REVIEW

Controversies in Hypertension III: Dipping,

Nocturnal Hypertension, and the Morning Surge
Edward J. Filippone, MD,a Andrew J. Foy, MD,b Gerald V. Naccarelli, MDb
a
Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pa;
b
Department of Medicine, Penn State University Heart and Vascular Institute; Penn State M.S Hershey Medical Center and College of
Medicine, Hershey, Pa.

ABSTRACT

A comprehensive approach to hypertension requires out-of-office determinations by home or ambulatory

monitoring. The 4 phenotypes comparing office and out-of-office pressures in treated and untreated
patients include normotension, hypertension, white-coat phenomena, and masked phenomena. Compo-
nents of out-of-office pressure may be equally as important as mean values. Nighttime pressures are nor-
mally 10%-20% lower than daytime (normal “dipping”) pressures. Abnormalities include dipping more
than 20% (extreme dippers), less than 10 % (nondippers), or rising above daytime (risers) and have been
associated with elevated cardiovascular risk. Nighttime pressure may be elevated (nocturnal hypertension)
in isolation or together with daytime hypertension. Isolated nocturnal hypertension theoretically changes
white-coat hypertension to true hypertension and normotension to masked hypertension. Pressure normally
peaks in the morning hours (“morning surge”) when cardiovascular events are most common. Morning
hypertension may result from residual nocturnal hypertension or an exaggerated surge and has been associ-
ated with enhanced cardiovascular risk, especially in Asian populations. Randomized trials are needed to
determine whether altering therapy based solely on either abnormal dipping, isolated nocturnal hyperten-
sion, or an abnormal surge is justified.
Ó 2023 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2023) 136:629−637

KEYWORDS: Ambulatory blood pressure monitoring; Dipping; Home blood pressure monitoring; Hypertension; Iso-
lated nocturnal hypertension; Masked hypertension; Morning surge; Nocturnal hypertension; White coat hypertension

INTRODUCTION and every 30-60 minutes while asleep. Nighttime pressure

Although most studies of hypertension were based on clinic
blood pressure (herein referred to as pressure), it is increas-
ingly evident that out-of-office pressure is more important,
and recent guidelines recommend its determination.1-4 Two
methods are available, 24-hour ambulatory monitoring
(ambulatory-pressure) and home monitoring (home pres-
sure), with pros and cons for each (Table 1). The former
allows measurements every 15-30 minutes while awake
Funding: None.
Conflicts of Interest: EJF and AJF report none; GVN reports serving
as consultant to Sanofi, Glaxo, Smith Kline, Acesion, Milestone.
Authorship: All authors had access to the data and a role in writing
this manuscript.
Requests for reprints should be addressed to Edward J. Filippone, MD,
2228 South Broad St., Philadelphia, PA, 19145.
E-mail address: edward.filippone@jefferson.edu
allows for assessment of circadian variation. However,
ambulatory pressure is limited by availability and discom-
fort. Home monitoring can be done repeatedly and is more
accessible. However, nighttime pressure cannot be assessed
with currently available home monitors, although such
monitors have been developed.5,6
Four phenotypes of hypertension compare clinic and out-
of-office pressure (Tables 2 and 3).11 In untreated patients,
these include normotension (both metrics are below thresh-
old), sustained hypertension (both are above threshold), white-
coat hypertension (clinic pressure is above but out-of-office
pressure is below threshold), and masked hypertension (clinic
below, out-of-office above threshold). On antihypertensive
treatment, the terminology is different: treated controlled
hypertension, treated uncontrolled hypertension, white-coat
effect, and masked uncontrolled hypertension, respectively.

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https://doi.org/10.1016/j.amjmed.2023.02.018

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630 The American Journal of Medicine, Vol 136, No 7, July 2023

Guidelines recommend initiation of treatment for sus- the general population13,14 and in patients with hyperten-
tained hypertension and intensification of therapy for treated sion,15 diabetes (types 116 and 217), chronic kidney
uncontrolled hypertension. Masked hypertension requires disease,18,19 and disordered sleep breathing.20 Nondipping
therapy, and masked uncontrolled hypertension requires generally had adverse prognostic significance for both
intensification. Treatment for white-coat hypertension is not hypertensive target organ damage and cardiovascular
recommended but may be considered in certain cases. The events, especially reverse dipping.21 Extreme dipping had
white-coat effect does not require intensification. less certain implications.22
These phenotypes are based on Boggia et al23 found that reduced
mean out-of-office pressures. Some CLINICAL SIGNIFICANCE dipping predicted total mortality but
patients with normal mean pressure not cardiovascular events, reverse
but abnormal circadian variations
The phenotypes of abnormal nighttime dipping predicted both mortality and
may still be at increased risk, dipping, isolated nocturnal hyperten- cardiovascular events, and extreme
equivalent to patients with elevated sion, and an exaggerated morning dipping was predictive of neither. A
mean pressures. Considering blood pressure surge have each been meta-analysis found that 1-standard
daytime and nocturnal pressure associated with adverse cardiovascular deviation increase in night-to-day
separately results in additional phe- events in some studies. ratio predicted mortality and cardio-
15
notypes, including altered night-to-
Each of these phenotypes may occur vascular events; reverse dipping
day ratios, isolated nocturnal or predicted all endpoints; reduced
with normal or elevated mean 24-hour
daytime hypertension, and altera- dipping only cardiovascular events;
tions within daytime pressures, or daytime blood pressures. and extreme dipping cardiovascular
including morning hypertension or
It remains uncertain whether patients events but only in untreated patients.
an exaggerated morning pressure should be routinely evaluated for any Extreme dipping predicted stroke in
surge (Table 3). Herein we discuss of these phenotypes with the intent of 1 study but only with controlled 24-
the cardiovascular risk of these var- altering therapy. hour pressure.24 In another study,
ious phenotypes with therapeutic extreme dipping was associated with
implications. increased cardiovascular events only
in those older than 70 years of age.25
Others assessed nondipping in normotensive patients.
NIGHTTIME DIPPING Lopez-Sublet et al26 found no relation between nondipping
Pressure follows a circadian rhythm being lowest at night. and cardiovascular or kidney damage. In contrast, both
In 1988, O’Brien et al12 divided patients into “dippers” Mezue et al27 and Hoshide et al28 found structural cardiac
(≥10/5 mm Hg fall) and “non-dippers” (all others) noting a abnormalities in normotensive nondippers, and Soylu et
higher incidence of stroke in nondippers. Subsequently, al29 found abnormal cardiac remodeling and diastolic dys-
dippers have been divided into normal dippers (≥10% to function. In 1 study, normotensive nondippers had a relative
<20% fall) and extreme dippers (≥20% fall), and nondip- hazard for cardiovascular mortality of 2.35 compared to
pers divided into reduced dippers (<10% to 0% fall) and dippers, similar to the relative hazard of hypertensive dip-
reverse dippers (>0% rise, known as risers). Studies pers; nondippers with elevated pressure had the highest rel-
assessed the prognostic significance of these categories in ative hazard (5.37).14 Another study also found that

Table 1 Comparison of ABPM versus HBPM*

ABPM HBPM
Pros Pros
1. Provides 24-h mean, daytime, and nocturnal pressures. 1. Widely available.
2. Allows for pressure measurement with activities of daily living. 2. Allows for repeated measurements.

Cons Cons
1. Limited availability especially for repeat evaluation. 1. Unable to provide nocturnal pressures with currently available
2. Poor reproducibility. monitors.
3. Patient discomfort may limit compliance. 2. Assesses pressures only at rest.
3. Requires patient education.
4. Requires patients purchase monitors that have been validated.
ABPM = ambulatory blood pressure monitoring; HBPM = home blood pressure monitoring.
*ABPM and HBPM should be considered complimentary and not equivalent. Studies show imperfect agreement in classifying hypertension phenotypes
between these 2 techniques.7-9 It is uncertain which, if either, is superior, and a systematic review comparing the ability of both to predict cardiovascu-
lar events and/or mortality found a lack of strong evidence in support of either.10

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Filippone et al Controversies in Hypotension III
Table 2 Comparative Blood Pressure Thresholds for Office and Out-of-Office Hypertension Diagnosis*
Office blood pressure Home blood pressure
130/80* 130/80
140/90y 135/85
ACC/AHA = American College of Cardiology/American Heart Association.
*Current ACC/AHA Guideline recommended comparative thresholds for hypertension diagnosis.
yComparative thresholds used by the majority of studies addressing hypertension phenotypes.
Table 3 Hypertension Phenotypes Based on Antihypertension Treatment
Untreated Patient
1. Sustained normotension: Both office and out-of-office pres-
sure below threshold.
2. Sustained hypertension: Both office and out-of-office pres-
sure above threshold.
3. White coat hypertension: Both office and out-of-office pres-
sure above threshold.
4. Masked hypertension: Office pressure below threshold, out-
of-office above threshold.
5. Isolated nocturnal hypertension: Nocturnal pressure above
threshold, daytime pressure below threshold.
6. Masked isolated nocturnal hypertension: Isolated nocturnal
hypertension with office pressure below threshold.
7. Isolated daytime hypertension: Daytime pressure above
threshold, nocturnal pressure below threshold.
8. Day-night hypertension: Both daytime and nocturnal pres-
sures above thresholds.
9. Morning hypertension: Morning pressure above threshold.
10. Dipping status: Percentage drop of nocturnal pressure versus
daytime pressure:
Dipper: ≥10 to <20%
Extreme dipper: ≥20%
Nondipper: <10%-0%
Riser: nocturnal BP > daytime BP
normotensive nondippers had a similar increased risk for
cardiovascular events as hypertensive dippers, both less
than hypertensive nondippers in both treated and untreated
partcipants.13 Borrelli et al19 found that normotensive non-
dipping was associated with both kidney disease progres-
sion and cardiovascular events equivalent to uncontrolled
pressure but normal dipping.
Hence, nondipping is a risk factor for adverse outcomes
supporting ambulatory monitoring to identify higher-risk
patients with controlled pressure. However, it is unclear if
systolic, diastolic, both, or mean pressure should be used to
determine dipping and how to reconcile discrepancies.
Assessment may be confounded by sleep/awake timing,
with fixed time intervals, patient diaries, or actigraphy pos-
sible. One study comparing fixed-interval and diary-
adjusted timing suggested insignificant differences unless
sleeping pattern differed from fixed intervals by more than
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631
Out-of-office blood pressure
Ambulatory blood pressure
Daytime Nighttime 24-hour
130/80 110/65 125/75
135/85 120/70 130/80
Treated Patient
1. Controlled hypertension: Both office and out-of-office pres-
sure below threshold.
2. Uncontrolled hypertension: Both office and out-of-office
pressure above threshold.
3. White coat effect: Both office and out-of-office pressure
above threshold.
4. Masked uncontrolled hypertension: Office pressure below
threshold, out-of-office above threshold.
5. Isolated uncontrolled nocturnal hypertension: Nocturnal
pressure above threshold, daytime pressure below threshold.
6. Masked isolated uncontrolled nocturnal hypertension: Iso-
lated nocturnal hypertension with office pressure below
threshold.
7. Isolated uncontrolled daytime hypertension: Daytime pres-
sure above threshold, nocturnal pressure below threshold.
8. Day-night uncontrolled hypertension: Both daytime and noc-
turnal pressures above thresholds.
9. Morning uncontrolled hypertension: Morning pressure above
threshold.
10. Dipping status: Same as for untreated
2 hours.30 Furthermore, dipping status suffers from poor
reproducibility with approximately one-third of patients
changing status on repeat testing.31
The pathophysiology of abnormal dipping remains
incompletely understood.32 Postulated mechanisms
include disordered circadian rhythms,33 autonomic sys-
tem dysfunction (predominantly enhanced sympathetic
activity), and disordered sodium metabolism such that
greater nighttime pressure is required to effect the pres-
sure natriuresis necessary for maintaining balance.34
Disordered sleep has been repeatedly associated with
abnormal dipping in healthy individuals35 and patients
with sleep apnea,36-38 narcolepsy,39 and frequent noctu-
ria.40 Abnormal dipping was found in resistant hyperten-
sion41 and in secondary causes of hypertension,
including endocrine disorders, renovascular disease, and
autonomic nervous system disorders.32
632
NOCTURNAL HYPERTENSION
Multiple studies have shown that absolute nighttime pres-
sure is a better predictor of adverse outcomes compared to
daytime or clinic pressure.23,42-45 Nighttime pressure may
be elevated in 50% of patients with hypertension46 and
many without hypertension.47 Nighttime values ≥120 for
systolic or ≥70 diastolic were considered nocturnal hyper-
tension in most studies and can occur with normal daytime
pressure (isolated nocturnal hypertension) or with elevated
daytime pressure (day-night hypertension). Isolated noctur-
nal hypertension occurring with normal clinic and daytime
pressure is considered isolated masked nocturnal hyperten-
sion.5 Nocturnal hypertension is not synonymous with
nondipping. In 1 study, 14% of patients with nocturnal
hypertension were normal dippers.48
Absolute nocturnal pressure is potentially important for
diagnosing and treating both masked and white-coat phenom-
ena. Current guidelines recommend neither initiation of ther-
apy for white-coat hypertension nor intensification for white-
coat effect, although controversy surrounds white-coat hyper-
tension.11 Patients with elevated clinic pressure and normal
mean 24-hour pressure (white-coat hypertension) may still
have elevated nocturnal pressure theoretically reclassifying
them as sustained hypertensives in need of therapy.
Cuspidi et al49 analyzed patients with both white-coat
hypertension and white-coat effect based on normal mean
24-hour pressures and found that roughly 30% had nocturnal
hypertension in both groups, changing classifications to sus-
tained hypertension/treated uncontrolled hypertension. An
analysis of 33,855 untreated individuals with office hyperten-
sion found that 41% had white-coat hypertension using just
daytime pressure, dropping to 35% if normal 24-hour mean
pressure; only 26% had white-coat hypertension when 24-
hour, daytime, and nocturnal pressures were all required to
be normal.50 The former 2 groups more frequently had target
organ damage than sustained normotensives, whereas the lat-
ter group did not. Additionally, a multicenter study demon-
strated that development of cardiovascular events in patients
with white-coat hypertension defined by normal daytime,
nocturnal, and 24-hour mean pressures was no greater than
in sustained normotensives.51 Hence, in our opinion, before
withholding initiation or intensification of therapy for white-
coat phenomena in high-risk patients, nocturnal pressures
should be monitored if possible.
Nocturnal hypertension is prevalent.52 An analysis of
8,711 participants found 7% of untreated individuals had
isolated nocturnal hypertension53 of which 20% had office
hypertension. Similarly, 11% of 677 participants had it with
only about 5% having elevated clinic pressure.54 Another
study found 13% of 1,344 patients had isolated nocturnal
hypertension, with a similar prevalence of about 17% in the
normotensive categories of optimal, normal, and high-nor-
mal.55 A higher incidence was found in South African
Blacks, Japanese, and Chinese (around 10%) than Eastern
or Western Europeans (around 6%).54 Certain groups have
an increased prevalence, including high cardiovascular-risk
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The American Journal of Medicine, Vol 136, No 7, July 2023
patients, African Americans, kidney disease patients, and
those with sleep disordered breathing. Fujiwara et al56 stud-
ied high cardiovascular-risk patients and found 27% had
masked isolated nocturnal hypertension, as did 19% in a
population-based cohort of African Americans.57 Elevated
nighttime pressure is common in patients with kidney dis-
ease, resulting in both isolated nocturnal hypertension and
nondipping.58
A recent analysis of 1,724 patients with office pressure
<130/80 extracted from 5 studies found significant race/eth-
nicity differences in reclassification considering nocturnal
pressure.59 The percentage of non-Hispanic whites with
masked hypertension increased from 34.5% using just day-
time pressure to 48.7% considering daytime, nocturnal, and
24-hour mean pressure. The percentage in non-Hispanic
blacks increased from 39.7% to 67.6%. By multivariable
analysis, non-Hispanic blacks were twice more likely than
non-Hispanic whites to have masked hypertension uncov-
ered when considering nocturnal or 24-hour pressures ver-
sus just daytime pressure.
Isolated nocturnal hypertension has been associated with
hypertension-induced target organ damage48,57,60-62 as well
as cardiovascular events and mortality. A study of 8,711
participants found that untreated individuals with isolated
nocturnal hypertension had a significantly higher risk of
total mortality and cardiovascular events compared to nor-
motensives.53 Similarly, another study showed isolated noc-
turnal hypertension had a significantly elevated risk for
cardiovascular events compared to normotension.56
Although isolated nocturnal hypertension is common
and associated with adverse outcomes, it is untenable to
perform ambulatory monitoring on all normotensive
patients. Jaeger et al63 derived equations for predicting
either nocturnal hypertension or nondipping that were addi-
tionally validated. A web-based applicator is available. Nar-
ita et al64 developed and validated simplified scores for
predicting both nocturnal hypertension and isolated noctur-
nal hypertension using home monitoring. In contrast, a
recent study found that in patients with controlled office
and home pressure (morning, evening, and mean), more
than 80% will have controlled nocturnal pressure.65
A significant limitation to implementing nocturnal
hypertension as a target for treatment is poor reproduc-
ibility. In a study repeating ambulatory monitoring after
about 30 days, the k for reproducibility was 0.21.
Hence, repeat testing should be considered before alter-
ing therapy.
MORNING HYPERTENSION
Morning pressure is defined as the pressure in the first
2 hours upon awakening with ambulatory monitoring
and as the pressure before breakfast and medication
administration with home monitoring. Evening pressure
is variously defined as pressure before dinner66 or pres-
sure at bedtime.4 The peak time for both fatal67 and
Filippone et al Controversies in Hypotension III
nonfatal cardiovascular events68,69 is the morning hours
following awakening, corresponding to the morning
surge.70 The surge may be defined as the difference
between the average pressure the first 2 hours after
awakening and either the average of the lowest noctur-
nal and surrounding 2 pressures (sleep-trough surge) or
the average pressure over the 2 hours immediately prior
to awakening (preawakening surge).
Morning hypertension has been defined as ≥135/85 and
may result from an exaggerated surge or more commonly
because of sustained nocturnal hypertension.71 In 1 study,
35% had morning hypertension associated with nocturnal
hypertension and 9% an exaggerated surge.72 Differences
in circadian and diurnal pressure patterns exist between eth-
nic and racial populations. European subjects were found to
have a greater decrease in morning pressure compared to
clinic pressure in Asians.73 An exaggerated surge appears
more common in Asian than European populations. The
adjusted sleep-trough surge was significantly higher in
hypertensive Japanese (40.1 mm Hg) versus hypertensive
Europeans (23.0).74 Similar to dipping status and isolated
nocturnal hypertension, an exaggerated surge also suffers
from poor reproducibility.75
A high surge has been associated with adverse conse-
quences. Kario et al76 linked the top decile with stroke risk
independent of 24-hour pressure and dipping status in
hypertensive Japanese. A study of subjects from 8 interna-
tional populations (including Asian and European) con-
firmed the association of the top decile with all-cause
mortality and cardiovascular events, although not cerebro-
vascular events.77 In contrast, an Italian study found a
strong relationship between percentage reduction in day/
night systolic pressure and the surge,78 and unexpectedly, a
blunted surge (not an excessive surge) was associated with
an increased risk of cardiovascular events.
A higher surge would seem more likely associated with
dipping/extreme dipping and, hence, have an associated
better prognosis. One analysis confirmed that dipping asso-
ciated with an elevated surge and nondipping with reduced
surge; however, 53% of dippers did not have an elevated
surge and 15% nondippers did.79 Another study also found
an exaggerated surge in some nondippers,80 although a riser
pattern was associated with blunted surge.
Importantly, normotensive patients with elevated surge
may still be at elevated risk. Pierdomenico et al81 followed
Italian patients with controlled ambulatory pressure (both
daytime and nighttime) divided into nondippers and dippers
and further divided into high surge (top tertile) or nonele-
vated surge. After adjustment, dippers with high surge had
2.5 times the risk of major cardiovascular events compared
to dippers with nonelevated surge, similar to the 2-time ele-
vated risk of nondippers.
DISCUSSION
A comprehensive approach to hypertension requires out-of-
office determinations. The complimentary approaches of
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633
home monitoring and ambulatory monitoring have
strengths and weaknesses (Table 1). Current guidelines rec-
ognize 4 phenotypes comparing office and out-of-office
pressures (Table 2 and 3). However, various components of
out-of-office measurements should also be considered indi-
vidually.
Using ambulatory-monitoring, true out-of-office normo-
tension requires that all 3 components (daytime, nocturnal,
24-hour mean) are controlled,51 although current American
guidelines only specify daytime normotension. Isolated ele-
vated nocturnal pressure in an otherwise controlled patient
theoretically changes classification from normotension to a
masked phenomenon requiring initiation or intensification
of therapy. Likewise, an elevated nighttime pressure in a
patient with an elevated office but normal out-of-office day-
time pressure theoretically changes classification from a
white-coat phenomenon to sustained hypertension, again
requiring initiation or intensification of therapy. Optimally,
randomized controlled trials in such patients are required to
support these therapeutic alterations based solely on iso-
lated nocturnal elevations. Patients at the highest risk for
nocturnal hypertension and most likely to benefit from initi-
ation or intensification of therapy include those with sleep
apnea, kidney disease, diabetes, documented cardiovascular
disease, and resistant hypertension.5
Morning hypertension appears to be especially problem-
atic for Asian patients, representing masked morning hyper-
tension when associated with normal clinic pressure. The
HOPE Asia network 2022 consensus statement recom-
mends treating morning hypertension to <135/85 regardless
of office pressure, with a more stringent target of <125/75
in high-risk patients.71 Morning hypertension may be
caused by an exaggerated surge,82 which is also more com-
mon in Asia. It is uncertain whether alteration of therapy is
indicated solely for an exaggerated surge when other pres-
sure metrics are acceptable.
Dipping status affects prognosis but current guidelines
do not specify alterations of therapy. Two approaches to
restore normal dipping include chronotherapy and address-
ing underlying pathophysiology. Chronotherapy, adminis-
tration of 1 or more antihypertensives at bedtime, reduced
nocturnal pressure and restored normal dipping in some
studies83,84 but not others85-87 and may reduce hard cardio-
vascular events.88-90 However, the validity of these end-
point trials has been questioned.91-93 A more recent
multicenter randomized trial found no significant reduction
with chronotherapy in the primary cardiovascular end-
point.94 Hence, we also do not recommend chronother-
apy.95 More studies are pending, including the BedMed
(NCT02990663) and the BedMed-Frail (NCT04054648)
trials.
Measures directed at the potential pathophysiology of
nondipping may be implemented. Dietary salt
restriction96,97 and diuretics98 have both been shown to
restore dipping abnormalities, and both are measures that
have obvious wide applicability for treating hypertension.
Whether sympathetic overactivity underlying nondipping
634
Table 4 Summary and Recommendations
1. Assess out-of-office pressure to diagnose and treat hyperten-
sion by either home-monitoring or ambulatory-monitoring.
2. Home-monitoring and ambulatory-monitoring should be con-
sidered complimentary and not equivalent.*
3. If neither home-monitoring nor ambulatory monitoring is
available, pressure should be assessed in the office at multi-
ple time points to diagnose and treat hypertension.
4. Home-monitoring is a reasonable start due to wide applicabil-
ity but cannot provide nighttime pressure with currently
available monitors. It is also reasonable to initially perform
ambulatory monitoring with home-monitoring used for long-
term follow-up.
5. Nocturnal pressure assessment should be considered before
diagnosing white-coat hypertension or white-coat effect in a
high-risk patient more likely to have nocturnal hypertension
(African American, diabetes, kidney disease, disordered sleep,
established hypertension target organ damage, or prior car-
diovascular events).
6. Nocturnal pressure assessment should be considered in nor-
motensive patients at higher risk for masked isolated noctur-
nal hypertension (African American, diabetes, kidney disease,
disordered sleep, established hypertension target organ dam-
age, or prior cardiovascular events).
7. Optimal out-of-office control requires that daytime, noctur-
nal, and 24-h mean pressures are all controlled by ambulatory
monitoring, and morning and mean daytime pressures are
both controlled by home monitoring, although current guide-
lines stress 24-h mean or daytime pressures; isolated noctur-
nal hypertension is not specifically addressed.
8. Abnormal dipping status does not necessitate alteration or
intensification of antihypertensive therapy.
9. Chronotherapy (bedtime administration of 1 or more antihy-
pertensive medications) is not recommended at this time to
treat nondipping, nocturnal hypertension, or an elevated
surge.
10. It is uncertain how to define an elevated morning surge
(absolute number, top decile, etc.)
11. An elevated morning surge (no matter how defined) per se
does not warrant alteration or intensification of therapy when
all other metrics are controlled.
12. Abnormal nighttime dipping, nocturnal hypertension, and an
exaggerated morning surge can each be found with either
elevated or normal mean 24-h/daytime pressures, and all 3
have imperfect reproducibility on repeat testing.
*See Table 1.
should be targeted with beta-blockers or peripheral alpha-
blockers remains to be proven.
LIMITATIONS OF OUT-OF-OFFICE PRESSURE
MEASUREMENTS
Although the data presented suggest a benefit to altering
therapy based on abnormal dipping, isolated nocturnal
hypertension, or an exaggerated surge, the study designs
have inherent limitations due mainly to issues with multiple
hypothesis testing and positive outcome bias. Even if statis-
tically significant on a population level, the improvement in
the area-under-the-curve for predicting cardiovascular
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The American Journal of Medicine, Vol 136, No 7, July 2023
events was quite small when this was evaluated. In 1 study
the areas-under-the-curve for predicting mortality (0.83)
and cardiovascular events (0.84) were increased by 0.0023
and 0.0031 when adding nocturnal pressure to daytime
pressure.99 Mancia et al100 also found small increases in
areas-under-the-curve adding home or ambulatory pres-
sures to office pressure. In another study, adding nighttime
pressure to the base model (office pressure) increased the
C-statistic from 0.717 to 0.728.24 Although statistically sig-
nificant, such small gains in event prediction challenge
widespread adoption and clinical implementation. Current
American and European Guidelines do not recommend
alterations of therapy based solely on abnormal dipping sta-
tus nor on an exaggerated surge. Specific alteration based
on isolated nocturnal hypertension is not addressed. Current
Asian Guidelines recommend targeting morning hyperten-
sion, whether resulting from nocturnal hypertension or an
elevated surge.71 Proof of causality for these abnormal phe-
notypes would best be obtained from randomized controlled
trials proving a benefit to therapy as noted. However, such
trials would require large numbers of patients to show an
effect based on event rates reported in these observational
studies.
CONCLUSION
A comprehensive approach to hypertension requires
obtaining out-of-office pressure measurements. Available
research suggests that the additional phenotypes described
in this manuscript are associated with increased cardiovas-
cular risk. Optimally, randomized controlled trials are
required to determine whether tailoring therapy to any of
these specific phenotypes leads to improvement in this risk.
As a minimum, mean out-of-office pressure should be con-
trolled as recommended in current guidelines (Table 4). We
refrain from making generalized recommendations for
altering therapy when mean out-of-office pressures are con-
trolled but an additional phenotype is present. We suggest
each patient should be evaluated individually for overall
cardiovascular risk and the magnitude of pressure abnor-
mality.
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