease in BP during the second trimester of gestation in
normotensive but not hypertensive pregnant women,
and significant differences in the 24-h BP pattern
between healthy and complicated pregnancies at all
gestational ages have yet to be taken into consideration
when establishing reference BP thresholds for the diag-
nosis of hypertension in pregnancy.
Despite the unquestionably high prognostic value of
ABPM as compared to conventional clinic BP measure-
ments for the prediction of pregnancy outcome, due to
poor results from the awkward approach used by many
investigators in their attempt to identify by ABPM women
who might or might not show elevated clinic BP later in
pregnancy, the most extended conclusion in the obstetric
fieldsofar isthat ABPMdoes not enable earlyidentification
of gestational hypertensionor preeclampsiaand, therefore,
should not be used in pregnancy (Higgins et al., 1997).
As discussed previously (Section 8.3), the sensitivity
and specificity of the early identification of hypertension
in pregnancy based on the awake and asleep SBP/DBP
threshold values provided in Table 4 can be improved
by the use of other indices also derived from ABPM. In
particular, the tolerance-hyperbaric test has been pro-
spectively shown to be a reproducible, non-invasive,
Guidelines for ambulatory blood pressure monitoring {8{
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and highly sensitive test for the early identification of sub-
sequent hypertension in pregnancy, including pre-
eclampsia (Hermida & Ayala, 2002; Hermida et al.,
1998, 2003a, 2004a). ABPM during gestation, commen-
cing preferably at the time of the first obstetric examin-
ation following positive confirmation of pregnancy, thus
provides sensitive endpoints for early hypertension-
related risk assessment and guidance of prophylactic
and/or therapeutic intervention. Among these, low-
dose aspirin (100 mg/d) ingested regularly at bedtime,
but not upon awakening, commencing before 16 wks of
gestation has been shown to efficiently control elevated
gestational ambulatory BP and to significantly reduce
the incidence of preeclampsia, gestational hypertension,
intrauterine growth retardation, and preterm delivery
(Ayala et al., 2013c; Hermida et al., 1997a, 1999, 2003b).
Accordingly, ABPM properly executed and analyzed
using the tolerance-hyperbaric test is the recommended
replacement for unreliable clinic BP measurements;
thus, ABPM should be considered as the gold standard
for the diagnosis of hypertension in pregnancy and the
screening of pregnant women at high risk for other com-
plications during gestation, such as preeclampsia, fetal
growth retardation, and preterm delivery.
9.9. Evaluation of Treatment Efficacy
As indicated previously, ABPM is particularly useful for
defining the efficacy of hypertension medications, in
individual patients (Waeber & Brunner, 1999) and also
populations of patients taking part in clinical trials
(Coats et al., 1996), especially with respect to the admin-
istration-time, i.e., awakening versus bedtime, treatment
regimen as a cost-effective means of improving the man-
agement of CVD risk (Hermida, 2007; Hermida & Smo-
lensky, 2004; Hermida et al., 2005a, 2007a, 2008a,
2010b, 2011a, 2011b, 2011d, 2013c; Portaluppi &
Hermida, 2007; Portaluppi & Smolensky, 2010; Portalup-
pi et al., 2012; Smolensky et al., 2010, 2012).
Several methods are traditionally used to assess the
duration of action of BP-lowering medications. Most of
them aim to quantify the efficacy of the medications in
terms of the duration and homogeneity of their BP-low-
ering effect (Aboy et al., 2005). The prevailing contention
today is the optimal control and management of BP
should be based upon therapeutic strategies that
reduce BP in a homogeneous and smooth manner
throughout the entire 24 h. The trough:peak ratio (TP)
and smoothness index (SI) are two popular indices that
have been used for over two decades to evaluate hyper-
tension medications and also as the basis for their, some-
times misleading, marketing campaigns to doctors and
patients (Elliot & Meredith, 1994; Meredith, 1999;
Omboni et al., 1995, 1998; Parati et al., 1998). However,
in the case of the TP ratio, the use of different methods
of its calculation has resulted in inconsistencies and dis-
crepancies in reported values, thereby calling into ques-
tion the validity of this index such that its use is not
currently recommended (Aboy et al., 2005). The main
limitation of the SI is its interpretation. A medication
having negligible and poor BP control, but, nonetheless,
having a highly homogeneous BP-lowering effect during
the 24-h dosing interval will have a very large SI. Thus, for
this and other reasons discussed below, the SI is not a
useful index to guide the selection of medications to
manage hypertension patients. To overcome this
problem, some years ago Aboy et al. (2005) proposed a
new so-called normalized smoothness index (SI). In
addition, Aboy et al. (2006a, 2006b) proposed a novel
index for the proper statistical assessment of hyperten-
sion medications, both for application to the individual
patient as well as participants of clinical trials, based
upon the reduction, duration, and homogeneity, i.e.,
RDH index, of BP-lowering. The advantages of the RDH
index over the TP, SI, and normalized SI have been
clearly documented (Aboy et al., 2006a, 2006b).
Accordingly, the RDH index is recommended for the
evaluation of treatment efficacy of hypertension medi-
cations assessed by ABPM.
International practice guidelines recommend pre-
scription of long-acting, once-daily hypertension medi-
cations that have 24-h efficacy (Mancia et al., 2007); this
recommendation is based on the assumptions these
medications improve adherence to therapy, minimize
BP variability, and provide smoother and more consistent
BP control. As reported in the published literature (see in
particular: de la Sierra et al., 2009; Hermida et al., 2002c)
in the absence of individual patient evaluation by ABPM,
practicing physicians are prone to treat all hypertensive
patients by a common strategy involving morning-time
dosing of once-a-day, long-acting BP-lowering medi-
cations. However, morning-time ingestion of a hyperten-
sion medication with high 24-h homogeneous and
sustained efficacy is unlikely to correct abnormalities of
the 24-h BP profile; thus, from our perspective this con-
stitutes a rationale therapeutic plan only, if any, for
dipper hypertensive patients. Taking into consideration
the facts that not all marketed BP-lowering medications
provide entirely homogeneous and complete 24-h effi-
cacy and that there exists high prevalence of the non-
dipper BP pattern in the population (Ayala et al., 2013b;
Crespo JJ et al., 2013; Hermida et al., 2013j; Mojn
et al., 2013; Moy et al., 2013; Ros et al., 2013), the clini-
cal practice of treating all hypertensive patients at the
same time of day, by means of a morning once-a-day
therapeutic strategy, necessitates reconsideration.
The graph presented on the left side of Figure 12 rep-
resents the SBP pattern (continuous thick line) of a
normotensive man whose measurements are plotted
relative to the circadian time-specified tolerance limits
(continuous thin lines) calculated from the data of a ref-
erence population of normotensive individuals (Hermida
et al., 2004d), as a function of the persons sex and rest-
activity cycle (time expressed in hours after awakening).
The dark bar displayed on the lower horizontal axis indi-
cates the nighttime sleep span for this person, as deter-
mined by wrist actigraphy. The graph shows that SBP is
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within the normotensive range delimited by the upper
and lower tolerance limits throughout the 24 h, corrobor-
ating the diagnosis of normotension. The awake and
asleep SBP means are also below the reference
thresholds provided in Table 3 for the diagnosis of
hypertension in uncomplicated men. The sleep-time
relative SBP decline of 17% indicates the individual has
a normal dipper 24-h BP pattern.
The graph shown on the right side of Figure 12 rep-
resents the SBP data (dashed thick line) of a different
man. The awake/asleep SBP means of 155/126 mmHg
are both above the corresponding reference threshold
values for the diagnosis of hypertension. The sleep-
time relative SBP decline is 18.5%, indicating he has a
normal dipper 24-h BP pattern. The shadowed area
delimited by the upper tolerance limit with regard to
the 24-h SBP profile of this individual represents the
area of BP excess, i.e., HBI, which is 305 mmHg X h,
well above the threshold for the diagnosis hypertension
presented in Table 3 (Hermida et al., 2000b). For com-
parative purposes, the graph also includes the 24-h SBP
pattern of the normotensive man shown on the left side
of Figure 12 (continuous thick line). Visual inspection
of the graph on the right side of Figure 12 indicates that
normalizing the BP of the hypertensive dipper patient
to the usual ideal pattern of normotensive dipper sub-
jects requires lowering of BP homogeneously, in the
same amount, throughout the entire 24 h, as the patients
BP is consistently elevated throughout the day and night
to a similar extent above the upper limit of the time-
varying tolerance limit.
Figure 13 represents two different hypertensive
patients with a non-dipper BP pattern. The data of the
patient presented on the left side reveal awake/asleep
FIGURE 12. Left: 24-h SBP pattern (thick line) of a normotensive dipper man, plotted with respect to circadian time-specified tolerance
limits (continuous thin lines), calculated froma reference population of normotensive individuals as a function of sex and rest-activity cycle.
Right: 24-h SBP pattern (dashed thick line) of a hypertensive dipper man, plotted with respect to the circadian time-specified tolerance
limits (continuous thin lines) of the same reference population of normotensive individuals. The shadowed area that is delimited by the
upper tolerance limit and the BP profile of this individual represents the area of BP excess (hyperbaric index). For comparative purposes,
the graph also includes the SBP pattern of the normotensive man shown in the left panel (continuous thick line).
FIGURE 13. 24-h SBP pattern (dashed thick lines) of two hypertensive non-dipper male patients, plotted with respect to circadian time-
specified tolerance limits (continuous thin lines), calculated from a reference population of normotensive individuals as a function of sex
and rest-activity cycle. The shadowed areas delimited by the upper tolerance limit and the BP profiles of these individuals represent the area
of BP excess (hyperbaric index). For comparative purposes, the graphs also include the SBP pattern of the normotensive man shown in the
left panel of Figure 12 (continuous thick line).
Guidelines for ambulatory blood pressure monitoring {8,
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SBP means of 143/134 mmHg, sleep-time relative SBP
decline of 6.1%, and BP elevation above the upper refer-
ence limit equal to 94% of the 24-h activity-rest span.
Normalizing BP to the level and pattern of normoten-
sive dipper persons would require reduction of BP
throughout the 24 h, but to a different extent during
the daytime activity versus nighttime sleep spans in
keeping with the marked non-dipper BP baseline
profile. The data of the patient shown on the right
side of Figure 13 reveal awake/asleep SBP means of
131/129 mmHg, indicating isolated nocturnal hyperten-
sion; sleep-time relative SBP decline of 1.7%, corre-
sponding to non-dipper 24-h BP patterning; and BP
excess mainly during the nighttime sleep period.
While this patient is also a hypertensive non-dipper,
like the one whose data are shown in the left side of
Figure 13, BP control in this case would require reduc-
ing BP only during nighttime sleep, as his awake BP
mean is already within normal limits. Interestingly,
the diagnosis of hypertension for this patient would
probably not be established by relying on daytime
clinic BP determinations, alone, or with supplemental
at-home self-assessments, since for most of his activity
span he is normotensive.
The graph on the left side of Figure 14 shows the 24-h
SBP pattern of yet another male patient with awake/
asleep SBP means of 148/112 mmHg and sleep-time
relative SBP decline of 24%, which means he is an
extreme-dipper with isolated daytime hypertension.
Ambulatory BP control would require efficient treatment
of the awake BP level, only, as shown by comparing the
patients BP profile (dashed thick line) with that derived
for the reference normotensive man whose data are
shown on the left side of Figure 12 (continuous thick
line). However, one must keep in mind the therapeutic
goal of preserving/increasing towards normal the sleep-
time relative BP decline to minimize CVD risk.
Finally, the data of the male patient presented on the
right side of Figure 14 reveals awake/asleep SBP means
of 140/150 mmHg and sleep-time relative SBP decline
of -7% indicating he has a riser BP pattern. Proper man-
agement of this patient entails reduction of BP to the
normotensive range plus restructuring of the 24-h
profile to the desired dipper pattern by means of a thera-
peutic strategy (e.g., bedtime medication regimen) that
attenuates the asleep BP mean to a much greater extent
than the awake BP mean.
Collectively, the different cases of hypertensive
patients presented in Figures 12-14 constitute all possible
24-h BP patterns in terms of the sleep-time relative SBP
decline, a significant prognostic marker of the risk of
CVD events (Agarwal & Andersen, 2006a, 2006b; Astrup
et al., 2007; Ayala et al., 2013a; Boggia et al., 2007;
Bouhanick et al., 2008; Brotman et al., 2008; Burr et al.,
2008; Dolan et al., 2005; Eguchi et al., 2008; Hermida
et al., 2011b, 2011c, 2011d, 2013b, 2012b; Ingelsson
et al., 2006; Kario et al., 2001; Liu et al., 2003; Minutolo
et al., 2011; Nakano et al., 1998; Ohkubo et al., 2002;
Salles et al., 2008; Sturrock et al., 2000; Tripepi et al.,
2005; Verdecchia et al., 1994). Recognition of the prog-
nostic value of the sleep-time relative SBP decline and
the asleep SBP mean (Hermida et al., 2011c) highlights
the limitations and deficiencies of clinic BP measurment
as a valid diagnostic procedure. Moreover, it calls into
question the use of clinic BP, at-home self-measurments,
and even the ABPM-derived 24-h BP mean as a reliable
measure of the efficacy of BP-lowering medications. By
considering the regulation (i.e., normalization) of the
24-h BP pattern as a worthy therapeutic target as a
means of reducing CVD risk (Hermida et al., 2011c), it
should be obvious (Figures 12-14) that one cannot rec-
ommend the same hypertension medication, in the
same dose, and at the same, usually morning, time of
day as the optimal unique therapeutic strategy for all
FIGURE 14. 24-h SBP pattern (dashed thick lines) of a hypertensive extreme-dipper male patient (left) and a male hypertensive riser
patient (right), plotted with respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference popu-
lation of normotensive individuals as a function of sex and rest-activity cycle. The shadowed areas delimited by the upper tolerance limit
and the BP profiles of these individuals represent the area of BP excess (hyperbaric index). For comparative purposes, the graphs also
include the SBP pattern of the normotensive man shown in the left panel of Figure 12 (continuous thick line).
{8 R. C. Hermida et al.
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hypertensive patients. Indeed, the examples presented in
Figures 12-14 illustrate the rationale for the use in adult
patients of ABPM to correctly diagnose hypertension,
devise optimal treatment regimen, and assess attainment
of desired therapeutic goals.
In hypertensive patients, pharmacologic therapy
should take into account the seldom considered, yet
crucial, variable of treatment-time (with respect to the
rest-activity pattern of each individual patient) to opti-
mally manage and normalize the features of the ABPM-
determined 24-h BP pattern that are indicative of target
tissue injury and CVD risk. Given the fact the teaching
of medical and pharmaceutical sciences today continues
to be based exclusively on the concept of homeostasis, i.
e., constancy of biological functions and processes, it is
not surprising that most practitioners continue to
assume when, i.e., the time of day, once-a-day medi-
cations are ingested is of little or no importance
(Morgan, 2009; Parati & Bilo, 2010). An extensive review
of ingestion-time (i.e., circadian rhythm-dependent)
influences on both the desired and undesired effects of
hypertension therapies (Hermida et al., 2013c) shows
such an assumption is not only invalid, at least when
awakening versus bedtime administration times are com-
pared, but that it is possible to significantly improve the
clinical management of hypertension simply by selecting
the correct time of treatment, and without any additional
financial cost to patients or public and private health in-
surance agencies that would accrue in many cases by the
unnecessary prescription of an increased dose or
number of therapeutic agents due to improper timing
(Hermida et al., 2013g). The chronotherapy of conven-
tional hypertension medications thus constitutes a cost-
effective strategy for: (i) enhancing the control of awake
and asleep SBP and DBP levels, (ii) normalizing the
dipping status of their 24-h patterning, and (iii) poten-
tially reducing the risk of CVD events and end-organ
injury, for example, to the blood vessels and tissues of
the heart, brain, kidney, and retina (Ayala et al., 2013a;
Hermida et al., 2010b, 2011b, 2011c, 2011d, 2013g).
10. ABPM: PRACTICAL CONSIDERATIONS
10.1. Sampling Rate and Duration of ABPM
Most past ABPM patient studies were performed with
measurements gathered every 15 to 60 min over a
single 24-h span, mainly using mean BP values as criteria
to diagnose hypertension (Chobanian et al., 2003; Head
et al., 2012; Mancia et al., 2007; Pickering et al., 2005)
and assess hypertension therapy (Waeber & Brunner,
1999). In actuality, the sampling requirements for
ABPM have only been occasionally addressed (Enstrm
& Pennert, 2001; Hermida & Ayala, 2003; Hermida
et al., 2007c, 2013d). Previous reports have documented
the expected increased reproducibility of mean BP
values associated with the increased number of BP
measurements per 24 h, i.e., greater sampling rate
(Mancia et al., 1994). In addition, ABPM has been also
validated against direct intra-arterial BP measurement,
documenting that sampling at 30- to 60-min intervals
precisely reproduces the true beat-to-beat mean BP
values (di Rienzo et al., 1983).
The majority of these previous studies have focused on
24-h ABPM to primarily investigate only the influence of
BP sampling rate on reproducibility of 24-h mean BP
values. Thus, most past studies have not evaluated the
impact of the duration of ABPM on the reproducibility
of results. Along these lines, the findings of previous
studies have already documented advantages of extend-
ing the duration of ABPM from 24 to 48 h in terms of
the reproducibility of derived clinical parameters
(Hermida & Ayala, 2003; Hermida et al., 2002b, 2007c,
2013d; Mochizuki et al., 1998; Tamura et al., 1990). In
summary, these studies have consistently documented
the reproducibility of BP characteristics, including
mean BP values and sleep-time relative BP decline
(measure of BP dipping), depends markedly on the dur-
ation, and to a much lesser extent on the frequency, of
BP sampling.
A recent study evaluated the influence of the duration
(48 vs. 24 h) and sampling rate of BP measurement (from
every 20 to 30 min up to every 2 h) on the prognostic
value of ABPM utilizing the data from the prospective
MAPEC Study in which 3344 participants whose baseline
BP ranged from normotension to sustained hypertension
were systematically evaluated by periodic, at least
annually, 48-h ABPM (Hermida et al., 2013d). The
ABPM profiles of these participants were modified to
generate reconstructed time series of identical 48-h dur-
ation but with data sampled at different intervals every 1
or 2 h or shorter time series for just the first 24-h span
with data sampled at the original rate, i.e., at 20- to 30-
min intervals. The authors compared the reproducibility
of the 48-h, awake, and asleep BP means, and of the
sleep-time relative BP decline derived from the complete
BP profiles (original 48-h time series with BP measure-
ments obtained at 20- to 30-min intervals from each
participant) against each set of modified BP series.
Additionally, the Cox proportional-hazard model,
adjusted for significant confounding variables, was
used to estimate the HR with 95%CI for events associated
with each tested potential prognostic BP parameter, cal-
culated from the original complete 48-h BP profiles and
from each set of modified BP series.
As an illustrative example, Figure 15 shows the limits
of agreement for the asleep means of SBP (top) and
DBP (bottom) of the original complete 48-h ABPM pro-
files versus the modified ABPM series, i.e., less-dense
sampling of either one BP measurement per hour for
48 h or the original sampling rate of one BP measure-
ment per 20 to 30 min for the first 24-h span. Each
Bland-Altman plot represents the difference between
the asleep BP mean calculated from the original series
and the value calculated from the modified series
(in the vertical axis), plotted against the average of
those two values (in the horizontal axis) (Bland &
Guidelines for ambulatory blood pressure monitoring {8;
Informa Healthcare USA, Inc.
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Altman, 1986, 1995). The average of the individual differ-
ences in the asleep BP mean was slightly, but, nonethe-
less, significantly greater for data sampled every 20 to
30 min during the first 24 h than for the reconstructed
time series that simulated data sampled every 1 h for
48 h (.3 4.4 vs. -.1 1.6 mmHg in asleep SBP mean; .2
3.0 vs. -.1 1.4 mmHg in asleep DBP mean; p < .001).
Of more direct clinical relevance, Figure 15 further illus-
trates the asleep SBP and DBP means obtained from the
original complete 48-h ABPM profiles were much better
reproduced with data sampled every 1 h for 48 h (time
series composed of up to 48 of the maximum original
128 BP measurements/participant; right panels of
Figure 15) than with the data obtained at the original
sampling rate of 20- to 30-min intervals for the first 24
h, only (time series composed of up to 64 BP measure-
ments/participant; left panels of Figure 15). In particular,
reduction of ABPM duration to just 24 h resulted in very
significant error, in the range of -21.4 to +23.9 mmHg,
totally unacceptable in clinical practice, in estimating
the asleep SBP mean, the most significant prognostic
marker of CVD events. Similar findings related to the
advantages of extending the duration of ABPM versus in-
creasing the sampling rate were documented for the esti-
mation of the 48-h and awake BP means and sleep-time
relative BP decline (Hermida et al., 2013d). Additionally,
Cox proportional-hazard analyses revealed a comparable
HRfor mean BP values and sleep-time relative BP decline
derived from the original complete 48-h ABPM profiles
and those modified to simulate a sampling rate of one
BP measurement every 1 or 2 h for 48 h. However,
when the duration of ABPM was reduced from 48 to
only 24 h, the HRs were markedly overestimated for
SBP and underestimated for DBP (Hermida et al., 2013d).
This study on the impact of the duration and the fre-
quency of sampling by ABPM on the reproducibility
and accurate estimation of BP parameters currently
used to establish the diagnosis of hypertension, evaluate
patient response to treatment, and assess CVD risk fully
corroborates previous findings (Hermida & Ayala, 2003;
Hermida et al., 2002b, 2007c; Tamura et al., 1990),
thereby establishing the estimation of BP indices is
much more dependent on the duration than sampling
rate of ABPM. The HR of CVD events associated with in-
creased ambulatory BP is less accurately estimated by
relying on 24-h than 48-h ABPM, indicating ABPM con-
ducted for only 24 h may be insufficient to reliably
make the diagnosis of hypertension, identify dipping
status, evaluate treatment efficacy, and, most important,
stratify CVD risk. These collective findings indicate
ABPM should ideally be performed at least hourly for
two consecutive 24-h periods to achieve best reproduci-
bility of mean BP values and to accurately classify
dipping status. Moreover, expanding the length of moni-
toring to 48 h, even at the reduced sampling rate of, e.g.,
one measurement per hour that does not compromise
FIGURE 15. Bland-Altman plots assessing agreement in estimates of the asleep means of SBP (top) and DBP (bottom) for data originally
sampled by ABPM every 20 to 30 min for 48 consecutive hours versus those for modified time series reconstructed with data sampling every
1 h for 48 consecutive hours (right), or at the original rate of every 20 to 30 min for the first 24 h only (left). Dotted horizontal line of each plot
represents the average of the differences across the entire studied population. Dashed lines represent the values of the average difference 2
SD (assumingly containing 95% of the individual values). Updated from Hermida et al. (2013d).
{88 R. C. Hermida et al.
Chronobiology International
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accurate determination of the indices of the 24-h BP
profile, does not impact patient compliance (Hermida
& Ayala, 2003; Hermida et al., 2002a, 200b), rendering
ABPM an individually reproducible approach for proper
BP measurement.
10.2. Time Interval between Repeated ABPM Evaluations
ABPM is the recommended means for the diagnosis of
true hypertension, proper CVD risk assessment, and
evaluation of treatment efficacy in the general population.
Moreover, among the different individual parameters
derived from ABPM, the asleep SBP mean is the most
significant predictor of CVD events, both individually as
well as jointly when combined with other ABPM-derived
potential prognostic markers (Hermida et al., 2011c).
Most important, the progressive decrease in the asleep
BP mean is the most significant predictor of event-free
interval (Ayala et al., 2013a; Hermida et al., 2010b,
2011b, 2011c, 2011d, 2012b, 2013b). Accordingly, ABPM
should be considered as a requirement for systematic
follow-up of individual subjects, and this, in turn, requires
a standard protocol for repeated ABPMevaluations. So far,
periodic (at least yearly) 48-h ABPM evaluations on the
same subjects have been performed in the MAPEC
Study (Hermida et al., 2010b, 2011b, 2011c, 2011d) and
the on-going Hygia Project (Ayala et al., 2013b; Crespo JJ
et al., 2013; Hermida et al., 2013j; Mojn et al., 2013;
Moy et al., 2013; Ros et al., 2013).
As a general guide, the following protocol is rec-
ommended for periodic evaluation and follow-up of
patients by ABPM: (i) for uncomplicated persons with
either normotension or masked normotension, accord-
ing to the ambulatory BP reference thresholds listed in
Table 3, and unaffected by compelling clinical conditions
associated with increased CVD risk including diabetes,
CKD, and past CVD events ABPM should be repeated
within 2 yrs; the time interval should be reduced to 1 yr
for complicated normotensive subjects; (ii) for hyperten-
sive patients, diagnosed according to the ambulatory BP
reference thresholds given in Table 3 and whose thera-
peutic regimen is modified in any way (prescription of
treatment to nave patients, prescription of additional
medications to previously treated patients, exchange of
medications, change of dose or time-of-day of medi-
cations, etc.), ABPM should be repeated preferably
within the ensuing 3 mo; (iii) for hypertensive patients
whose BP is established to be properly controlled accord-
ing to the ambulatory BP reference thresholds shown in
Table 3 and whose therapeutic regimen, therefore,
necessitates no modification, ABPM should be repeated
every 6 mo (complicated patients) to every 12 mo
(uncomplicated patients).
10.3. Editing and Validation of ABPM
As previously discussed in more extensive detail (Section
3), ABPM should not be analyzed in terms of the clock
time of BP sampling, neither on a population nor on an
individual basis. Proper synchronization of BP data so
that they are expressed in terms of the actual rest-activity
cycle of the individual evaluated, e.g., hours from
bedtime or hours after awakening, is strongly rec-
ommended. In so doing, information on the rest-activity
cycle must be properly collected from each person
undergoing ABPM evaluation, either by requesting
the individual to keep a diary or, preferably, by wrist
actigraphy.
Although not free from controversy (OBrien et al.,
2003), it is recommended that ABPM profiles be edited
to correct for measurement errors and outliers. Several
methods for the editing of ABPM-derived data have
been proposed and evaluated in terms of reproducibility
(Winnicki et al., 1997). As a general rule, SBP readings
>250 or <70 mmHg, DBP >150 or <40 mmHg, and PP
(difference between SBP and DBP) >150 or <20 mmHg
should be eliminated. Moreover, ABPM measurements
may be invalid when taken during physical exercise, ex-
cessive movement, driving, or under unusual mood/
emotional states.
As a general recommendation, ABPM data series
should be considered invalid for analysis if 30% of the
scheduled measurements are absent, if data are lacking
for >2 consecutive hourly intervals, if data are obtained
while patients maintain an irregular rest-activity sched-
ule during consecutive 24-h periods of monitoring, or if
the nighttime sleep span is <6 h or >12 h.
10.4. Requirements for Healthcare Personnel in Charge of
ABPM
ABPM is a specialized diagnostic technique that requires
initial and periodic updated training to specific protocols
for both BP measurement and ABPM analysis and
interpretation. Accordingly, only properly trained per-
sonnel should perform ABPM. Analyses and interpret-
ation of ABPM results, in particular, require proper
training. The recommendedapproachis to use a standard-
ized data entry booklet (DEB) to record patient medical
history and, in addition, a separate standardized report
to detail ABPM findings. This helps ensure that all evalu-
ated patients undergo equivalent diagnostic procedures
and that healthcare personnel utilize identical criteria
and therapeutic approaches for optimal BP control and
CVD risk reduction. Such a standardized approach
might be easily implemented on-line; thus, all patient
information might be obtained with an electronic DEB,
allowing automatic validation programs to check for
data discrepancies in the DEB and by appropriate error
messages to prompt the clinical site staff for verification
or modification of data in question. Most important,
ABPM profiles can be analyzed on-line in real time,
thus avoiding costly maintenance and actualization of
software programs required to generate an adequate
ABPM report in keeping with the recommendations pro-
vided above in Sections 3, 4, and 8. This approach has
already proven valuable for conducting not only individ-
ualized patient assessments but also long-term popu-
lation-based morbidity and mortality outcome studies
Guidelines for ambulatory blood pressure monitoring {8
Informa Healthcare USA, Inc.
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(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermida et al.,
2013j; Mojn et al., 2013; Moy et al., 2013; Ros et al.,
2013).
10.5. Maintenance and Utilization of ABPM Devices
ABPM should be performed using only properly vali-
dated devices that have been verified to meet published
international standards (American National Standard,
2009; OBrien et al., 1993, 2010). ABPM devices should
be calibrated regularly, at least yearly. The internal
battery of each ABPM device should be checked regularly
and replaced as needed.
At the time of initializing the device for use in a new
patient, trained personnel must program the correct
sampling interval for daytime and nighttime measure-
ments, confirm the internal clock of the computer is set
to the correct date and clock time, and set the ABPM
device to the so-called blind function, i.e., to block
display of BP measurements to avoid potential additional
stress to the patient. Some devices sound a warning tone
just preceding each BP measurement; this feature must
be switched off during the nighttime span to minimize
sleep disturbances. To ensure BP measurement through-
out the entire monitoring time span, use of rechargeable,
e.g., nickel metal hydride, batteries is highly rec-
ommended. Since these batteries have little memory
effect, they can be recharged many times to their
maximum capacity thereby enabling the ABPM device
to operate during many consecutive days (Ayala et al.,
2013b; Hermida et al., 2004d). The use of rechargeable
batteries saves great expense (>750$/yr per ABPM
device) as compared to the use of alkaline batteries that
requires replacement prior to every ABPM application.
The batteries should be removed when the ABPM
device is not in use.
It is essential to choose the correct cuff size to avoid
measurement errors due to use of inadequately sized
cuffs. Proper cuff size must be determined by measure-
ment of the upper arm circumference at each study
visit. The BP cuff should be worn on the non-dominant
arm and an actigraph, if used, on the dominant wrist.
The cuff and the handling bag for the ABPM device
must be washed regularly to ensure hygienic conditions.
10.6. Patient Instructions
Individuals should be given detailed information about
the advantages of ABPM, procedure of BP measurement,
and handling and operation of the ABPM device. The
provision of a written set of instructions is recommended
to complement verbal instructions provided by trained
healthcare personnel. Patients must be aware of the
potential discomfort of ABPM mainly during sleep, the
programmed sampling rate, the setting of the blind-func-
tion (so that the non-display of BP readings is not mistak-
enly interpreted as malfunctioning of the device), and the
programmed feature on most devices to automatically
repeat a BP measurement 2 min after the occurrence
of a measurement error. Finally, patients should be
informed of the precise date and time the ABPM device
is to be returned to the clinical setting.
Patients must be specifically instructed to: keep the
cuff at heart level, cease moving or talking, keep the
arm still and relaxed, and breathe normally when
the cuff starts to inflate; fit and properly adjust the cuff
to the non-dominant arm; preferably wear a thin layer
of cotton clothing under the cuff to minimize risk of
bruising and thus increase compliance; switch the
device off every time it is removed, e.g., to shower/
bathe, change clothes, etc., and switch it on again there-
after; keep the device on during nighttime sleep and not
switch it off; adhere to usual activities with minimal
restrictions, but to keep a similar activity-rest schedule
and avoid daytime napping during the days of ABPM;
avoid activities that might interfere with operation of
the device or ascertainment of representative BP values;
and fill in all required entries in the diary.
All individuals undergoing ABPM must maintain a
diary listing the time of retiring to bed at night, awakening
in the morning, consumption of meals, ingestion of all
medications, participation in exercise, and episodes of
unusual physical activity, mood/emotional states, and
other atypical events that might affect BP. This individual-
ized information can be utilized to edit the ABPM data, if
required, and to determine the commencement and ter-
mination of the daytime activity and nighttime sleep
spans to accurately derive the awake and asleep BP
means of each subject, after referring each individuals
clock-hour BP values to, e.g., hours after awakening
from nighttime sleep.
10.7. Scheduling of Patient Appointments for ABPM
To optimize the utilization of the available ABPMdevices,
it is recommended that healthcare personnel in charge of
ABPM keep a calendar of the date and clock time of all
programmed appointments in keeping with the follow-
up recommendations presented in Section 10.2. A suffi-
cient amount of time, typically more than an hour, is rec-
ommended between the scheduled return time of the
device and the next appointment time for its application
to another patient. This allows for possible delays by
patients in returning the device and permits sufficient
time for personnel to transfer measurement data from
the device to the computer, perform data analyses, gen-
erate the medical report, and re-initialize the device.
Special seasonal periods, such as holidays, local festiv-
ities, and vacation time, should be avoided when sched-
uling a patient for ABPM. Special attention should be
given when performing ABPM on shiftworkers; ideally,
ABPM should be avoided during the first days following
a non-daytime work shift.
11. CONCLUSIONS
Worldwide, elevated BP is responsible for at least 7.6
million, i.e., nearly 13%, of all deaths annually, more
than any other medical condition, and for 57 million,
{o R. C. Hermida et al.
Chronobiology International
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i.e., approximately 3.7%, of total disability-adjusted life
yrs. Moreover, around 54% of strokes and 47% of coron-
ary heart disease cases are attributed to suboptimal BP
control (Arima et al., 2011). The worldwide reported
prevalence of hypertension, based only on clinic BP
measurements, is >40%, while in most Western countries
the prevalence of poor hypertension control is extremely
high, >65%. Thus, according to the WHO, uncontrolled
BP is epidemic worldwide, affecting in total an estimated
1 billion adults 25 yrs. Unfortunately, the prevalence of
BP control has not improved in recent years, despite the
increased intensity of therapy and progressive increase in
the proportion of patients treated with 2 hypertension
medications (Catal-Lpez et al., 2012; Tocci et al.,
2012). Hence, the pharmacotherapy of hypertension is
markedly suboptimal and must be improved by: (i)
proper early identification of at-risk individuals, more
feasible with ABPM as clearly summarized above and
documented in numerous publications (e.g., Ayala &
Hermida, 2013; Clement et al., 2003; Dolan et al., 2005;
Eguchi et al., 2008; Hansen et al., 2007; Hermida &
Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,
2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;
Salles et al., 2008; Staessen et al., 1999; Verdecchia
et al., 1994); (ii) establishment of more cost-effective in-
dividualized therapeutic schemes, more feasible by the
combined use of ABPMand bedtime chronotherapy regi-
mens (Hermida & Ayala, 2009; Hermida & Smolensky,
2004; Hermida et al., 2003d, 2004c, 2005a, 2007a,
2007b, 2007e, 2008b, 2009a, 2010a, 2010b, 2010c,
2011a, 2011c, 2013c; Portaluppi & Smolensky, 2010; Por-
taluppi et al., 2012; Smolensky & Portaluppi, 1999; Smo-
lensky et al., 2010, 2012); and (iii) targeting therapy to the
clinical indices of the BP 24-h pattern most sensitive and
representative of the elevated vulnerability of the blood
vessels of the brain, heart, kidney, retina, etc., to injury
and patient CVD disability and death (Ayala et al.,
2013a; Hermida et al., 2010b, 2011b, 2011c, 2011d,
2012b, 2013b).
The objective of treating hypertension is to reduce BP
in a manner that diminishes or, ideally, eliminates the
risk of end-organ injury, maternal/fetal vulnerability,
and CVD events associated with BP elevation. The epide-
miologic relationship between BP and CVD risk is con-
sistent, although far stronger for ambulatory than clinic
BP measurements (Ayala & Hermida, 2013; Clement
et al., 2003; Dolan et al., 2005; Eguchi et al., 2008;
Hansen et al., 2007; Hermida et al., 2011c, 2012a,
2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;
Salles et al., 2008; Staessen et al., 1999; Verdecchia
et al., 1994). The salutary effect of BP reduction is consis-
tent and, to a certain extent, independent of the interven-
tions used to achieve it. Unfortunately, popular current
hypertension therapy strategies do not entirely eliminate
the CVD hazards associated with BP elevation. Rather, it
only decreases themby approximately one-third a note-
worthy but clearly suboptimal result (Gradman, 2011).
Review of the CVD-event incidence of past hypertension
outcome studies reveals that a relatively low level of
major CVD events has been achieved only in those
trials that specifically enrolled low-risk hypertensive
patients, i.e., trials that avoided the inclusion of higher
risk persons, such as ones 65 yrs of age, with diabetes,
CKD, previous CVD events, and/or advanced organ
damage (Zanchetti, 2009). Collectively, the findings of
past outcome CVD morbidity and mortality studies en-
tailing such high-risk patients indicate current hyperten-
sion therapy strategies fail to sufficiently lower CVD risk,
giving rise to the belief that they have a residual CVD
risk that cannot be reduced by conventional treatment
(Mancia et al., 2009). This questionable conclusion
(Hermida et al., 2013g) is based on the evaluation of
data from outcome studies of hypertensive patients
prescribed a morning-time regimen for their once-a-
day BP-lowering medications and assessed for the
extent of BP control on the unique basis of a very
limited number of unreliable in-clinic daytime cuff
measurements.
The design of all these previous studies and their
associated conclusions disregard the facts: (i) correlation
between BP level and CVD risk is stronger for ambulatory
than clinic BP, and (ii) BP-lowering efficacy and effects on
the 24-h BP pattern of different classes of hypertension
medications exhibit statistically and clinically significant,
morning versus evening, treatment-time differences
(Hermida et al., 2007a, 2010b, 2013c; Smolensky & Porta-
luppi, 1999; Smolensky et al., 2010, 2012). Independent
prospective studies report the sleep-time BP mean deter-
mined by ABPM is a much better independent predictor
of CVD events than either the awake or 24-h BP means
(Agarwal & Andersen, 2006a, 2006b; Amar et al., 2000;
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., 2011c,
2012b, 2013b, 2013e; Kikuya et al., 2005; Minutolo
et al., 2011). Most important, recently published findings
of the MAPEC Study document, based upon periodic sys-
tematic 48-h ABPMevaluation of all participants during a
median follow-up of 5.6 yrs, progressive decrease in the
asleep SBP mean and increase in the sleep-time relative
SBP decline towards a more normal dipper BP pattern
two new important therapeutic targets that require ap-
propriate patient evaluation by ABPM and best achieved
by a bedtime hypertension treatment schedule are the
most significant predictors of reduced CVD risk
(Hermida et al., 2010b, 2011b, 2011c, 2011d). In this
regard, the MAPEC Study found patients randomized to
a bedtime hypertension medication regimen benefited
from a very significant reduction in the HR of CVD
events, i.e., to the risk level of normotensive subjects, in-
dependent of the number of hypertension medications
required to achieve proper ambulatory BP control
(Hermida et al., 2013g). These findings challenge the
medical concept, and also the common belief of many
doctors, of residual CVD risk of patients that, in fact,
may be a consequential artifact of morning-time
Guidelines for ambulatory blood pressure monitoring {+
Informa Healthcare USA, Inc.
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treatment strategies coupled with inadequate patient
evaluation procedures based only upon a very restricted
number of daytime clinic BP measurements, even if sup-
plemented with at-home patient self-assessments.
While current international guidelines recognize the
prognostic value of ABPM, at this time it is recommended
only in a very limited number of clinical circumstances,
specifically, suspected isolated-office hypertension,
resistant hypertension, hypotensive symptoms after
treatment, episodic hypertension, and autonomic dys-
function (Mancia et al., 2007a). The recent update of
the guidelines for the clinical management of primary
hypertension in adults from the National Institute for
Health and Clinical Excellence (NICE), however, pro-
poses for the very first time the need for ABPM to cor-
roborate the diagnosis of hypertension in all adults with
elevated clinic BP (National Institute for Health and
Clinical Excellence, 2011). This recommendation, as out-
lined, is mainly based on the potential reduction of
healthcare expenditures, primarily, those associated
with unnecessary long-term pharmacotherapy and man-
agement of its adverse effects, through identification of
people with masked normotension, i.e., individuals erro-
neously considered to be hypertensive based solely upon
the manifestation of high clinic BP values (Lovibond
et al., 2011). The NICE guidelines, however, fail to recog-
nize the high prevalence and markedly elevated CVD risk
of patients with either masked hypertension and/or
non-dipping normotension. Moreover, they rec-
ommend the diagnosis of hypertension be based only
upon ABPM-determined daytime SBP/DBP means
135/85 mmHg, thus totally disregarding the most rel-
evant information of the asleep SBP/DBP means
(Figures 6-8). In other words, the indisputable medical
advance represented by the wider recommendation in
the NICE guidelines to employ ABPM for the diagnosis
of hypertension is tarnished by the restriction that
ABPM be performed exclusively on subjects with ele-
vated clinic BP and with emphasis only upon the use of
the daytime SBP and DBP means as diagnostic criteria,
which are bound to fail to properly identify individuals
having masked hypertension, nocturnal hypertension,
and normotensive non-dipper BP profile. Relying on
clinic BP measurements, at-home self-measurements,
or even the ABPM-determined 24-h mean for identifi-
cation of high-risk subjects, disregarding the vital infor-
mation of circadian BP patterning and asleep BP level,
is likely to result in potential misclassification of as
many as 50% of all evaluated individuals. Accordingly,
the proper interpretation of the data derived from
around-the-clock ABPM must include examination of
the sleep as well as daytime BP values as the gold stand-
ard for the diagnosis of true hypertension and, thus, the
recommended means for accurate end-organ and CVD
risk assessment in the general population, independent
of clinic BP measurements.
The potential utility and applicability in the United
States (US) of the NICE guidelines for extended, although
yet arguably limited, ABPM use for the diagnosis of hy-
pertension have been questioned in a recent editorial
(Bloch & Basile, 2011). According to its authors, the con-
cerns regarding the use of ABPM in the US are: (i) lack of
wide availability of ABPM devices in primary care prac-
tice settings; (ii) ABPMis presently only covered by insur-
ance companies to determine the presence/absence of
isolated-office hypertension, i.e., masked normoten-
sion; (iii) routine application of ABPMto diagnose hyper-
tension is impractical due to an insufficient number of
ABPM devices available at specialized centers and
needed time-consuming training to properly apply
them and interpreted the data they generate (Bloch &
Basile, 2011). These concerns reduce down to the pre-
sumed elevated cost of ABPM, although without ac-
counting for the cost-savings derived from the more
accurate diagnosis and comprehensive treatment of hy-
pertension with the associated reduction of CVD risk
and events; and the obvious need for training. In the
past, such unjustified objections were made against
other clinically significant biomedical and technological
advances involving improved patient management,
which if rejected would have greatly inhibited several
breakthroughs routinely utilized today in clinical medi-
cine to enhance patient disease-free interval and
quality life.
Concerns have been raised about the expense of
implementing ABPM patient programs in the US and
elsewhere, but without evidence in the absence of appro-
priate economic assessment studies. However, those
knowledgeable of the many advantages of around-the-
clock application of ABPM are equally concerned about
the misguided reliance upon daytime cuff measures,
not only in the clinic as it relates to individual patient
health, but also hypertension research, and its associated
cost-effectiveness and pertinence to public health policy.
For example, Giles et al. (2012) recommend 24-h ABPM
replace the long-used conventional daytime cuff BP
method to gather BP data in all future US National
Health and Nutritional Examination Surveys (NHANES)
to estimate with greater accuracy the prevalence and
control of hypertension in the general population. The
rationale for this recommendation is concern about
white coat and masked hypertension effects con-
founding national survey data. Nonetheless, Giles et al.
(2012) do not specify exactly how the derived 24-h
ABPM data are to be reduced and interpreted. We
support the recommendations set forth by Giles et al.
(2012), not only with respect to the utilization of ABPM
for future NHANES, but also for the assessment of new
hypertension therapies, as has been the requirement by
governmental agencies for several decades. In addition,
around-the-clock ABPM methods ought to be required
for all US National Heart, Lung, and Blood Institute
(NIH) funded hypertension research and also that spon-
sored by government agencies elsewhere. Moreover, in
consideration of the huge prevalence of hypertension
in the general population, ABPM ought to be instituted
{: R. C. Hermida et al.
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in clinical medicine as the gold standard for the diagnosis
of hypertension, determining CVD and other hyperten-
sion-associated risk, and evaluating attainment of treat-
ment goals, in adherence with the procedures, indices
(including the sleep-time BP decline and sleep-time
SBP/DBP means), and thresholds specified in the pre-
ceding sections of this document.
Recently, the NIH announced the funding of a $114
multicenter randomized clinical trial, based entirely
upon clinical cuff BP measures, aimed at determining
whether reducing clinic BP levels below the currently rec-
ommended ones results in further reduction of CVD risk,
in keeping with the ongoing debate relating to whether or
not there exists a J-curve relationship between treatment-
achieved BP and CVDrisk (see Section 7). The major goal
of this long-term outcomes study, the Systolic Blood
Pressure Intervention Trial (SPRINT; information avail-
able at www.clinicaltrials.gov and www.nhlbi.nih.gov/
news/press-releases), is to determine if hypertensive
patients treated to achieve a daytime clinic SBP of
either <140 mmHg (standard group) versus <120
mmHg (treatment group) differ significantly in CVD
risk and diseasefree interval; those randomized to the
treatment group are expected to be managed on
average by 3-4 hypertension medications, while those
randomized to the standard group are expected to be
managed on average by 2 medications. The merit of
this study seems dubious, since several previous rather
large-scale studies (Appel et al., 2010; Bangalore et al.,
2010; Cushman et al., 2010; Okumura et al., 2005;
TRANSCEND Investigators, 2008; Voko et al., 1999;
Yusuf et al., 2008) have already shown that increasing
the number of medications ingested in the morning
with the goal of aggressively decreasing daytime clinic
BP, in the absence of appropriate evaluation of the treat-
ment effect on the indices of the 24-h BP pattern poten-
tially increases, not decreases, CVD risk. Thus, this NIH-
funded hypertension treatment study, based entirely on
traditional clinical cuff BP determinations, considered
by some opinion leaders to be an outdated approach
when compared to the more modern, comprehensive,
and accurate around-the-clock ABPM one, appears to
be an incredible waste of money, time, and effort. Fur-
thermore, based on the findings of the most recently pub-
lished ABPM-based outcome studies, the most important
treatment targets ought to be the: (i) asleep SBP and DBP
means, and (ii) sleep-time relative BP decline, two clini-
cally meaningful parameters of the 24-h BP pattern best
managed by a bedtime-treatment regimen. This unique
treatment-time strategy that best achieves asleep BP
control as the primary therapeutic goal has been shown
in prospective investigations to reduce clinic SBP <120
mmHg without increasing CVD risk (Hermida et al.,
2013g, 2013h). This finding is in exact opposition to
that mistakenly predicted by the J-curve phenomenon
based entirely on the relationship established between
daytime clinic BP, only, and CVD risk in patients
treated with a morning-time schedule of hypertension
medications (Hermida et al., 2013h). Without proper
24-h patient evaluation by ABPM and by pursuing
lower clinic BP through increase in the number of medi-
cations prescribed for morning ingestion, the SPRINT
study, unfortunately for patients randomized to the
more aggressive treatment group, could very well culmi-
nate in the unintended consequence of increased CVD
events. Moreover, considering the current cost of an
ABPM device, number of patients/yr that can be evalu-
ated by a 48-h ABPM study, plus average expected per-
formance life in years per device, the $114 million
granted to the SPRINT study investigators would enable
assessment in total of 136 million American adults!
The overall very low cost/very high benefit ratio of
ABPM and its proven ability to significantly reduce the
risk of fatal and non-fatal CVD events and enhance
disease-free interval, are among the issues that have
either yet to be recognized or properly appreciated by ad-
ministrators of private and government health insurance
programs. The incorporation of around-the-clock ABPM
into state-of-the-art medical programs should be the pre-
ferred means of significantly increasing the accuracy of
diagnosing hypertension, assessing CVD risk, and estab-
lishing optimal individualized therapeutic intervention
to minimize injury to all at-risk blood vessels and
tissues of the body, improve the early detection of gesta-
tional hypertension and prevent associated maternal
and fetal risk, and increase CVD event-free interval.
12. ABPM: SUMMARY OF RECOMMENDATIONS
1. Clinic BP for assessment of CVD risk. There are
several major disadvantages of conventional clinic BP
measurements; 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. Accord-
ingly, clinic BP values should no longer be considered
to be the gold standard for the diagnosis of hyperten-
sion and assessment of CVD risk.
2. BP representation and analysis. Analysis of ABPM
data in terms of clock time of BP sampling can be mis-
leading, both in population studies and in individual
patient evaluations. Proper synchronization of BP data
to the patients specific rest-activity cycle, such as hours
from bedtime or hours after awakening, is preferable. In
so doing, accurate information on the rest-activity cycle
must be properly collected from all individuals under-
going ABPM evaluation, either by requesting them to
maintain a diary or, preferably, by wrist actigraphy.
3. Prognostic value of ABPM-derived characteristics.
3.1. 24-h BP mean for CVD risk assessment. The
commonly used 24-h BP mean for deciding the diag-
nosis of hypertension totally disregards the extremely
valuable clinical information conveyed by specific
Guidelines for ambulatory blood pressure monitoring {{
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features of the circadian BP pattern. Individuals with
the same 24-h BP mean may display radically different
circadian BP patterns, ranging from extreme-dipper to
riser types, thus constituting markedly different CVD
risk states. Therefore, the 24-h BP mean is insufficient
and not recommended for making the diagnosis of hy-
pertension and assessing CVD risk.
3.2. Asleep vs. awake BP means for CVD risk as-
sessment. Among the different individual parameters
derived from ABPM, the asleep SBP mean is the most
significant 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
model that already includes the asleep SBP mean
and corrected for relevant confounding variables. Ac-
cordingly, the asleep, rather than awake, SBP mean
derived from ABPM is preferred to diagnose hyperten-
sion and assess CVD risk. Most important, the pro-
gressive decrease in the asleep BP mean, a novel
therapeutic target that requires accurate evaluation
by ABPM, is a highly significant predictor of event-
free interval.
3.3. Sleep-time relative BP decline vs. dipping
classification. CVD risk increases exponentially
when the sleep-time relative SBP decline is <6% and
slightly, but not significantly, decreases for decline
values above this threshold. Accordingly, the sleep-
time relative SBP decline as a continuous variable,
and not the dipping classification per se that is typi-
cally based on an arbitrary 10% threshold value,
should be used for appropriate CVD risk assessment.
Moreover, the risk of CVD events is different for the
sleep-time relative declines of SBP and DBP. There-
fore, use of the same 10% threshold value for the
sleep-time relative decline of SBP and DBP to categor-
ize subjects according to their dipping status is mis-
leading and should be avoided.
3.4. Prognostic value of other ABPM-derived par-
ameters. Additional ABPM-derived parameters, in-
cluding the morning BP surge, standard deviation
(SD), and ambulatory arterial stiffness index (AASI),
add little additional increase in prognostic value to
the asleep SBP mean. Interestingly, a greater
morning BP surge is associated with lower, not
higher, CVD risk, in agreement with the highly sig-
nificant association between increased sleep-time
relative BP decline and reduced CVD risk. Further re-
search is needed to properly ascertain if the prognos-
tic value of the asleep BP mean can be improved by
concomitant use of other ABPM-derived parameters.
4. Masked normotension (also known as isolated-
office hypertension). Masked normotension is defined
as elevated clinic BP (140/90 mmHg) but normal
awake and asleep ABPM SBP/DBP means (<135/85 and
<120/70 mmHg, respectively). These threshold values
should be replaced by those listed in Table 3 for special
populations (see Section 8). Classification of subjects in
this category by comparison of clinic with either the 24-
h or awake BP mean, disregarding the clinical signifi-
cance of the asleep BP mean, is misleading and should
be avoided. Accordingly, masked normotension cannot
be defined by comparing clinic BP with at-home self-
measurements. The relative CVD risk of subjects with
normal awake and asleep SBP/DBP means is low; accord-
ingly, the termisolated-office hypertension should pre-
ferably be replaced by the more appropriate term
masked normotension.
5. Masked hypertension. Masked hypertension is
defined as normal clinic BP (<140/90 mmHg) but
elevated awake and/or asleep ABPM SBP/DBP means
(135/85 or 120/70 mmHg, respectively). These
threshold values should be replaced by those listed in
Table 3 for special populations (see Section 8). Classifi-
cation of subjects in this category by comparison of
clinic with either the 24-h or awake BP mean, disregard-
ing the clinical significance of the asleep BP mean, is mis-
leading and should be avoided. Accordingly, masked
hypertension cannot be defined by comparing clinic BP
with at-home self-measurements. When categorizing
patients as masked hypertensive, one needs to be aware
that subjects with an elevated awake BP mean and
normal asleep BP mean are at significantly lower CVD
risk than those with elevated asleep BP.
6. Normotensive non-dippers. Non-dippers have sig-
nificantly higher CVD risk than dippers, whether they
have normal or elevated ambulatory BP. Non-dippers
with normal awake and asleep SBP/DBP means, who
might account for >20% of adults, have a similar hazard
ratio as dippers with elevated ambulatory BP. Accordingly,
CVD risk is influenced not only by ambulatory BP
elevation, but also by blunted nighttime BP decline, even
within the normotensive range, thus supporting ABPM as
a requirement for accurate CVD risk assessment in the
general population. Normotensive individuals with a
non-dipper BP profile represent a clear paradox, as those
persons neither have normal BP nor low CVD risk.
7. The J-curve phenomenon. The J-shaped relation-
ship with CVD risk, described so far only for clinic BP
determined in patients presumably treated with hyper-
tension medications in the morning, does not apply to
the ABPM-determined asleep BP mean, a more signifi-
cant predictor of CVD morbidity and mortality than the
daytime clinic BP or ambulatory awake BP mean. More-
over, no J-curve relationship is found between CVD risk
and achieved clinic BP, awake BP mean, or asleep BP
mean in patients managed by a bedtime treatment
regimen, thus suggesting the J-curve is mainly associated
with over-treatment of patients in the morning with the
misdirected therapeutic goal of progressive reduction
of clinic BP measurements, while disregarding entirely
asleep BP control.
8. References thresholds for ABPM. Reference
thresholds for the diagnosis of hypertension should
be established taking into consideration documented
factors significantly affecting BP regulation and
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CVD risk. All the reference thresholds listed below
for the diagnosis of hypertension, i.e., high CVD risk,
should also be used as the therapeutic goal for treated
patients.
8.1. Reference ABPMthresholds in uncomplicated
men. Outcome-based ABPM reference thresholds
for men, in the absence of compelling clinical con-
ditions, are 135/85 mmHg for the awake and 120/
70 mmHg for the asleep SBP/DBP means.
8.2. Reference ABPMthresholds in uncomplicated
women. Outcome-based reference thresholds for the
diagnosis of hypertension are lower by 10/5 mmHg
for ambulatory SBP/DBP in uncomplicated women,
i.e., 125/80 mmHg for the awake and 110/65 mmHg
for the asleep SBP/DBP means.
8.3. Reference ABPM thresholds in high-risk
patients. 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 with diabetes, CKD, and/or past CVD
events, i.e., 120/75 mmHg for the awake and 105/60
mmHg for the asleep SBP/DBP means.
8.4. Reference ABPM thresholds in pregnancy.
Conventional clinic BP measurements are neither diag-
nostic nor sufficiently predictive of the development of
hypertension during gestation or pregnancy outcome.
Proper diagnostic thresholds should reflect the
normal and predictable BP changes that occur during
gestation, in particular, the expected diminished BP
in pregnant as compared to non-pregnant women. In-
dependent of maternal age and parity, the ABPM refer-
ence thresholds for identification of hypertension in
pregnancy are: 115/70 mmHg for the awake SBP/DBP
means in the first trimester of pregnancy (<14 wks ges-
tation), 115/69 mmHg in the second trimester (14-27
wks gestation), and 118/72 mmHg inthe thirdtrimester
(27 wks gestation); and 99/58, 98/56, and 104/60
mmHg for the asleep SBP/DBP means in each of the
respective trimesters of pregnancy. Alternatively, hyper-
tension in pregnancy might be defined as a hyperbaric
index (HBI) 15 mmHg X h. The HBI is defined as the
total area during the entire 24-h period of any given
subjects ambulatory BP above a time-varying
threshold defined by a tolerance interval calculated as
a function of gestational age and derived from
around-the-clock ABPM assessment of an appropriate
reference population.
9. Clinical applications of ABPM.
9.1. ABPM in the general population. The joint
prevalence of masked normotension and masked hy-
pertension is >35% in the adult population. Moreover,
>20% of normotensive adults have a non-dipper BP
profile and, thus, are at high CVD risk. Therefore,
relying on clinic BP measurements, even when sup-
plemented with at-home self-measurements, for
identification of high-risk subjects, disregarding the
vital information pertaining to circadian BP patterning
and asleep BP level, leads to potential misclassification
of up 50% of all evaluated individuals. Accordingly,
ABPMis the gold standard for the diagnosis of true hy-
pertension and the accurate assessment of CVD risk in
the general population.
9.2. ABPM in secondary hypertension. A high
prevalence of nocturnal hypertension and/or non-
dipping has been reported, among other conditions,
in patients with orthostatic autonomic failure, Shy-
Drager syndrome, vascular dementia, Alzheimer-
type dementia, cerebral atrophy, phaeochromocyto-
ma, autonomic neuropathy, cerebrovascular disease,
ischemic arterial disease after carotid endarterectomy,
neurogenic hypertension, fatal familial insomnia, cat-
echolamine-producing tumors, Cushings syndrome,
exogenous glucocorticoid administration, mineralo-
corticoid excess syndromes, Addisons disease,
pseudohypoparathyroidism, asthma, salt-sensitive es-
sential hypertension, essential hypertension with
renal, liver, and cardiac transplantation, congestive
heart failure, and recombinant human erythropoietin
therapy. Accordingly, ABPM is the recommended gold
standard for patients with suspected secondary
hypertension, to correctly assess both BP status and
CVD risk.
9.3. ABPM in resistant hypertension. A patient
should be categorized as resistant to treatment if the
ABPM-determined awake and/or asleep SBP or DBP
means are greater than the reference diagnostic
thresholds (see Table 3 and Section 8) when ingesting
3 hypertension medications of different classes
(ideally including a diuretic unless contraindicated),
with at least one of them ingested as a full daily dose
at bedtime. Accordingly, patients with properly con-
trolled awake and asleep SBP/DBP means when
treated with 4 medications are also resistant to treat-
ment. Clinic BP values and at-home self-measure-
ments should no longer be used to diagnose
resistant hypertension; according to the above defi-
nition, it must be based on ABPM. A bedtime hyper-
tension medication regimen, in conjunction with
proper patient evaluation by ABPM to corroborate
the diagnosis of true resistant hypertension, should
be the preferred therapeutic approach for patients
with resistant hypertension.
9.4. ABPM in the elderly. There is progressive in-
crease with aging in the prevalence of non-dipping
and nocturnal hypertension after 40 yrs of age.
Elderly subjects, at a threshold age even <60 yrs,
should be evaluated by ABPM to corroborate the diag-
nosis of hypertension, ensure proper evaluation of
CVD risk associated with alterations in the 24-h BP
pattern, and establish the most appropriate chrono-
therapeutic scheme to increase CVD event-free inter-
val. In the elderly, bedtime treatment with the entire
daily dose of 1 hypertension medications is associ-
ated with significantly higher prevalence of properly
controlled awake and asleep BP means and lower
prevalence of the non-dipper/riser BP pattern.
Guidelines for ambulatory blood pressure monitoring {,
Informa Healthcare USA, Inc.
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Therefore, a bedtime hypertension regimen is the rec-
ommended strategy for elderly hypertension patients.
9.5. ABPM in diabetes. The prevalence of non-
dipping is significantly greater in patients with than
without diabetes. Elevated asleep SBP mean is the
major basis for the diagnosis of hypertension and/or
suboptimal BP control among patients with diabetes;
thus, among uncontrolled hypertensive patients with
diabetes, >89% might potentially exhibit nocturnal hy-
pertension. Accordingly, ABPM is the gold standard
for the proper diagnosis of hypertension and assess-
ment of CVD risk in patients with diabetes. In dia-
betes, the ingestion of the full daily dose of 1 BP-
lowering medications at bedtime, compared to the in-
gestion of all such medications upon awakening, is
associated with lower asleep BP mean, attenuated
prevalence of non-dipping, and significant reduction
in CVD morbidity and mortality. Therefore, bedtime
hypertension treatment is the strategy of choice for
patients with diabetes.
9.6. ABPM in obesity and metabolic syndrome.
There is significantly increased prevalence of non-
dipping and other markers of CVD risk in patients
with metabolic syndrome and/or abdominal obesity.
Bedtime treatment with the entire daily dose of 1 hy-
pertension medications is significantly associated with
attenuated prevalence of the high-risk non-dipper BP
profile, both in patients with and without metabolic
syndrome. Accordingly, metabolic syndrome and
abdominal obesity must be included among the
medical conditions for which ABPM is recommended
to make the diagnosis of hypertension, accurately
evaluate CVD risk, and determine the most advan-
tageous therapeutic scheme, the preference being a
bedtime dosing strategy.
9.7. ABPMinchronic kidney disease (CKD). There is
significantly elevated prevalence of non-dipping in
patients with CKD. Prevalence of the riser BP pattern is
2.5-fold greater in CKD, and up to 5-fold greater in
end-stage renal disease. Among uncontrolled hyperten-
sive patients with CKD, >90% exhibit nocturnal hyper-
tension. Patients with CKD also show significantly
elevated ambulatory PP, reflecting increased arterial
stiffness and enhanced CVD risk. Furthermore, patients
with CKD who ingest the entire daily dose of 1 hyper-
tension medications at bedtime, as compared to those
who ingest all of them upon awakening, show signifi-
cantly lower asleep SBP/DBP means and attenuated
prevalence of non-dipping, i.e., lower prevalence of
markers of CVDrisk. Collectively, these findings indicate
CKD must be included among the clinical conditions
for which ABPMis recommended for the accurate diag-
nosis of hypertension and assessment of CVD risk. In
addition, bedtime treatment should be the preferred
therapeutic scheme for hypertensive patients with CKD.
9.8. ABPM in obstructive sleep apnea and other
sleep disorders. The non-dipper BP pattern is fre-
quent in obstructive sleep apnea, so that undiagnosed
sleep-disordered breathing might play a role in the
genesis of the altered BP pattern of some non-dipper
hypertensives. Sleep apnea and arterial hypertension
are frequently associated conditions. Therefore,
ABPM is recommended for the accurate diagnosis of
hypertension and assessment of CVD risk in all indi-
viduals with suspected or confirmed sleep disorders.
Nonetheless, the highly unspecific nature of a
blunted nocturnal BP fall makes ABPM, even when
accompanied by measurement of activity level by
wrist actigraphy during nighttime sleep, unsuited for
identifying the diagnosis of obstructive sleep apnea.
Thus, the gold standard to achieve the diagnosis of
apneic snoring and to assess its severity remains
polysomnography with incorporated continuous BP
measurements, which permits also distinguishing
sleep apnea from other sleep disturbances. Assess-
ment of the subjects sleep history as part of the
routine diagnostic screening of hypertension is
highly recommended and should not be omitted
when non-dipping is found by ABPM evaluation.
When the patients sleep history suggests significant
sleep disturbance, polysomnography is the appropri-
ate subsequent diagnostic step.
9.9. ABPM in pregnancy. ABPM during gestation,
commencing preferably at the time of the first obste-
tric examination following positive confirmation of
pregnancy, provides sensitive endpoints for early hy-
pertension-related risk assessment and guidance of
prophylactic and/or therapeutic intervention. Among
these, low-dose aspirin (100 mg/d) when ingested
regularly at bedtime, commencing before 16 wks of
gestation, has been shown to efficiently control ele-
vated gestational ambulatory BP and to significantly
reduce the incidence of preeclampsia, gestational
hypertension, intrauterine growth retardation, and
preterm delivery. Accordingly, ABPM is the rec-
ommended replacement for unreliable clinic BP
measurements as the gold standard for the diagnosis
of hypertension in pregnancy and the screening of
pregnant women at high risk for other hypertension-
related complications during gestation, such as
preeclampsia, fetal growth retardation, and
preterm delivery.
9.10. ABPM for evaluation of treatment efficacy.
ABPM is particularly useful for defining the efficacy
of hypertension medication, in individual patients
and also populations of patients taking part in clini-
cal trials. The trough:peak ratio and smoothness
index have too many limitations and are not useful
parameters to guide the selection of medications to
manage hypertension patients. The reduction, dur-
ation, and homogeneity (RDH) index is rec-
ommended for the evaluation of treatment efficacy
of hypertension medications assessed by ABPM. In
hypertensive patients, pharmacologic therapy
should take into account the crucial variable of treat-
ment time with respect to the 24-h rest-activity
{ R. C. Hermida et al.
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pattern of each individual patient to optimally
manage and normalize the features of the ABPM-de-
termined circadian BP pattern that are indicative of
target tissue injury and CVD risk. The chronotherapy
of conventional hypertension medications constitutes
a cost-effective strategy to enhance control of
daytime and nighttime SBP and DBP levels, normal-
ize dipping status of the 24-h BP pattern, and poten-
tially reduce risk of CVD events and end-organ injury
to the blood vessels and tissues of the heart, brain,
kidney, and retina.
9.11. ABPM in treated patients. The differing CVD
risk of patients categorized in terms of clinic vs. ambu-
latory BP measurements indicates ABPM should not
be used for the first-time evaluation of patients
already treated with 1 or 2 BP-lowering medications.
In the absence of a baseline ABPM performed before
initiation of treatment, therapy was undoubtedly pre-
scribed in keeping with a diagnosis based only upon
clinic BP measurements and, therefore, potentially
highly misleading. As such, ABPM performed for the
very first time in treated patients is unable to dis-
tinguish who, indeed, is hypertensive but properly
controlled by therapy from those prescribed
unnecessary therapy because of masked normoten-
sion. These limitations must be taken into consider-
ation when performing first-time ABPM in patients
treated with 2 medications who cannot be washed-
out, e.g., for about 2 wks before ABPM. In principle,
first-time evaluation by ABPM should be restricted to
untreated subjects and patients treated with 3 BP-
lowering medications, those who might thus be truly
resistant to treatment if the awake and/or asleep BP
means are inadequately controlled (see Table 3 and
Section 8).
10. ABPM: Practical considerations.
10.1. Sampling rate and duration of ABPM.
. The reproducibility and reliable estimation of
parameters currently used to establish the diagnosis
of hypertension, evaluate patient response to
treatment, and assess CVD risk based on ABPM is
much more dependent on the duration than
sampling rate of ABPM.
. ABPM conducted for only 24 h may be insufficient
to reliably make the diagnosis of hypertension,
identify dipping status, evaluate treatment efficacy
and, most important, stratify CVD risk.
. Ideally, ABPM should be performed at least hourly
for two consecutive 24-h periods to achieve the
highest reproducibility of mean BP values and
most reliable classification of patients according to
dipping status.
10.2. Time-interval between repeated ABPM
evaluations. The following protocol is recommended
for the periodic evaluation and follow-up of patients
by ABPM:
. For uncomplicated persons with either normoten-
sion or masked normotension, according to the
ambulatory BP reference thresholds listed in
Table 3, and unaffected by compelling clinical
conditions associated with increased CVD risk
including diabetes, CKD, and past CVD events
ABPMshould be repeated within 2 yrs; the time in-
terval should be reduced to 1 yr for complicated
normotensive subjects.
. For hypertensive patients, diagnosed according to
the ambulatory BP reference thresholds given in
Table 3, and whose therapeutic regimen is modi-
fied in any way (prescription of treatment to
nave patients, prescription of additional medi-
cations to previously treated patients, exchange
of medications, change of dose or time-of-day of
medications, etc.), ABPM should be repeated pre-
ferably within the ensuing 3 mo.
. For hypertensive patients whose BP is established
to be properly controlled according to the ambu-
latory BP reference thresholds shown in Table 3
and whose therapeutic regimen, therefore,
necessitates no modification, ABPM should be
repeated every 6 mo (complicated patients) to
every 12 mo (uncomplicated patients).
10.3. Editing and validation of ABPM.
. Proper synchronization of the BP data so that they
are expressed in terms of the actual rest-activity
cycle of the individual evaluated, e.g., hours
from bedtime or hours after awakening, is
strongly recommended.
. ABPM profiles should be edited to correct for
measurement errors and outliers.
. ABPM measurements may be invalid when taken
during physical exercise, excessive movement,
driving, or under unusual mood/emotional states.
. ABPM data series should be considered invalid for
analysis if:
30% of the scheduled measurements are
absent,
if data are lacking for >2 consecutive hourly
intervals,
if data are obtained while patients maintain an
irregular rest-activity schedule during the two
consecutive 24-h periods of monitoring, or
if the nighttime sleep span is <6 h or >12 h.
10.4. Requirements for healthcare personnel in
charge of ABPM.
. Only properly trained personnel should
perform ABPM.
. Analyses and interpretation of ABPM results also
require proper training.
. The recommended approach is to use a standard-
ized data entry booklet for recording the medical
history and a standardized ABPM report. This
helps ensure that all evaluated patients undergo
equivalent diagnostic procedures and that health-
care personnel utilize identical criteria and thera-
peutic approaches for optimal BP control and
CVD risk reduction.
Guidelines for ambulatory blood pressure monitoring {;
Informa Healthcare USA, Inc.
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. On-line ABPM evaluation is an approach that
has already proven valuable for conducting
individualized patient assessment and popu-
lation-based morbidity and mortality long-term
outcome studies.
10.5. Maintenance and utilization of ABPM
devices.
. ABPM should be performed using only properly
validated devices that have been verified to meet
published international standards.
. Devices should be calibrated regularly, at
least yearly.
. The internal battery of each ABPM device
should be checked regularly and replaced
as needed.
. Trained personnel must program the correct
sampling interval for daytime and nighttime
measurements, confirm the internal clock of the
computer is set to the correct date and clock
time, ensure the warning tone that signals a BP
measurement is switched off during the nighttime
sleep span, and set the ABPM device to the so-
called blind function.
. To ensure BP measurement throughout the entire
monitoring span, use of rechargeable batteries is
highly recommended.
. The batteries should be removed when the ABPM
device is not in use.
. It is essential to choose the correct cuff size to
avoid measurement errors due to use of inade-
quately sized cuffs.
. Proper cuff size must be determined by measure-
ment of the upper arm circumference at each
study visit.
. The BP cuff should be worn on the non-dominant
armandanactigraph, if used, onthedominant wrist.
. The cuff and the handling bag for the ABPM
device must be washed regularly to ensure
hygienic conditions.
10.6. Patient instructions.
. Patients must be aware of the:
Potential discomfort of ABPM mainly
during sleep.
Programmed sampling rate.
Setting of the blind-function so that the
non-display of BP readings is not mista-
kenly interpreted as malfunctioning of
the device.
Programmed feature on most devices
to automatically repeat a BP measurement
2 min after the occurrence of a
measurement error.
Patients should be informed of the precise
date and time the ABPM device is to be re-
turned to the clinical setting.
. Subjects must be specifically instructed to:
Keep the cuff at heart level, cease moving
or talking, keep the arm still and relaxed,
and breathe normally when the cuff starts
to inflate.
Fit and properly adjust the cuff to the non-
dominant arm.
Preferably wear a thin layer of cotton cloth-
ing under the cuff to minimize risk of bruis-
ing and thus increase compliance.
Switchthedeviceoff every timeit is removed,
e.g., to shower/bathe, change clothes, etc.,
and switch it on again thereafter.
Keep the device on during nighttime sleep
and not switch it off.
Adhere to usual activities with minimal re-
strictions, but keep a similar activity-rest
schedule and avoid daytime napping
during the days of ABPM.
Avoid activities that might interfere with
operation of the device or ascertainment
of representative BP values
Fill in all required entries in the diary.
. Patients must keep a diary listing the time of retiring
to bed at night, awakening in the morning, con-
sumption of meals, ingestion of all medications,
participation in exercise, and episodes of unusual
physical activity, mood/emotional states, and
other atypical events that might affect BP.
10.7. Scheduling of patient appointments for
ABPM. To optimize the utilization of the available
ABPM devices, it is recommended that healthcare
personnel in charge of ABPM keep a calendar of
the date and clock time of all programmed
appointments in keeping with the follow-up
recommendations presented in Section 10.2.
Declaration of Interest: The authors report no conflicts
of interest.
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