Brief Reviews

Predictive Role of the Nighttime Blood Pressure

Tine W. Hansen, Yan Li, José Boggia, Lutgarde Thijs, Tom Richart, Jan A. Staessen

Abstract—Numerous studies addressed the predictive value of the nighttime blood pressure (BP) as captured by
ambulatory monitoring. However, arbitrary cutoff limits in dichotomized analyses of continuous variables, data
dredging across selected subgroups, extrapolation of cross-sectional studies to prospective outcomes, and lack of
comprehensive adjustments for confounders make interpretation of the literature difficult. We reviewed prospective
studies with total mortality or a composite cardiovascular end point as an outcome in relation to the level and the
circadian profile of systolic BP. We analyzed studies in hypertensive patients (n⫽23 856) separately from those in
individuals randomly recruited from populations (n⫽9641). We pooled summary statistics and individual subject data,
respectively. In both patients and populations, in analyses in which nighttime BP was additionally adjusted for daytime
BP and vice versa, nighttime BP was a stronger predictor than daytime BP. With adjustment for the 24-hour BP, both
the night-to-day BP ratio and dipping status remained significant predictors of outcome but added little prognostic value
over and beyond the 24-hour BP level. In the absence of conclusive evidence proving that nondipping is a reversible
risk factor, the option whether or not to restore the diurnal blood pressure profile to a normal pattern should be left to
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the clinical judgment of doctors and should be individualized for each patient. Current guidelines on the interpretation
of ambulatory BP recording need to be updated. (Hypertension. 2011;57:3-10.) ● Online Data Supplement
Key Words: ambulatory blood pressure monitoring 䡲 dipping status 䡲 nighttime blood pressure
䡲 night-to-day blood pressure ratio 䡲 population science 䡲 risk factors

A mbulatory monitoring enables recording the blood pres-

sure throughout the entire day, while subjects engage in
their usual day-to-day activities.1,2 The diurnal blood pressure
profile normally includes a 10% to 20% fall in blood pressure
during sleep, which is driven by physical inactivity and which
is largely independent of an endogenous rhythm.3 Indeed, in
shift workers, the 24-hour blood pressure level and the fall in
blood pressure during sleep were similar on days with
daytime and nighttime work.3 In 1988, O’Brien et al4 reported
for the first time that patients with an abnormal circadian
blood pressure profile with a less marked decrease in the
nighttime blood pressure had a more frequent history of
stroke. O’Brien and colleagues thereby coined the terms
dipping versus nondipping. Subsequent studies of hyperten-
sive cohorts5–24 and populations25–30 did not all8,15,18,26,30
corroborate the worse prognosis associated with a high
nighttime blood pressure. Moreover, interpretation of these
studies is not always easy. First, positive results based on
arbitrary and varying definitions of nondipping were some-
times not supported by analysis of the nocturnal blood
pressure fall as a continuous variable.7,15 Second, in some
reports significant results were only obtained in arbitrarily
selected subgroups.11,18 Third, most studies had a cross-
sectional design (see supplemental Table S1 available at
http://hyper.ahajournals.org), which according to Hill’s31 cri-
teria is a weak source of evidence to establish causality.
Finally, the associations of outcome with nighttime blood
pressure8,9,17,19,20 or with dipping status15,19 often stayed
unadjusted for the daytime or 24-hour blood pressure level,
respectively.
This review is an attempt to derive more precise estimates
for the association between outcome and the ambulatory
blood pressure during sleep as reflected by the nocturnal
blood pressure level, the night-to-day blood pressure ratio, or
dipping status. In our systematic review, we only included
prospective cohort studies of hypertensive patients or ran-
domly selected population samples. We evaluated the influ-
ence of accounting for blood pressure level on the associa-
tions between outcome and indexes derived from the
circadian blood pressure profile.
Search Strategy and Statistical Methods
We based our analyses of cohorts of hypertensive patients
and population studies on summary statistics and individual

Received June 29, 2010; first decision July 16, 2010; revision accepted October 18, 2010.
From the Research Center for Prevention and Health and Department of Clinical Physiology, Nuclear Medicine and PET (T.W.H.), Rigshospitalet,
Copenhagen University Hospital, Faculty of Health Sciences, Rigshospitalet, Copenhagen, Denmark; Center for Epidemiological Studies and Clinical
Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension (Y.L.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine,
Shanghai, China; Departamento de Fisiopatología (J.B.), Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay; Studies Coordinating
Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases (Y.L., L.T., T.R., J.A.S.), University of
Leuven, Leuven, Belgium; Department of Epidemiology (T.R., J.A.S.), Maastricht University, Maastricht, The Netherlands.
Correspondence to Tine W. Hansen, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital,
Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail tw@heart.dk
© 2010 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.109.133900

3
 4 Hypertension January 2011
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subject data, respectively. For both patients and populations,
we limited our analyses to systolic blood pressure, because at
middle and older age this is the predominant risk factor.32
Search methods, selection of studies, and statistical methods
are described in detail in the supplemental Methods available
online. Figure 1 shows the articles retrieved, reviewed, and
included in the analysis of cohorts of hypertensive patients.
Studies in Hypertensive Patients
Table 1 lists the characteristics of the studies reporting on
outcome in patient cohorts. Studies included from 10411 to
52925 patients (median 809). All studies enrolled hyperten-
sive participants of either sex with the proportion of women
ranging from 13%11 to 71%18 (median 52%). Chronic kidney
disease and diabetes mellitus were comorbid conditions in 116
and 311,15,19 studies, respectively. Mean age at enrollment
ranged from 518 to 7316 years. Ethnicity was white in 8
studies,5,6,9 –11,13,17,20 Japanese in 37,15,16 studies, and mixed in
5 studies.8,12,14,18,19 The technique of ambulatory blood pres-
sure measurement was exclusively5,7,10,12–14,16,17,19,20 or pre-
dominantly6,9,11,15,18 oscillometric in all but 1 study,8 in which
blood pressure was measured intra-arterially. In the studies
that used an intermittent technique, the interval between
readings ranged from 1510,11,13,14,18,20 to 305–7,9,15–17 minutes
during daytime and from 1513 to 609 minutes during night-
time. Of the reviewed studies, 6 implemented a diary to
differentiate awake from asleep blood pressures,7,12,15,16,18,19
while 4 and 6 studies used long7,11,14,20 or short5,6,9,10,13,17
fixed clock-time intervals, respectively.
Total mortality was available from 11 studies.5–7,9,11–14,18 –20
Nine studies6,8 –10,13,15–18 reported on a composite cardiovascular
end point that always included cardiovascular mortality, myo-
cardial infarction, and stroke. In some studies, the composite end
point also encompassed coronary revascularization,8,17,18 cardiac
surgery,13 or heart failure.6,9,13,18 Follow up ranged from 3.47,16
Figure 1. Flow chart of articles identified,
screened, and included in the analysis of
cohorts of hypertensive patients. ABPM indi-
cates ambulatory blood pressure monitoring.
to 10.910 years (median 5.9). All studies considered sex and
age as confounders with the exception of one with 52%
women,14 in which the hazard ratio was only adjusted for
age but not sex. The other covariables, in order of
frequency, were smoking in 12 studies,5,6,8 –10,13,15–20 diabe-
tes mellitus in 10 studies,5,8–10,12,13,16–20 body mass index in 9
studies,5,7,9,10,15–18,20 serum cholesterol in 9 studies,8 –10,13,16 –20
antihypertensive treatment in 8 studies,6,7,10,12,16 –18,20 previous
cardiovascular disease in 7 studies,5,6,8,9,18 –20 and/or an index
of renal function in 6 studies.11,14,16,18 –20 All5–13,15–20 but 1
study14 included in our quantitative review considered mul-
tiple confounders. All studies had a prospective design with
blinded end point adjudication against source documents. The
median impact factor of the journals at the time of publication
was 6.3 (range 2.4 to 34.8).
The supplemental Results and Tables S2 and S3 list the
hazard ratios as extracted from published papers5–20 or as
provided by the principal investigators.7,10,13,16 They express the
risk associated with a 10-mm Hg increase in the nighttime or
daytime systolic blood pressure, with a 10% increase in the
systolic night-to-day blood pressure ratio, or with systolic
nondipping as defined in each publication (Table S4). Multivari-
able-adjusted pooled estimates that combined the statistics from
available studies showed that the nighttime and daytime blood
pressures, the night-to-day blood pressure ratio, and the dipping
status were all significant predictors of total mortality and
cardiovascular outcome (Figure 2A). However, fully adjusted
pooled statistics that accounted for nighttime as well as daytime
blood pressure in the same model were significant only for
nighttime blood pressure, whereas daytime blood pressure lost
its prognostic value. The hazard ratios associated with each
10-mm Hg increment in the nighttime blood pressure were
1.16 for total mortality and 1.19 for cardiovascular events
(Figure 2B). In fully adjusted models, which in addition to the
night-to-day blood pressure ratio or dipping status also included the
 Hansen et al Risk Prediction From Nighttime Blood Pressure 5

Table 1. Studies in Hypertensive Patients

No. of Enrolled Age Proportion of Day/Night (h) TM/CVE FU Main Covariables Other Than
Publication Patients Ethnicity (Years) Women (%) (Intervals 关min兴) (N) (Years) ABPM-Derived Variables
Staessen, 19996 808 Whites 70 62 10 –20/0 – 6 (30/30) 68/98 4.4 S, A, SMK, CVD, Rx
Kario, 20017 572 Japanese 72 60 Diary (30/30) 38/. . . 3.4 S, A, BMI, AHT
Khattar, 20018 688 77% Whites 51 36 6–10/10–6 (BtB) . . ./157 9.2 E, S, A, SMK, CHL, CVD, DM
Clement, 20039 1963 Whites 56 48 8–20/0–6 (30/60) 78/157 5.0 S, A, BMI, SMK, CHL, CVD, DM
Dolan, 20055 5292 Whites 53 52 9–21/1–6 (30/30) 646/. . . 7.9 S, A, BMI, SMK, CVD, DM
Fagard, 200510 391 Whites 71 60 10–20/0–6 (15/30) . . ./86 10.9 S, A, BMI, SMK, CHL,
AHT, DM
Astrup, 200711 104 Whites 61 13 7–23/23–7 (15/30) 54/. . . 9.2 S, A, RF, HRV, LVH
Ben-Dov, 200712 3957 94% Whites 55 53 Diary (20/30) 303/. . . 6.5 S, A, AHT, DM
Verdecchia, 200713 2934 Whites 51 46 10–20/0–6 (15/15) 176/356 7.0 S, A, SMK, CHL, DM
Brotman, 200814 621 82% Whites 61 52 6–23/23–6 (15/30) 61/. . . 6.3 A, RF
Eguchi, 200815 1268 Japanese 70 62 Diary (30/30) . . ./100 4.2 S, A, BMI, SMK, RF
Ishikawa, 200816 811 Japanese 73 62 Diary (30/30) . . ./66 3.4 S, A, BMI, SMK, CHL, RF,
AHT, DM
Dolan, 200917 1905 Whites 63 23 9–21/1–6 (30/30) . . ./239 5.5 S, A, OBP, BMI, SMK, CHL,
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DM, Rx
Muxfeldt, 200918 556 Brazilians 66 71 Diary (15/30) 70/109 4.8 S, A, OBP, BMI, SMK, PA, CHL,
RF, AHT, CVD, DM
Palmas, 200919 1178 48% Whites 71 59 Diary (20/20) 215/. . . 6.6 S, A, OHR, SMK, CHL, RF,
CVD, DM
Ungar, 200920 805 Whites 72 52 7–22/22–7 (15/20) 107/. . . 3.8 S, A, BMI, SMK, CHL, RF,
AHT, CVD, DM
TM/CVE indicates number of deaths/cardiovascular events; FU, average follow-up duration in years; ABPM, ambulatory blood pressure monitoring; E, ethnicity; S,
sex; A, age; OBP, office blood pressure; OHR, heart rate in the office; BMI, body mass index; SMK, smoking; PA, level of physical activity; CHL, serum cholesterol;
RF, index of renal function, such as serum creatinine or micro-albuminuria; HRV, heart rate variability; AHT, antihypertensive drug treatment; CVD, history of
cardiovascular disease; DM, diabetes mellitus; Rx, group of randomization.

24-hour blood pressure, both indexes based on the diurnal blood
pressure profile retained significance with the exception of the
night-to-day blood pressure ratio as predictor of total mortality
(Figure 2B).
Population Studies
Of 11 790 subjects available in the IDACO (International
Database on Ambulatory Blood Pressure Monitoring in Re-
lation to Cardiovascular Outcomes) database, we excluded
2149 (18.2%), because their daytime (n⫽169) or nighttime
(n⫽1951) blood pressure had not been measured or were
averages of fewer than 10 or 5 readings, respectively, or
because the participants were less than 18 years old at the
moment of enrollment (n⫽29). Thus, the number of subjects
statistically analyzed totaled 9641. For the present analysis,
participants recruited for the European Project on Genes in
Hypertension in Novosibirsk (n⫽244), Pilsen (n⫽165),
Padova (n⫽310), and Kraków (n⫽308) were combined.
Table 2 lists the characteristics of the population cohorts.
Studies included from 35133 to 214226 subjects (median
1114). One study30 included only men. In the other studies,
the proportion of women ranged from 48%26 to 63%34
(median 54%). Mean age at enrollment ranged from 3635 to
7130 years. Ethnicity was white in 5 studies26,30,35–37 and
Asian in 2 studies,33,34 while 1 study38 included South
Americans. The technique of ambulatory blood pressure
measurement was auscultatory (Accutracker II) in 1 study30
and oscillometric (SpaceLabs 90202 and 90207, Nippon
Colin, and ABPM-630) in all other cohorts.26,33–38 In each
cohort, outcomes were adjudicated against source documents,
as described in previous publications.26,30,33,34,37– 40 The com-
posite cardiovascular end point included cardiovascular mor-
tality, nonfatal myocardial infarction, coronary revasculariza-
tion, heart failure, and stroke. Follow up ranged from 2.533 to
17.637 years (median 11.2 years).
The supplemental Results and Tables S5 and S6 list the
hazard ratios for total mortality and for the combined cardio-
vascular end point in the individual populations. The
multivariable-adjusted models, combining all population co-
horts, showed that the nighttime and daytime blood pressures,
the night-to-day blood pressure ratio, and the dipping status
were all significant predictors of total mortality and cardio-
vascular outcome (Figure 3A). Fully adjusted models, which
accounted for nighttime as well as daytime blood pressure,
revealed that the level of nighttime blood pressure remained
a significant predictor of both outcomes. The hazard ratios
associated with each 10-mm Hg increment in the nighttime
blood pressure were 1.14 for total mortality and 1.15 for
cardiovascular events (Figure 3B). In these models, the
daytime blood pressure lost its prognostic value for total
mortality but remained a significant predictor of the compos-
ite cardiovascular outcome. In fully adjusted models, which
in addition to the night-to-day blood pressure ratio or dipping
status also included the 24-hour blood pressure, both indexes
based on the diurnal blood pressure profile retained signifi-
cance with the exception of dipping status as predictor of
cardiovascular events (Figure 3B).
 6 Hypertension January 2011

A Adjusted
Ns Ne /N
-- r HR (95% CI) Q PQ P
Total mortality
Nighttime (+10 mm Hg) 7 1539 / 16937 1.15 (1.11 - 1.20) 132.9 <0.001 <0.001
Daytime (+10 mm Hg) 6 1378 / 15759 1.16 (1.09 - 1.23) 92.8 <0.001 <0.001
Night-to-day ratio (+0.1) 4 748 / 8173 1.19 (1.12 - 1.27) 33.5 <0.001 <0.001
Nondipping (0.1) 3 694 / 8069 1.37 (1.17 - 1.61) 15.9 <0.001 <0.001

Cardiovascular events
Nighttime (+10 mm Hg) 7 1193 / 9957 1.23 (1.18 - 1.28) 134.9 <0.001 <0.001
Daytime (+10 mm Hg) 7 1193 / 9957 1.23 (1.17 - 1.31) 100.9 <0.001 <0.001
Night-to-day ratio (+0.1) 2 442 / 3325 1.23 (1.11 - 1.37) 14.2 <0.001 <0.001
Nondipping (0.1) 2 456 / 4202 1.34 (1.09 - 1.64) 7.8 0.005 0.006

0.5 1.0 1.5 2.0

B Fully adjusted
Total mortality
Nighttime (+10 mm Hg) 5 1231 / 13566 1.16 (1.12 - 1.22) 62.0 <0.001 <0.001
Daytime (+10 mm Hg) 5 1231 / 13566 0.99 (0.93 - 1.06) 2.3 0.68 0.84
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Night-to-day ratio (+0.1) 3 307 / 4111 1.23 (0.96 - 1.57) 9.4 0.009 0.10
Nondipping (0.1) 4 345 / 4686 1.30 (1.06 - 1.60) 8.5 0.04 0.01

Cardiovascular events
Nighttime (+10 mm Hg) 5 706 / 6212 1.19 (1.12 - 1.27) 32.4 0.04 <0.001
Daytime (+10 mm Hg) 5 706 / 6212 1.06 (0.98 - 1.13) 5.4 0.35 0.13
Night-to-day ratio (+0.1) 2 442 / 3325 1.13 (1.00 - 1.27) 4.1 0.04 0.04
Nondipping (0.1) 2 422 / 3745 1.25 (1.02 - 1.52) 4.7 0.03 0.03

0.5 1.0 1.5 2.0

Figure 2. Prediction of total mortality and all cardiovascular events from ambulatory blood pressure measurement at baseline in
cohorts of hypertensive patients. Filled squares represent the pooled hazard ratios (HR) and have a size proportional to the inverse of
the variance of the pooled estimates. Horizontal lines denote the 95% confidence interval (CI). In case of significant heterogeneity,
pooled HRs were computed from random-effect models and otherwise from fixed-effect models. NS, NE, and NAR indicate the number
of studies, events, and subjects at risk. Q is the test statistic for heterogeneity. PQ and P indicate the significance of Q and HR,
respectively. Adjusted and fully adjusted refer to the Cox models as reported in published papers or as provided by authors. A,
Adjusted refers to the most extensively adjusted risk estimate reported. B, Fully adjusted refers to models in which risk estimates
based on daytime blood pressure were additionally adjusted for nighttime blood pressure and vice versa, or in which risk estimates
based on the night-to-day blood pressure ratio or dipping status were also adjusted for the 24-hour blood pressure.

Interpretation of the Evidence
This systematic review revealed that systolic nighttime blood
pressure was a stronger predictor than systolic daytime blood
pressure in hypertensive patients as well as in subjects randomly
selected from populations in Asia, Europe, and South America.
The night-to-day blood pressure ratio and dipping status re-
mained significant predictors of outcome, even with adjustments
applied for the 24-hour blood pressure level in addition to other
covariables. There was a striking similarity between the findings
in hypertensive patients and populations. For a correct interpre-
tation and clinical application of these findings, several issues
need careful consideration.
Why Should Nighttime Blood Pressure be a Better Predictor?
Various hypothetical mechanisms support the plausibility of
an enhanced cardiovascular risk associated with an increased
night-to-day blood pressure ratio or higher nighttime blood
pressure, such as alterations in the sympathetic modulation of

Table 2. Studies in Population Cohorts

No. of Enrolled Age Proportion of Day/Night (h) TM/CVE FU
Cohort Subjects Ethnicity (Years) Women (%) (Intervals 关min兴) (N) (Years)
Copenhagen26 2142 White 56 48 10 –20/0 – 6 (15/30) 371/285 12.5
Ohasama34 1526 Asian 62 63 8–18/22–4 (30/30) 344/247 13.3
Noorderkempen36 1127 White 49 51 10–20/0–6 (20/45) 136/99 13.1
Uppsala30 1100 White 71 0 10–20/0–6 (30/60) 300/317 10.0
Montevideo38 1438 South American 50 54 10–20/0–6 (20/40) 96/121 9.0
JingNing33 351 Asian 47 55 8–18/22–4 (20/45) 14/8 2.5
EPOGH35 1027 White 39 55 10–20/0–6 (15/30) 23/32 6.6
Allied Irish Bank37 930 White 36 50 10–20/0–6 (30/30) 36/19 17.6
EPOGH indicates European Project on Genes in Hypertension; TM/CVE, number of deaths/cardiovascular events; FU, median
follow-up duration in years.
 Hansen et al Risk Prediction From Nighttime Blood Pressure 7

A Adjusted
HR (95% CI) P
Total mortality
Nighttime (+10 mm Hg) 1.11 (1.07 - 1.16) <0.001
Daytime (+10 mm Hg) 1.06 (1.01 - 1.10) 0.011
Night-to-day ratio (+0.1) 1.18 (1.10 - 1.26) <0.001
Nondipping (0.1) 1.26 (1.11 - 1.44) <0.001

Cardiovascular events
Nighttime (+10 mm Hg) 1.21 (1.17 - 1.26) <0.001
Daytime (+10 mm Hg) 1.21 (1.16 - 1.27) <0.001
Night-to-day ratio (+0.1) 1.16 (1.08 - 1.24) <0.001
Nondipping (0.1) 1.29 (1.12 - 1.48) 0.006

0.5 1.0 1.5 2.0

B Fully adjusted
Total mortality
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Nighttime (+10 mm Hg) 1.14 (1.08 - 1.20) <0.001

Daytime (+10 mm Hg) 0.96 (0.91 - 1.02) 0.17
Night-to-day ratio (+0.1) 1.15 (1.08 - 1.24) <0.001
Nondipping (0.1) 1.22 (1.07 - 1.39) 0.004

Cardiovascular events
Nighttime (+10 mm Hg) 1.15 (1.09 - 1.21) <0.001
Daytime (+10 mm Hg) 1.09 (1.03 - 1.16) <0.001
Night-to-day ratio (+0.1) 1.08 (1.01 - 1.16) 0.035
Nondipping (0.1) 1.15 (1.00 - 1.33) 0.054

0.5 1.0 1.5 2.0

Figure 3. Prediction of total mortality and all cardiovascular events from ambulatory blood pressure measurements at baseline in popu-
lation cohorts. Filled squares represent the hazard ratios (HR), and horizontal lines denote the 95% confidence interval (CI). All analyses
included 9641 subjects representing 11 cohorts. Total mortality and all cardiovascular events amounted to 1320 and 1128 events,
respectively. A, Adjusted refers to models stratified for cohort and adjusted for sex, age, body mass index, smoking and drinking,
serum total cholesterol, history of cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. B, Fully
adjusted refers to models in which risk estimates based on daytime blood pressure were additionally adjusted for nighttime blood pres-
sure and vice versa, or in which risk estimates based on the night-to-day blood pressure ratio or dipping status were also adjusted for
the 24-hour blood pressure.

the nighttime blood pressure,41 disturbed baroreflex sensitiv-
ity,42 sleep apnea,43 or an increased salt sensitivity necessi-
tating a higher blood pressure at night to drive pressure
natriuresis.44,45 Furthermore, in terms of physical and mental
activity as well as body position, the nighttime blood pressure
is better standardized than the daytime blood pressure.
However, sleep quality13 and nocturnal urination46 are of
importance. The tactile stimuli and noise produced by re-
peated cuff inflations may disturb sleep.47 Manning et al48
assessed sleep quality in 79 untreated subjects from a simple
self-administered questionnaire. Ambulatory asleep systolic
blood pressure and the proportion of nondippers was signif-
icantly lower in the group that reported good sleep than in
those reporting intermediate or poor sleep (101 versus 108
versus 111 mm Hg and 5.9% versus 18.2% versus 13.8%,
respectively).48 Verdecchia et al13 studied a cohort of 2934
initially untreated hypertensive patients. In the presence of
sleep deprivation by ⱖ2 hours (n⫽399) during ambulatory
monitoring, nighttime systolic blood pressure was signifi-
cantly higher (124.6 versus 128.3 mm Hg) but lost its
prognostic significance over 7 years of follow up of mortality
and a composite cardiovascular end point.13
Implications for Clinical Practice
Our review speaks in favor of recording the ambulatory blood
pressure during the entire day. However, in all population
cohorts combined, once the 24-hour blood pressure was in the
Cox model, the night-to-day blood pressure ratio and dipping
status contributed only 0.1% to the explained variance49 in the
incidence of total mortality or the cardiovascular end point
(Table 3). Moreover, when the night-to-day blood pressure
ratio or dipping status was first entered into the Cox model,
without the 24-hour blood pressure level, they sometimes
explained more of the variability in outcome than the 24-hour
blood pressure (Table 3). In previous analyses,29 we demon-
strated that daytime systolic pressure added to the prediction
of total mortality by the nighttime systolic pressure in treated
hypertensive patients, but not in untreated subjects. Higher
daytime blood pressure was associated with lower mortality in
treated patients but with higher cardiovascular risk in untreated
subjects.29 The systolic night-to-day blood pressure ratio, ad-
 8 Hypertension January 2011

Table 3. Risk Explained in Cox Regression in All Population Cohorts (nⴝ9641)

Total Mortality Cardiovascular Events
2
Model Likelihood Ratio P Value R (%) Likelihood Ratio P Value R 2 (%)
Basic model* 13 097.4 ... 13.8 11 499.4 ... 10.2
⫹ 24-hour blood pressure 13 080.5 0.00004 14.0 11 390.8 ⬍0.00001 11.3
⫹ Night-to-day ratio 13 064.6 0.00006 14.1 11 386.4 0.036 11.4
⫹ Dipping status 13 072.1 0.004 14.1 11 387.1 0.054 11.4
⫹ Night-to-day ratio 13 076.5 ⬍0.00001 14.1 11 484.2 0.0001 10.3
⫹ 24-hour blood pressure 13 064.6 0.0005 14.1 11 386.4 ⬍0.00001 11.4
⫹ Dipping status 13 085.3 0.0005 14.0 11 487.1 0.0005 10.3
⫹ 24-hour blood pressure 13 072.1 0.0003 14.1 11 387.1 ⬍0.00001 11.4
⫹ Nighttime blood pressure 13 068.0 ⬍0.00001 14.1 11 404.2 ⬍0.00001 11.2
⫹ Daytime blood pressure 13 066.1 0.17 14.2 11 395.0 0.0024 11.4
⫹ Daytime blood pressure 13 091.0 0.011 13.9 11 424.2 ⬍0.00001 11.0
⫹ Nighttime blood pressure 13 066.1 0.00001 14.2 11 395.0 ⬍0.00001 11.3
*The basic Cox model was stratified by cohort and adjusted for sex, age, body mass index, smoking and drinking, serum total
cholesterol, history of cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. P values are for the
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improvement of the fit across nested models.

justed for the 24-hour blood pressure level and other covariables
conferred higher risk in older (ⱖ60 years) than younger sub-
jects.29 The variance explained by the 24-hour blood pressure
and the indexes derived from the nighttime blood pressure in
Cox models stratified for age and treatment status appear in the
supplemental data (Tables S7 to S10). These tables not only
confirmed our previous findings but also corroborated that the
variance explained depends on the order in which various blood
pressure components are added to the model.
Chronotherapy50 means timing the administration of anti-
hypertensive drugs in such a way that the blood pressure is
lowered over 24 hours, while preserving a normal dipping
pattern. Hermida et al51,52 provided the proof of concept. The
classification of patients according to the night-to-day blood
pressure ratio heavily depends on arbitrary criteria, is poorly
reproducible,48,53–55 and has a different prognostic meaning
according to the outcome under study,29 the prevailing
24-hour blood pressure level,29 and treatment status.29 Re-
verse dippers have the highest cardiovascular risk but die at
an older age than do subjects with a normal dipping pattern,
which raises the issue of reverse causality.29
How to Measure Daytime and Nighttime Blood Pressure?
The current US guidelines do not present any specific
recommendation for definitions of daytime and nighttime
blood pressure.56 The European Society of Hypertension
Working Group on Blood Pressure Monitoring 200357 stated
that “one simple and popular method of determining the time
of awakening and sleeping is to assess them from diary card
entries.” The diary should also provide information on
physical activity, intake of medications, and special events
that might explain a particular diurnal pattern.58 Accelerom-
etry allows distinguishing awake from asleep periods but is
out of reach for most clinicians. One alternative is to use short
fixed clock-time intervals, which eliminate the transition
periods in the morning and evening during which the blood
pressure rapidly changes in most subjects.59 The daytime and
nighttime blood pressures defined in this way approximate
within 1 to 2 mm Hg to the awake and asleep blood
pressures.59 In defining the clock-time intervals, one should
account for differences in lifestyle across different cultures.29
Although the last European guideline recommends that pro-
portionally to the duration of daytime and nighttime the
number of valid blood pressure readings should be similar,58
it is common practice to space the readings at a greater
interval during the night in order not to impair sleep quality.13
It is therefore important to weigh the mean of the 24-hour
blood pressure by the intervals between readings.
Limitations of Our Review
The present results have to be interpreted within the context
of their limitations. First, in our review of studies of hyper-
tensive patients, we could not address the potential method-
ological limitations of the original studies. In particular, we
had to accept that the estimates of risk accounted for different
sets of covariables. We could not retrieve all missing infor-
mation from the principal investigators of original studies.
Aggregate-level analyses of summary statistics have less
power than an analysis of pooled individual subject data.60
Nevertheless, our results from both types of meta-analyses, in
hypertensive patients and populations, respectively, were
remarkably similar. Second, individual studies in patients
varied greatly with respect to the demographic characteristics
of the participants and methodology, resulting in significant
heterogeneity. We addressed this issue by computing pooled
estimates from random-effect models. Third, we included
only from 2 up to 7 studies in our review of data in
hypertensive patients. This number of studies is small com-
pared to the vast literature and did not allow us to check for
publication bias in a reliable way. On the other hand, limiting
our analyses to prospective studies is a strong point. The
systematic and quantitative nature of our review also avoids
bias in the selection of studies and the computation of pooled
estimates. Finally, neither in hypertensive patients nor in
populations could we account for physical activity during
ambulatory monitoring or for antihypertensive treatment after
enrollment.
 Hansen et al
Perspectives
Our review identified several gaps in our current knowledge
and therefore sets an agenda for researchers and experts
writing guidelines. Further prospective studies should clarify
the influence of treatment and age on the predictive value of
the nighttime compared to the 24-hour or daytime blood
pressure. Based on Hill’s31 criteria, such observational studies
should exclude the issue of reverse causality. Because clas-
sification of patients according to the night-to-day blood
pressure ratio greatly depends on arbitrary criteria and be-
cause it is poorly reproducible, we suggest that in future
publications any categorical representation of the night-to-
day blood pressure ratio be supported by continuous analyses
adjusted for the 24-hour blood pressure.
Our current findings highlight the necessity to translate
statistical parameters into clinically meaningful recommen-
dations. By tradition, clinicians reason first in terms of blood
pressure level rather than diurnal blood pressure profile.
Downloaded from http://hyper.ahajournals.org/ by guest on March 2, 2018
Properly designed randomized clinical trials should prove the
reversibility of the risk associated with a nondipping blood
pressure profile. In the absence of conclusive evidence
proving that nondipping is a reversible risk factor, the option
whether or not to restore the diurnal blood pressure profile to
a normal pattern should be left to the clinical judgment of
doctors and be individualized for each patient. Expert com-
mittees might draft new recommendations to help clinicians
apply current knowledge in their day-to-day practice.
Acknowledgments
We gratefully acknowledge the expert assistance of Sandra Covens
and Ya Zhu (Studies Coordinating Centre, Leuven, Belgium). We
thank Robert Fagard (Leuven, Belgium), Kazuomi Kario (Tochigi,
Japan), Gianpaolo Reboldi (Assisi, Italy), and Paolo Verdecchia
(Assisi, Italy) for providing additional data from their studies. The
IDACO (International Database on Ambulatory Blood Pressure
Monitoring in Relation to Cardiovascular Outcomes) investigators
are listed in the supplemental data.
Sources of Funding
The European Union (grants IC15-CT98-0329-EPOGH, LSHM-CT-
2006-037093, and HEALTH-F4-2007-201550), the Fonds voor
Wetenschappelijk Onderzoek Vlaanderen (Ministry of the Flemish
Community, Brussels, Belgium; grants G.0575.06 and G.0734.09),
and the Katholieke Universiteit Leuven (grants OT/00/25 and OT/
05/49) supported the Studies Coordinating Centre in Leuven, Bel-
gium. The Lundbeck Fonden (grant R32-A2740) supported Dr. T.W.
Hansen’s research.
Disclosures
None.
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 Predictive Role of the Nighttime Blood Pressure
Tine W. Hansen, Yan Li, José Boggia, Lutgarde Thijs, Tom Richart and Jan A. Staessen

Hypertension. 2011;57:3-10; originally published online November 15, 2010;

doi: 10.1161/HYPERTENSIONAHA.109.133900
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 ONLINE SUPPLEMENT

The Predictive Role of the Nighttime Blood Pressure

Short title: Risk Prediction from Nighttime Blood Pressure

Tine W. Hansen, Yan Li, José Boggia,

Lutgarde Thijs, Tom Richart, Jan A. Staessen

Correspondence to:
Tine Willum Hansen, MD, PhD,
Department of Clinical Physiology, Nuclear Medicine
and PET, Rigshospitalet,
Copenhagen University Hospital
Blegdamsvej 9 2100 Copenhagen
Denmark.

Telephone: +45-35-45 4012 (office)

+45-60-88 2122 (mobile)
Facsimile: +45-35-45 4015
E-mail: tw@heart.dk
Research Center for Prevention and Health and Department of Clinical Physiology, Nuclear Medicine
and PET, Rigshospitalet, Copenhagen University Hospital, Faculty of Health Sciences, Rigshospitalet,
Copenhagen, Denmark (T.W.H.); Center for Epidemiological Studies and Clinical Trials and Center for
Vascular Evaluations, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong Universi-
ty School of Medicine, Shanghai, China (Y.L.); Departamento de Fisiopatología, Hospital de Clínicas,
Universidad de la República, Montevideo, Uruguay (J.B.); Studies Coordinating Centre, Division of
Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, University
of Leuven, Belgium (Y.L., L.T., T.R., J.A.S.); and Department of Epidemiology, Maastricht University,
Maastricht, The Netherlands (T.R., J.A.S.).

Correspondence to: Tine Willum Hansen, MD, PhD, Department of Clinical Physiology, Nuclear Medi-
cine and PET, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenha-
gen Denmark. Telephone:+45-60-88 2122 (mobile); Facsimile: +45-35-45 4015. E-mail: tw@heart.dk

IDACO Centers and Investigators:

Belgium (Noorderkempen): R. Fagard, Y. Jin, T. Kuznetsova, T. Richart, J. A. Staessen, L. Thijs;
China (JingNing): Y. Li, J.G. Wang; the Czech Republic (Pilsen): J. Filipovský, J. Sleiderová, M. Tichá;
Denmark (Copenhagen): T. W. Hansen, H. Ibsen, J. Jeppesen, S. Rasmussen, C Torp-Pedersen;
Italy (Padua): E. Casiglia, A. Pizzioli, V. Tikhonoff; Ireland (Dublin): E. Dolan, E. O’Brien; Japan (Oha-
sama): K. Asayama, J. Hashimoto, H. Hoshi, Y. Imai, R. Inoue, M. Kikuya, H. Metoki, T. Obara, T.
Ohkubo, H. Satoh, K. Totsune; Poland (Kraków): A. Adamkiewicz-Piejko, M. Cwynar, J. Gąsowski, T.
Grodzicki, K. Kawecka-Jaszcz, W. Lubaszewski, A. Olszanecka, K. Stolarz-Skrzypek, B. Wizner, W.
Wojciechowska, J. Zyczkowska; the Russian Federation (Novosibirsk): T. Kuznetsova, S. Malyutina, Y.
Nikitin, E. Pello, G. Simonova, M. Voevoda; Sweden (Uppsala): B. Andrén, L. Berglund, K. Björklund-
Bodegård, L. Lind, B. Zethelius; Uruguay (Montevideo): M. Bianchi, V. Moreira, E. Sandoya, C. Schet-
tini, E. Schwedt, H. Senra; Venezuela (Maracaibo): G. Maestre, L. Mena.
 Expanded Methods

Search Strategy and Statistical Methods

We based our analyses of cohorts of hypertensive patients and population studies on summary statis-
tics and individual subject data, respectively. For both patients and populations, we limited our ana-
lyses to systolic blood pressure, because at middle and older age this is the predominant risk factor.1

Cohorts Studies of Hypertensive Patients

To identify studies of hypertensive patients, in March 2010, we searched the PubMed database
(http://www.ncbi.nlm.nih.gov/sites/entrez) for publications in English without any restraint on the year
of publication. Starting from the preview/index tab, we choose as search terms for titles and abstracts:
“dipping”, “daytime”, or “nighttime” in combination with “hypertension”, “risk”, or “mortality”. Eligible
studies had to be prospective. Enrolled patients had to be 18 years or older. We only considered
studies, in which the ambulatory blood pressure was recorded outside the hospital. Required end-
points were total mortality and/or a composite of fatal and nonfatal cardiovascular events. We ma-
nually checked the reference lists of fully reviewed papers for articles not found by the PubMed
search. When relevant information was not included in the published papers, we requested additional
data from the senior authors.
Our initial search identified 169 articles for possible inclusion in the systematic review of hyperten-
sive cohorts (Figure 1). Of these, we excluded 145 on initial screen of the abstract because of a
cross-sectional design (Table S1). The remaining 24 articles were fully reviewed. By checking the
reference lists, we found 4 additional studies.2-5 On the other hand, we excluded 12 reports of longi-
tudinal cohort studies, because the eligibility criteria were not met6-9 (n=4) or because the same
patients had been included in more than one report10-17 (n=8). In the latter case, we used the publi-
cation with the most complete information. The articles were ordered by year of publication and the
name of the first author, given a unique identification number, and entered into a dedicated literature
database, using Reference Manager, version 12.0.1 (Thomson Reuters; http://www.refman.com).
One investigator (T.W.H.) read all papers, extracted, and computerized the relevant information, and
provided copies of the papers to the senior author (J.A.S.), who checked the data extraction and
summary statistics. Inconsistencies were discussed until a unanimous interpretation of the source
data was reached. As measures of quality control, we considered blinded endpoint ascertainment,
adjustments applied in regression analysis, and the impact factor of the journal at the time of publica-
tion of each reviewed article.18
We used SAS software (SAS Institute Inc., Cary, NC) for entering the extracted summary statistics
into a database for subsequent statistical analysis. In our analyses, we used adjusted and fully ad-
justed hazard ratios as reported in published papers or as provided by authors on our request. Ad-
justed refers to the most extensively adjusted risk estimate reported. Fully adjusted refers to Cox
models, in which risk estimates based on daytime blood pressure were additionally adjusted for night-
time blood pressure and vice versa, or in which risk estimates based on the night-to-day blood pres-
sure ratio or dipping status were also adjusted for the 24-h blood pressure.
We used the PROC MIXED procedure of the SAS package and the method of moments to com-
pute pooled estimates of the hazard ratios as extracted from published papers or as provided by the
authors.19 Pooled hazard ratios were weighted by the inverse of the variance in individual studies.
We assessed the null-hypothesis of homogeneity across individual studies by the Q test.19 In case of
significant heterogeneity, pooled hazard ratios were computed from random effect models and other-
wise from fixed effect models.

Prospective Population Studies

For the population studies, we did an electronic search of the English literature, using as search terms
“ambulatory blood pressure”, “population”, “mortality”, and “morbidity”, which identified 14 prospective
studies.20-31 As described in detail elsewhere, we constructed the International Database on Ambu-
latory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO).32 Studies were
eligible for inclusion if they included a random population sample, if information about the conventional
and ambulatory blood pressures and cardiovascular risk factors were available at baseline, and if the
subsequent follow-up included both fatal and nonfatal outcomes. We excluded the Maracaibo Aging
Study22 and the Jackson Heart Study,23 because at the time of writing this review outcome data had
not yet been made available for inclusion into the IDACO database. The Pressioni Arteriose Monito-
rate e Loro Associazioni (PAMELA) study21 was omitted, because only fatal outcomes were available.
Our systematic review of population studies was a meta-analysis of individual subject data. The
same SAS macro processed all ambulatory recordings, which generally stayed unedited. The Oha-
sama recordings were edited sparsely according to previously published criteria.33 While accounting
for the daily pattern of activities of the participants, we defined daytime as the interval from 10 AM to 8
PM in Europeans20,24,31 and South Americans,29 and from 8 AM to 6 PM in Asians.27,28 The cor-
responding nighttime intervals ranged from midnight to 6 AM20,24,29,31 and from 10 PM to 4 AM,
27,28 respectively. These fixed intervals eliminate the transition periods in the morning and evening
when blood pressure changes rapidly, resulting in daytime and nighttime blood pressure levels that
are within 1–2 mm Hg of the awake and asleep levels.34 We weighted the individual means of the
ambulatory blood pressure by the interval between readings. In dichotomous analyses, we defined
nondipping as a night-to-day blood pressure ratio of 0.90 or higher.
We used Cox regression to compute hazard ratios. We checked the proportional hazards assump-
tion by the Kolmogorov-type supremum test, as implemented in the PROC PHREG procedure of the
SAS package and by testing the interaction terms between follow-up duration and either blood pres-
sure or the night-to-day blood pressure ratio. In adjusted models, we stratified for cohort and we
adjusted for sex, age, body mass index, smoking and drinking, serum total cholesterol, history of
cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. Fully adjusted
models for the daytime blood pressure additionally included the nighttime blood pressure, and vice
versa, and for the night-to-day blood pressure ratio and the dipping status they additionally included
the 24-h blood pressure. We applied the generalized R2 statistic to assess the risks explained in Cox
regression35 by consecutively entering the 24-h blood pressure and indexes derived from the noctur-
nal blood pressure and vice versa as predictor variables into the models for total mortality and the
cardiovascular endpoint.
 Expanded Results

Studies in Hypertensive Patients

Nighttime Blood Pressure

Total Mortality
Across 6 studies2,36-40 (Table S2), the hazard ratio (HR) expressing the risk of death associated with
the nighttime blood pressure as continuous variable ranged from 1.06 (P=0.11)2 to 1.20
(P<0.0001).40 Of these 7 HRs, 5 were significant.36,38-41 The pooled HR combining these 7 studies
(Figure 2, Panel A) was 1.15 (95% confidence interval [CI], 1.11–1.20; P<0.0001). HRs with addition-
al adjustment for the daytime blood pressure were available from 5 studies,36,38-40,42 ranging from
1.03 (P=0.87)42 to 1.21 (P=0.020).36 Of these 5 fully adjusted HRs, 4 were significant. 36,38-40 The
pooled HR combining these 5 studies (Figure 2, Panel B) was 1.16 (CI, 1.12–1.22; P<0.0001).
Cardiovascular Events
Among 7 studies4,36,37,40,43-45 (Table S3), the HRs ranged from 1.10 (P=0.060)43 to 1.31
(P=0.0001)37 of which 6 were significant.4,36,37,40,44,45 The pooled HR (Figure 2, Panel A) was 1.23
(CI, 1.18–1.28; P<0.0001). HRs with additional adjustment for the daytime blood pressure were
available from 5 studies,3,4,36,40,44 ranging from 1.00 (P=0.99)3 to 1.26 (P=0.0010).36 Of these 5
fully adjusted HRs, 3 were significant.36,40,44 The pooled HR combining these 5 studies (Figure 2,
Panel B) was 1.19 (CI, 1.12–1.27; P<0.0001).

Daytime Blood Pressure

Total Mortality
Among 5 studies36-40 (Table S2), the HRs expressing the risk of death associated with the daytime
blood pressure ranged from 1.07 (P=0.39)36 to 1.40 (P<0.0001).41 Of these 6 HRs, 4 were signifi-
cant.38-41 The pooled HR (Figure 2, Panel A) was 1.16 (CI, 1.09–1.23; P<0.0001). HRs with addi-
tional adjustment for the nighttime blood pressure, available from 5 studies,36,38-40,42 ranged from
0.83 (P=0.44)42 to 1.10 (P=0.18),40 but none was significant. The pooled HR (Figure 2, Panel B) was
0.99 (CI, 0.93–1.06; P=0.84).
Cardiovascular Events
Across 7 studies4,36,37,40,43-45 (Table S3), the HRs ranged from 1.10 (P=0.060)43 to 1.42
(P=0.0001),37 6 reaching significance.4,36,37,40,44,45 The pooled HR combining these 7 studies
(Figure 2, Panel A) was 1.23 (CI, 1.17–1.31; P<0.0001). HRs with additional adjustment for the
nighttime blood pressure were available from 5 studies,3,4,36,40,44 ranging from 0.94 (P=0.45)36 to
1.14 (P=0.27).4 Of these 5 fully adjusted HRs, none was significant. The pooled fully adjusted HR
(Figure 2, Panel B) was 1.06 (CI, 0.98–1.13; P=0.13).

Night-to-Day Blood Pressure Ratio

Total Mortality
Across 4 studies2,5,39,40 (Table S2), the HRs expressing the risk of death associated with the night-
to-day blood pressure ratio ranged from 1.14 (P=0.16)40 to 1.35 (P=0.027).5 Of these 4 HRs, 3 were
significant.2,5,39 The pooled HR (Figure 2, Panel A) was 1.19 (CI, 1.12–1.27; P<0.0001). HRs with
additional adjustment for the 24-h blood pressure, available from 3 studies,40,46,47 ranged from 1.06
(P=0.54)40 to 1.63 (P=0.0020),46 but only 1 was significant.46 The pooled HR combining these 3
studies (Figure 2, Panel B) was 1.23 (CI, 0.96–1.57; P=0.10).
Cardiovascular Events
In 2 studies40,44 (Table S3), the HRs were 1.23 (P=0.0018) and 1.24 (P=0.033), respectively. The
pooled HR (Figure 2, Panel A) was 1.23 (CI, 1.11–1.37; P<0.0001). HRs with additional adjustment
for the 24-h blood pressure amounted to 1.12 (P=0.31)44 and 1.13 (P=0.081),40 respectively. The
pooled fully adjusted HR (Figure 2, Panel B) was 1.13 (CI, 1.00–1.27; P=0.04).
Dipping Status
Total Mortality
Across 3 studies2,39,40 (Table S2), the HRs expressing the risk of death associated with nondipping
ranged from 1.25 (P=0.15)40 to 1.45 (P=0.0017).39 Of these 3 HRs, 2 were significant.2,39 The
pooled HR combining 3 studies (Figure 2, Panel A) was 1.37 (CI, 1.17–1.61; P<0.0001). HRs for the
dipping status with additional adjustment for the 24-h blood pressure, available from 4
studies,40,42,46,47 ranged from 1.10 (P=0.80)42 to 1.67 (P=0.075),47 but only 1 reached signific-
ance.46 The pooled fully adjusted HR (Figure 2, Panel B) was 1.30 (CI, 1.06–1.60; P=0.012).
Cardiovascular Events
In 2 studies4,40 (Table S3), the HRs expressing the cardiovascular risk associated with nondipping
were 1.15 (P=0.66)4 to 1.36 (P=0.0060).40 The pooled HR (Figure 2, Panel A) was 1.34 (CI, 1.09–
1.64; P=0.006). While accounting for the 24-h blood pressure, the HRs expressing the cardiovascular
risk associated with nondipping were 1.22 (P=0.076)40 and 1.39 (P=0.20).3 The pooled fully adjusted
HR (Figure 2, Panel B) was 1.25 (CI, 1.02–1.52; P=0.028).

Studies in Population Cohorts

Nighttime Blood Pressure

Total Mortality
In 11 cohorts (Table S5), the HRs expressing the risk of death associated with the nighttime blood
pressure ranged from 1.03 (P>0.46)29,48 to 1.57 (P=0.0007).28 Of these 11 HRs, 4 were
significant.27,28,31,49 The HR combing all the cohorts (Figure 3, Panel A) was 1.11 (CI, 1.07–1.16;
P<0.0001). HRs with additional adjustment for the daytime blood pressure ranged from 1.04
(P=0.45)48 to 1.73 (P=0.0017).28 Of these 11 fully adjusted HRs, 4 were significant.27,28,31,49 The
combined HR (Figure 3, Panel B) was 1.14 (CI, 1.08–1.20; P<0.0001).
Cardiovascular Events
HRs ranged from 1.11 (P=0.0012)48 to 1.86 (P=0.0005),28 and 6 were significant (Table S6).27-
29,31,48,49 The HR combing all the cohorts (Figure 3, Panel A) was 1.21 (CI, 1.17–1.26; P<0.0001).
HRs with additional adjustment for the daytime blood pressure ranged from 1.02 (P=0.91)26 to 1.86
(P=0.0005),28 of which only 3 were significant.27,28,49 The combined fully adjusted HR (Figure 3,
Panel B) was 1.15 (CI, 1.09–1.21; P<0.0001).

Daytime Blood Pressure

Total Mortality
The HRs expressing the risk of death associated with the daytime blood pressure ranged from 0.92
(P>0.64)26 to 1.23 (P=0.21),28 but only 2 were significant.31,49 The HR combining the 11 cohorts
(Figure 3, Panel A) was 1.06 (CI, 1.01–1.10; P=0.0075). HRs with additional adjustment for the
nighttime blood pressure ranged from 0.77 (P=0.46)26 to 1.01 (P=0.92),31 but none was significant.
The pooled fully adjusted HR (Figure 3, Panel B) was 0.96 (CI, 0.91–1.02; P=0.16).
Cardiovascular Events
The HRs ranged from 1.14 (P=0.0020)48 to 1.81 (P=0.0018).28 Of these 11 HRs, 7 were
significant.26-29,31,48,49 The HR combing all the cohorts (Figure 3, Panel A) was 1.21 (CI, 1.16–1.27;
P<0.0001). HRs with additional adjustment for the nighttime blood pressure ranged from 1.00
(P>0.99)49 to 1.27 (P=0.15),26 but none was significant. The pooled fully adjusted HR (Figure 3,
Panel B) was 1.09 (CI, 1.03–1.16; P=0.0045).

Night-to-Day Blood Pressure Ratio

Total Mortality
The HRs expressing the risk of death associated with the night-to-day blood pressure ratio ranged
from 1.06 (P=0.45)48 to 1.86 (P=0.0079).28 Of these 11 HRs, 3 were significant.27,28,49 The pooled
HR (Figure 3, Panel A) was 1.18 (CI, 1.10–1.26; P<0.0001). HRs with additional adjustment for the
24-h blood pressure ranged from 1.05 (P=0.53)48 to 1.77 (P=0.014).28 Of these 11 fully adjusted
HRs, 3 were significant.27,28,49 The HR combining all the cohorts (Figure 3, Panel B) was 1.15 (CI,
1.08–1.24; P<0.0001).
Cardiovascular Events
The HRs ranged from 0.89 (P=0.63)26 to 1.69 (P=0.089).28 Only 2 were significant.27,49 The pooled
HR (Figure 3, Panel A) was 1.16 (CI, 1.08–1.24; P<0.0001). HRs with additional adjustment for the
24-h blood pressure ranged from 0.87 (P=0.55)26 to 1.46 (P=0.22).28 Of these 11 fully adjusted HRs,
only 2 were significant.27,49 The HR combining all the cohorts (Figure 3, Panel B) was 1.08 (CI,
1.01–1.16; P=0.029).

Dipping status
Total Mortality
Across the 11 cohorts (Table S5), the HRs expressing the risk of death associated with nondipping
ranged from 1.02 (P=0.96)30 to 2.51 (P=0.11),28 but only 1 was significant.27 The pooled HR (Figure
3, Panel A) was 1.26 (CI, 1.11–1.44; P=0.0005). HRs for the dipping status with additional adjustment
for the 24-h blood pressure ranged from 1.01 (P=0.98)30 to 2.41 (P=0.13),28 but only 1 was signifi-
cant.27 The pooled fully adjusted HR (Figure 3, Panel B) was 1.22 (CI, 1.07–1.39; P=0.0029).
Cardiovascular Events
The HRs expressing the cardiovascular risk associated with nondipping ranged from 0.57 (P=0.37)30
to 4.93 (P=0.073) (Table S6),28 Only 2 were significant.27,49 The pooled HR (Figure 3, Panel A) was
1.29 (CI, 1.12–1.48; P=0.0003). HRs for the dipping status with additional adjustment for the 24-h
blood pressure ranged from 0.62 (P=0.45)30 to 4.23 (P=0.12),28 of which 2 were significant.27,49 The
pooled fully adjusted HR (Figure 3, Panel B) was 1.15 (CI, 1.00–1.33; P=0.054).
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TABLE S1. Studies with Cross-Sectional Design Not Included in the Quantitative Overview

1. Kaya MG, Yarlioglues M, Gunebakmaz O, Gunturk E, Inanc T, Dogan A, Kalay N, Top-

sakal R. Platelet activation and inflammatory response in patients with non-dipper hyper-
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TABLE S2. Adjusted Hazard Ratios for Total Mortality in Individual Cohorts of Hypertensive Patients

Nighttime BP Daytime BP Night-to-Day Ratio Nondipping

Publication Ne/Ns
(+10 mm Hg) (+10 mm Hg) (+10%) (0,1)

Staessen, 199936 68/808 1.17 (1.03-1.33)* 1.07 (0.91-1.24) … …

FA 1.21 (1.03-1.42)* 0.93 (0.77-1.13) … …

Kario, 200142 38/575 FA 1.03 (0.72-1.47) 0.83 (0.52-1.33) … 1.10 (0.53-2.31)

Clement, 200337 78/1963 1.14 (0.95-1.38) 1.17 (0.94-1.46) … …

Dolan, 200538 646/5292 1.14 (1.10-1.18)‡ 1.09 (1.04-1.13)‡ … …

FA 1.18 (1.12-1.24)‡ 0.95 (0.90-1.00) … …

Astrup, 20075 54/104 … … 1.35 (1.05 -1.79)* …

Ben-Dov, 200739 303/3957 1.17 (1.11-1.23)‡ 1.18 (1.11-1.25)‡ 1.21 (1.10 -1.30)‡ 1.45 (1.15- 1.83)†
FA 1.15 (1.06-1.24)‡ 1.04 (0.94-1.15) … …

Verdecchia, 200740 176/2934 1.20 (1.12-1.31)‡ 1.22 (1.12-1.34)‡ 1.14 (0.95- 1.37) 1.25 (0.92- 1.69)
FA 1.13 (1.00-1.28)‡ 1.10 (0.96-1.27) 1.06 (0.88- 1.28) 1.14 (0.84- 1.56)

Brotman, 200846 61/621 FA … … 1.63 (1.19-2.21)† 1.47 (1.06- 2.15)*

Muxfeldt, 200947 70/556 FA … … 1.15 (0.87-1.51) 1.67 (0.95- 2.94)

Palmas, 20092 215/1178 1.06 (0.99-1.14) … 1.16 (1.03-1.29)† 1.37 (1.01-1.87)*

Ungar, 200941 107/805 1.40 (1.14-1.71)† 1.40 (1.14-1.75)† … …

Ne/Ns refers to the number of events/patients at risk. BP indicates blood pressure. All hazard ratio were adjusted. The covariables are listed
in Table 1 in main paper. Fully adjusted (FA) refers to models in which risk estimates based on nighttime blood pressure were additionally
adjusted for daytime blood pressure and vice versa, or in which risk estimates based on the night-to-day blood pressure ratio or dipping status
were also adjusted for the 24-h blood pressure. … indicate not applicable. Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001.
TABLE S3. Adjusted Hazard Ratios for Cardiovascular Events in Individual Cohorts of Hypertensive Patients

Nighttime BP Daytime BP Night-to-Day Ratio Nondipping

Publication Ne/Ns
(+10 mm Hg) (+10 mm Hg) (+10%) (0,1)

Staessen, 199936 98/808 1.21 (1.09-1.35)‡ 1.26 (1.10-1.45)‡ … …

FA 1.26 (1.10-1.45)‡ 0.94 (0.80-1.10) … …

Khattar, 200143 157/688 1.10 (1.00-1.22) 1.10 (1.00-1.22) … …

Clement, 200337 157/1963 1.31 (1.16-1.50)‡ 1.42 (1.22-1.67)‡ … …

Fagard, 200544 86/391 1.22 (1.09-1.38)‡ 1.18 (1.04-1.33)† 1.24 (1.01–1.50)* …

FA 1.18 (1.01-1.38)* 1.11 (0.90-1.27) 1.12 (0.90-1.39) …

Verdecchia, 200740 356/2934 1.26 (1.19-1.33)‡ 1.25 (1.17-1.34)‡ 1.23 (1.08-1.40)† 1.36 (1.09-1.69)†
FA 1.20 (1.10-1.31)‡ 1.08 (0.97-1.19) 1.13 (0.98-1.29) 1.22 (0.98-1.52)

Eguchi, 20084 100/1268 1.23 (1.05-1.43)† 1.25 (1.04-1.50)* … 1.15 (0.62-2.15)

FA 1.14 (0.94-1.39) 1.14 (0.90-1.44) … …

Ishikawa, 20083 66/811 FA 1.00 (0.78-1.28) 1.00 (0.73-1.37) … 1.39 (0.84-2.31)

Muxfeldt, 200947 109/556 FA … … 1.25 (1.00-1.56)* 1.74 (1.12- 2.71)†

Dolan, 200945 239/1905 1.28 (1.16-1.41)‡ 1.29 (1.14-1.46)‡ … …

Ne/Ns refers to the number of events/patients at risk. BP indicates blood pressure. All hazard ratio were adjusted. The covariables are listed
in Table 1 in main paper. Fully adjusted (FA) refers to models in which risk estimates based on nighttime blood pressure were additionally
adjusted for daytime blood pressure and vice versa, or in which risk estimates based on the night-to-day blood pressure ratio or dipping status
were also adjusted for the 24-h blood pressure. … indicate not applicable. Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001.
TABLE S4. Studies in Hypertensive Patients

Publication Definition of night-to-day blood pressure ratio Definition of nondipping

Staessen, 199936 … …
Kario, 200142 … nighttime SBP/daytime SBP ≥ 0.90
Khattar, 200143 … …
Clement, 200337 … …
Dolan, 200538 … …
Fagard, 200544 nighttime SBP/daytime SBP …
((daytime SBP - nighttime SBP)/ daytime SBP) + …
Astrup, 20075
(daytime DBP - nighttime DBP)/ daytime DBP)/2
Ben-Dov, 200739 nighttime SBP/daytime SBP nighttime SBP/daytime SBP > 0.90
Verdecchia, 200740 nighttime SBP/daytime SBP nighttime SBP/daytime SBP ≥ 0.90
Brotman, 200846 (daytime SBP –nighttime SBP)/daytime SBP (daytime SBP –nighttime SBP)/daytime SBP <0.10
Eguchi, 20084 … (daytime SBP –nighttime SBP)/daytime SBP <0.10
Ishikawa, 20083 … nighttime SBP/daytime SBP ≥ 0.90
Dolan, 200945 … …
Muxfeldt, 200947 nighttime SBP/daytime SBP nighttime SBP/daytime SBP > 0.90
Palmas, 20092 nighttime SBP/daytime SBP nighttime SBP/daytime SBP > 0.90
Ungar, 200941 … …

SBP and DBP indicate systolic blood pressure and diastolic blood pressure, respectively. … indicate not applicable.
TABLE S5. Adjusted Hazard Ratios for Total Mortality in Population Cohorts

Nighttime BP Daytime BP Night-to-Day Ratio Nondipping

Cohort Ne/Ns
(+10 mm Hg) (+10 mm Hg) (+10%) (0,1)

Copenhagen24 371/2142 1.15 (1.07–1.23)‡ 1.10 (1.02–1.18)* 1.23 (1.07–1.40)† 1.19 (0.94–1.50)
FA 1.17 (1.06–1.29)† 0.97 (0.87–1.08) 1.18 (1.03–1.36)* 1.10 (0.87–1.40)
Ohasama27 344/1526 1.11 (1.01–1.22)‡ 1.02 (0.93–1.13) 1.16 (1.02–1.33)* 1.46 (1.11–1.91)†
FA 1.15 (1.02–1.28)* 0.95 (0.84–1.06) 1.16 (1.01–1.33)* 1.45 (1.11–1.90)†
Noorderkempen31 136/1127 1.21 (1.08–1.35)‡ 1.18 (1.04–1.34)† 1.24 (0.98–1.57) 1.30 (0.91–1.87)
FA 1.20 (1.00–1.43)* 1.01 (0.83–1.23) 1.16 (0.91–1.47) 1.15 (0.79–1.67)
Uppsala20 300/1100 1.03 (0.95–1.11) 1.00 (0.91–1.11) 1.06 (0.91–1.23) 1.17 (0.81–1.70)
FA 1.04 (0.94–1.15) 0.98 (0.86–1.11) 1.05 (0.90–1.22) 1.15 (0.78–1.69)
Montevideo29 96/1438 1.03 (0.91–1.17) 0.98 (0.86–1.12) 1.13 (0.90–1.41) 1.20 (0.79–1.82)
FA 1.09 (0.92–1.31) 0.92 (0.76–1.11) 1.13 (0.90–1.41) 1.20 (0.79–1.82)
JingNing28 14/351 1.57 (1.21–2.04)‡ 1.23 (0.89–1.70) 1.86 (1.18–2.95)† 2.51 (0.81–7.83)
FA 1.73 (1.23–2.44)† 0.84 (0.57–1.24) 1.77 (1.12–2.79)* 2.41 (0.78–7.43)
EPOGH26 23/1027 1.08 (0.80–1.46) 0.92 (0.64–1.29) 1.37 (0.80–2.35) 1.12 (0.46–2.74)
FA 1.26 (0.84–1.90) 0.77 (0.48–1.90) 1.40 (0.81–2.43) 1.15 (0.47–2.82)
Allied Irish Bank30 36/930 1.07 (0.82–1.38) 0.96 (0.76–1.22) 1.29 (0.79–2.10) 1.02 (0.46–2.22)
FA 1.23 (0.84–1.81) 0.84 (0.60–1.19) 1.29 (0.79–2.10) 1.01 (0.46–2.22)
All Participants 1320/9641 1.11 (1.07–1.16)‡ 1.06 (1.01–1.10)† 1.18 (1.10–1.26)‡ 1.26 (1.11–1.44)‡
FA 1.14 (1.08–1.20)‡ 0.96 (0.91–1.02) 1.15 (1.08–1.24)‡ 1.22 (1.07–1.39)†

Ne/Ns refers to the number of events/persons at risk. BP indicates blood pressure. Nondipping was a night-to-day blood pressure ratio of
0.90 or higher. EPOGH denotes all the studies contributing to the European Project on Genes in Hypertension (Novosibirsk, Pilsen, Padova,
and Kraków). All hazard ratios were adjusted for sex, age, body mass index, smoking and drinking, serum total cholesterol, history of cardi-
ovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. The analyses of all participants were additionally stratified by
cohort. Fully adjusted (FA) refers to models, in which risk estimates based on nighttime blood pressure were additionally adjusted for daytime
blood pressure and vice versa, or in which risk estimates based on the night-to-day blood pressure ratio or dipping status were also adjusted
for the 24-h blood pressure. Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001.
TABLE S6. Adjusted Hazard Ratios for Cardiovascular Events in Population Cohorts

Nighttime BP Daytime BP Night-to-Day Ratio Nondipping

Cohort Ne/Ns
(+10 mm Hg) (+10 mm Hg) (+10%) (0,1)

Copenhagen24 285/2142 1.28 (1.19–1.38)‡ 1.21 (1.12–1.32)‡ 1.35 (1.16–1.57)‡ 1.56 (1.21–2.02)‡
FA 1.28 (1.15–1.48)‡ 1.00 (0.89–1.13) 1.26 (1.08–1.47)† 1.37 (1.06–1.78)*
Ohasama27 247/1526 1.32 (1.20–1.47)‡ 1.21 (1.09–1.34)‡ 1.24 (1.06–1.45)† 1.61 (1.18–2.19)†
FA 1.30 (1.15–1.48)‡ 1.03 (0.91–1.18) 1.23 (1.05–1.46)† 1.56 (1.15–2.12)†
Noorderkempen31 99/1127 1.22 (1.07–1.40)† 1.29 (1.12–1.48)‡ 0.98 (0.75–1.30) 0.76 (0.48–1.19)
FA 1.06 (0.86–1.30) 1.23 (0.99–1.53) 0.91 (0.69–1.20) 0.63 (0.39–1.01)
Uppsala20 317/1100 1.11 (1.04–1.18)† 1.14 (1.05–1.24)† 1.07 (0.94–1.22) 1.39 (1.00–1.94)*
FA 1.06 (0.97–1.15) 1.09 (0.98–1.22) 1.00 (0.88–1.14) 1.20 (0.85–1.69)
Montevideo29 121/1438 1.20 (1.07–1.34)† 1.22 (1.08–1.37)‡ 1.03 (0.84–1.26) 0.92 (0.63–1.33)
FA 1.10 (0.94–1.29) 1.14 (0.97–1.33) 1.01 (0.82–1.24) 0.86 (0.59–1.25)
JingNing28 8/351 1.86 (1.31–2.63)‡ 1.81 (1.14–2.87)* 1.69 (0.92–3.08) 4.93 (0.86–28.2)
FA 1.67 (1.09–2.56)* 1.24 (0.73–2.10) 1.46 (0.79–2.68) 4.23 (0.70–25.7)
EPOGH26 32/1027 1.21 (0.94–1.56) 1.29 (1.02–1.64)* 0.89 (0.56–1.43) 1.02 (0.48–2.20)
FA 1.02 (0.73–1.43) 1.27 (0.92–1.76) 0.87 (0.55–1.38) 0.95 (0.44–2.07)
Allied Irish Bank30 19/930 1.26 (0.89–1.79) 1.20 (0.90–1.61) 0.99 (0.49–2.00) 0.57 (0.17–1.97)
FA 1.17 (0.67–2.02) 1.09 (0.69–1.73) 1.04 (0.52–2.09) 0.62 (0.18–2.13)
All Participants 1128/9641 1.21 (1.17–1.26)‡ 1.21 (1.16–1.27)‡ 1.16 (1.08–1.24)‡ 1.29 (1.12–1.48)‡
FA 1.15 (1.09–1.21)‡ 1.09 (1.03–1.16)‡ 1.08 (1.01–1.16)* 1.15 (1.00–1.33)
Ne/Ns refers to the number of events/persons at risk. BP indicates blood pressure. Nondipping was a night-to-day blood pressure ratio of 0.90
or higher. EPOGH denotes all the studies contributing to the European Project on Genes in Hypertension (Novosibirsk, Pilsen, Padova, and
Kraków). All hazard ratios were adjusted for age, sex, body mass index, smoking and drinking, serum total cholesterol, history of cardiovascular
disease, diabetes mellitus, and treatment with antihypertensive drugs. The analyses of all participants were additionally stratified by cohort. Fully
adjusted (FA) refers to models , in which risk estimates based on daytime blood pressure were additionally adjusted for nighttime blood pressure
and vice versa, or in which risk estimates based on the night-to-day blood pressure ratio or dipping status were also adjusted for the 24-h blood
pressure. Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001
TABLE S7. Risk Explained in Cox Regression in All Population Cohorts in Subjects < 60 Years (n=5780)
Model Total Mortality Cardiovascular Events
Likelihood ratio P-value R2 (%) Likelihood ratio P-value R2 (%)
Basic model* 2264.3 – 3.1 2174.2 – 4.0
+ 24-h blood pressure 2260.1 0.040 3.2 2133.7 <0.00001 4.7
+ Night-to-day ratio 2258.2 0.17 3.2 2133.4 0.58 4.7
+ Dipping status 2258.2 0.17 3.2 2133.1 0.44 4.7
+ Night-to-day ratio 2261.9 0.12 3.2 2174.1 0.75 4.0
+ 24-h blood pressure 2258.2 0.17 3.2 2133.4 <0.00001 4.7
+ Dipping status 2261.9 0.12 3.2 2174.1 0.75 4.0
+ 24-h blood pressure 2258.2 0.17 3.2 2133.1 <0.00001 4.7
+ Nighttime blood pressure 2257.3 0.0082 3.3 2144.4 <0.00001 4.5
+ Daytime blood pressure 2257.2 0.75 3.3 2132.0 0.0004 4.7
+ Daytime blood pressure 2261.3 0.083 3.2 2134.5 <0.00001 4.7
+ Nighttime blood pressure 2257.3 0.0046 3.3 2132.0 0.11 4.7

*The basic Cox model was stratified by cohort and adjusted for sex, age, body mass index, smoking and drinking, serum total cholesterol, history
of cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. P-values are for the improvement of the fit across nested
models.
TABLE S8. Risk Explained in Cox Regression in All Population Cohorts in Subjects ≥ 60 Years (n=3861)

Model Total Mortality Cardiovascular Events

Likelihood ratio P-value R2 (%) Likelihood ratio P-value R2 (%)
Basic model* 9991.0 – 12.6 8547.1 – 7.8
+ 24-h blood pressure 9978.7 0.0005 12.9 8475.3 <0.00001 9.7
+ Night-to-day ratio 9964.5 0.0001 13.3 8467.8 0.0062 9.9
+ Dipping status 9971.8 0.0086 13.1 8467.7 0.0058 9.9
+ Night-to-day ratio 9972.6 0.0001 13.1 8528.5 0.00002 8.3
+ 24-h blood pressure 9964.5 0.0044 13.3 8467.8 <0.00001 9.9
+ Dipping status 9981.1 0.0016 12.9 8529.7 0.00003 8.3
+ 24-h blood pressure 9971.8 0.0023 13.1 8467.7 <0.00001 9.9
+ Nighttime blood pressure 9968.9 <0.00001 13.2 8479.0 <0.00001 9.6
+ Daytime blood pressure 9966.5 0.12 13.3 8476.7 0.13 9.6
+ Daytime blood pressure 9987.3 0.054 12.7 8505.1 <0.00001 8.9
+ Nighttime blood pressure 9966.5 <0.00001 13.3 8476.7 <0.00001 9.6

*The basic Cox model was stratified by cohort and adjusted for sex, age, body mass index, smoking and drinking, serum total cholesterol, history
of cardiovascular disease, diabetes mellitus, and treatment with antihypertensive drugs. P-values are for the improvement of the fit across nested
models.
TABLE S9. Risk Explained in Cox Regression in All Population Cohorts in Untreated Subjects (n=7736)

Model Total Mortality Cardiovascular Events

Likelihood ratio P-value R2 (%) Likelihood ratio P-value R2 (%)
Basic model* 8027.3 – 10.6 6491.8 – 7.4
+ 24-h blood pressure 8014.3 0.0003 10.8 6412.7 <0.00001 8.4
+ Night-to-day ratio 8006.2 0.0044 10.9 6412.6 0.75 8.4
+ Dipping status 8011.7 0.11 10.8 6412.6 0.75 8.4
+ Night-to-day ratio 8015.9 0.0007 10.8 6489.8 0.17 7.4
+ 24-h blood pressure 8006.2 0.0018 10.9 6412.6 <0.00001 8.4
+ Dipping status 8022.8 0.034 10.7 6490.0 0.18 7.4
+ 24-h blood pressure 8011.7 0.0009 10.8 6412.6 <0.00001 8.4
+ Nighttime blood pressure 8007.1 <0.00001 10.9 6433.6 <0.00001 8.1
+ Daytime blood pressure 8006.7 0.53 10.9 6414.1 0.00001 8.4
+ Daytime blood pressure 8020.4 0.0086 10.7 6420.6 <0.00001 8.3
+ Nighttime blood pressure 8006.7 0.0002 10.9 6414.1 0.011 8.4

*The basic Cox model was a stratified by cohort and adjusted for sex age, , body mass index, smoking and drinking, serum total cholesterol,
history of cardiovascular disease, and diabetes mellitus. P-values are for the improvement of the fit across nested models.
TABLE S10. Risk Explained in Cox Regression in All Population Cohorts in treated Patients (n=1899)

Model Total Mortality Cardiovascular Events

Likelihood ratio P-value R2 (%) Likelihood ratio P-value R2 (%)
Basic model* 3763.8 – 17.8 3834.4 – 9.8
+ 24-h blood pressure 3759.1 0.30 18.1 3805.7 <0.00001 11.3
+ Night-to-day ratio 3751.4 0.0055 18.5 3794.5 0.0008 11.9
+ Dipping status 3752.5 0.010 18.4 3796.1 0.0027 11.8
+ Night-to-day ratio 3754.3 0.0021 18.3 3816.8 0.00003 10.8
+ 24-h blood pressure 3751.4 0.088 18.5 3794.5 <0.00001 11.9
+ Dipping status 3755.7 0.0044 18.3 3820.1 0.0002 10.6
+ 24-h blood pressure 3752.5 0.074 18.4 3796.1 <0.00001 11.8
+ Nighttime blood pressure 3754.1 0.0018 18.4 3799.7 <0.00001 11.7
+ Daytime blood pressure 3752.1 0.16 18.4 3799.5 0.65 11.7
+ Daytime blood pressure 3763.1 0.40 17.9 3823.9 0.0012 10.4
+ Nighttime blood pressure 3752.1 0.0009 18.4 3799.5 <0.00001 11.7

*The basic Cox model was stratified by cohort and adjusted for sex, age, body mass index, smoking and drinking, serum total cholesterol, history of
cardiovascular disease, and diabetes mellitus. P-values are for the improvement of the fit across nested models.