Epidemiology/Population
Outcome-Driven Thresholds for Ambulatory Pulse Pressure
in 9938 Participants Recruited From 11 Populations
Yu-Mei Gu, Lutgarde Thijs, Yan Li, Kei Asayama, José Boggia, Tine W. Hansen,
Yan-Ping Liu, Takayoshi Ohkubo, Kristina Björklund-Bodegård, Jørgen Jeppesen,
Eamon Dolan, Christian Torp-Pedersen, Tatiana Kuznetsova, Katarzyna Stolarz-Skrzypek,
Valérie Tikhonoff, Sofia Malyutina, Edoardo Casiglia, Yuri Nikitin, Lars Lind,
Edgardo Sandoya, Kalina Kawecka-Jaszcz, Yutaka Imai, Luis J. Mena, Jiguang Wang,
Eoin O’Brien, Peter Verhamme, Jan Filipovský, Gladys E. Maestre, Jan A. Staessen, on behalf of
the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes
(IDACO) Investigators
See Editorial Commentary, pp 217–219
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Abstract—Evidence-based thresholds for risk stratification based on pulse pressure (PP) are currently unavailable. To derive
outcome-driven thresholds for the 24-hour ambulatory PP, we analyzed 9938 participants randomly recruited from 11
populations (47.3% women). After age stratification (<60 versus ≥60 years) and using average risk as reference, we
computed multivariable-adjusted hazard ratios (HRs) to assess risk by tenths of the PP distribution or risk associated
with stepwise increasing (+1 mm Hg) PP levels. All adjustments included mean arterial pressure. Among 6028 younger
participants (68 853 person-years), the risk of cardiovascular (HR, 1.58; P=0.011) or cardiac (HR, 1.52; P=0.056) events
increased only in the top PP tenth (mean, 60.6 mm Hg). Using stepwise increasing PP levels, the lower boundary of
the 95% confidence interval of the successive thresholds did not cross unity. Among 3910 older participants (39 923
person-years), risk increased (P≤0.028) in the top PP tenth (mean, 76.1 mm Hg). HRs were 1.30 and 1.62 for total and
cardiovascular mortality, and 1.52, 1.69, and 1.40 for all cardiovascular, cardiac, and cerebrovascular events. The lower
boundary of the 95% confidence interval of the HRs associated with stepwise increasing PP levels crossed unity at 64
mm Hg. While accounting for all covariables, the top tenth of PP contributed less than 0.3% (generalized R2 statistic) to the
overall risk among the elderly. Thus, in randomly recruited people, ambulatory PP does not add to risk stratification below
age 60; in the elderly, PP is a weak risk factor with levels below 64 mm Hg probably being innocuous. (Hypertension.
2014;63:229-237.) Online Data Supplement
•
Key Words: ambulatory blood pressure ◼ epidemiology ◼ population science ◼ pulse pressure
T
he blood pressure wave consists of a steady and pulsatile
component, mean arterial pressure, and pulse pressure
(PP).1 Mean arterial pressure, the product of cardiac output
with peripheral arterial resistance, is the force driving blood
flow.1 PP, the difference between systolic and diastolic blood
pressure, depends on left ventricular ejection, the elasticity of
Received August 6, 2013; first decision August 28, 2013; revision accepted October 22, 2013.
From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Sciences, University of
Leuven, Leuven, Belgium (Y.-M.G., L.T., K.A., Y.-P.L., T.K., P.V., J.A.S.); Center for Epidemiological Studies and Clinical Trials (Y.L., J.W.) and Center for
Vascular Evaluation, Shanghai Key Laboratory of Hypertension (Y.L.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Tohoku
University Graduate School of Pharmaceutical Science and Medicine, Sendai, Japan (K.A., T.O., Y.I.); Centro de Nefrología and Departamento de Fisiopatología,
Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay (J.B.); Steno Diabetes Center, Gentofte and Research Center for Prevention and Health,
Glostrup, Denmark (T.W.H.); Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan (T.O.); Division of Cardiovascular
Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden (K.B.-B); Copenhagen University Hospital, Copenhagen,
Denmark (J.J.); Cambridge University Hospitals, Addenbrook’s Hospital, Cambridge, United Kingdom (E.D.); Department of Health Science and Technology,
Aalborg University, Aalborg, Denmark (C.T.-P); Institute of Internal Medicine, Novosibirsk, Russia Federation (T.K., S.M., Y.N.); First Department of Cardiology
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.); 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.J.M., G.E.M.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland (E.O.); Department of
Internal Medicine, Charles University, Pilsen, Czech Republic (J.F.); Department of Psychiatry, Neurology and G.H. Sergievsky Center, Columbia University, New
York, NY (G.E.M.); and Department of Epidemiology, Maastricht University, Maastricht, the Netherlands (J.A.S.).
This paper was sent to David Calhoun, Guest editor, for review by expert referees, editorial decision, and final disposition.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
113.02179/-/DC1.
Correspondence to Jan A. Staessen, Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of
Cardiovascular Sciences, University of Leuven, Kapucijnenvoer 35, Block D, Box 7001, BE-3000 Leuven, Belgium. E-mail [email protected].
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.113.02179
229
230 Hypertension February 2014
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
the central arteries, and the timing and intensity of the backward wave originating at refection sites in the peripheral
circulation. PP widens in the elderly, because systolic blood
pressure continues to rise with advancing age, whereas the agerelated increase in diastolic blood pressure levels off or even
reverses in the fifth decade of life.2
Under the premise that systolic blood pressure and PP reflect
arterial stiffness, the Framingham investigators demonstrated
that with increasing age a gradual shift occurs from diastolic to
systolic pressure and then to PP as predictors of coronary heart
disease.3 Several other studies showed that PP, derived from
the conventionally measured blood pressure, predicts adverse
outcomes in patients with cardiovascular4 or renal disease5,6 as
well as in populations.7–11 Compared with the conventionally
measured blood pressure, ambulatory monitoring substantially
refines risk stratification, but the 5 studies that examined the
predictive value of ambulatory PP only included hypertensive
patients12–16 or patients with end-stage renal disease.5 Although
described as a priority in 2006,17 to our knowledge, current
guidelines for the management of hypertension18–20 do not propose outcome-driven thresholds for PP discriminating normal
from abnormal values. We addressed these issues in a subjectlevel meta-analysis of 9938 people recruited from 11 populations
and enrolled in the International Database on Ambulatory blood
pressure in relation to Cardiovascular Outcomes (IDACO).
Methods
Study Population
Previous publications described the construction of the IDACO
database.21 All studies received ethical approval and qualified for
inclusion if they involved a random population sample, contained
baseline information on the ambulatory blood pressure and cardiovascular risk factors, and follow-up of fatal and nonfatal outcomes.
All participants gave informed written consent. The IDACO database21 included 12 randomly recruited population cohorts and 12 725
participants, but at the time of writing this report, validated information on outcome was available in only 11 studies (details and references provided in the online-only Data Supplement), leaving 12 148
participants. Of those, we excluded 2210 because they were younger
than 18 years (n=74) or had fewer than 10 daytime or 5 nighttime
blood pressure readings (n=2136). Thus, the number of subjects
included in the present analysis totaled 9938.
Blood Pressure Measurement
Methods used for conventional and ambulatory blood pressure
measurement are described in the online-only Data Supplement.
­
Conventional blood pressure was the average of 2 consecutive readings. Hypertension was as a conventional blood pressure of ≥140
mm Hg systolic or ≥90 mm Hg diastolic, or use of antihypertensive
drugs. Portable monitors were programmed to obtain ambulatory
blood pressure readings at 30-minute intervals throughout the whole
day, or at intervals ranging from 15 to 30 minutes during daytime and
from 15 to 60 minutes at night. Daytime ranged from 10:00 am to
8:00 pm in Europeans and South Americans, and from 8:00 am to 6:00
pm in Asians. The corresponding nighttime intervals ranged midnight
to 6:00 am, and from 10:00 pm to 4:00 am. PP was the difference
between systolic and diastolic blood pressure, and mean arterial pressure was diastolic blood pressure plus one third of PP.
Other Measurements
We used questionnaires to obtain information on each participant’s medical history and smoking and drinking habits. We measured serum cholesterol and blood glucose by automated enzymatic
methods. Diabetes mellitus was the use of antidiabetic drugs, a fasting blood glucose concentration of ≥7.0 mmol/L,22 a random blood
glucose concentration of ≥11.1 mmol/L,22 a self-reported diagnosis,
or diabetes mellitus documented in practice or hospital records.
Ascertainment of Events
We ascertained vital status and the incidence of fatal and nonfatal
diseases from the appropriate sources in each country, as described
in previous publications21 and in the online-only Data Supplement.
Fatal and nonfatal stroke did not include transient ischemic attacks.
Coronary events encompassed death from ischemic heart disease, sudden death, nonfatal myocardial infarction, and coronary revascularization. Cardiac events comprised coronary end points and fatal and
nonfatal heart failure. The composite cardiovascular end point included
all aforementioned end points plus cardiovascular mortality. In all outcome analyses, we only considered the first event within each category.
We informed sample size calculations with the event rate of the
composite cardiovascular end point in the IDACO cohort (10.7 per
1000 person-years). We used the one-sample test as implemented in
the PROC POWER procedure of the SAS package. To demonstrate
a 10% change in the relative risk associated with each 10 mm Hg
increase in 24-hour PP, ≈7000 subjects would be needed with the
2-sided α-level set at 0.05 and power at 0.90.
Statistical Analysis
For database management and statistical analysis, we used SAS software, version 9.3 (SAS Institute, Cary, NC). We compared means and
proportions using the large-sample z-test and χ2 statistic, respectively.
After stratification for cohort and sex, we interpolated missing values of body mass index (n=46) and total serum cholesterol (n=683)
from the regression slope on age. In subjects with unknown drinking
(n=813) or smoking habits (n=69), we set the design variable to the
cohort- and sex-specific mean of the codes (0,1). Statistical significance was a 2-sided P value of ≤0.05.
To relate outcome to PP, while adjusting for covariables, we applied Cox regression. The baseline characteristics used for adjustment included cohort, sex, age (continuous), mean arterial pressure,
heart rate, body mass index (continuous), current smoking and drinking (0,1), serum cholesterol (continuous), history of cardiovascular
disease (0,1) and diabetes mellitus (0,1), and antihypertensive drug
treatment (0,1). For adjustment, mean arterial pressure and heart
rate were derived from the same recordings as PP (24-hour, daytime,
nighttime, or conventional measurements).
Because of the Framingham results23 and the lower age boundary in several randomized clinical trials on antihypertensive treatment in the elderly,24 we stratified our analyses by 60 years of age.
Exploratory analyses demonstrated that the association of end points
with 24-hour PP was not always log-linear. To account for this nonlinear association, we applied the deviation from mean coding25 to
compute hazard ratios (HRs) in tenths of the 24-hour PP distribution.
This approach expresses the risk in each tenth relative to the overall
risk in the whole study population and allows computing 95% confidence intervals (CIs) for the HRs in all tenths without definition of
an arbitrary reference group. HRs relating end points to mean arterial
pressure expressed the risk associated with a 1-SD increase in the level. We tested heterogeneity in the HRs across subgroups by introducing the appropriate interaction term in the Cox model. We applied the
generalized R2 statistic to assess the risks additionally explained by
24-hour PP over and beyond mean arterial pressure and other covariables.26 To assess whether collinearity between PP and mean arterial
pressure affected our estimates, we applied penalized Cox regression
as applied in the RIDGING=RELATIVE model option of the PROC
PHREG procedure of the SAS package.
In an attempt to refine the level of PP that was associated with
significantly increased risk, we did a stepwise analysis. We calculated HRs for 1-mm Hg increments in PP for thresholds ranging from
the 10th to the 90th percentile. These HRs expressed the risk in participants whose PP exceeded the cutoff point versus average risk. We
plotted these HRs and their 95% confidence limits versus the increasing cutoff points with the goal to determine at which level the lower
confidence limit of the HRs crossed unity.
Gu et al Risk Associated With Pulse Pressure 231
Results
Analyses of Younger Participants
Characteristics of Participants
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
The whole study population comprised 6623 Europeans
(66.6%), 1877 Asians (18.9%), and 1438 South Americans
(14.5%). Of the 9938 participants, 4703 were women
(47.3%), 4058 (40.8%) had hypertension on conventional
blood pressure measurement, and 1946 (19.6%) were taking blood pressure–lowering drugs. Mean age was 52.7±15.8
years. In the whole study population, average 24-hour blood
pressure levels were 123.5±14.0 mm Hg systolic, 73.6±8.3
mm Hg diastolic, 49.9±9.6 mm Hg for PP, and 90.2±9.5
mm Hg for mean arterial pressure. At enrollment, 2789 participants (28.1%) were current smokers, and 4759 (47.9%)
reported intake of alcohol.
The Table shows the characteristics of the participants by
age group. The median number of readings averaged to estimate the 24-hour PP was 50 (5th to 95th percentile interval,
35–81; range, 21–95) in younger participants and 56 (5th to
95th percentile interval, 35–82; range, 20–99) in the elderly.
Table S1 in the online-only Data Supplement additionally lists
the conventional blood pressure and the daytime and nighttime
blood pressure by age group. All of the differences between
age groups were significant (P≤0.0012) with the exception of
the proportion of Asians (P=0.057).
Table. Baseline Characteristics of Participants by Age Group
Characteristics
<60 y
(N=6028)
≥60 y
(N=3910)
Ethnicity
Asian
953 (15.8)
924 (23.6)
European
4061 (67.4)
2562 (65.5)
South American
1014 (16.8)
424 (10.8)
Women
3239 (53.7)
1464 (37.4)
Cardiovascular risk factors
Smoking
1857 (30.9)
932 (24.1)
Drinking alcohol
2795 (47.7)
1964 (60.1)
Diabetes mellitus
247 (4.1)
411 (10.5)
Cardiovascular disease
269 (4.5)
521 (13.3)
Hypertension
1529 (25.4)
2529 (64.7)
Antihypertensive drug treatment
619 (10.3)
1327 (34.1)
Age, y
42.5±11.1
68.6±5.6
Body mass index, kg/m2
25.1±4.3
25.7±4.0
Serum total cholesterol, mmol/L
5.45±1.14
5.83±1.15
Blood glucose, mmol/L
5.01±1.14
5.52±1.60
Systolic blood pressure, mm Hg
119.4±12.0
129.8±14.5
Diastolic blood pressure, mm Hg
73.0±8.3
74.6±8.3
Pulse pressure, mm Hg
46.4±7.2
55.2±10.5
Mean arterial pressure, mm Hg
88.5±9.1
93.0±9.6
Heart rate, bpm
73.6±8.9
69.9±9.1
24-h blood pressure measurements
Data are No. (%) or mean±SD. Hypertension is a conventional blood pressure
of ≥140 mm Hg systolic or ≥90 mm Hg diastolic or use of antihypertensive drugs.
To convert glucose and cholesterol from mmol/L to mg/dL, multiply by 18.01 and
38.61, respectively. All of the differences between age groups were significant
(P<0.0001) with the exception of the proportion of Asians (P=0.057).
Incidence of End Points
Among 6028 younger participants (<60 years), median followup was 12.1 years (5th to 95th percentile interval, 2.5–18.2
years). Over 68 853 person-years, 228 participants died (3.3
per 1000 person-years) and 221 experienced a fatal or nonfatal cardiovascular complication (3.2 per 1000 person-years).
The online-only Data Supplement provides information on the
overall and cause-specific number of fatal and nonfatal events.
Categorical Analysis of 24-Hour PP
Figure 1 shows the HRs expressing the risk in each tenth of
the distribution of the 24-hour ambulatory PP versus average
risk. Only in the highest tenth of the PP distribution (threshold, ≥55.6 mm Hg; mean, 60.1 mm Hg) the risk of the composite cardiovascular end point was elevated (HR, 1.58; 95%
CI, 1.11–2.25; P=0.011) with a similar trend for cardiac end
points (HR, 1.52; CI, 0.99–2.33; P=0.056). Otherwise, the
risks across tenths of the PP distribution (Figure 1) did not
deviate from average (P≥0.058). For stroke, Cox models
across tenths of the PP distribution did not converge, because
of the low number of events (n=63). The HRs expressing the
risk associated with a 1-SD increase in mean arterial pressure
were 1.11 (CI, 0.95–1.29; P=0.19) for total mortality, 1.40
(CI, 1.09–1.80; P=0.009) for cardiovascular mortality, 1.37
(CI, 1.19–1.59; P<0.0001) for a composite cardiovascular end
point, and 1.40 (CI, 1.18–1.66; P=0.0001) for a cardiac event.
Stepwise Analysis of PP
Figure S1 shows the HRs of 24-hour PP levels that stepwise
increased by 1 mm Hg from the 10th to the 90th percentile.
For all end points under study, the lower boundary of the confidence interval of the successive HRs did not cross unity.
Analyses of Older Participants
Incidence of End Points
Among 3910 older participants (≥60 years), median follow-up
was 10.7 years (5th to 95th percentile interval, 2.5–16.1 years).
Over 39 923 person-years, 1160 participants died (29.0 per 1000
person-years) and 940 experienced a fatal or nonfatal cardiovascular complication (23.5 per 1000 person-years). The online-only
Data Supplement lists the number of fatal and nonfatal events.
Categorical Analysis of 24-Hour PP
Figure 2 shows the HRs expressing the risk in each tenth of the
distribution of the 24-hour ambulatory PP versus average risk.
The risk of any death, cardiovascular mortality, a composite
cardiovascular end point, or a cardiac event was consistently
elevated in the top tenth of the PP distribution (threshold, ≥68.8
mm Hg; mean, 76.1 mm Hg). The HRs were 1.30 (CI, 1.09–
1.55; P=0.004), 1.62 (CI, 1.26–2.10; P=0.0002), 1.52 (CI,
1.26–1.83; P<0.0001), and 1.69 (CI, 1.33–2.15; P<0.0001),
respectively. The HR for stroke in the top tenth of the PP distribution was 1.40 (CI, 1.04–1.89; P=0.028; Figure S2). For
cardiovascular mortality and the composite cardiovascular end
point, the HRs were 0.66 (CI, 0.45–0.97; P=0.033) and 0.78
(CI, 0.61–0.99; P=0.040) in the second and third tenth of the
PP distribution, respectively (Figure 2). Otherwise, the risks
across tenths of the PP distribution (Figure 2 and Figure S2)
did not deviate from average (P>0.05). The HRs expressing
232 Hypertension February 2014
A
B
All-Cause Mortality
4.64
2.91
2.84
2.0
2.0
P=0.50
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Adjusted Hazard Ratio (95%CI)
Cardiovascular Mortality
2.5
2.5
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
30
40
50
60
C
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
40
50
60
50
70
No. of
Events 17 7 16 14 18 14 24 25 30 56
Rate 2.8 1.2 2.6 2.3 3.0 2.3 4.0 4.1 5.1 9.3
60
70
Cardiac Events
2.5
P=0.011
30
40
No. of
Events 6 2 3 6 4 4 10 4 11 17
Rate 1.0 0.3 0.5 1.0 0.7 0.7 1.7 0.7 1.8 2.8
D
Cardiovascular Events
2.5
P=0.11
30
70
No. of
Events 15 18 14 26 15 22 32 23 28 35
Rate 2.5 3.0 2.3 4.3 2.5 3.6 5.3 3.8 4.6 5.8
3.32
P=0.056
30
40
50
60
Figure 1. Hazard ratios (HRs) in tenths
of the distribution of 24-h pulse pressure
(PP) in 6028 younger participants. HRs for
total (A) and cardiovascular (B) mortality
and for cardiovascular (C) and cardiac
(D) events express the risk in each tenth
compared with average risk. HRs were
adjusted for cohort, sex, age, 24-h mean
arterial pressure, 24-h heart rate, body
mass index, smoking and drinking, serum
cholesterol, history of cardiovascular
disease and diabetes mellitus, and
antihypertensive drug treatment. Vertical
bars denote 95% confidence intervals.
For each tenth, the number of events
and unadjusted incidence rates (in
percent) are given. P value refers to the
significance of the HR in the top tenth of
the 24-h PP distribution.
70
No. of
Events 14 6 13 8 14 10 15 18 18 37
Rate 2.3 1.0 2.2 1.3 2.3 1.7 2.5 3.0 3.0 6.1
24−H Pulse Pressure (mm Hg)
the risk associated with a 1-SD increase in mean arterial pressure were 1.04 (CI, 0.96–1.12; P=0.31) for total mortality,
1.15 (CI, 1.02–1.29; P=0.02) for cardiovascular mortality, 1.19
(CI, 1.10–1.29; P<0.0001) for a composite cardiovascular end
point, 1.07 (CI, 0.96–1.19; P=0.22) for a cardiac event, and
1.39 (CI, 1.23–1.58; P<0.0001) for stroke. The R2 statistic for
adding a design variable coding for the top tenth of the 24-hour
PP distribution to Cox models including all other covariables
was 0.10% and 0.12% for total and cardiovascular mortality,
and 0.27%, 0.21%, and 0.09% for the composite cardiovascular end point, all cardiac events, and stroke, respectively.
Stepwise Analysis of PP
Figure 3 shows the HRs for 24-hour PP levels increasing by
1-mm Hg steps from the 10th up to the 90th percentile in older
participants. For most end points under study (Figure 3) with
the exception of stroke (Figure S2), the lower boundary of the
confidence interval of the successive HRs crossed the reference
line at levels ranging from 64 mm Hg (composite cardiovascular end point) to 69 mm Hg (total mortality and cardiac events).
Sensitivity Analyses
Excluding 1 cohort at a time produced confirmatory results
as shown for cardiovascular mortality and composite cardiovascular end point in Table S2. Similarly, when we stratified
our analyses in older participants for ethnicity, sex, presence
versus absence of conventional hypertension, or use versus
nonuse of antihypertensive drugs, the results remained consistent (0.16≤P≤0.75 for interaction between subgroups;
Table S3). After excluding 863 older participants with a history of cardiovascular disease or diabetes mellitus, the significance of these interaction terms did not materially change
(0.37≤P≤0.97). Modeling cohort as a random effect in the
Cox model instead of adjusting the model for cohort (Figures
S3 and S4), applying ridge regression (Table S4), or adjusting
for systolic or diastolic blood pressure instead of mean arterial
pressure (Table S5) produced consistent results. Finally, when
we substituted 24-hour PP by daytime, nighttime, or the conventionally measured PP, the results did not change (Figure 4).
Analyses of Younger and Older Participants
Combined
We tested the interaction between 24-hour PP and age modeled
as a categorical or continuous variable in 9938 participants. In
the categorical analyses (Table S6), using age cutoff limits 50,
55, or 60 years, none of the interaction terms reached significance (0.14≤P≤0.72) except for cardiovascular events with 50
years as age cut-off (P=0.005). In the continuous analyses, the
HRs associated with 10-mm Hg higher 24-hour PP in younger
and older participants (<60 versus ≥60 years) were 1.12 (CI,
0.91–1.38) versus 1.08 (1.00–1.15) for total mortality (P value
Gu et al Risk Associated With Pulse Pressure 233
A
B
All-Cause Mortality
2.5
2.5
2.0
2.0
P=0.004
1.5
Adjusted Hazard Ratio (95%CI)
Cardiovascular Mortality
P=0.0002
1.5
1.0
1.0
0.5
0.5
0.0
0.0
30
40
50
60
70
80
30
40
50
60
70
80
No. of
Events 84 92 96 96 119 121 110 134 139 165
Rate 21 23 25 25 30 31 28 34 35 42
No. of
Events 25 24 36 32 46 42 47 58 66 93
Rate
6 6 19 8 12 11 12 15 17 24
C
D
Cardiovascular Events
2.5
2.5
2.0
2.0
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
P<0.0001
1.5
Cardiac Events
P<0.0001
1.5
1.0
1.0
0.5
0.5
Figure 2. Hazard ratios (HRs) in tenths
of the distribution of 24-h pulse pressure
(PP) in 3910 older participants. HRs for
total (A) and cardiovascular (B) mortality
and for cardiovascular (C) and cardiac
(D) events express the risk in each tenth
compared with average risk. The HRs
were adjusted as in Figure 1. Vertical
bars denote 95% confidence intervals.
For each tenth, the number of events
and unadjusted incidence rates (in
percent) are given. P value refers to the
significance of the HR in the top tenth of
the 24-h PP distribution.
0.0
0.0
30
40
50
60
70
80
No. of
Events 58 65 62 69 87 88 102 111 127 171
Rate 15 17 16 18 22 22 26 28 32 44
30
40
50
60
70
80
No. of
Events 40 31 33 33 47 46 49 60 64 102
Rate 10 8 8 8 12 12 12 15 16 26
24−H Pulse Pressure (mm Hg)
for difference, 0.085), 1.24 (0.86–1.81) versus 1.13 (1.01–
1.25) for cardiovascular mortality (P=0.020), 1.28 (1.05–1.57)
versus 1.13 (1.05–1.21) for the composite cardiovascular end
point (P=0.009), and 1.21 (CI, 0.96–1.53) versus 1.17 (1.06–
1.28) for cardiac events (P=0.22).
Discussion
After more than 2 decades of research,7 PP remains an elusive cardiovascular risk factor with findings being inconsistent
across studies. Previous cohort studies found that peripheral
PP, as measured by conventional sphygmomanometry, was an
independent risk factor in populations3,7–11 or in patients with
hypertension,4,27–29 coronary heart disease,4 or severe renal
dysfunction.5,6 Other population studies failed to confirm
the risk associated with PP30,31 or reported that it was present only in women7 or in diabetic10 or treated hypertensive
patients.29 In addition to the conventional method of blood
pressure measurement, the aforementioned studies had limitations, because they recorded only fatal end points5–8,10,11,30,31
or applied recruitment criteria confined to high-risk patie
nts,4,6,27–29,31 a narrow age range,7,8 or the elderly.11,28 To address
these drawbacks, we applied ambulatory blood pressure monitoring, the current state-of-the-art for blood pressure measurement,32 and we recorded both fatal and nonfatal end points in
randomly recruited populations with age ranging from 18 to
93 years. The key finding of our study was that 24-hour PP did
not substantially add to risk stratification below age 60; in the
elderly, 24-hour PP was a weak risk factor with levels below
64 mm Hg probably being innocuous. For all end points under
study, 24-hour PP remained a significant predictor of outcome
with either 24-hour mean arterial pressure or 24-hour diastolic
blood pressure as covariable in the Cox models, but it lost
significance for all-cause mortality and stroke with 24-hour
systolic blood pressure in the model. These findings suggest
that systolic blood pressure might be the major blood pressure component driving the risk associated with PP. Using
continuous analyses in our current study, the HRs expressing
the risk associated with 10-mm Hg wider 24-hour PP, were
higher in younger than in older participants for the composite
cardiovascular end point (1.28 versus 1.13). However, these
HRs only reflect relative risk. The composite cardiovascular
end point was running at rates of 3.2 and 23.5 events per 1000
person-years in younger and older participants, respectively.
In terms of absolute risk, 24-hour PP, therefore, was a more
important predictor in older than in younger participants.
Already in 1971, the Framingham investigators33 demonstrated that the role of diastolic and systolic blood pressure as
risk indicators depends on age. In 2001, they reported that with
increasing age there was a gradual shift from diastolic blood
pressure to systolic blood pressure and then to PP as predictors
of coronary heart disease.3 In 1989, the Multiple Risk Factor
Trial researchers demonstrated that both systolic and diastolic
blood pressure determine cardiovascular risk.34 Also in 1989,
Darne et al,7 by applying principal component analysis, established a steady and pulsatile component of blood pressure,
which were unrelated to each other but strongly correlated with
mean arterial pressure and PP, respectively. Guided by these
seminal publications,3,7,33,34 we stratified our main analyses by
234 Hypertension February 2014
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Adjusted Hazard Ratio (95%CI)
A
1.6
B
1.6
All-Cause Mortality
1.4
1.4
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
40
C
1.6
50
60
70
40
D
1.6
Cardiovascular Events
1.4
1.4
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
40
50
60
Cardiovascular Mortality
70
50
60
70
Cardiac Events
40
50
60
Figure 3. Hazard ratios (HRs) according
to 24-h pulse pressure (PP) levels ranging
from the 10th to the 90th percentile in
3910 older participants. HRs for total
(A) and cardiovascular (B) mortality and
for cardiovascular (C) and cardiac (D)
events express the risk at each level of
PP compared with average risk. Solid and
dotted lines denote the point estimates
and the 95% confidence intervals,
respectively. The HRs were adjusted as
in Figure 1.
70
24−H Pulse Pressure (mm Hg)
age (<60 versus ≥60 years) and we modeled PP as risk factor,
after accounting for mean arterial pressure.
The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure18 proposed that PP is only marginally stronger
than systolic blood pressure for risk stratification in individuals over age 60, and that under age 60, PP is not predictive.
According to the 2007 European guideline,19 PP is a derived
measure, which combines the imprecision of the original systolic and diastolic measurements. The 2007 guideline stated
that, although levels of 50 to 55 mm Hg have been suggested,17
no practical cutoff values separating PP normality from abnormality is available. The 2013 European guideline increased
this threshold to 60 mm Hg without any justification.20 Our
current analyses established that below age 60, a 24-hour PP
level ≈60 mm Hg might be associated with increased risk,
but that a safe threshold could not be established. Among the
elderly participants, a 24-hour PP of ≈76 mm Hg was definitely associated with higher risk, and levels below 64 mm Hg
were probably safe. Using intra-arterial monitoring, Khattar
et al14 observed that survival rates were highest below age 60,
if the 24-hour PP was less than 70 and highest among elderly
participants with a 24-hour PP of 70 mm Hg or more. To our
knowledge, Khattar’s report14 is the only other study proposing an outcome-driven threshold for 24-hour PP. However,
this article does not include any justification why 70 mm Hg
was chosen as threshold in a dichotomized analysis. The
results rested on an unadjusted Kaplan–Meier survival function analysis, and the study population consisted of patients
with essential hypertension, in whom treatment had been
withdrawn for 8 weeks.14 To our knowledge, all other proposals for PP thresholds relied on conventional blood pressure
measurement. In analyses adjusted but not stratified for age, 2
studies9,27 derived a threshold from the 66th percentile of the
PP distribution. Madhavan et al27 proposed 63 mm Hg based
on the incidence of myocardial infarction in 2207 hypertensive patients aged 55 years, and Borghi et al9 suggested
67 mm Hg based on the incidence of cardiovascular disease
among 2939 Italian participants (14–84 years). Asmar et al35
derived a threshold of 65 mm Hg from the mean PP plus 2 SDs
in 61 724 French people (16–90 years).
Our current results must be interpreted within the context
of some limitations. First, because of the low event rates
below the middle age, our analyses did not answer the issue
whether PP has a different prognostic impact in young compared with older people. However, as reviewed elsewhere,36
Gu et al Risk Associated With Pulse Pressure 235
A
B
24-H Pulse Pressure
Daytime Pulse Pressure
E/R1−9
E/R10
P
E/R1−9
E/R10
P
Total Mortality
995/3519
165/391
0.004
1007/3519
153/391
0.066
CV Mortality
376/3519
93/391
0.0002
389/3519
80/391
0.018
CV Events
769/3519
171/391
<0.0001
780/3519
160/391
0.0003
Cardiac Events 403/3519
102/391
<0.0001
407/3519
98/391
0.0002
0
C
1
2
3
4
0
D
Nighttime Pulse Pressure
1
2
3
4
Conventional Pulse Pressure
E/R1−9
E/R10
P
E/R1−9
E/R10
P
Total Mortality
988/3519
172/391
0.008
996/3519
164/391
0.058
CV Mortality
374/3519
95/391
0.0007
380/3519
89/391
0.014
150/391
0.045
77/391
0.063
549/3519
172/391
<0.0001
790/3519
Cardiac Events 409/3519
96/391
0.0003
428/3519
CV Events
0
1
2
3
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Hazard Ratio
4
0
1
2
3
4
Hazard Ratio
Figure 4. Multivariable-adjusted hazard ratios (HRs) for outcomes in relation to 24-h (A), daytime (B), nighttime (C), and conventional (D)
pulse pressure (PP) in 3910 older participants. The HRs, presented with 95% confidence interval (CI), express the risk in the top tenth
compared with the average risk in the participants. PP thresholds delineating the top tenth were ≥68.8, ≥71.3, ≥66.8, and ≥80.0 mm Hg
for 24-h, daytime, nighttime, and conventional blood pressure measurement; the corresponding mean levels of PP in the top tenth were
76.1, 78.8, 75.6, and 89.0 mm Hg, respectively. All models were adjusted for cohort, sex, age, mean arterial pressure and heart rate (on
24-h, daytime, nighttime, conventional measurement in panels A, B, C, and D, respectively), body mass index, smoking and drinking,
serum cholesterol, history of cardiovascular disease and diabetes mellitus, and antihypertensive drug treatment. P values are for the
risk in the top tenth relative to the overall risk in the whole study population. CV indicates cardiovascular. E/R1–9 and E/R10 indicate the
number of events and participants at risk below the 90th percentile of the PP distribution and in the top tenth, respectively.
our current study, along with the Framingham report,3 is one
of the few with long-term follow-up of subjects less than 40
years. Second, we did not account for regression dilution
bias.30 However, we previously demonstrated that such correction is not necessary for blood pressure indexes obtained
by 24-hour ambulatory monitoring.37 Third, we had no information on central PP. As demonstrated in Europeans38 and
Chinese participants,39 with advancing age, systolic augmentation increases and pressure amplification, the difference between peripheral and central systolic blood pressure,
decreases. By measuring PP at a peripheral site, we might
have underestimated its prognostic significance, in particular in younger people. Finally, oscillometric and auscultatory
estimates of PP might differ. However, our findings were
consistent regardless of the interval over which the ambulatory blood pressure was measured, as well as on ambulatory
(oscillometric) and conventional (predominantly auscultatory) measurements.
Perspectives
Based on our observations in randomly recruited people, PP
adds little information on cardiovascular outcomes below age
60. In the elderly participants, ambulatory PP is a risk factor
with levels below 64 mm Hg probably being harmless. However,
using this threshold in clinical practice might be of little value,
because ambulatory PP does not substantially enhance risk
stratification over and beyond the steady component of the
blood pressure level and other cardiovascular risk factors. We
suggest that the threshold proposed for PP in the European 2013
guideline,20 irrespective of measurement technique, might be
revised from the perspective of our current findings.
Acknowledgments
This study would not have been possible without the collaboration of
the participants and the expert assistance of Sandra Covens (Studies
Coordinating Centre, Leuven, Belgium). The IDACO investigators
are listed in Thijs et al.21
Sources of Funding
The
European
Union
(grants
IC15-CT98-0329EPOGH,
LSHM-CT-2006–037093
InGenious
HyperCare,
HEALTH-F4-2007–201550
HyperGenes,
HEALTH-F7-2011278249
EU-MASCARA,
HEALTHF7-305507 HOMAGE and the European Research Council Ad­
vanced Research 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.0880.13N) 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 Grant-in-Aid for
Scientific Research (23249036, 23390171, 24591060, 24390084,
24591060, 24790654, 25461205, 25461083, and 25860156)
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan; a Health Labour Sciences 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, Beijing, China (grants 30871360, 30871081, 81170245,
and 81270373), 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
236 Hypertension February 2014
Universidad de la República (Grant I+D GEFA-HT-UY) and the
Agencia Nacional de Innovación e Investigación supported research in Uruguay. The 1R01AG036469-01A1 from the National
Institute on Aging and Fogarty International Center is supporting
the Maracaibo Aging Study.
Disclosures
None.
References
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
1. Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial
stiffness and pulse pressure in hypertension and cardiovascular diseases.
Circulation. 2003;107:2864–2869.
2. Staessen J, Amery A, Fagard R. Editorial review. Isolated systolic hypertension. J Hypertens. 1990;8:393–405.
3. Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB,
Levy D. Does the relation of blood pressure to coronary heart disease
risk change with aging? The Framingham Heart Study. Circulation.
2001;103:1245–1249.
4.Bangalore S, Messerli FH, Franklin SS, Mancia G, Champion A,
Pepine CJ. Pulse pressure and risk of cardiovascular outcomes in
patients with hypertension and coronary artery disease: an INternational
VErapamil SR-trandolapril STudy (INVEST) analysis. Eur Heart J.
2009;30:1395–1401.
5. Amar J, Vernier I, Rossignol E, Bongard V, Arnaud C, Conte JJ, Salvador
M, Chamontin B. Nocturnal blood pressure and 24-hour pulse pressure
are potent indicators of mortality in hemodialysis patients. Kidney Int.
2000;57:2485–2491.
6.Liu JH, Chen CC, Wang SM, Chou CY, Liu YL, Kuo HL, Lin HH,
Wang IK, Yang YF, Huang CC. Association between pulse pressure
and 30-month all-cause mortality in peritoneal dialysis patients. Am J
Hypertens. 2008;21:1318–1323.
7. Darne B, Girerd X, Safar M, Cambien F, Guize L. Pulsatile versus steady
component of blood pressure: a cross-sectional analysis and a prospective
analysis on cardiovascular mortality. Hypertension. 1989;13:392–400.
8. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetieère P,
Guize L. Pulse pressure: a predictor of long-term cardiovascular mortality
in a French male population. Hypertension. 1997;30:1410–1415.
9. Borghi C, Dormi A, Ambrosioni E, Gaddi A; Brisighella Heart Study
Working Party. Relative role of systolic, diastolic and pulse pressure
as risk factors for cardiovascular events in the Brisighella Heart Study.
J Hypertens. 2002;20:1737–1742.
10. Schram MT, Kostense PJ, Van Dijk RA, Dekker JM, Nijpels G, Bouter
LM, Heine RJ, Stehouwer CD. Diabetes, pulse pressure and cardiovascular mortality: the Hoorn Study. J Hypertens. 2002;20:1743–1751.
11. Glynn RJ, Chae CU, Guralnik JM, Taylor JO, Hennekens CH. Pulse
pressure and mortality in older people. Arch Intern Med. 2000;160:
2765–2772.
12. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Pede S, Porcellati C.
Ambulatory pulse pressure: a potent predictor of total cardiovascular risk
in hypertension. Hypertension. 1998;32:983–988.
13. Verdecchia P, Schillaci G, Reboldi G, Franklin SS, Porcellati C. Different
prognostic impact of 24-hour mean blood pressure and pulse pressure on
stroke and coronary artery disease in essential hypertension. Circulation.
2001;103:2579–2584.
14. Khattar RS, Swales JD, Dore C, Senior R, Lahiri A. Effect of aging on the
prognostic significance of ambulatory systolic, diastolic, and pulse pressure in essential hypertension. Circulation. 2001;104:783–789.
15.Staessen JA, Thijs L, O’Brien ET, Bulpitt CJ, de Leeuw PW, Fagard
RH, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster J, Safar ME;
Syst-Eur Trial Investigators. Ambulatory pulse pressure as predictor of
outcome in older patients with systolic hypertension. Am J Hypertens.
2002;15(10 Pt 1):835–843.
16. Kao YT, Huang CC, Leu HB, Wu TC, Huang PH, Lin SJ, Chen JW.
Ambulatory pulse pressure as a novel predictor for long-term prognosis
in essential hypertensive patients. J Hum Hypertens. 2011;25:444–450.
17.Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C,
Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier
H; European Network for Non-invasive Investigation of Large Arteries.
Expert consensus document on arterial stiffness: methodological issues
and clinical applications. Eur Heart J. 2006;27:2588–2605.
18. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ;
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. National Heart, Lung, and Blood
Institute; National High Blood Pressure Education Program Coordinating
Committee. Seventh report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Hypertension. 2003;42:1206–1252.
19. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the
management of arterial hypertension: The Task Force for the Management
of Arterial Hypertension of the European Society of Hypertension
(ESH) and of the European Society of Cardiology (ESC). Eur Heart J.
2007;28:1462–1536.
20.Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for
the Management of Arterial Hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC).
Eur Heart J. 2013;34:2159–2219.
21.Thijs L, Hansen TW, Kikuya M, et al; IDACO Investigators. The
International Database of Ambulatory Blood Pressure in relation to
Cardiovascular Outcome (IDACO): protocol and research perspectives.
Blood Press Monit. 2007;12:255–262.
22.Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26 (suppl 1):S5–S20.
23. Franklin SS, Gustin W IV, Wong ND, Larson MG, Weber MA, Kannel
WB, Levy D. Hemodynamic patterns of age-related changes in blood
pressure. The Framingham Heart Study. Circulation. 1997;96:308–315.
24.Staessen JA, Thijs L, Fagard R, O’Brien ET, Clement D, de Leeuw
PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster
J. Predicting cardiovascular risk using conventional vs ambulatory
blood pressure in older patients with systolic hypertension. Systolic
Hypertension in Europe Trial Investigators. JAMA. 1999;282:539–546.
25. Hosmer DW, Jr, Leleshow S. Applied Logistic Regression. New York:
John Wiley & Sons;1989:47–56.
26. Gillespie BW. Use of generalized R-squared in Cox regression https://
apha.confex.com/apha/134am/techprogram/paper_135906.htm. APHA
Scientific Session and Event Listing. 2006. Accessed August 26, 2013.
27. Madhavan S, Ooi WL, Cohen H, Alderman MH. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension. 1994;23:395–401.
28. Domanski MJ, Davis BR, Pfeffer MA, Kastantin M, Mitchell GF. Isolated
systolic hypertension: prognostic information provided by pulse pressure.
Hypertension. 1999;34:375–380.
29.Greenberg J. Antihypertensive treatment alters the predictive strength
of pulse pressure and other blood pressure measures. Am J Hypertens.
2005;18:1033–1039.
30.Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective
Studies Collaboration. Age-specific relevance of usual blood pressure
to vascular mortality: a meta-analysis of individual data for one million
adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
31. Domanski M, Mitchell G, Pfeffer M, Neaton JD, Norman J, Svendsen K,
Grimm R, Cohen J, Stamler J; MRFIT Research Group. Pulse pressure and
cardiovascular disease-related mortality. JAMA. 2002;287:2677–2683.
32. O’Brien E, Asmar R, Beilin L, et al; European Society of Hypertension
Working Group on Blood Pressure Monitoring. European Society of
Hypertension recommendations for conventional, ambulatory and home
blood pressure measurement. J Hypertens. 2003;21:821–848.
33. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk of coronary heart disease. Am J Cardiol. 1971;27:335–346.
34. Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension. 1989;13
(suppl I):I2–I12.
35. Asmar R, Vol S, Brisac AM, Tichet J, Topouchian J. Reference values
for clinic pulse pressure in a nonselected population. Am J Hypertens.
2001;14(5 Pt 1):415–418.
36.Franklin SS. Pulse pressure as a risk factor. Clin Exp Hypertens.
2004;26:645–652.
37. Gasowski J, Li Y, Kuznetsova T, Richart T, Thijs L, Grodzicki T, Clarke
R, Staessen JA. Is “usual” blood pressure a proxy for 24-h ambulatory
blood pressure in predicting cardiovascular outcomes? Am J Hypertens.
2008;21:994–1000.
38. Wojciechowska W, Stolarz-Skrzypek K, Tikhonoff V, Richart T, Seidlerová
J, Cwynar M, Thijs L, Li Y, Kuznetsova T, Filipovský J, Casiglia E,
Gu et al Risk Associated With Pulse Pressure 237
Grodzicki T, Kawecka-Jaszcz K, O’Rourke M, Staessen JA; European
Project On Genes In Hypertension (Epogh) Investigators. Age dependency
of central and peripheral systolic blood pressures: cross-sectional and longitudinal observations in European populations. Blood Press. 2012;21:58–68.
39. Li Y, Staessen JA, Sheng CS, Huang QF, O’Rourke M, Wang JG. Age
dependency of peripheral and central systolic blood pressures: cross-sectional and longitudinal observations in a Chinese population. Hypertens
Res. 2012;35:115–122.
Novelty and Significance
What Is New?
• This is the first population-based study to derive outcome-driven threshold for 24-hour pulse pressure (PP).
What Is Relevant?
• Twenty-four-hour PP does not substantially add to risk stratification below age 60.
• Starting from 60 years onwards, 24-hour PP levels of 70 mm Hg or high-
er carry an increased cardiovascular risk, whereas levels <64 mm Hg
are probably innocuous. However, while accounting for all covariables,
having a 24-hour PP in the top tenth of the distribution contributed less
than 0.3% to the overall risk among the elderly.
• Findings for daytime, nighttime, and conventional PP were similar to
those for 24-hour ambulatory PP.
Summary
The present report is the first to provide outcome-driven thresholds
for PP on 24-hour ambulatory measurement. These findings could
inform guidelines and be of help to clinicians in diagnosing and
managing patients.
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Outcome-Driven Thresholds for Ambulatory Pulse Pressure in 9938 Participants
Recruited From 11 Populations
Yu-Mei Gu, Lutgarde Thijs, Yan Li, Kei Asayama, José Boggia, Tine W. Hansen, Yan-Ping
Liu, Takayoshi Ohkubo, Kristina Björklund-Bodegård, Jørgen Jeppesen, Eamon Dolan,
Christian Torp-Pedersen, Tatiana Kuznetsova, Katarzyna Stolarz-Skrzypek, Valérie Tikhonoff,
Sofia Malyutina, Edoardo Casiglia, Yuri Nikitin, Lars Lind, Edgardo Sandoya, Kalina
Kawecka-Jaszcz, Yutaka Imai, Luis J. Mena, Jiguang Wang, Eoin O'Brien, Peter Verhamme,
Jan Filipovský, Gladys E. Maestre and Jan A. Staessen
on behalf of the International Database on Ambulatory blood pressure in relation to
Cardiovascular Outcomes (IDACO) Investigators
Hypertension. 2014;63:229-237; originally published online December 9, 2013;
doi: 10.1161/HYPERTENSIONAHA.113.02179
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/63/2/229
Data Supplement (unedited) at:
http://hyper.ahajournals.org/content/suppl/2013/12/09/HYPERTENSIONAHA.113.02179.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/
Risk Associated with Pulse Pressure -1DVIII (06/12/13 16:53)
Idpp8_spl.doc and ABP.RMD
Hypertension HYPE201302179R3
Data Supplement
Outcome-Driven Thresholds for Ambulatory Pulse Pressure
in 9938 People Recruited from 11 Populations
Risk Associated with Pulse Pressure
Yu-Mei Gu, Lutgarde Thijs, Yan Li, Kei Asayama, José Boggia,
Tine W. Hansen, Yan-Ping Liu, Takayoshi Ohkubo, Kristina Björklund-Bodegård,
Jørgen Jeppesen, Eamon Dolan, Christian Torp-Pedersen, Tatiana Kuznetsova,
Katarzyna Stolarz-Skrzypek, Valérie Tikhonoff, Sofia Malyutina, Edoardo Casiglia,
Yuri Nikitin, Lars Lind, Edgardo Sandoya, Kalina Kawecka-Jaszcz, Yutaka Imai,
Luis J. Mena, Jiguang Wang, Eoin O’Brien, Peter Verhamme,
Jan Filipovský, Gladys E. Maestre, Jan A. Staessen,
on behalf of the International Database on Ambulatory blood pressure
in relation to Cardiovascular Outcomes (IDACO) Investigators
Correspondence:
Jan A. Staessen, MD, PhD,
Research Unit Hypertension and Cardiovascular Epidemiology,
KU Leuven Department of Cardiovascular Sciences,
University of Leuven,
Kapucijnenvoer 35, Box 7001,
BE-3000 Leuven, Belgium
Telephone:
+31-43-3388-2374 (office)
+32-15-41-1747 (home)
+32-47-632-4928 (mobile)
Facsimile:
+32-43-388-4128 (office)
+32-15-41-4542 (home)
email:
[email protected]
[email protected]
Risk Associated with Pulse Pressure -2-
From the Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation,
Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (Y.-M.G., L.T., K.A.,
Y.-P.L., T.K., P.V., J.A.S.); Center for Epidemiological Studies and Clinical Trials (Y.L., J.W.) and
Center for Vascular Evaluation, Shanghai Key Laboratory of Hypertension (Y.L.), Ruijin Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai, China; Tohoku University Graduate
School of Pharmaceutical Science and Medicine, Sendai, Japan (K.A., T.O., Y.I.); Centro de
Nefrología and Departamento de Fisiopatología, Hospital de Clínicas, Universidad de la República,
Montevideo, Uruguay (J.B.); Steno Diabetes Center, Gentofte and Research Center for Prevention
and Health, Glostrup, Denmark (T.W.H.); Department of Hygiene and Public Health, Teikyo University
School of Medicine, Tokyo, Japan (T.O.); Division of Cardiovascular Medicine, Department of Clinical
Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden (K.B.-B);Copenhagen
University Hospital, Copenhagen, Denmark (J.J., C.T.-P.); Cambridge University Hospitals,
Addenbrook’s Hospital, Cambridge, United Kingdom (E.D.); Institute of Internal Medicine, Novosibirsk,
Russian Federation (T.K., S.M., Y.N.); First Department of Cardiology 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.); 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.J.M.,
G.E.M.); Conway Institute of Biomolecular and Biomedical Research, University College Dublin,
Ireland (E.O.); Department of Internal Medicine, Charles University, Pilsen, Czech Republic (J.F.);
Department of Psychiatry, Neurology and G.H. Sergievsky Center, Columbia University, New York,
USA (G.E.M.); Department of Epidemiology (J.A.S.), Maastricht University, Maastricht, The
Netherlands.
Correspondence: Jan A. Staessen, Studies Coordinating Centre, Research Unit Hypertension and
Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Kapucijnenvoer 35, Block D, Box 7001, BE-3000 Leuven, Belgium; Email: [email protected]
Risk Associated with Pulse Pressure -3-
Expanded Methods
Study Population
Analyzed participants were 2142 residents from Copenhagen, Denmark;1 1526 inhabitants
from Ohasama, Japan;2 1424 subjects from Noorderkempen, Belgium;3 1100 older men from
Uppsala, Sweden;4 1438 subjects from Montevideo, Uruguay;5 351 villagers from the JingNing county, China;6 930 employees of the Irish Allied Bank, Dublin, Ireland;7 244 subjects
from Novosibirsk, the Russian Federation;8 165 from Pilsen, Czech Republic;9 310 from Padova, Italy;9 and 308 from Kraków, Poland.9 All participants gave informed written consent.
Subjects recruited in Kraków, Novosibirsk, Pilsen, and Padova took part in the European
Project on Genes in Hypertension (EPOGH).9
Blood Pressure Measurements
Conventional blood pressure was measured by trained observers with a mercury sphygmomanometer,6,7,9 with validated auscultatory2 (USM-700F, UEDA Electronic Works, Tokyo,
Japan) or oscillometric5 (OMRON HEM-705CP, Omron Corporation, Tokyo, Japan) devices,
using the appropriate cuff size, with participants in the sitting1-3,5,6,8,9 or supine4 position.
Conventional blood pressure was the average of 2 consecutive readings obtained by an observer either at the person’s home3,5,6,8,9 or at an examination center.1,2,4 In line with current guidelines,10,11 we defined conventional hypertension as a blood pressure equal to or
exceeding 140 mm Hg systolic or 90 mm Hg diastolic, or as the use of antihypertensive
drugs.
We programmed portable monitors to obtain ambulatory blood pressure readings at 30
minute intervals throughout the whole day,2,7 or at intervals ranging from 151,4,5,9 to 304 minutes during daytime and from 151,4,5,9 to 604 minutes at night. The devices implemented
an auscultatory algorithm (Accutracker II) in Uppsala4 or an oscillometric technique (SpaceLabs 90202 and 90207, Nippon Colin, and ABPM 630) in the other cohorts.2-9
The same SAS macro processed all ambulatory recordings, which stayed unedited. The
Ohasama recordings were edited sparsely according to previously published criteria.12 Within individual subjects, we weighted the means of the ambulatory blood pressure by the interval between readings. When accounting for the daily pattern of activities of the participants,
we defined daytime as the interval ranging from 1000 h to 2000 h in people from
Europe1,3,4,7-9 and South America,5 and from 0800 h to 1800 h in those from Asia.2,6 The
corresponding nighttime intervals ranged from midnight to 0600 h1,3-5,8,9 and from 2200 h to
0400 h.2,6 These fixed intervals eliminate the transition periods in the morning and evening
when blood pressure changes rapidly, resulting in daytime and nighttime blood pressure levels that are within 1–2 mm Hg of the awake and asleep levels.6,13
Coding of Events
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 ischemic attacks. Coronary events encompassed death from ischemic heart disease (ICD8 411–412, ICD9 411 and 414, and ICD10 I20, I24–I25), sudden death (CD8 427.2
and 795, ICD9 427.5 and 798, and ICD10 I46 and R96), nonfatal myocardial infarction
(ICD8/9 410, and ICD10 I21–I22), and coronary revascularization. Cardiac events were
composed of coronary events and fatal and nonfatal heart failure (ICD8 428, 427.1, 427.2
and 429, ICD9 429, and ICD10 I50 and J81). Hospitalizations for unstable angina were
Risk Associated with Pulse Pressure -4-
coded as ischemic heart disease. In the Danish and Swedish cohorts, the diagnosis of heart
failure required admission to the hospital. In the other cohorts, 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
events included all aforementioned endpoints plus cardiovascular mortality (ICD8 390 to 448,
ICD9 390.0 to 459.9, and ICD10 I00 to I79 and R96).
Statistical Analysis
Interpolation of missing values—After stratification for cohort and sex, we interpolated
missing values of body mass index (n=46) and total serum cholesterol (n=683) from the within-cohort regression slope on age. In subjects with unknown drinking (n=813) or smoking
habits (n=96), we set the design variable to the cohort- and sex-specific mean of the codes
(0,1). Statistical significance was a 2-sided P value of 0.05.
Sensitivity analyses—In sensitivity analyses, we excluded one center at a time. We also
ran analyses stratified for ethnicity, sex, presence vs. absence of hypertension and use vs.
nonuse of antihypertensive drugs. We tested heterogeneity in the hazard ratios across subgroups by introducing the appropriate interaction term in the Cox model. Instead of adjusting
for cohort, we also modeled center as a random effect in Cox models.
Expanded Results
Incidence of endpoints
Among 6028 younger participants (<60 years), median follow-up was 12.1 years (5th to 95th
percentile interval, 2.5 to 18.2 years). Across cohorts, median follow-up ranged from 2.46
years (2.34 to 2.55 years) in JingNing to 17.6 years (16.6 to 18.2 years) in Dublin. During
68,853 person-years of follow-up, 228 participants died (3.3 per 1000 person-years) and 221
experienced a fatal or nonfatal cardiovascular complication (3.2 per 1000 person-years).
Mortality included 67 and 141 cardiovascular and noncardiovascular deaths, 4 deaths from
renal failure and 16 from unknown causes. Considering cause-specific first cardiovascular
events, 17 and 49 younger participants experienced a fatal or nonfatal stroke. Fatal or nonfatal cardiac events occurred in 153 younger participants. The 153 cardiac events consisted
of 15 fatal and 53 nonfatal cases of acute myocardial infarction, 2 sudden deaths, 13 deaths
from ischemic heart diseases, 2 fatal and 26 nonfatal cases of heart failure, and 42 cases of
surgical or percutaneous coronary revascularization.
Among 3910 older participants (≥60 years), median follow-up was 10.7 years (5th to 95th
percentile interval, 2.5 to 16.1 years). Across cohorts, median follow-up ranged from 2.4
years (0.5 to 2.6 years) in JingNing to 16.0 years (3.3 to 18.1 years) in Dublin. During
39,923 person-years of follow-up, 1160 participants died (29.0 per 1000 person-years) and
940 experienced a fatal or nonfatal cardiovascular complication (23.5 per 1000 person-years).
Mortality included 469 and 653 cardiovascular and noncardiovascular deaths, 14 deaths from
renal failure and 24 from unknown causes. Considering cause-specific first cardiovascular
events, 118 and 284 older participants experienced a fatal or nonfatal stroke. Fatal or nonfatal cardiac events occurred in 505 older participants. The 505 cardiac events consisted of
71 fatal and 164 nonfatal cases of acute myocardial infarction, 64 sudden deaths, 10 deaths
from ischemic heart diseases, 27 fatal and 144 nonfatal cases of heart failure, and 25 cases
of surgical or percutaneous coronary revascularization.
Risk Associated with Pulse Pressure -5-
Reference
1. Hansen TW, Jeppesen J, Rasmussen F, Ibsen H, Torp-Pedersen C. Ambulatory blood
pressure monitoring and mortality: a population-based study. Hypertension.
2005;45:499–504.
2. Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, Matsubara M,
Hashimoto J, Hoshi H, Araki T, Tsuji I, Satoh H, Hisamichi S, Imai Y. Prognostic
significance of the nocturnal decline in blood pressure in individuals with and without high
24-h blood pressure: the Ohasama study. J Hypertens. 2002;20:2183–2189.
3. Staessen JA, Bieniaszewski L, O'Brien ET, Imai Y, Fagard R. An epidemiological
approach to ambulatory blood pressure monitoring: the Belgian population study. Blood
Press Monit. 1996;1:13–26.
4. Ingelsson E, Björklund K, Lind L, Ärnlöv J, Sundström J. Diurnal blood pressure pattern
and risk of congestive heart failure. JAMA. 2006;295:2859–2866.
5. Schettini C, Bianchi M, Nieto F, Sandoya E, Senra H, Hypertension Working Group.
Ambulatory blood pressure. Normality and comparison with other measurements.
Hypertension. 1999;34 (part 2):818–825.
6. Li Y, Wang JG, Gao HF, Nawrot T, Wang G, Qian Y, Staessen JA, Zhu D. Are
published characteristics of the ambulatory blood pressure generalizable to rural Chinese?
The JingNing population study. Blood Press Monit. 2005;10:125–134.
7. O'Brien E, Murphy J, Tyndall A, Atkins N, Mee F, McCarthy G, Staessen J, Cox J,
O'Malley K. Twenty-four-hour ambulatory blood pressure in men and women aged 17 to
80 years: the Allied Irish Bank Study. J Hypertens. 1991;9:355–360.
8. Kuznetsova T, Malyutina S, Pello E, Thijs L, Nikitin Y, Staessen JA. Ambulatory blood
pressure of adults in Novosibirsk, Russia: interim report on a population study. Blood
Press Monit. 2000;5:291–296.
9. Kuznetsova T, Staessen JA, Kawecka-Jaszcz K, Babeanu S, Casiglia E, Filipovský J,
Nachev C, Nikitin Y, Peleskã J, O'Brien E. Quality control of the blood pressure
phenotype in the European Project on Genes in Hypertension. Blood Press Monit.
2002;7:215–224.
10. O'Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, Myers M, Padfield P,
Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G, Verdecchia P;
European Society of Hypertension Working Group on Blood Pressure Monitoring.
Practice guidelines of the European Society of Hypertension for clinic, ambulatory and
self blood pressure measurement. J Hypertens. 2005;23:697–701.
11. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW,
Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart,
Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating
Risk Associated with Pulse Pressure -6-
Committee. Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.
12. Ohkubo T, Imai Y, Tsuji I, Nagai K, Ito S, Satoh H, Hisamichi S. Reference values for
24–hour ambulatory blood pressure monitoring based on a prognositic criterion. The
Ohasama Study. Hypertension. 1998;32:255–259.
13. Fagard R, Brguljan J, Thijs L, Staessen J. Prediction of the actual awake and asleep
blood pressures by various methods of 24 h pressure analysis. J Hypertens.
1996;14:557–563.
Risk Associated with Pulse Pressure -7-
Legends to Figures
Figure S1. Hazard ratios according to 24–h pulse pressure levels ranging from the 10th to
the 90th percentile in 6028 younger participants.
Hazard ratios for total mortality (A) and cardiovascular (B) mortality and for cardiovascular
(C) and cardiac (D) events express the risk at each level of pulse pressure compared with
average risk. Solid and dotted lined denote the point estimates and the 95% confidence intervals, respectively. The hazard ratios were adjusted as in Figure 1.
Figure S2. Hazard ratios for stroke in relation to 24–h pulse pressure in 3910 older participants.
All hazard ratios were adjusted for cohort, sex, age, 24–h mean arterial pressure, 24–h heart
rate, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular
disease and diabetes, and antihypertensive drug treatment. (A) Hazard ratios express the
risk in each tenth compared with the average risk. Vertical bars denote 95% confidence intervals. For each tenth, the number of events and unadjusted incidence rates (in percent)
are given. (B) Hazard ratios express the risk at each level of pulse pressure compared with
average risk. Solid and dotted lines denote point estimates and the 95% confidence intervals,
respectively. The P value refers to the significance of the hazard ratio in the top tenth of the
24–h pulse pressure distribution.
Figure S3. Hazard ratios in tenths of the distribution of 24–h pulse pressure in 3910 older
participants.
Hazard ratios for total mortality (A) and cardiovascular (B) mortality and for cardiovascular (C)
and cardiac (D) events express the risk in each tenth compared with average risk. All hazard
ratios were adjusted for sex, age, 24–h mean arterial pressure, 24–h heart rate, body mass
index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes, and antihypertensive drug treatment. Cohort was modeled as a random effect. Vertical bars denote 95% confidence intervals. For each tenth, the number of events and unadjusted incidence rates (in percent) are given. The P value refers to the significance of the
hazard ratio in the top tenth of the 24–h pulse pressure distribution.
Figure S4. Hazard ratios according to 24–h pulse pressure levels ranging from the 10th to
the 90th percentile in 3910 older participants.
Hazard ratios for total (A) and cardiovascular (B) mortality and for cardiovascular (C) and
cardiac (D) events express the risk at each level of pulse pressure compared with average
risk. All hazard ratios were adjusted for sex, age, 24–h mean arterial pressure, 24–h heart
rate, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular
disease and diabetes, and antihypertensive drug treatment. Cohort was modeled as a random effect. Solid and dotted lined denote the point estimates and the 95% confidence intervals, respectively.
Risk Associated with Pulse Pressure -8-
Table S1. Blood Pressure at Baseline by Age Group
Characteristic
<60 years
(N=6028)
≥60 years
(N=3910)
Systolic blood pressure, mm Hg
123.2±17.2
141.1±20.0
Diastolic blood pressure, mm Hg
78.0±11.4
81.7±11.4
Pulse pressure, mm Hg
45.2±11.3
59.4±15.4
Mean arterial pressure, mm Hg
93.0±12.5
101.5±12.9
Heart rate, beats per minute
72.0±11.4
68.0±10.9
Systolic blood pressure, mm Hg
119.4±12.0
129.8±14.5
Diastolic blood pressure, mm Hg
73.0±8.3
74.6±8.3
Pulse pressure, mm Hg
46.4±7.2
55.2±10.5
Mean arterial pressure, mm Hg
88.5±9.1
93.0±9.6
Heart rate, beats per minute
73.6±8.9
69.9±9.1
Systolic blood pressure, mm Hg
125.8±13.2
136.0±15.5
Diastolic blood pressure, mm Hg
78.5±9.1
79.1±9.2
Pulse pressure, mm Hg
47.3±8.1
56.9±11.2
Mean arterial pressure, mm Hg
94.3±9.9
98.1±10.4
Heart rate, beats per minute
79.4±10.3
75.0±10.6
Systolic blood pressure, mm Hg
108.2±12.3
118.0±16.6
Diastolic blood pressure, mm Hg
63.3±8.9
66.1±9.2
Pulse pressure, mm Hg
44.9±7.3
51.9±11.7
Mean arterial pressure, mm Hg
78.3±9.6
83.4±10.9
Heart rate, beats per minute
64.6±9.5
62.1±9.1
Conventional blood pressure
24–h blood pressure
Daytime blood pressure
Nighttime blood pressure
Plus—minus values are means ±SD. Conventional blood pressure was the average of 2 consecutive readings.
Daytime ranged from 10 AM to 8 PM in Europeans and South Americans and from 8 AM h to 6 PM in Asians.
The corresponding nighttime intervals ranged midnight to 6 AM and from 10 PM to 4 AM. All of the differences
between the age groups were significant (P≤0.0012).
Risk Associated with Pulse Pressure -9-
Table S2. Multivariable-Adjusted Hazard Ratios for Cardiovascular Mortality and Events in
3910 Older Participants in Relation to 24–H Pulse Pressure Excluding One Center at a Time
Excluded Cohort
by Endpoint
Nº
At Risk
Nº of
Events
Hazard Ratio
(95% CI )
P
3910
469
1.62 (1.26–2.10)
0.0002
Copenhagen
2835
357
1.91 (1.42–2.57)
<0.0001
Ohasama
3066
357
1.37 (1.02–1.85)
0.035
Noorderkempen
3576
400
1.42 (1.08–1.88)
0.013
Uppsala
2810
338
1.84 (1.37–2.47)
<0.0001
Montevideo
3486
435
1.53 (1.17–2.00)
0.0018
JingNing
3830
465
1.62 (1.25–2.09)
0.0002
Novosibirsk
3892
467
1.63 (1.26–2.10)
0.0002
Pilsen
3909
469
1.62 (1.26–2.10)
0.0002
Dublin
3892
464
1.59 (1.23–2.06)
0.0004
Padua
3897
469
1.63 (1.26–2.10)
0.0002
Kraków
3907
469
1.63 (1.26–2.10)
0.0002
3910
940
1.52 (1.26–1.83)
<0.0001
Copenhagen
2835
713
1.57 (1.27–1.95)
<0.0001
Ohasama
3066
736
1.56 (1.27–1.91)
<0.0001
Noorderkempen
3576
856
1.42 (1.17–1.73)
0.0004
Uppsala
2810
623
1.59 (1.27–1.98)
<0.0001
Cardiovascular Mortality
All centers
Excluded center
Cardiovascular Events
All centers
Excluded center
Montevideo
3486
850
1.50 (1.24–1.83)
<0.0001
JingNing
3830
934
1.52 (1.27–1.83)
<0.0001
Novosibirsk
3892
935
1.51 (1.25–1.81)
<0.0001
Pilsen
3909
940
1.52 (1.26–1.83)
<0.0001
Dublin
3892
935
1.50 (1.25–1.80)
<0.0001
Padua
3897
938
1.52 (1.26–1.83)
<0.0001
Kraków
3907
940
1.52 (1.27–1.83)
<0.0001
Hazard ratios, presented with 95% confidence interval (CI), express the risk in the top tenth of the 24–h pulse
pressure distribution compared with the average risk. Hazard ratios were adjusted for cohort, sex, age, 24–h
mean arterial pressure, 24–h mean heart rate, body mass index, smoking and drinking, serum cholesterol, history
of cardiovascular disease and diabetes, and antihypertensive drug treatment. P denotes the significance of the
hazard ratios.
Risk Associated with Pulse Pressure -10-
Table S3. Multivariable-Adjusted Hazard Ratios for Cardiovascular Mortality and Events in
3910 Older Participants in Relation to 24–H Pulse Pressure in Different Strata
Stratification
by Endpoint
Nº
at Risk
Nº of
Events
Hazard Ratio
(95% CI)
P
3910
469
1.62 (1.26–2.10)
0.0002
Women
1461 (37.4%)
147 (31.3%)
2.14 (1.39–3.31)
0.0006
Men
2446 (62.6%)
322 (68.7%)
1.54 (1.12–2.13)
0.008
Hypertension
2529 (64.7%)
363 (77.4%)
1.32 (0.98–1.78)
0.06
Cardiovascular Mortality
All participants
Normotensive
1381 (35.5%)
106 (22.6%)
1.62 (0.94–2.79)
0.08
Treated
1327 (33.9%)
234 (49.9%)
1.18 (0.80–1.75)
0.41
Untreated
2583 (66.1%)
235 (50.1%)
1.58 (1.10–2.28)
0.014
Asian
924 (23.6%)
116 (24.7%)
1.84 (1.08–3.15)
0.026
European
2562 (65.5%)
319 (68.0%)
1.29 (0.94–1.77)
0.12
South American
424 (10.9%)
34 (7.3%)
…
3910
940
1.52 (1.26–1.83)
Women
1464 (37.4%)
280 (29.8%)
1.72 (1.25–2.36)
0.0009
Men
2446 (62.6%)
660 (70.2%)
1.56 (1.24–1.96)
0.0001
Hypertension
2529 (64.7%)
724 (77.0%)
1.49 (1.21–1.83)
0.0002
Normotensive
1381 (35.5%)
216 (230%)
1.48 (1.02–2.16)
0.040
Treated
1327 (33.9%)
443 (47.1%)
1.40 (1.05–1.85)
0.019
Untreated
2583 (66.1%)
497 (52.9%)
1.33 (1.03–1.71)
0.027
Asian
924 (23.6%)
210 (22.3%)
1.30 (0.86–1.98)
0.21
European
2562 (65.5%)
640 (68.1%)
1.56 (1.25–1.95)
<0.0001
South American
424 (10.9%)
90 (9.6%)
1.30 (0.74–2.30)
0.36
…
Cardiovascular Events
All participants
<0.0001
Hazard ratios, presented with 95% confidence interval (CI), express the risk in the top tenth of the 24–h pulse
pressure distribution compared with the average risk. Hazard ratios were adjusted for cohort, sex, age, 24–h
mean arterial pressure, 24–h mean heart rate, body mass index, smoking and drinking, serum cholesterol, history
of cardiovascular disease and diabetes, and antihypertensive drug treatment. P denotes the significance of the
hazard ratios. An ellipsis indicates that the P value was not computed because the number of events was lower
than 50. Hazard ratios were not different across corresponding strata (0.16≤P≤0.75).
Risk Associated with Pulse Pressure -11-
Table S4. Multivariable-Adjusted Hazard Ratios Derived by Ridge Cox Regression
Stratification by Age
Total Mortality
Cardiovascular
Mortality
Cardiovascular
Events
Cardiac
Events
Stroke
Younger participants
24–h pulse pressure
1.14 (0.78–1.68)
1.72 (0.89–3.32)
1.58 (1.11–2.26)*
1.52 (0.99–2.33)
…
24–h mean arterial pressure
1.11 (0.95–1.29)
1.40 (1.09–1.80)†
1.37 (1.19–1.59)§
1.40 (1.18–1.66)§
…
24–h pulse pressure
1.30 (1.09–1.56)†
1.62 (1.26–2.10)‡
1.52 (1.26–1.83)§
1.69 (1.33–2.15)§
1.40 (1.04–1.89)*
24–h mean arterial pressure
1.04 (0.96–1.12)
1.15 (1.02–1.29)*
1.19 (1.10–1.29)§
1.07 (0.96–1.19)
1.39 (1.23–1.58)§
Older participants
Hazard ratios for 24–h pulse pressure (PP) express the risk in the top tenth of the distribution compared with average risk. Hazard ratios for 24–h mean arterial
pressure (MAP) express the risk associated with 1–SD increase in the level (9.1 mm Hg for the young and 9.6 mm Hg for the older participants, respectively). All
hazard ratios, given with 95% confidence interval, were adjusted for cohort, sex, age, 24–h heart rate, body mass index, smoking and drinking, serum cholesterol,
history of cardiovascular disease and diabetes, and antihypertensive drug treatment. An ellipsis indicates that the model did not converge. Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001; and § P≤0.0001.
Risk Associated with Pulse Pressure -12-
Table S5. Multivariable-Adjusted Hazard Ratios for Various Blood Pressure Components in 3910 Older Participants
Modeled Blood
Pressure
Components
PP plus MAP
PP plus SBP
PP plus DBP
Total Mortality
Cardiovascular
Mortality
Cardiovascular
Events
Cardiac
Events
PP
1.30 (1.09–1.56)†
1.62 (1.26–2.10)‡
1.52 (1.26–1.83)§
1.69 (1.33–2.15)§
1.40 (1.04–1.89)*
MAP
1.04 (0.96–1.12)
1.15 (1.02–1.29)*
1.19 (1.10–1.29)§
1.07 (0.96–1.19)
1.39 (1.23–1.58)§
PP
1.26 (0.99–1.61)
1.52 (1.07–2.16)*
1.31 (1.02–1.68)*
1.61 (1.16–2.24)†
1.01 (0.68–1.51)
SBP
1.04 (0.94–1.16)
1.14 (0.97–1.33)
1.22 (1.10–1.36)‡
1.07 (0.93–1.24)
1.51 (1.28–1.77)§
PP
1.34 (1.14–1.57)‡
1.78 (1.42–2.23)§
1.72 (1.46–2.02)§
1.77 (1.43–2.18)§
1.78 (1.37–2.32)§
DBP
1.04 (0.97–1.11)
1.15 (1.04–1.27)†
1.17 (1.09–1.26)§
1.07 (0.97–1.17)
1.34 (1.20–1.50)§
Stroke
Hazard ratios for pulse pressure (PP) express the risk in the top tenth of the distribution compared with average risk. Hazard ratios for mean arterial pressure
(MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) express the risk associated with 1–SD increase in the level. SDs for MAP, SBP and DBP
were 9.3, 13.8, and 8.2 mm Hg, respectively. The main analysis as reported in the paper was based on the combination of PP with MAP. All hazard ratios, given
with 95% confidence interval, were adjusted for cohort, sex, age, 24–h heart rate, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular disease and diabetes, and antihypertensive drug treatment.
Significance of the hazard ratios: * P≤0.05; † P≤0.01; ‡ P≤0.001; and § P≤0.0001.
Risk Associated with Pulse Pressure -13-
Table S6. Multivariable-Adjusted Hazard Ratios for Cardiovascular Mortality and Events by Different Age Strata
Nº in Age
Stratum
Nº
at Risk
Nº of
Events
Hazard Ratio
(95% CI)
P
< 50 years
3968
397
4 (1.0)
…
…
≥50 years
5970
597
127 (21.3)
1.76 (1.38–2.23)
<0.0001
< 55 years
5235
524
11 (2.1)
1.56 (0.66–3.68)
0.31
≥55 years
4703
471
103 (21.9)
1.58 (1.23–2.03)
0.0003
< 60 years
6028
603
17 (2.8)
1.72 (0.89–3.32)
0.11
≥60 years
3910
469
93 (19.8)
1.62 (1.26-2.10)
0.0002
< 50 years
3968
397
11 (2.8)
0.86 (0.39–1.88)
0.70
≥50 years
5970
597
245 (41.0)
1.67 (1.42–1.98)
<0.0001
< 55 years
5235
524
36 (6.9)
1.47 (0.95–2.29)
0.086
≥55 years
4703
471
197 (41.8)
1.56 (1.31–2.86)
<0.0001
<60 years
6028
603
56 (9.3)
1.58 (1.11–2.25)
0.011
≥60 years
3910
469
171 (36.5)
1.52 (1.26–1.83)
<0.0001
Endpoint
Cardiovascular Mortality
Cardiovascular Events
Hazard ratios, presented with 95% confidence interval (CI), express the risk in the top tenth of the 24–h pulse pressure distribution compared with the average risk. Hazard ratios were adjusted for cohort, sex, age, 24–h mean arterial pressure and heart rate, body mass index, smoking and drinking, serum cholesterol, history of cardiovascular
disease and diabetes, and antihypertensive drug treatment. P denotes the significance of the hazard ratios. An ellipsis indicates that the model did not converge.
Risk Associated with Pulse Pressure -14-
Risk Associated with Pulse Pressure -15-
Risk Associated with Pulse Pressure -16-
Risk Associated with Pulse Pressure -17-