Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations

466

Background—Data on risk associated with 24-hour ambulatory diastolic (DBP24

) versus systolic (SBP24

) blood pressure are scarce.

Methods and Results—We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP

24≥80

mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs≤1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P≤0.0054). Isolated systolic hypertension (SBP

24≥130 mm Hg) and mixed diastolic plus systolic hypertension were

associated with increased risks of all aforementioned end points (P≤0.0012). Below age 50, DBP24

was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP

24 (HR≤0.92; P≥0.068); above age 50, SBP

24 predicted all end points (HR≥1.19; P≤0.0002) with a nonsignificant

contribution of DBP24

(0.96≤HR≤1.14; P≥0.10). The interactions of age with SBP24

and DBP24

were significant for all cardiovascular and coronary events (P≤0.043).

© 2014 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.004876

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.Received July 5, 2013; accepted May 22, 2014.From the Center for Epidemiological Studies and Clinical Trials and Center for Vascular Evaluations, Shanghai Institute of Hypertension, Shanghai Key

Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (Y.L., F.-F.W., J.-G.W.); Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium (L.T., Y.-M.G., Y.-P.L., T.K., J.A.S.); Centro de Nefrología and Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay (J.B.); Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, Sendai, Japan (K.A., M.K., T.O., Y.I.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (K.A., T.O.); Research Center for Prevention and Health and Steno Diabetes Center, Gentofte, Denmark (T.W.H.); Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden (K.B.-B.); Department of Medicine, Glostrup Hopsital, University of Copenhagen, Copenhagen, Denmark (J.J.); Copenhagen University Hospital, Copenhagen, Denmark (C.-T.P.); Cambridge University Hospitals, Addenbrook’s Hospital, Cambridge, United Kingdom (E.D.); First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland (K.S.-S., K.K.-J.); Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy (V.T., E.C.); Institute of Internal Medicine, Novosibirsk, Russian Federation (S.M., Y.N.); Section of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden (L.L.); Asociación Española Primera de Socorros Mutuos, Montevideo, Uruguay (E.S.); Laboratorio de Neurociencias and Instituto Cardiovascular, Universidad del Zulia, Maracaibo, Venezuela (L.M., G.E.M.); Faculty of Medicine, Charles University, Pilsen, Czech Republic (J.F.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland (E.O.); and the Department of Epidemiology, Maastricht University, Maastricht, The Netherlands (J.A.S.).

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA. 113.004876/-/DC1.

Correspondence to Jan A. Staessen, MD, PhD, Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Box 7001, BE-3000 Leuven, Belgium. E-mail [email protected] or [email protected]

Ambulatory Hypertension Subtypes and 24-Hour Systolic and Diastolic Blood Pressure as Distinct Outcome Predictors

in 8341 Untreated People Recruited From 12 PopulationsYan Li, MD, PhD; Fang-Fei Wei, MD; Lutgarde Thijs, MSc; José Boggia, MD, PhD; Kei Asayama, MD, PhD; Tine W. Hansen, MD, PhD; Masahiro Kikuya, MD, PhD;

Kristina Björklund-Bodegård, MD, PhD; Takayoshi Ohkubo, MD, PhD; Jørgen Jeppesen, MD; Yu-Mei Gu, MD; Christian Torp-Pedersen, MD, PhD; Eamon Dolan, MD, PhD;

Yan-Ping Liu, MD; Tatiana Kuznetsova, MD, PhD; Katarzyna Stolarz-Skrzypek, MD, PhD; Valérie Tikhonoff, MD, PhD; Sofia Malyutina, MD, PhD; Edoardo Casiglia, MD, PhD;

Yuri Nikitin, MD, PhD; Lars Lind, MD, PhD; Edgardo Sandoya, MD, PhD; Kalina Kawecka-Jaszcz, MD, PhD; Luis Mena, MD; Gladys E. Maestre, MD, PhD;

Jan Filipovský, MD, PhD; Yutaka Imai, MD, PhD; Eoin O’Brien, MD, PhD; Ji-Guang Wang, MD, PhD; Jan A. Staessen, MD, PhD; on behalf of the International Database on

Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) Investigators

Hypertension

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Li et al Cardiovascular Risk and Ambulatory Hypertension 467

Conclusions—The risks conferred by DBP24

and SBP24

are age dependent. DBP24

and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP

24 and isolated systolic and mixed hypertension are the

predominant risk factors. (Circulation. 2014;130:466-474.)

Key Words: ambulatory blood pressure monitoring ◼ blood pressure component ◼ cardiovascular diseases ◼ population

Hypertension remains the predominant driver of cardio-vascular disease. In 2001, hypertension caused 8 mil-

lion deaths worldwide, representing 14% of global mortality.1 In an individual-subject meta-analysis of close to 1 million people, the risk of coronary heart disease and stroke gradu-ally increased with blood pressure from levels as low as 115 mm Hg systolic and 75 mm Hg diastolic.2 The Framingham investigators3,4 and other researchers5 showed in studies pub-lished as early as 1971 that diastolic pressure was the stron-gest predictor of coronary heart disease below age 50 with an increase in the importance of systolic blood pressure with advancing age.

Clinical Perspective on p 474

Using blood pressure levels of 140 mm Hg systolic and 90 mm Hg diastolic, current guidelines subdivide hypertension on conventional sphygmomanometry into isolated diastolic, isolated systolic, and diastolic combined with systolic (mixed) hypertension.6 Several population studies have demonstrated that isolated diastolic hypertension confers a cardiovascular risk that was intermediate between normotension and iso-lated systolic or mixed hypertension.7,8 Compared with con-ventional sphygmomanometry, ambulatory blood pressure monitoring substantially refines risk stratification.9 To our knowledge, no previous study has assessed the risks asso-ciated with isolated diastolic, isolated systolic, and mixed hypertension on 24-hour ambulatory monitoring or examined the age dependency of 24-hour diastolic and systolic ambu-latory blood pressure as independent risk factors in the gen-eral population. We addressed these issues by analyzing the International Database on Ambulatory blood pressure in rela-tion to Cardiovascular Outcomes (IDACO).10

MethodsStudy PopulationAt the time of writing this report, the IDACO database10 included 12 randomly recruited population cohorts11–20 and 12 711 participants with available data on the conventional and ambulatory blood pressure. All participants gave informed written consent. We excluded participants if they were younger than 18 years (n=303), if they were taking antihy-pertensive drugs at baseline (n=2144), or if they had <10 daytime or 5 nighttime blood pressure readings (n=1923). Thus, the number of sub-jects included in the present analysis totaled 8341. (for details, see the Expanded Methods and Table I in the online-only Data Supplement).

Blood Pressure MeasurementMethods used for conventional and ambulatory blood pressure mea-surement are described in detail in the Expanded Methods in the online-only Data Supplement. Conventional blood pressure was the average of 2 consecutive readings. Portable monitors were pro-grammed to obtain ambulatory blood pressure readings at 30-minute intervals throughout the whole day,12,19 or at intervals ranging from 1511,17,18 to 3012,19 minutes during daytime and from 3011,12,17–19 to 6014 minutes at night. To categorize levels of the ambulatory blood

pressure, we followed the guidelines of the European Societies of Cardiology and Hypertension.6 Ambulatory hypertension was a 24-hour level of ≥130 mm Hg systolic or ≥80 mm Hg diastolic. Using these thresholds, we categorized participants as being normotensive, or as having isolated diastolic, isolated systolic, or mixed hyperten-sion on 24-hour ambulatory monitoring.

Other MeasurementsWe used the questionnaires originally administered in each cohort to obtain information on each participant’s medical history and smoking and drinking habits. Body mass index was body weight in kilograms divided by height in meters squared. We measured serum choles-terol and blood glucose by automated enzymatic methods. Diabetes mellitus was the use of antidiabetic drugs, a fasting glucose of ≥7.0 mmol/L,21 a random glucose of ≥11.1 mmol/L,21 a self-reported diag-nosis, or diabetes mellitus documented in practice or hospital records.

Ascertainment of EventsWe ascertained vital status and the incidence of fatal and nonfatal diseases from the appropriate sources in each country, as described in previous publications.10,22 In most cohorts,11–18 information on vital status was obtained, even if participants dropped out from follow-up. Outcomes were coded according to the international classification of diseases, as described in the Expanded Methods in the online-only Data Supplement. Fatal and nonfatal stroke did not include transient ischemic attacks. Coronary events encompassed death from isch-emic heart disease, sudden death, nonfatal myocardial infarction, and coronary revascularization. Cardiac events comprised coronary end points and fatal and nonfatal heart failure. Hospitalizations for unstable angina were coded as ischemic heart disease. In the Danish11 and Swedish14 cohorts, the diagnosis of heart failure required admis-sion to hospital. In the other cohorts,12,13,15–20 heart failure was either a clinical diagnosis or the diagnosis on the death certificate, but in all cases it was validated against hospital files or the records held by family doctors. The composite cardiovascular end point included all aforementioned end points plus cardiovascular mortality. In analyses of fatal combined with nonfatal outcomes, we only considered the first event within each disease cluster.

Statistical AnalysisFor database management and statistical analysis, we used SAS software, version 9.3 (SAS Institute, Cary, NC). Missing data were imputed using cohort- and sex-specific regression equations with age as explanatory variable (for details, see the Expanded Methods and Table II in the online-only Data Supplement). We tabulated the incidence of end points by blood pressure status on ambulatory mea-surement. We computed 95% confidence intervals (CIs) of rates as R±1.96 × √(R/T), where R and T are the rate and the denominator used to calculate the rate. We compared means and rates using the large-sample z test and proportions by the χ2 statistic, respectively. We plotted the incidence of end points across categories of the ambu-latory blood pressure, using Cox models standardized to the sex dis-tribution and mean age in the whole study population. We compared hazard ratios (HRs) between categories of the ambulatory blood pres-sure using the Wald χ2 statistic.

In multivariable-adjusted Cox regression analyses, we accounted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, and diabetes mellitus. To adjust for cohort, we pooled participants recruited in the European Project on Genes in Hypertension (Kraków, Novosibirsk, Padova,

by guest on January 30, 2016http://circ.ahajournals.org/Downloaded from


468 Circulation August 5, 2014

and Pilsen).18 We ascertained that the proportional hazard assump-tion was fulfilled by testing the interaction between blood pressure and follow-up time. We compared hazard ratios between subgroups according to age, sex, or ethnicity, using the appropriate interaction terms. To assess the prognostic significance of diastolic blood pres-sure at different levels of systolic blood pressure, and vice versa, we modeled the 10-year absolute risk of a composite cardiovascular end point using Cox regression, while standardizing to the average of the distributions in the whole study population (mean or ratio) of cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, and diabetes mellitus. Statistical significance was a α-level <0.05 on 2-sided tests.

ResultsBaseline CharacteristicsThe 8341 participants included 5489 Europeans (65.8%), 1280 Asians (15.3%), and 1572 South Americans (18.9%), and 3888 women (46.6%). Age ranged from 18 to 94 years and averaged (±SD) 50.8±15.8 years. At enrollment, 2474 participants (29.7%) were smokers and 4061 (48.7%) reported intake of alcohol. In the whole study population, conventional blood pressure averaged (±SD) 128.7±21.4 mm Hg systolic and 78.6±11.3 mm Hg diastolic, whereas the 24-hour ambu-latory blood pressure was 122.1±13.5 mm Hg systolic and 73.1±8.2 mm Hg diastolic.

Table 1 shows the participants’ baseline characteristics by categories of the 24-hour ambulatory blood pressure. Normotensive participants and patients with isolated diastolic hypertension had similar characteristics except for the propor-tion of women (52.6 versus 36.5%) and drinkers (45.0 versus 54.4%), and body mass index (24.5 versus 25.9 kg/m2) and

serum cholesterol (5.48 versus 5.67 mmol/L). Patients with mixed or isolated systolic hypertension were older, more obese, had higher serum cholesterol and blood glucose levels, and were more likely to be diabetic than those with isolated diastolic hypertension (Table 1). The proportions of isolated diastolic, isolated systolic, and mixed hypertension were 5.9%, 3.9%, and 6.1%, respectively, among younger partici-pants (aged <50 years), whereas the corresponding frequen-cies were 4.1%, 16.3%, and 18.4% among older adults (aged ≥50 years).

Incidence of EventsIn the whole study population, median follow-up was 11.2 years (5th to 95th percentile interval, 2.5 –18.2). Across cohorts, median follow-up ranged from 2.5 years (2.3–2.6) in Jingning to 17.2 years (5.3–20.4) in Noorderkempen. During 92 379 person-years of follow-up, 927 participants died (10.0 per 1000 person-years) and 744 experienced a fatal or nonfatal cardiovascular event (8.25 per 1000 person-years). Mortality included 356 cardiovascular and 548 non-cardiovascular deaths and 23 deaths from unknown cause. Considering cause-specific first cardiovascular events, the incidence of fatal and nonfatal stroke amounted to 78 and 203, respectively. Cardiac events consisted of 216 fatal and 425 nonfatal events, including 90 fatal and 141 nonfa-tal cases of acute myocardial infarction, 122 deaths from ischemic heart disease, 56 sudden deaths, 37 fatal and 140 nonfatal cases of heart failure, and 71 cases of surgical or percutaneous coronary revascularization.

Table 1. Baseline Characteristics of Participants by Categories of 24-Hour Ambulatory Blood Pressure

Characteristic Normotension Isolated Diastolic Hypertension Mixed Hypertension Isolated Systolic Hypertension

Number of subjects 5969 408 1071 893

European, (%) 3908 (65.5)‡ 221 (54.2) 720 (67.2)‡ 640 (71.7)‡

Asian, (%) 983 (16.5) 55 (13.5) 140 (13.1) 102 (11.4)

South American, (%) 1078 (18.1)‡ 132 (32.4) 211 (19.7)‡ 151 (16.9)‡

Women, (%) 3141 (52.6)‡ 149 (36.5) 315 (29.4)† 283 (31.7)

Smokers, (%) 1741 (29.2) 132 (32.4) 348 (32.5) 253 (28.3)

Drinking alcohol, (%) 2684 (45.0)‡ 222 (54.4) 652 (60.9)† 503 (56.3)

Diabetes mellitus, (%) 266 (4.5) 23 (5.6) 89 (8.3) 92 (10.3)†

Cardiovascular disorders, (%) 243 (4.1) 23 (5.6) 59 (5.5) 67 (7.5)

Mean characteristic (SD)

Age, y 47.9 (15.7) 48.7 (11.4) 58.0 (12.0)‡ 62.3 (13.8)‡

Body mass index, kg/m2 24.5 (3.9)‡ 25.9 (4.2) 26.6 (4.2)† 26.5 (4.4)*

Conventional blood pressure

Systolic, mm Hg 121.7 (16.3) 131.5 (13.2) 151.3 (22.8) 146.8 (22.8)

Diastolic, mm Hg 75.1 (9.3) 86.6 (8.2) 92.0 (10.9) 82.0 (10.3)

24-hour blood pressure

Systolic, mm Hg 115.7 (7.9) 124.5 (4.0) 143.6 (11.4) 137.6 (7.8)

Diastolic, mm Hg 69.6 (5.3) 82.9 (2.7) 87.2 (6.0) 74.5 (4.1)

Blood glucose, mmol/L 5.03 (1.17) 5.11 (1.25) 5.44 (1.66)† 5.45 (1.64)†

Serum cholesterol, mmol/L 5.48 (1.13)† 5.67 (1.13) 5.78 (1.14) 5.86 (1.14)†

Hypertension was a 24-hour ambulatory blood pressure ≥130 mm Hg or 80 mm Hg diastolic. Mixed hypertension refers to diastolic combined with systolic hypertension. Significance of the difference with isolated diastolic hypertension: *P≤0.05; †P≤0.01; and ‡P≤0.001. Significance levels were not calculated for blood pressure values, used to categorize participants.




Risk by Categories of Ambulatory Blood PressureMedian years of follow-up (5th to 95th percentile interval) amounted to 11.4 (2.6–18.3), 9.7 (2.4–18.2), 11.0 (2.7–17.3), and 10.8 (2.5–17.8) in normotensive individuals and in patients with isolated diastolic, isolated systolic, and mixed hyperten-sion, respectively. Table 2 shows that the incidence rates were similar (P≥0.13) in normotensive participants and in patients with isolated diastolic hypertension except for cardiac end points (3.1 versus 5.9 events per 1000 person-years; P=0.021) and coronary events (2.2 versus 4.6 events per 1000 person-years; P=0.024). Compared with isolated diastolic hyperten-sion, event rates were higher (P<0.001) in patients with mixed or isolated systolic hypertension. After standardization to the sex distribution (46.6% women) and mean age (50.8 years) in the whole study population, the incidence of a composite car-diovascular end point gradually increased from normotension, over isolated diastolic hypertension onto isolated systolic and mixed hypertension (Figure 1). Detailed information on the number of participants at risk, those retained in the analysis, and those with a cardiovascular (Table III in the online-only Data Supplement) or cardiac (Table IV in the online-only Data Supplement) end point is available by 2-year intervals in the online Data Supplement.

In further multivariable-adjusted analyses with normoten-sion as reference (Table 3), isolated diastolic hypertension did not increase the risk of total and cardiovascular mortality or stroke (HRs ≤1.54; P≥0.18), but was associated with a higher

risk of a composite cardiovascular end point and of fatal com-bined with nonfatal cardiac and coronary events (HRs ≥1.75; P≤0.0054). With normotension as reference, both mixed and isolated systolic hypertension were associated with an increased risk of all end points under study (P≤0.0012) with the exception of noncardiovascular mortality (P≥0.096). The HRs were significantly higher (P≤0.046) in patients with mixed hypertension than in those with isolated systolic hypertension, except for fatal combined with nonfatal cardiac (P=0.065) and coronary events (P=0.17).

Risks Associated with Diastolic and Systolic Blood PressuresIn line with previous publications based on the conventionally measured blood pressure,4–6 we stratified our multivariable-adjusted analyses by age group (<50 and ≥50 years, Table 4). Median years of follow-up (5th to 95th percentile interval) amounted to 12.1 (2.5–18.6) and 11.1 (2.6–17.6) in younger and older participants, respectively. In younger participants, in fully adjusted models, which included both diastolic and sys-tolic blood pressure, diastolic blood pressure predicted total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and the composite cardiovas-cular end point (HR, 1.74; P=0.039), whereas 24-hour systolic blood pressure was not significantly associated with these end points (HR, ≤0.92; P≥0.068; Table 4). In older participants, systolic pressure predicted total and cardiovascular mortality

Table 2. Incidence of End Points by Categories of 24-Hour Ambulatory Blood Pressure

End Point NormotensionIsolated Diastolic

HypertensionMixed

HypertensionIsolated Systolic

Hypertension

Number of participants 5969 408 1071 893

Total mortality

Number of deaths 493 25 204 205

Rate 7.3 (6.6–7.9) 6.0 (3.6–8.3) 18.3 (15.8–20.8)‡ 22.0 (19.0–25.0)‡

Cardiovascular mortality


Rate 2.2 (1.9–2.6) 2.6 (1.1–4.2) 9.1 (7.3–10.8)‡ 10.0 (7.9–12.0)‡

Noncardiovascular mortality


Rate 4.8 (4.3–5.4) 3.4 (1.6–5.1) 9.0 (7.2–10.7)‡ 11.4 (9.2–13.5)‡

All cardiovascular events

Number of events 329 28 200 187

Rate 4.9 (4.4–5.5) 6.8 (4.3–9.4) 18.9 (16.3–21.5)‡ 21.1 (18.1–24.1)‡

Cardiac events


Rate 3.1 (2.7–3.6)* 5.9 (3.5–8.2) 11.5 (9.5–13.5)‡ 13.1 (10.7–15.4)‡

Coronary events


Rate 2.2 (1.9–2.6)* 4.6 (2.5–6.7) 8.3 (6.6–10.0)‡ 9.5 (7.5–11.5)‡

Stroke


Rate 1.6 (1.3–1.9) 1.2 (0.1–2.3) 7.0 (5.4–8.6)‡ 7.6 (5.8–9.3)‡

Hypertension was a 24-hour ambulatory blood pressure ≥130 mm Hg systolic or 80 mm Hg diastolic. Incidence rates reflect the number of events per 1000 person-years. Significance of the difference with isolated diastolic hypertension: *P≤0.05; and ‡P≤0.001.




and all of the end points combining fatal with nonfatal events (HR, ≥1.19; P≤0.0002), whereas diastolic pressure did not significantly predict any outcome (0.96≤HR≤1.14; P≥0.10). Analyses based on daytime (Table V in the online-only Data Supplement) or nighttime (Table VI in the online-only Data Supplement) blood pressure, or restricted to the 7949 subjects free of cardiovascular disease at baseline (Table VII in the online-only Data Supplement), or excluding 1 cohort at a time (Table VIII in the online-only Data Supplement), confirmed the results given in Table 4. Compared with the conven-tional blood pressure, 24-hour diastolic and systolic pressure retained their predictive superiority in all participants (Table IX in the online-only Data Supplement) as well as in catego-ries based on blood pressure status on conventional measure-ment (online-only Data Supplement, pages 5–6).

Next, based on the data given in Table 4, we tested the interactions of 24-hour systolic and diastolic blood pressures with age, ethnicity, and sex. Using age as a continuous vari-able, the interaction terms with diastolic and systolic pres-sure in fully adjusted models were significant or borderline significant for cardiovascular mortality (0.036≤P≤0.058), the composite cardiovascular end point (0.0037≤P≤0.0048), and coronary events (0.012≤P≤0.043). When excluding 1 cohort at a time (Table VIII in the online-only Data Supplement), the

interactions with age consistently retained significance for the composite cardiovascular end point (0.0009≤P≤0.050). For cardiovascular mortality and coronary events the interactions of age with systolic and diastolic blood pressure remained formally or borderline significant (0.0079≤P≤0.093), but lost significance for cardiovascular mortality after excluding Ohasama, Jingning, or Noorderkempen (0.12≤P≤0.20) and for coronary events with Montevideo removed (0.10≤P≤0.15). The hazard ratios associated with systolic and diastolic blood pressure were similar in Asians and whites (Table X in the online-only Data Supplement). As reported previously,22 the hazard ratios associated with 24-hour systolic blood pressure were higher in women than men (Table XI in the online-only Data Supplement) for all cardiovascular end points (P≤0.019) with the exception of cardiovascular mortality (P=0.079) and stroke (P=0.64). For 24-hour diastolic blood pressure, the fully adjusted hazard ratios were similar in women and men (P≥0.45).

Finally, we used Cox regression to model the 10-year absolute risk of a composite cardiovascular end point in relation to 24-hour diastolic pressure at different levels of 24-hour systolic pressure and vice versa. Figure 2 shows that the 10-year risk of fatal combined with nonfatal cardio-vascular events increased (P<0.001) with 24-hour diastolic

Figure 1. Incidence of the composite cardiovascular (CV) end point (A) and fatal combined with nonfatal cardiac events (B) in 4 categories of the ambulatory blood pressure. Incidence was standardized to the sex distribution (46.6% women) and mean age (50.8 years) in the whole study population. For each blood pressure category, the number of subjects at risk is given at the beginning of each 4-year interval. The time axis was curtailed at 16 years when ≈10% of participants were still being followed up. Tables III and IV in the online-only Data Supplement provide more detailed information by 2-year intervals up to 22 years on the number of participants at risk, the number of events, and the number of participants no longer followed up. Vertical bars denote the standard error. P values are for the differences across the 4 blood pressure categories.

Table 3. Multivariable-Adjusted Hazard Ratios Associated With Isolated Diastolic, Isolated Systolic, and Mixed Ambulatory Hypertension

End Point (Number of End Points)

Isolated Diastolic Hypertension P

Mixed Hypertension P

Isolated Systolic Hypertension P

Mortality

Total (927) 1.14 (0.76–1.71) 0.54 1.63 (1.37–1.93) <0.0001 1.33 (1.12–1.57) 0.0012

Cardiovascular (356) 1.54 (0.82–2.87) 0.18 2.49 (1.91–3.25) <0.0001 1.86 (1.42–2.44) <0.0001

Noncardiovascular (548) 1.00 (0.58–1.72) 0.99 1.22 (0.97–1.53) 0.096 1.05 (0.84–1.32) 0.66

Fatal and nonfatal events combined

All cardiovascular (744) 1.75 (1.18–2.59) 0.0054 2.44 (2.03–2.93) <0.0001 1.81 (1.50–2.19) <0.0001

Cardiac (477) 1.96 (1.28–3.01) 0.0022 2.16 (1.72–2.73) <0.0001 1.70 (1.34–2.16) <0.0001

Coronary (348) 2.00 (1.23–3.25) 0.0052 2.19 (1.67–2.87) <0.0001 1.77 (1.34–2.35) <0.0001

Stroke (256) 1.33 (0.53–3.33) 0.54 3.06 (2.25–4.16) <0.0001 2.13 (1.55–2.92) <0.0001

Ambulatory normotension is the referent group. All models were adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, and diabetes mellitus. The cause of death was unknown in 23 cases.




pressure irrespective of the level of systolic pressure. Risk also increased with the 24-hour systolic pressure independent of the 24-hour diastolic pressure.

DiscussionOur analysis included 8341 untreated people randomly recruited from 12 populations and covered on average >11 years of follow-up (median). The key finding was that the risks conferred by diastolic and systolic blood pressure as measured by noninvasive 24-hour ambulatory monitoring were age dependent. Diastolic pressure and isolated diastolic hypertension were the drivers of coronary complications, in particular below age 50 years, whereas above age 50 years

systolic pressure and isolated systolic and mixed hypertension became the predominant determinants of risk.

Systolic pressure increases with age until the eighth decade of life.23 By contrast, diastolic pressure rises only until 50 years of age, after which it becomes steady or even slightly decreases.23 In the Framingham Heart Study,3,4 increasing age entailed a shift from diastolic to systolic pressure as the main predictor of cardiovascular risk. Below age 50 years, diastolic pressure was the strongest predictor, whereas the opposite occurred above 50 years of age. Khattar and colleagues used intra-arterial ambulatory blood pressure monitoring in 688 untreated hypertensive patients and obtained similar findings.24 Our current study, based on noninvasive 24-hour ambulatory

Figure 2. Ten-year absolute risk of a composite cardiovascular (CV) end point associated with 24-hour diastolic blood pressure (DBP, A) and 24-hour systolic blood pressure (SBP, B) in participants with normal (full line) or elevated (dashed line) systolic pressure (A) or normal or elevated diastolic pressure (B) on ambulatory measurement. The cut-off points for 24-hour hypertension were ≥130 mm Hg systolic and ≥80 mm Hg diastolic, respectively. For each risk function, the number (n) of subjects contributing to the risk function is given. In the Cox regression models, 10-year absolute risk was standardized to the average of the distributions in the whole study population (mean or ratio) of cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, and diabetes mellitus. Ne indicates the number of events in each group. P values denote the significance of the independent contribution of diastolic pressure (A) or systolic pressure (B).

Table 4. Multivariable-Adjusted Standardized Hazard Ratios for 24-Hour Systolic and Diastolic Blood Pressures by Age Group

End Point

<50 years (n=3761) ≥50 years (n=4580)

n Diastolic Pressure Systolic Pressure n Diastolic Pressure Systolic Pressure

Mortality

Total A 64 1.38 (1.08–1.77)† 1.20 (0.86–1.66) 863 1.17 (1.10–1.25)‡ 1.21 (1.14–1.29)‡

FA 2.05 (1.26–3.33)† 0.56 (0.30–1.05) 1.03 (0.94–1.13) 1.19 (1.08–1.30)‡

Cardiovascular A 16 2.34 (1.61–3.39)‡ 2.23 (1.32–3.78)† 340 1.31 (1.18–1.44)‡ 1.47 (1.35–1.61)‡

FA 4.07 (1.60–10.4)† 0.44 (0.13–1.56) 0.96 (0.85–1.10) 1.51 (1.34–1.70)‡

Noncardiovascular A 46 1.13 (0.83–1.55) 0.93 (0.61–1.42) 502 1.06 (0.97–1.16) 1.03 (0.94–1.12)

FA 1.73 (0.96–3.12) 0.53 (0.25–1.13) 1.09 (0.95–1.25) 0.96 (0.84–1.10)

Fatal plus nonfatal events

All cardiovascular A 47 1.65 (1.27–2.14)‡ 1.68 (1.19–2.36)† 697 1.36 (1.27–1.46)‡ 1.44 (1.35–1.53)‡

FA 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 1.06 (0.97–1.17) 1.39 (1.27–1.51)‡

Cardiac A 37 1.53 (1.12–2.08)† 1.52 (1.01–2.27)* 440 1.26 (1.16–1.38)‡ 1.37 (1.26–1.48)‡

FA 1.67 (0.92–3.03) 0.88 (0.40–1.90) 1.01 (0.90–1.14) 1.36 (1.22–1.52)‡

Coronary A 28 1.63 (1.16–2.30)† 1.67 (1.07–2.62)* 320 1.25 (1.13–1.38)‡ 1.35 (1.23–1.48)‡

FA 1.73 (0.87–3.45) 0.92 (0.37–2.24) 1.01 (0.88–1.15) 1.35 (1.18–1.53)‡

Stroke A 7 2.31 (1.25–4.27)† 2.43 (1.12–5.26)* 249 1.61 (1.43–1.81)‡ 1.65 (1.49–1.83)‡

FA 2.24 (0.62–8.20) 1.04 (0.21–5.26) 1.14 (0.97–1.34) 1.52 (1.32–1.76)‡

n indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk associated with a 1-SD increase in 24-hour systolic (13.5 mm Hg) or diastolic (8.2 mm Hg) blood pressures. All models were adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease, and diabetes mellitus. Adjusted models (A) include either systolic or diastolic blood pressure, whereas fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Significance of the hazard ratios: *P≤0.05; †P≤0.01, and ‡P≤0.001. The interactions of diastolic and systolic pressure with age (continuous) in fully adjusted models were significant or borderline significant for cardiovascular mortality (0.036≤P≤0.058), all cardiovascular events (0.0037≤P≤0.0048), and coronary events (0.012≤P≤0.043).




blood pressure monitoring and the analysis of cause-specific outcomes in general populations, consolidated these findings.

Several studies based on conventional sphygmomanom-etry25–27 or on the self-measured blood pressure at home28 reported that isolated diastolic hypertension confers low car-diovascular risk, in particular at young age. The Honolulu Heart Program25 reported on 8006 Japanese-American men followed for 20 years. Cutoff levels for diastolic and systolic hypertension were levels of 90 and 160 mm Hg, respectively. For men aged 45 to 54 years, the relative risks compared with normotension were 1.4 (95% CI, 1.0–2.1), 4.3 (2.9–6.3), and 4.8 (2.1–11.0) for isolated diastolic, mixed, and isolated sys-tolic hypertension.25 For men aged 55 to 68 years, the corre-sponding hazard ratios were 1.8 (1.3–2.5), 1.7 (1.2–2.4), and 1.2 (0.7–2.0), respectively.25 Fang and colleagues26 used the same blood pressure criteria as the Honolulu investigators to categorize systolic and diastolic hypertension in 1560 partici-pants (<60 years) in a worksite hypertension control program. Over 4.5 years of follow-up, 24 participants got a myocardial infarction (3.9 events per 1000 person-years). The rate was higher in the patients with mixed hypertension than in those with isolated diastolic hypertension (5.2 versus 2.2 per 1000 patient-years).26 No myocardial infarction occurred in partici-pants with diastolic hypertension and a systolic blood pressure <140 mm Hg.26 Strandberg and coworkers recruited 3267 ini-tially healthy Finnish men, aged 30 to 45 years, and followed mortality for up to 32 years.27 With normotension as reference (blood pressure <160 mm Hg systolic and <90 mm Hg dia-stolic), the hazard ratios for mortality were 2.71 (2.00–3.66) in patients with mixed hypertension, but only 1.39 (1.04–1.87) or 1.14 (0.77–1.69) in patients with isolated diastolic hyper-tension and systolic pressure between 140 and 160 mm Hg or <140 mm Hg, respectively.27

The Ohasama investigators28 followed 1913 participants aged 40 or older (average 61 years) for 8 years. The blood pressure thresholds based on home blood pressure were 137 mm Hg systolic and 84 mm Hg diastolic. The cardiovascu-lar death rate was similar (0.33 versus 0.26 deaths per 100 person-years) in normotensive participants and in those with isolated diastolic hypertension. Patients with mixed or iso-lated systolic hypertension on self-measurement at home had significantly elevated death rates amounting to 1.11 and 2.04 per 100 person-years, respectively.

Several subject-level meta-analyses2,7,8 addressed the role of systolic and diastolic blood pressure or various subtypes of hypertension as cardiovascular risk factors. All were based on conventional sphygmomanometry. Kelly and colleagues7 did a prospective cohort study (from 1991 until 2000) in a nation-ally representative sample of 169 577 Chinese women and men, aged 40 years or more. These investigators used blood pres-sure levels of 90 mm Hg diastolic and 140 mm Hg systolic to classify subjects. Compared with normotension, relative risks of cardiovascular disease incidence and mortality were 2.73 (2.60–2.86) and 2.53 (2.39–2.68) for combined systolic and diastolic hypertension, 1.78 (1.69–1.87) and 1.68 (1.58–1.78) for isolated systolic hypertension, and 1.59 (1.43–1.76) and 1.45 (1.27–1.65) for isolated diastolic hypertension.7 The Asia Pacific Cohort Studies Collaboration8 studied 346 570 partici-pants from 36 cohort studies. Outcomes were fatal and nonfatal

cardiovascular disease. In multivariable-adjusted Cox regres-sion, with normal blood pressure (<80 mm Hg diastolic and 120 mm Hg systolic) as the reference, hazard ratios were 1.81 (1.61–2.04), 2.18 (2.00–2.37), and 3.42 (3.17–3.70) for isolated diastolic, isolated systolic, and mixed hypertension, respec-tively.8 The Prospective Studies Collaboration2 demonstrated in 958 074 participants (61 cohort studies) that at ages 40 to 69 years, each 20-mm Hg increase in systolic blood pressure or 10-mm Hg increase in diastolic blood pressure was associated with more than a doubling in the death rates of stroke, ischemic heart disease, or other vascular death. These findings in subject-level meta-analyses with a large sample size are in keeping with our current study that made use of ambulatory blood pressure monitoring instead of conventional sphygmomanometry.

Our findings argue against the suggestion to abandon dia-stolic pressure measurement and to rely only on systolic blood pressure for the management of hypertension.29 Moreover, reversibility of the risk by blood pressure lowering treatment in patients with isolated diastolic hypertension30 confirms that certainly in younger individuals diastolic blood pressure is a risk factor that must be treated. The prevalence of isolated diastolic hypertension on 24-hour ambulatory blood pressure measurement was 4.9% in the whole untreated IDACO cohort and 17.2% among untreated patients with ambulatory hyper-tension. In the National Health Examination Survey (NHES) and National Health and Nutrition Examination Survey (NHANES) studies, 6% to 9% of subjects with elevated blood pressure readings had an isolated elevation of diastolic blood pressure with a normal systolic blood pressure.31

Our current study has some potential limitations. First, the number of end points in some subgroups was relatively small, in particular in the younger age group, in whom healthy elastic arteries might lead to a relatively less elevated systolic than diastolic blood pressure. Diastolic blood pressure is the driving force in the coronary circulation. This constellation might explain why diastolic hypertension is a risk factor for premature coronary heart disease and therefore for cardiac events below age 50. Second, patients with diastolic or mixed hypertension can progress to isolated systolic hypertension, so called burned-out hypertension, because with aging large arteries stiffen, so that systolic blood pressure rises and dia-stolic blood pressure falls. Our categorical analyses did not account for this phenomenon. Finally, we could not adjust for the serum lipid profile over and beyond total serum choles-terol, because too few participants had measurements of low-density or high-density cholesterol. We also did not account for measures of renal function, because they were only avail-able in 4808 of our participants. However, we previously demonstrated that the incremental predictive value of renal function in an epidemiological setting is small compared with the 24-hour ambulatory blood pressure.32 Other factors we did not account for include family history of heart disease, and use of medications after enrolment.

In conclusion, we show that the risks conferred by diastolic and systolic blood pressure on 24-hour ambulatory measure-ment are age dependent. The 24-hour diastolic blood pressure and isolated diastolic hypertension drive coronary complica-tions below age 50, whereas above age 50 the 24-hour systolic blood pressure is the predominant risk factor.




AppendixList of IDACO Investigators

Copenhagen, DenmarkTine W Hansen, MD, PhD; Hans Ibsen MD, DSci; Jørgen L Jeppesen, MD, DMSci; Susanne Rasmussen MD, PhD; Christian Torp-Pedersen, MD, DMSci

Ohasama, JapanKei Asayama, MD, PhD; Naomi Fukushima, MSc; Azusa Hara, PhD; Takuo Hirose, PhD; Miki Hosaka, MSc; Yutaka Imai, MD, PhD; Ryusuke Inoue, MD, PhD; Masahiro Kikuya, MD, PhD; Hirohito Metoki, MD, PhD; Kyoko Nomura, MD, PhD, MPH; Taku Obara, PhD; Takayoshi Ohkubo, MD, PhD; Michihiro Satoh, PhD; Megumi Tsubota-Utsugi, PhD, MPH

Noordenkempen, BelgiumYu-Mei Gu, MD; Azusa Hara, PhD; Lotte Jacobs, PhD; Yu Jin, MD, PhD; Tatyana Kuznetsova, MD, PhD; Yan-Ping Liu, MD; Thibault Petit, MD; Jan A Staessen, MD, PhD; Lutgarde Thijs, MSc; Zhenyu Zhang, MD

Uppsala, SwedenKristina Björklund-Bodegård, MD, PhD; Lars Lind, MD, PhD

Montevideo, UruguayJosé Boggia, MD, PhD; Inés Lujambio, MD; Leonella Luzardo, MD MSc; Edgardo Sandoya, MD; Carlos Schettini, MD; Emma Schwedt, MD; Hugo Senra, MD; Mariana Sottolano, MD

JingNing, ChinaQifang Huang, MD PhD; Lihua Li, MD PhD; Yan Li, MD, PhD; Changsheng Sheng, MD, PhD; Jiguang Wang, MD, PhD

Novosibirsk, Russian FederationSofia Malyutina, MD, PhD; Yuri Nikitin, MD, PhD

Dublin, IrelandEamon Dolan, MD, PhD; Eoin O’Brien, DSc, MD

Pilsen, Czech RepublicJan Filipovský, MD, PhD; Jitka Seidlrova, MD, PhD

Padova, ItalyEdoardo Casiglia, MD; Valérie Tikhonoff, MD, PhD

Kraków, PolandMarcin Cwynar, MD, PhD; Danuta Czarnecka, MD, PhD; Tomasz Grodzicki, MD, PhD; Kalina Kawecka-Jaszcz, MD, PhD; Agnieszka Olszanecka, MD, PhD; Katarzyna Stolarz-Skrzypek, MD, PhD; Wiktoria Wojciechowska, MD, PhD

Maracaibo, VenezuelaGustavo E. Calmon, MD, MSc; Inara J. Chacon, MD, MSc; Carlos A. Chavez, MD; Vanessa G. Felix, PhD; Gladys E. Maestre, MD, PhD; Jesus D. Melgarejo BSc; Luis J. Mena, PhD; Egle R. Silva, MD

AcknowledgmentsWe gratefully acknowledge the expert assistance of Sandra Covens and Annick De Soete (Studies Coordinating Center, Leuven, Belgium).

Sources of FundingThe European Union (grants IC15-CT98-0329-EPOGH, LSHM- CT-2006–037093 InGenious HyperCare, HEALTH-F4-2007–201550

HyperGenes, HEALTH-F7-2011- 278249 EU-MASCARA, HEALTH- F7-305507 HOMAGE, and the European Research Council Advanced Researcher Grant 294713 EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0734.09, G.0881.13 and G.088013) supported the Studies Coordinating Centre (Leuven, Belgium). The European Union (grants LSHM-CT-2006–037093 and HEALTH-F4-2007–201550) also supported the research groups in Shanghai, Kraków, Padova and Novosibirsk. The Danish Heart Foundation (grant 01-2-9-9A-22914), and the Lundbeck Fonden (grant R32-A2740) supported the studies in Copenhagen. The Ohasama study received support via the Grants for Scientific Research (23249036, 23390171, 24591060, 24390084, 24591060, 24790654, 25461205, 25461083 and 25860156) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and a Health Labour Science Research Grant (H23-Junkankitou [Seishuu]-Ippan-005) from the Ministry of Health, Labour, and Welfare, Japan; the Japan Arteriosclerosis Prevention Fund; and the Grant from the Daiwa Securities Health Foundation. The National Natural Science Foundation of China (grants 30871360, 30871081, 81170245, and 81270373), Beijing, China, and the Shanghai Commissions of Science and Technology (grant 07JC14047 and the “Rising Star” program 06QA14043 and 11QH1402000) and Education (grant 07ZZ32 and the “Dawn” project 08SG20) supported the JingNing study in China. The Comisión Sectorial de Investigación Científica de la Universidad de la República (Grant I+D GEFA-HT-UY) and the Agencia Nacional de Innovación e Investigación supported research in Uruguay. The 1R01AG036469 from the National Institute on Aging and Fogarty International Center is supporting the Maracaibo Aging Study.

DisclosuresNone.

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CLINICAL PERSPECTIvENo previous study has assessed the risks associated with isolated diastolic, isolated systolic, and mixed hypertension on 24-hour ambulatory monitoring or examined the age dependency of 24-hour systolic and diastolic ambulatory blood pres-sures as independent risk factors in the general population. In 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations and followed up for a median of 11.2 years, the risks conferred by diastolic and sys-tolic ambulatory blood pressure were age dependent. Ambulatory diastolic pressure and isolated diastolic hypertension drove coronary complications below age 50 years, whereas above 50 years of age 24-hour systolic pressure and isolated systolic and mixed hypertension were the predominant determinants of risk. Our findings argue against the suggestion to abandon diastolic pressure measurement and to rely only on systolic pressure for the management of hypertension. Moreover, in younger indi-viduals elevated diastolic pressure as assessed by 24-hour ambulatory monitoring is a risk factor that must be treated.

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Cardiovascular Outcomes (IDACO) Investigatorson behalf of the International Database on Ambulatory blood pressure in relation to

Filipovský, Yutaka Imai, Eoin O'Brien, Ji-Guang Wang and Jan A. StaessenLind, Edgardo Sandoya, Kalina Kawecka-Jaszcz, Luis Mena, Gladys E. Maestre, Jan

Stolarz-Skrzypek, Valérie Tikhonoff, Sofia Malyutina, Edoardo Casiglia, Yuri Nikitin, Lars Christian Torp-Pedersen, Eamon Dolan, Yan-Ping Liu, Tatiana Kuznetsova, Katarzyna

Kikuya, Kristina Björklund-Bodegård, Takayoshi Ohkubo, Jørgen Jeppesen, Yu-Mei Gu, Yan Li, Fang-Fei Wei, Lutgarde Thijs, José Boggia, Kei Asayama, Tine W. Hansen, MasahiroDistinct Outcome Predictors in 8341 Untreated People Recruited From 12 Populations

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SUPPLEMENTAL MATERIAL

Cardiovascular Risk and Ambulatory Hypertension -2-

Expanded Methods

Study Population

As described in detail elsewhere,1 we constructed the International Database on Ambulatory

blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO). Studies were el-

igible for inclusion, if they involved a random population sample, if baseline information on

the ambulatory blood pressure and cardiovascular risk factors was available, and if the sub-

sequent follow-up included both fatal and nonfatal outcomes.

Analyzed participants were 1823 residents from Copenhagen, Denmark (enrolment 1993–

1997);2 981 inhabitants from Ohasama, Japan (1988-1994);3 1175 subjects from

Noorderkempen, Belgium (1985–2008);4 714 older men from Uppsala, Sweden (1991–

1995);5 1188 subjects from Montevideo, Uruguay (1995–1998);6 299 villagers from the

Jingning county, China (2003–2004);7 204 subjects from Novosibirsk, the Russian Federa-

tion(1999–2001);8 133 from Pilsen, Czech Republic (2000–2001);9 930 from Dublin, Ireland

(1989–1991);10 266 from Padua, Italy(1991–2001);9 244 from Kraków, Poland (1999–2000);9

and 384 older (≥55 years) subjects from Maracaibo,11 Venezuela (1998–2007). Subjects re-

cruited in Kraków, Novosibirsk, Pilsen, and Padova took part in the European Project on

Genes in Hypertension (EPOGH).9

Blood Pressure Measurement

Conventional blood pressure was measured by trained observers with a mercury sphygmo-

manometer,7,9,10,12 with validated auscultatory3 (USM-700F, UEDA Electronic Works, To-

kyo, Japan) or oscillometric6 (OMRON HEM-705CP, Omron Corporation, Tokyo, Japan) de-

vices, using the appropriate cuff size, with participants in the sitting3,4,6-10,12 or supine5 posi-

tion. Conventional blood pressure was the average of 2 consecutive readings obtained ei-


ther at the person’s home4,6-9 or at an examination center.3,5,10,12 We programmed portable

monitors to obtain ambulatory blood pressure readings at 30 minute intervals throughout the

whole day,3,10 or at intervals ranging from 158,9,12 to 303,10 minutes during daytime and from

303,8-10,12 to 605 minutes at night. The devices implemented an auscultatory algorithm

(Accutracker II) in Uppsala5 or an oscillometric technique (SpaceLabs 90202 and 90207,

Nippon Colin, and ABPM 630) in the other cohorts.

The same SAS macro processed all ambulatory recordings, which generally stayed uned-

ited. The Ohasama recordings were edited sparsely according to previously published crite-

ria.13 Within individual subjects, we weighted the means of the ambulatory blood pressure

by the interval between readings. To categorize levels of the ambulatory blood pressure, we

followed the guidelines of the European Societies of Cardiology and Hypertension.14 Ambu-

latory hypertension was a 24-h level of 130 mm Hg systolic or 80 mm Hg diastolic or more.

Using these thresholds participants we categorized participants as being normotensive, or as

having isolated diastolic, isolated systolic, or mixed hypertension on 24-h ambulatory meas-

urement.

While accounting for the daily pattern of activities of the participants, we defined daytime

as the interval ranging from 8000 h to 2200 h in Europeans2,4,5,8-10,12 and South

Americans6,11, and from 0600 h to 2000 h in Asians3,7. The corresponding nighttime inter-

vals ranged from 2200 to 0800 h and from 2000 h to 0600 h.

Other Measurements

We used the questionnaires originally administered in each cohort to obtain information on

each participant’s medical history and smoking and drinking habits. Body mass index was

body weight in kilograms divided by height in meters squared. We measured serum choles-

terol and blood glucose by automated enzymatic methods. Diabetes mellitus was the use of


antidiabetic drugs, a fasting blood glucose concentration of at least 7.0 mmol/L,15 a random

blood glucose concentration of at least 11.1 mmol/L,15 a self-reported diagnosis, or diabetes

documented in practice or hospital records.

Ascertainment of Events

We ascertained vital status and the incidence of fatal and nonfatal diseases from the appro-

priate sources in each country, as described in previous publications.1,16 Outcomes were

coded according to the international classification of diseases (ICD). Fatal and nonfatal

stroke (ICD8/9 430-434 and 436, ICD10 I60-I64 and I67-I68) did not include transient is-

chemic attacks. Coronary events encompassed death from ischemic heart disease (ICD8

411-412, ICD9 411 and 414, ICD10 I20 and I24-I25), sudden death (ICD8 4272 and 795,

ICD9 4275 and 798, ICD10 I46 and R96), nonfatal myocardial infarction (ICD8/9 410, ICD10

I21-I22), and coronary revascularization. Cardiac events comprised coronary endpoints and

fatal and nonfatal heart failure (ICD8 428 and 4271-4272 and 4290, ICD9 428 and 429,

ICD10 I50 and J81). Hospitalizations for unstable angina were coded as ischemic heart dis-

ease. In the Danish12 and Swedish5 cohorts, the diagnosis of heart failure required admis-

sion to hospital. In the other cohorts3,4,6-11, heart failure was either a clinical diagnosis or

the diagnosis on the death certificate, but in all cases it was validated against hospital files or

the records held by family doctors. The composite cardiovascular endpoint included all

aforementioned endpoints plus cardiovascular mortality (ICD8 390-448, ICD9 3900-4599,

ICD10 I00-I79 and R96). In analyses of fatal combined with nonfatal outcomes, we only

considered the first event within each disease cluster.


Statistical Analysis

After stratification for cohort and sex, we interpolated missing values (eTable 2) of body

mass index (n=10 [0.1%]) and serum total cholesterol (n=668 [8.0%]) from the regression

slope on age. In subjects with unknown smoking status (n=22 [0.3%]) or drinking habits

(n=490 [5.9%]), we set the design variable to the cohort- and sex-specific mean of the codes

(0 and 1).

To assess the prognostic significance of diastolic blood pressure at different levels of systolic

blood pressure, and vice versa, we modeled the probability of the 10–year incidence of a

composite cardiovascular endpoint as follows: 1- S0(10)exp(β(X- )) , where S0(10) is the 10-

year survival rate at mean values of the covariates, β is the Cox regression coefficient corre-

sponding to the 24-hour blood pressure, is the mean of the 24-h blood pressure over all

subjects and X ranges from the P5 up to the P95 of the 24-hour blood pressure distribution.

Additional Results

Compared to conventional blood pressure, 24-hour systolic and diastolic blood pressures re-

tained their predictive superiority (eTable 9). We also categorized participants according to

their blood pressure status on conventional measurement into normotensive individuals and

patients with isolated diastolic, isolated systolic, or mixed hypertension. Cut-off thresholds

were 140 mm Hg systolic and 90 mm Hg diastolic. In multivariable-adjusted Cox models, we

applied the TEST statement as implemented in the PHREG procedure to compare hazard ra-

tios associated with blood pressure subtypes on conventional measurement. The between-

group differences were significant (P=0.004) in models not including 24-hour ambulatory

blood pressure. However, introducing 24-hour diastolic or 24-hour systolic blood pressure as


an additional covariable removed the significance (P≥0.26), thereby exemplifying the prog-

nostic superiority of ambulatory over conventional blood pressure.

Sources of Funding

Data The European Union (grants IC15-CT98-0329-EPOGH, LSHM-CT-2006-037093 In-

Genious HyperCare, HEALTH-F4-2007-201550 HyperGenes, HEALTH-F7-2011- 278249

EU-MASCARA, HEALTH-F7-305507 HOMAGE, and the European Research Council Ad-

vanced Researcher Grant 294713 EPLORE) and the Fonds voor Wetenschappelijk

Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0734.09,

G.0881.13 and G.088013) supported the Studies Coordinating Centre (Leuven, Belgium).

The European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550) also

supported the research groups in Shanghai, Kraków, Padova and Novosibirsk. The Danish

Heart Foundation (grant 01-2-9-9A-22914), and the Lundbeck Fonden (grant R32-A2740)

supported the studies in Copenhagen. The Ohasama study received support via the Grants

for Scientific Research (23249036, 23390171, 24591060, 24390084, 24591060, 24790654,

25461205, 25461083 and 25860156) from the Ministry of Education, Culture, Sports, Sci-

ence, and Technology, Japan; and a Health Labour Science Research Grant (H23-

Junkankitou [Seishuu]-Ippan-005) from the Ministry of Health, Labour, and Welfare, Japan;

the Japan Arteriosclerosis Prevention Fund; and the Grant from the Daiwa Securities Health

Foundation. The National Natural Science Foundation of China (grants 30871360,

30871081, 81170245, and 81270373), Beijing, China, and the Shanghai Commissions of

Science and Technology (grant 07JC14047 and the “Rising Star” program 06QA14043 and

11QH1402000) and Education (grant 07ZZ32 and the “Dawn” project 08SG20) supported the

JingNing study in China. The Comisión Sectorial de Investigación Científica de la Univer-

sidad de la República (Grant I+D GEFA-HT-UY) and the Agencia Nacional de Innovación e


Investigación supported research in Uruguay. The 1R01AG036469 from the National Insti-

tute on Aging and Fogarty International Center is supporting the Maracaibo Aging Study.


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Supplemental Table 1. Participation Rate, Enrollment and Duration of Follow-up in IDACO

Cohorts

Cohort Participation

rate (%) Enrollment

Follow-up (years)

Noorderkempen, Belgium 78 1985–2008 17.2 (2.9–20.4)

Jingning, China 62 2003–2004 2.5 (2.3–2.6)

Copenhagen, Denmark 83 1993–1997 12.5 (6.1–13.3)

EPOGH

Pilsen, Czech Republic 82 2000–2001 5.6 (5.2–6.0)

Mirano (Venice), Torrebelvicino (Vicenza), Valli del Pasubio (Vicenza), Italy

73 1999–2001 6.9 (5.9–8.1)

Niepolomice, Kraków, Poland 54 1999–2000 6.5 (5.5–6.9)

Novosibirsk, Russian Federation 68 1999–2001 7.3 (5.9–8.4)

Dublin, Ireland 14 1989-1991 17.6 (16.4–18.2)

Ohasama, Japan 78 1988–1994 13.3 (5.5–16.3)

Uppsala, Sweden 80 1991–1995 10.1 (3.7–12.2)

Montevideo, Uruguay 78 1995–1998 8.9 (4.5–10.7)

Maracaibo, Venezuela 70 1998–2007 8.7 (1.7–13.8)

Follow-up time is presented as median (5th–95th percentile interval). EPOGH refers to the European Project on Genes in Hypertension.


Supplemental Table 2. Interpolated Variables by Cohort Among 8341 Analyzed Partici-

pants

Variable Cohort Participants

analyzed Interpolated

(number) Interpolated

(%)

Body mass index All 8341 10 0.1

Jingning, China 299 5 1.7

Ohasama, Japan 981 2 0.2

EPOGH 847 2 0.2

Maracaibo, Venezuela 384 1 0.3

Total cholesterol All 8341 668 8.0

Noorderkempen, Belgium 1175 27 2.3

Jingning, China 299 2 0.7

Copenhagen, Denmark 1823 1 0.1

EPOGH 847 4 0.5


Dublin, Ireland 930 531 57.1

Montevideo, Uruguay 1188 7 0.6


Uppsala, Sweden 714 1 0.1

Smoking All 8341 22 0.3




Drinking alcohol All 8341 490 5.9



EPOGH 847 3 0.4





EPOGH refers to the European Project on Genes in Hypertension.


Supplemental Table 3. Number of Patients at Risk, with a Cardiovascular Event, or Without Further Follow-up Data by 2-Year

Intervals

Category according to 24-h ambulatory blood pressure

Follow-Up (Years)

0 2 4 6 8 10 12 14 16 18 20 22

Normotension

Nº of patients at risk 5969 5888 5490 4978 4205 3404 2803 1633 1440 491 98 4

Nº of events 35 85 136 197 247 286 302 314 320 325 329

Nº without further follow-up 46 394 855 1567 2318 2880 4034 4215 5158 5546 5636

Isolated Diastolic Hypertension


Nº of events 5 10 15 21 21 22 24 24 28 28 28


Isolated Systolic Hypertension


Nº of events 24 43 77 118 152 174 183 184 187 187 187


Mixed Hypertension


Nº of events 34 67 94 126 167 190 196 197 200 200 200



The information in this eTable completes the data given in Figure 1. Ambulatory hypertension was a 24-hour blood pressure of ≥130 mm Hg systolic or ≥80 mm Hg

diastolic. Using these thresholds, participants were categorized as normotensive, or as having isolated diastolic, isolated systolic, or mixed (diastolic plus systolic)

hypertension.


Supplemental Table 4. Number of Patients at Risk, with a Cardiac Event, or Without Further Follow-up Data by 2-Year

Intervals

Category according to 24-h ambulatory blood pressure

Follow-Up (Years)

0 2 4 6 8 10 12 14 16 18 20 22

Normotension


Nº of events 23 56 89 127 156 181 191 198 202 207 211


Isolated Diastolic Hypertension


Nº of events 5 9 14 19 19 19 21 21 24 24 24


Isolated Systolic Hypertension


Nº of events 15 29 51 77 95 109 116 116 118 118 118


Mixed Hypertension


Nº of events 18 41 56 77 103 116 121 121 123 124 124


The information in this eTable completes the data given in Figure 1. Ambulatory hypertension was a 24-hour blood pressure of ≥130 mm Hg systolic or ≥80 mm Hg diastolic. Using these thresholds, participants were categorized as normotensive, or as having isolated diastolic, isolated systolic, or mixed (diastolic plus systolic) hypertension.


Supplemental Table 5. Multivariable-Adjusted Standardized Hazard Ratios for Daytime Systolic and Diastolic Blood Pres-

sures by Age Group

Endpoint

<50 years (n=3761） ≥50 years (n=4580)

Nº Diastolic pressure Systolic pressure Nº Diastolic pressure Systolic pressure

Mortality

Total A 64 1.33 (1.03–1.70)* 1.12 (0.81–1.54) 863 1.12 (1.05–1.20)‡ 1.16 (1.09–1.24)‡

FA 1.89 (1.19–3.01)† 0.58 (0.32–1.05) 1.00 (0.91–1.11) 1.16 (1.06–1.28)†


FA 3.53 (1.46–8.51)† 0.57 (0.18–1.80) 0.91 (0.79–1.05) 1.54 (1.34–1.76)‡


FA 1.66 (0.94–2.90) 0.52 (0.25–1.07) 1.07 (0.94–1.23) 0.93 (0.81–1.06)



FA 1.61 (1.00–2.60) 1.01 (0.55–1.86) 1.01 (0.91–1.12) 1.41 (1.28–1.55)‡

Cardiac A 37 1.47 (1.08–1.99)* 1.40 (0.94–2.08) 440 1.22 (1.12–1.34)‡ 1.34 (1.23–1.46)‡

FA 1.64 (0.94–2.86) 0.84 (0.41–1.73) 0.98 (0.87–1.11) 1.36 (1.21–1.53)‡

Coronary A 28 1.50 (1.06–2.12)* 1.54 (0.99–2.40) 320 1.23 (1.11–1.37)‡ 1.35 (1.22–1.49)‡

FA 1.46 (0.78–2.74) 1.04 (0.47–2.34) 0.99 (0.85–1.14) 1.37 (1.19–1.57)‡

Stroke A 7 2.64 (1.39–5.01)† 3.01 (1.37–6.60)† 249 1.52 (1.35–1.72)‡ 1.65 (1.48–1.84)‡

FA 1.87 (0.60–5.79) 1.67 (0.42–6.71) 1.04 (0.87–1.25) 1.60 (1.35–1.89)‡

Nº indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk as-sociated with a 1-SD increase in daytime systolic (14.5 mm Hg) or diastolic (9.0 mm Hg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes mellitus. Adjusted models (A) include either systolic or di-astolic blood pressure, while fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Signif-

icance of the hazard ratios: * P0.05; † P0.01, and ‡ P0.001.


Supplemental Table 6. Multivariable-Adjusted Standardized Hazard Ratios for Nighttime Systolic and Diastolic Blood

Pressures by Age Group

Endpoint

<50 years (n=3761） ≥50 years (n=4580)


Mortality

Total A 64 1.43 (1.13–1.81)† 1.37 (1.01–1.87)* 863 1.20 (1.13–1.28)‡ 1.22 (1.15–1.29)‡

FA 1.64 (1.02–2.64)* 0.82 (0.45–1.49) 1.06 (0.97–1.16) 1.17 (1.08–1.27)‡


FA 2.27 (0.92–5.58) 0.85 (0.26–2.78) 1.01 (0.89–1.13) 1.39 (1.25–1.54)‡

Noncardiovascular A 46 1.23 (0.91–1.68) 1.14 (0.77–1.68) 502 1.13 (1.03–1.23)† 1.09 (1.00–1.18)*

FA 1.50 (0.84–2.67) 0.75 (0.37–1.55) 1.13 (0.99–1.29) 1.00 (0.88–1.13)


All cardiovascular A 47 1.47 (1.12–1.94)‡ 1.47 (1.03–2.08)* 697 1.32 (1.23–1.41)‡ 1.35 (1.27–1.42)‡

FA 1.55 (0.90–2.66) 0.93 (0.47–1.82) 1.09 (0.99–1.18) 1.29 (1.20–1.39)‡

Cardiac A 37 1.30 (0.93–1.82) 1.30 (0.85–1.98) 440 1.23 (1.13–1.34)‡ 1.30 (1.21–1.40)‡

FA 1.31 (0.71–2.40) 0.99 (0.46–2.10) 1.02 (0.92–1.14) 1.28 (1.16–1.41)‡

Coronary A 28 1.50 (1.05–2.14)* 1.54 (0.98–2.43) 320 1.19 (1.07–1.31)‡ 1.26 (1.16–1.38)‡

FA 1.49 (0.74–2.99) 1.01 (0.42–2.43) 1.00 (0.87–1.13) 1.27 (1.13–1.42)‡

Stroke A 7 2.06 (1.15–3.70)* 1.87 (0.85–4.14) 249 1.51 (1.35–1.69)‡ 1.46 (1.34–1.59)‡

FA 3.55 (0.90–14.0) 0.47 (0.08–2.76) 1.19 (1.02–1.38)* 1.35 (1.19–1.53)‡

Nº indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk as-sociated with a 1-SD increase in nighttime systolic (14.4 mm Hg) or diastolic (8.9 mm Hg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes mellitus. Adjusted models (A) include either systolic or di-astolic blood pressure, while fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Signif-

icance of the hazard ratios: * P0.05; † P0.01, and ‡ P0.001.


Supplemental Table 7. Multivariable-Adjusted Standardized Hazard Ratios for 24-Hour Systolic and Diastolic Blood Pres-

sures by Age Group in Subjects Without History of Cardiovascular Disease

Endpoint

<50 years (n=3678） ≥50 years (n=4271)


Mortality

Total A 64 1.38 (1.08–1.77)† 1.20 (0.86–1.66) 762 1.21 (1.13–1.30)‡ 1.24 (1.16–1.32)‡

FA 2.04 (1.26–3.32)† 0.56 (0.30–1.04) 1.05 (0.95–1.17) 1.20 (1.09–1.32)‡


FA 4.04 (1.60–10.2)† 0.44 (0.13–1.55) 0.98 (0.85–1.13) 1.54 (1.36–1.74)‡

Noncardiovascular A 46 1.13 (0.83–1.55) 0.93 (0.61–1.42) 456 1.11 (1.01–1.22) * 1.05 (0.96–1.16)

FA 1.72 (0.96–3.10) 0.53 (0.25–1.12) 1.15 (0.99–1.33) 0.96 (0.83–1.10)



FA 1.73 (1.03–2.91)* 0.92 (0.47–1.81) 1.06 (0.96–1.17) 1.40 (1.28–1.53)‡

Cardiac A 37 1.52 (1.12–2.07)† 1.51 (1.01–2.26)* 374 1.26 (1.15–1.39)‡ 1.39 (1.27–1.51)‡

FA 1.66 (0.92–3.01) 0.88 (0.41–1.89) 0.99 (0.87–1.12) 1.40 (1.25–1.56)‡

Coronary A 28 1.63 (1.16–2.29)† 1.66 (1.07–2.60)* 274 1.25 (1.12–1.40)‡ 1.36 (1.23–1.50)‡

FA 1.73 (0.87–3.43) 0.92 (0.38–2.23) 0.99 (0.86–1.14) 1.37 (1.20–1.56)‡

Stroke A 7 2.30 (1.25–4.23)† 2.41 (1.12–5.20)* 226 1.63 (1.44–1.85)‡ 1.64 (1.48–1.83)‡

FA 2.24 (0.62–8.11) 1.04 (0.21–5.20) 1.17 (0.98–1.39) 1.51 (1.29–1.75)‡

Nº indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk as-sociated with a 1-SD increase in 24-hour systolic (13.4 mm Hg) or diastolic (8.1 mm Hg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol and diabetes mellitus. Adjusted models (A) include either systolic or diastolic blood pressure, while fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Significance of the hazard ratios:

* P0.05; † P0.01, and ‡ P0.001.


Supplemental Table 8. Multivariable-Adjusted Standardized Hazard Ratios for a Fatal or Nonfatal Cardiovascular Event in Re-

lation to 24-Hour Systolic and Diastolic Blood Pressures by Age Group Excluding one Cohort at a Time

Cohort

Age < 50 years Age ≥ 50 years

At risk N° Diastolic pressure Systolic pressure At risk N° Diastolic pressure Systolic pressure

All cohorts 3761 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4580 697 1.06 (0.97–1.17) 1.39 (1.27–1.51)‡

Excluded center

Ohasama 3554 45 1.83 (1.07–3.13)* 0.82 (0.41–1.64) 3806 607 1.06 (0.96–1.17) 1.37 (1.26–1.50)‡

Jingning 3553 46 1.71 (1.00–2.92)* 0.86 (0.43–1.72) 4489 694 1.06 (0.96–1.16) 1.39 (1.27–1.51)‡

Copenhagen 3296 33 2.12 (1.08–4.19)* 0.72 (0.30–1.73) 3222 506 1.04 (0.94–1.16) 1.38 (1.26–1.52)‡

Dublin 2956 41 1.67 (0.96–2.89) 1.10 (0.54–2.62) 4455 684 1.06 (0.97–1.17) 1.38 (1.26–1.50)‡

Noorderkempen 3005 32 1.33 (0.73–2.43) 1.29 (0.60–2.74) 4161 618 1.07 (0.97–1.18) 1.39 (1.27–1.52)‡

Uppsala 3761 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 3866 534 0.99 (0.88–1.11) 1.49 (1.33–1.67)‡

EPOGH 3130 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4364 683 1.07 (0.97–1.17) 1.38 (1.26–1.50)‡

Kraków 3557 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4540 694 1.06 (0.97–1.17) 1.38 (1.27–1.51)‡

Novosibirsk 3611 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4526 690 1.06 (0.97–1.17) 1.38 (1.26–1.51)‡

Padova 3595 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4480 693 1.06 (0.97–1.17) 1.38 (1.27–1.51)‡

Pilsen 3650 47 1.74 (1.03–2.93)* 0.92 (0.47–1.81) 4558 697 1.06 (0.97–1.17) 1.39 (1.27–1.51)‡

Montevideo 3072 38 1.96 (1.09–3.54)* 0.81 (0.38–1.74) 4081 641 1.07 (0.97–1.18) 1.40 (1.28–1.53)‡

EPOGH refers to the European Project on Genes in Hypertension. Nº indicates the number of events. Hazard ratios, presented with 95% confidence interval, ex-press the risk associated with a 1-SD increase in 24-hour systolic (13.5 mm Hg) or diastolic (8.2 mm Hg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes mellitus. All models include both systolic and diastolic

blood pressures in addition to the aforementioned covariables. Significance of the hazard ratios: * P0.05; †P0.01, and ‡ P0.001.


Supplemental Table 9. Multivariable-Adjusted Hazard Ratios for Systolic and Diastolic Blood Pressures on Conven-

tional or 24-Hour Ambulatory Measurement

Endpoint

(Number of Endpoints )

Systolic Pressure Diastolic Pressure

Conventional 24-Hour Conventional 24-Hour

Mortality

Total (900) A 1.18 (1.10–1.27)‡ 1.21 (1.14–1.29)‡ 1.12 (1.05–1.20)† 1.18 (1.11–1.26)‡

FA 1.07 (0.97–1.16) 1.17 (1.09–1.27)‡ 1.02 (0.93–1.11) 1.17 (1.08–1.27)‡

Cardiovascular (347) A 1.32 (1.19–1.47)‡ 1.49 (1.36–1.62)‡ 1.25 (1.13–1.39)‡ 1.36 (1.23–1.49)‡

FA 1.02 (0.89–1.16) 1.47 (1.32–1.64)‡ 1.05 (0.92–1.20) 1.32 (1.17–1.49)‡

Noncardiovascular (530) A 1.07 (0.97–1.19) 1.03 (0.94–1.12) 1.03 (0.93–1.13) 1.06 (0.97–1.16)

FA 1.09 (0.96–1.23) 0.98 (0.88–1.10) 0.99 (0.88–1.11) 1.07 (0.96–1.19)


All cardiovascular (726) A 1.31 (1.22–1.42)‡ 1.44 (1.36–1.54)‡ 1.25 (1.16–1.35)‡ 1.39 (1.30–1.48)‡

FA 1.03 (0.94–1.13) 1.42 (1.32–1.54)‡ 1.02 (0.93–1.12) 1.37 (1.26–1.49)‡

Cardiac (471) A 1.23 (1.12–1.35)‡ 1.37 (1.27–1.48)‡ 1.21 (1.10–1.32)‡ 1.30 (1.19–1.41)‡

FA 0.99 (0.88–1.11) 1.38 (1.25–1.53)‡ 1.04 (0.93–1.17) 1.27 (1.14–1.41)‡

Coronary (345) A 1.21 (1.08–1.34)‡ 1.36 (1.24–1.49)‡ 1.24 (1.12–1.38)‡ 1.30 (1.18–1.43)‡

FA 0.98 (0.85–1.12) 1.37 (1.22–1.55)‡ 1.08 (0.95–1.24) 1.24 (1.10–1.40)‡

Stroke (241) A 1.66 (1.45–1.90)‡ 1.67 (1.51–1.85)‡ 1.41 (1.23–1.61)‡ 1.64 (1.46–1.85)‡

FA 1.23 (1.05–1.46)* 1.53 (1.34–1.73)‡ 1.04 (0.88–1.22) 1.61 (1.39–1.86)‡

The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk associated with a 1-SD increase in conventional or ambulatory systolic (21.4 or 13.5 mm Hg) or diastolic (11.3 or 8.2 mmHg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum total cholesterol, history of cardiovascular disease and diabetes mellitus. Adjusted models (A) include either conventional or ambulatory blood pressure, while fully adjusted models (FA) include both conventional and ambulatory blood pressures in addition to the

aforementioned covariables. Significance of the hazard ratios: * P0.05; † P0.01, and ‡ P0.001.


Supplemental Table 10. Multivariable-Adjusted Standardized Hazard Ratios for 24-Hour Systolic and Diastolic Blood

Pressures by Ethnicity

Endpoint

Caucasians (n=6763） Asians (n=1280)


Mortality

Total A 691 1.19 (1.10–1.28)‡ 1.17 (1.09–1.26)‡ 163 1.10 (0.92–1.32) 1.18 (0.99–1.39)

FA 1.12 (1.00–1.24)* 1.09 (0.98–1.21) 0.78 (0.54–1.14) 1.44 (1.01–2.07)*

Cardiovascular A 257 1.37 (1.22–1.54)‡ 1.39 (1.25–1.54)‡ 48 1.54 (1.13–2.10)† 1.72 (1.28–2.29)‡

FA 1.14 (0.97–1.34) 1.28 (1.10–1.49)† 0.67 (0.33–1.34) 2.42 (1.25–4.69)†


FA 1.10 (0.95–1.27) 0.96 (0.84–1.11) 0.92 (0.57–1.47) 1.07 (0.69–1.68)


All cardiovascular A 577 1.40 (1.29–1.51)‡ 1.41 (1.31–1.51)‡ 96 1.77 (1.41–2.21)‡ 1.77 (1.43–2.19)‡

FA 1.16 (1.04–1.28)† 1.29 (1.16–1.42)‡ 1.16 (0.71–1.91) 1.56 (0.98–2.49)

Cardiac A 398 1.33 (1.21–1.46)‡ 1.34 (1.22–1.46)‡ 14 0.99 (0.54–1.84) 1.22 (0.70–2.13)

FA 1.15 (1.01–1.31)* 1.22 (1.07–1.39)† 0.44 (0.12–1.60) 2.40 (0.73–7.89)

Coronary A 289 1.31 (1.17–1.46)‡ 1.28 (1.15–1.43)‡ 6 1.57 (0.66–3.75) 1.49 (0.66–3.38)

FA 1.19 (1.01–1.40)* 1.14 (0.97–1.33) 1.42 (0.32–6.26) 1.14 (0.27–4.81)

Stroke A 170 1.61 (1.41–1.85)‡ 1.64 (1.46–1.84)‡ 80 1.88 (1.47–2.40)‡ 1.88 (1.49–2.37)‡

FA 1.18 (0.99–1.40) 1.50 (1.28–1.76)‡ 1.17 (0.88–2.02) 1.64 (0.98–2.74)

Nº indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk as-sociated with a 1-SD increase in 24-hour systolic (13.5 mm Hg) or diastolic (8.2 mm Hg) blood pressures. All models are adjusted for cohort, sex, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes mellitus. Adjusted models (A) include either systolic or di-astolic blood pressure, while fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Signif-

icance of the hazard ratios: * P0.05; † P0.01, and ‡ P0.001. The interactions of ethnicity with diastolic (P≥0.28) or systolic (P≥0.12) blood pressure were not

significant.


Supplemental Table 11. Multivariable-Adjusted Standardized Hazard Ratios for 24-Hour Systolic and Diastolic Blood Pres-

sures by Sex

Endpoint

Men (n=4453） Women (n=3888)


Mortality

Total A 634 1.17 (1.08–1.26)‡ 1.16 (1.08–1.24)‡ 293 1.14 (1.03–1.28)* 1.31 (1.18–1.47)‡

FA 1.09 (0.97–1.22) 1.09 (0.98–1.22) 0.87 (0.74–1.02) 1.47 (1.24–1.73)‡

Cardiovascular A 244 1.35 (1.20–1.52)‡ 1.41 (1.27–1.57)‡ 112 1.25 (1.06–1.48)† 1.63 (1.39–1.91)‡

FA 1.05 (0.89–1.24) 1.37 (1.18–1.59)‡ 0.73 (0.57–0.93)* 2.09 (1.63–2.67)‡


FA 1.15 (0.98–1.36) 0.89 (0.76–1.04) 0.94 (0.76–1.18) 1.18 (0.93–1.49)


All cardiovascular A 525 1.38 (1.27–1.49)‡ 1.37 (1.28–1.48)‡ 219 1.32 (1.17–1.49)‡ 1.61 (1.43–1.81)‡

FA 1.14 (1.02–1.28)* 1.26 (1.14–1.40)‡ 0.86 (0.72–1.03) 1.81 (1.51–2.17)‡

Cardiac A 346 1.26 (1.14–1.40)‡ 1.30 (1.19–1.43)‡ 131 1.23 (1.05–1.43)† 1.57 (1.35–1.83)‡

FA 1.06 (0.92–1.22) 1.25 (1.10–1.43)‡ 0.79 (0.63–0.98)* 1.90 (1.51–2.40)‡

Coronary A 267 1.28 (1.14–1.43)‡ 1.29 (1.16–1.43)‡ 81 1.16 (0.96–1.39) 1.52 (1.26–1.82)‡

FA 1.10 (0.94–1.30) 1.21 (1.04–1.41)* 0.71 (0.54–0.92)* 2.04 (1.53–2.73)‡

Stroke A 174 1.69 (1.47–1.94)‡ 1.61 (1.43–1.81)‡ 82 1.51 (1.23–1.85)‡ 1.75 (1.43–2.15)‡

FA 1.28 (1.05–1.57)* 1.39 (1.16–1.66)‡ 0.94 (0.68–1.30) 1.83 (1.33–2.52)‡

Nº indicates the number of events. The cause of death was unknown in 23 cases. Hazard ratios, presented with 95% confidence interval, express the risk as-sociated with a 1-SD increase in 24-hour systolic (13.5 mm Hg) or diastolic (8.2 mm Hg) blood pressures. All models are adjusted for cohort, age, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes mellitus. Adjusted models (A) include either systolic or diastolic blood pressure, while fully adjusted models (FA) include both systolic and diastolic blood pressures in addition to the aforementioned covariables. Significance

of the hazard ratios: * P0.05; † P0.01, and ‡ P0.001. For 24-h diastolic pressure, the fully adjusted hazard ratios were similar in women and men (P≥0.45).


Fully adjusted hazard ratios associated with 24-h systolic pressure were higher in women than men (P≤0.019) with the exception of cardiovascular mortality (P=0.079) and stroke (P=0.64).

Documents

Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations