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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
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
subject data, respectively. For both patients and populations, to 10.910 years (median 5.9). All studies considered sex and
we limited our analyses to systolic blood pressure, because at age as confounders with the exception of one with 52%
middle and older age this is the predominant risk factor.32 women,14 in which the hazard ratio was only adjusted for
Search methods, selection of studies, and statistical methods age but not sex. The other covariables, in order of
are described in detail in the supplemental Methods available frequency, were smoking in 12 studies,5,6,8 –10,13,15–20 diabe-
online. Figure 1 shows the articles retrieved, reviewed, and tes mellitus in 10 studies,5,8–10,12,13,16–20 body mass index in 9
included in the analysis of cohorts of hypertensive patients. 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
Studies in Hypertensive Patients cardiovascular disease in 7 studies,5,6,8,9,18 –20 and/or an index
Table 1 lists the characteristics of the studies reporting on of renal function in 6 studies.11,14,16,18 –20 All5–13,15–20 but 1
outcome in patient cohorts. Studies included from 10411 to study14 included in our quantitative review considered mul-
52925 patients (median 809). All studies enrolled hyperten- tiple confounders. All studies had a prospective design with
sive participants of either sex with the proportion of women blinded end point adjudication against source documents. The
ranging from 13%11 to 71%18 (median 52%). Chronic kidney median impact factor of the journals at the time of publication
disease and diabetes mellitus were comorbid conditions in 116 was 6.3 (range 2.4 to 34.8).
and 311,15,19 studies, respectively. Mean age at enrollment The supplemental Results and Tables S2 and S3 list the
ranged from 518 to 7316 years. Ethnicity was white in 8 hazard ratios as extracted from published papers5–20 or as
studies,5,6,9 –11,13,17,20 Japanese in 37,15,16 studies, and mixed in provided by the principal investigators.7,10,13,16 They express the
5 studies.8,12,14,18,19 The technique of ambulatory blood pres- risk associated with a 10-mm Hg increase in the nighttime or
sure measurement was exclusively5,7,10,12–14,16,17,19,20 or pre- daytime systolic blood pressure, with a 10% increase in the
dominantly6,9,11,15,18 oscillometric in all but 1 study,8 in which systolic night-to-day blood pressure ratio, or with systolic
blood pressure was measured intra-arterially. In the studies nondipping as defined in each publication (Table S4). Multivari-
that used an intermittent technique, the interval between able-adjusted pooled estimates that combined the statistics from
readings ranged from 1510,11,13,14,18,20 to 305–7,9,15–17 minutes available studies showed that the nighttime and daytime blood
during daytime and from 1513 to 609 minutes during night- pressures, the night-to-day blood pressure ratio, and the dipping
time. Of the reviewed studies, 6 implemented a diary to status were all significant predictors of total mortality and
differentiate awake from asleep blood pressures,7,12,15,16,18,19 cardiovascular outcome (Figure 2A). However, fully adjusted
while 4 and 6 studies used long7,11,14,20 or short5,6,9,10,13,17 pooled statistics that accounted for nighttime as well as daytime
fixed clock-time intervals, respectively. blood pressure in the same model were significant only for
Total mortality was available from 11 studies.5–7,9,11–14,18 –20 nighttime blood pressure, whereas daytime blood pressure lost
Nine studies6,8 –10,13,15–18 reported on a composite cardiovascular its prognostic value. The hazard ratios associated with each
end point that always included cardiovascular mortality, myo- 10-mm Hg increment in the nighttime blood pressure were
cardial infarction, and stroke. In some studies, the composite end 1.16 for total mortality and 1.19 for cardiovascular events
point also encompassed coronary revascularization,8,17,18 cardiac (Figure 2B). In fully adjusted models, which in addition to the
surgery,13 or heart failure.6,9,13,18 Follow up ranged from 3.47,16 night-to-day blood pressure ratio or dipping status also included the
Hansen et al Risk Prediction From Nighttime Blood Pressure 5
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 cohort, outcomes were adjudicated against source documents,
pressure profile retained significance with the exception of the as described in previous publications.26,30,33,34,37– 40 The com-
night-to-day blood pressure ratio as predictor of total mortality posite cardiovascular end point included cardiovascular mor-
(Figure 2B). tality, nonfatal myocardial infarction, coronary revasculariza-
tion, heart failure, and stroke. Follow up ranged from 2.533 to
Population Studies 17.637 years (median 11.2 years).
Of 11 790 subjects available in the IDACO (International The supplemental Results and Tables S5 and S6 list the
Database on Ambulatory Blood Pressure Monitoring in Re- hazard ratios for total mortality and for the combined cardio-
lation to Cardiovascular Outcomes) database, we excluded vascular end point in the individual populations. The
2149 (18.2%), because their daytime (n⫽169) or nighttime
multivariable-adjusted models, combining all population co-
(n⫽1951) blood pressure had not been measured or were
horts, showed that the nighttime and daytime blood pressures,
averages of fewer than 10 or 5 readings, respectively, or
the night-to-day blood pressure ratio, and the dipping status
because the participants were less than 18 years old at the
were all significant predictors of total mortality and cardio-
moment of enrollment (n⫽29). Thus, the number of subjects
vascular outcome (Figure 3A). Fully adjusted models, which
statistically analyzed totaled 9641. For the present analysis,
accounted for nighttime as well as daytime blood pressure,
participants recruited for the European Project on Genes in
Hypertension in Novosibirsk (n⫽244), Pilsen (n⫽165), revealed that the level of nighttime blood pressure remained
Padova (n⫽310), and Kraków (n⫽308) were combined. a significant predictor of both outcomes. The hazard ratios
Table 2 lists the characteristics of the population cohorts. associated with each 10-mm Hg increment in the nighttime
Studies included from 35133 to 214226 subjects (median blood pressure were 1.14 for total mortality and 1.15 for
1114). One study30 included only men. In the other studies, cardiovascular events (Figure 3B). In these models, the
the proportion of women ranged from 48%26 to 63%34 daytime blood pressure lost its prognostic value for total
(median 54%). Mean age at enrollment ranged from 3635 to mortality but remained a significant predictor of the compos-
7130 years. Ethnicity was white in 5 studies26,30,35–37 and ite cardiovascular outcome. In fully adjusted models, which
Asian in 2 studies,33,34 while 1 study38 included South in addition to the night-to-day blood pressure ratio or dipping
Americans. The technique of ambulatory blood pressure status also included the 24-hour blood pressure, both indexes
measurement was auscultatory (Accutracker II) in 1 study30 based on the diurnal blood pressure profile retained signifi-
and oscillometric (SpaceLabs 90202 and 90207, Nippon cance with the exception of dipping status as predictor of
Colin, and ABPM-630) in all other cohorts.26,33–38 In each 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
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
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 in hypertensive patients and populations. For a correct interpre-
This systematic review revealed that systolic nighttime blood tation and clinical application of these findings, several issues
pressure was a stronger predictor than systolic daytime blood need careful consideration.
pressure in hypertensive patients as well as in subjects randomly
selected from populations in Asia, Europe, and South America. Why Should Nighttime Blood Pressure be a Better Predictor?
The night-to-day blood pressure ratio and dipping status re- Various hypothetical mechanisms support the plausibility of
mained significant predictors of outcome, even with adjustments an enhanced cardiovascular risk associated with an increased
applied for the 24-hour blood pressure level in addition to other night-to-day blood pressure ratio or higher nighttime blood
covariables. There was a striking similarity between the findings pressure, such as alterations in the sympathetic modulation of
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
B Fully adjusted
Total mortality
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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
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- prognostic significance over 7 years of follow up of mortality
ity,42 sleep apnea,43 or an increased salt sensitivity necessi- and a composite cardiovascular end point.13
tating a higher blood pressure at night to drive pressure
Implications for Clinical Practice
natriuresis.44,45 Furthermore, in terms of physical and mental
Our review speaks in favor of recording the ambulatory blood
activity as well as body position, the nighttime blood pressure
pressure during the entire day. However, in all population
is better standardized than the daytime blood pressure. cohorts combined, once the 24-hour blood pressure was in the
However, sleep quality13 and nocturnal urination46 are of Cox model, the night-to-day blood pressure ratio and dipping
importance. The tactile stimuli and noise produced by re- status contributed only 0.1% to the explained variance49 in the
peated cuff inflations may disturb sleep.47 Manning et al48 incidence of total mortality or the cardiovascular end point
assessed sleep quality in 79 untreated subjects from a simple (Table 3). Moreover, when the night-to-day blood pressure
self-administered questionnaire. Ambulatory asleep systolic ratio or dipping status was first entered into the Cox model,
blood pressure and the proportion of nondippers was signif- without the 24-hour blood pressure level, they sometimes
icantly lower in the group that reported good sleep than in explained more of the variability in outcome than the 24-hour
those reporting intermediate or poor sleep (101 versus 108 blood pressure (Table 3). In previous analyses,29 we demon-
versus 111 mm Hg and 5.9% versus 18.2% versus 13.8%, strated that daytime systolic pressure added to the prediction
respectively).48 Verdecchia et al13 studied a cohort of 2934 of total mortality by the nighttime systolic pressure in treated
initially untreated hypertensive patients. In the presence of hypertensive patients, but not in untreated subjects. Higher
sleep deprivation by ⱖ2 hours (n⫽399) during ambulatory daytime blood pressure was associated with lower mortality in
monitoring, nighttime systolic blood pressure was signifi- treated patients but with higher cardiovascular risk in untreated
cantly higher (124.6 versus 128.3 mm Hg) but lost its subjects.29 The systolic night-to-day blood pressure ratio, ad-
8 Hypertension January 2011
justed for the 24-hour blood pressure level and other covariables pressures.59 In defining the clock-time intervals, one should
conferred higher risk in older (ⱖ60 years) than younger sub- account for differences in lifestyle across different cultures.29
jects.29 The variance explained by the 24-hour blood pressure Although the last European guideline recommends that pro-
and the indexes derived from the nighttime blood pressure in portionally to the duration of daytime and nighttime the
Cox models stratified for age and treatment status appear in the number of valid blood pressure readings should be similar,58
supplemental data (Tables S7 to S10). These tables not only it is common practice to space the readings at a greater
confirmed our previous findings but also corroborated that the interval during the night in order not to impair sleep quality.13
variance explained depends on the order in which various blood It is therefore important to weigh the mean of the 24-hour
pressure components are added to the model. blood pressure by the intervals between readings.
Chronotherapy50 means timing the administration of anti-
hypertensive drugs in such a way that the blood pressure is Limitations of Our Review
lowered over 24 hours, while preserving a normal dipping The present results have to be interpreted within the context
pattern. Hermida et al51,52 provided the proof of concept. The of their limitations. First, in our review of studies of hyper-
classification of patients according to the night-to-day blood tensive patients, we could not address the potential method-
pressure ratio heavily depends on arbitrary criteria, is poorly ological limitations of the original studies. In particular, we
reproducible,48,53–55 and has a different prognostic meaning had to accept that the estimates of risk accounted for different
according to the outcome under study,29 the prevailing sets of covariables. We could not retrieve all missing infor-
24-hour blood pressure level,29 and treatment status.29 Re- mation from the principal investigators of original studies.
verse dippers have the highest cardiovascular risk but die at Aggregate-level analyses of summary statistics have less
an older age than do subjects with a normal dipping pattern, power than an analysis of pooled individual subject data.60
which raises the issue of reverse causality.29 Nevertheless, our results from both types of meta-analyses, in
hypertensive patients and populations, respectively, were
How to Measure Daytime and Nighttime Blood Pressure?
remarkably similar. Second, individual studies in patients
The current US guidelines do not present any specific
recommendation for definitions of daytime and nighttime varied greatly with respect to the demographic characteristics
blood pressure.56 The European Society of Hypertension of the participants and methodology, resulting in significant
Working Group on Blood Pressure Monitoring 200357 stated heterogeneity. We addressed this issue by computing pooled
that “one simple and popular method of determining the time estimates from random-effect models. Third, we included
of awakening and sleeping is to assess them from diary card only from 2 up to 7 studies in our review of data in
entries.” The diary should also provide information on hypertensive patients. This number of studies is small com-
physical activity, intake of medications, and special events pared to the vast literature and did not allow us to check for
that might explain a particular diurnal pattern.58 Accelerom- publication bias in a reliable way. On the other hand, limiting
etry allows distinguishing awake from asleep periods but is our analyses to prospective studies is a strong point. The
out of reach for most clinicians. One alternative is to use short systematic and quantitative nature of our review also avoids
fixed clock-time intervals, which eliminate the transition bias in the selection of studies and the computation of pooled
periods in the morning and evening during which the blood estimates. Finally, neither in hypertensive patients nor in
pressure rapidly changes in most subjects.59 The daytime and populations could we account for physical activity during
nighttime blood pressures defined in this way approximate ambulatory monitoring or for antihypertensive treatment after
within 1 to 2 mm Hg to the awake and asleep blood enrollment.
Hansen et al Risk Prediction From Nighttime Blood Pressure 9
Properly designed randomized clinical trials should prove the toring in older patients in general practice. J Hum Hypertens. 2005;19:
801– 807.
reversibility of the risk associated with a nondipping blood 11. Astrup AS, Nielsen FS, Rossing P, Ali S, Kastrup J, Smidt UM, Parving
pressure profile. In the absence of conclusive evidence HH. Predictors of mortality in patients with type 2 diabetes with or
proving that nondipping is a reversible risk factor, the option without diabetic nephropathy: a follow-up study. J Hypertens. 2007;25:
whether or not to restore the diurnal blood pressure profile to 2479 –2485.
12. Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M.
a normal pattern should be left to the clinical judgment of Predictors of all-cause mortality in clinical ambulatory monitoring.
doctors and be individualized for each patient. Expert com- Unique aspects of blood pressure during sleep. Hypertension. 2007;49:
mittees might draft new recommendations to help clinicians 1235–1241.
13. Verdecchia P, Angeli F, Borgioni C, Gattobigio R, Reboldi G. Ambu-
apply current knowledge in their day-to-day practice. latory blood pressure and cardiovascular outcome in relation to perceived
sleep deprivation. Hypertension. 2007;49:777–783.
Acknowledgments 14. Brotman DJ, Davidson MB, Boumitri M, Vidt DG. Impaired diurnal
We gratefully acknowledge the expert assistance of Sandra Covens blood pressure variation and all-cause mortality. Am J Hypertens. 2008;
and Ya Zhu (Studies Coordinating Centre, Leuven, Belgium). We 21:92–94.
15. Eguchi K, Pickering TG, Hoshide S, Ishikawa J, Ishikawa S, Schwartz JE,
thank Robert Fagard (Leuven, Belgium), Kazuomi Kario (Tochigi,
Shimada K, Kario K. Ambulatory blood pressure is a better marker than
Japan), Gianpaolo Reboldi (Assisi, Italy), and Paolo Verdecchia
clinic blood pressure in predicting cardiovascular events in patients with/
(Assisi, Italy) for providing additional data from their studies. The without Type 2 diabetes. Am J Hypertens. 2008;21:443– 450.
IDACO (International Database on Ambulatory Blood Pressure 16. Ishikawa J, Shimizu M, Hoshide S, Eguchi K, Pickering TG, Shimada K,
Monitoring in Relation to Cardiovascular Outcomes) investigators Kario K. Cardiovascular risks of dipping status and chronic kidney
are listed in the supplemental data. disease in elderly Japanese hypertensive patients. J Clin Hypertens. 2008;
10:787–794.
Sources of Funding 17. Dolan E, Stanton AV, Thom S, Caulfield M, Atkins N, McInnes G,
The European Union (grants IC15-CT98-0329-EPOGH, LSHM-CT- Collier D, Dicker P, O’Brien E, on behalf of the ASCOT investigators.
2006-037093, and HEALTH-F4-2007-201550), the Fonds voor Ambulatory blood pressure monitoring predicts cardiovascular events in
treated hypertensive patients—an Anglo-Scandinavian cardiac outcomes
Wetenschappelijk Onderzoek Vlaanderen (Ministry of the Flemish
trial substudy. J Hypertens. 2009;27:876 – 885.
Community, Brussels, Belgium; grants G.0575.06 and G.0734.09),
18. Muxfeldt ES, Cardoso CR, Salles GF. Prognostic value of nocturnal
and the Katholieke Universiteit Leuven (grants OT/00/25 and OT/ blood pressure reduction in resistant hypertension. Arch Intern Med.
05/49) supported the Studies Coordinating Centre in Leuven, Bel- 2009;169:874 – 880.
gium. The Lundbeck Fonden (grant R32-A2740) supported Dr. T.W. 19. Palmas W, Pickering TG, Teresi J, Schwartz JE, Moran A, Weinstock RS,
Hansen’s research. Shea S. Ambulatory blood pressure monitoring and all-cause mortality in
elderly people with diabetes mellitus. Hypertension. 2009;53:120 –127.
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None. Gabbani L, Masotti G, Marchionni N, Di Bari M. Low diastolic ambu-
latory blood pressure is associated with greater all-cause mortality in
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Imai Y, Wang JG, Sandoya E, O’Brien E, Staessen JA, on behalf of the status in untreated hypertensive and normotensive subjects Am J
Hypertens. 2000;13:1035–1038.
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Correspondence to:
Tine Willum Hansen, MD, PhD,
Department of Clinical Physiology, Nuclear Medicine
and PET, Rigshospitalet,
Copenhagen University Hospital
Blegdamsvej 9 2100 Copenhagen
Denmark.
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
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 S2. Adjusted Hazard Ratios for Total Mortality in Individual Cohorts of Hypertensive Patients
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)
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
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)
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
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
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
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)
*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)
*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)
*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.