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Original Article

Pulse Pressure Within 3 Months After Ischemic Stroke Is


Associated With Long-Term Stroke Outcomes
Ning Su,1,* Fei-Fei Zhai,1,* Jun Ni,1 Li-Xin Zhou,1 Ming Yao,1 Bin Peng,1 Yi-Cheng Zhu,1,†
and Li-Ying Cui1,†

BACKGROUND significantly correlate with long-term stroke outcomes. In the group ≥60
Pulse pressure (PP) is a surrogate marker of arterial stiffness. Studies on years of age, PP was significantly associated with combined end-points
baseline PP and long-term outcomes in patients with stroke are limited. (hazards ratio [HR] = 1.35; 95% confidence interval [CI], 1.18–1.54) and
We aimed to evaluate whether PP within 3 months after ischemic stroke recurrent stroke (HR = 1.46; 95% CI, 1.24–1.72). Combination of SBP and
was associated with long-term stroke outcomes. PP, DBP and PP, or MAP and PP, respectively, showed no incremental
value of SBP, DBP, or MAP in predicting long-term stroke outcomes.
METHODS
A total of 4,195 patients (61.2 ± 11.6 years, 68.4% men) with first-ever CONCLUSIONS
ischemic stroke in 3  months had baseline blood pressure (BP) meas- PP was significantly associated with long-term stroke outcomes, and
ured. Study end-points were the combined end-points (recurrent vas- this association was prominent in patients with stroke older than
cular events and all-cause mortality) and recurrent stroke. 60 years of age.

Keywords: blood pressure; hypertension; ischemic stroke; long-term


RESULTS outcome; pulse pressure.
In the group <60 years of age, the BP components of systolic BP
(SBP), diastolic BP (DBP), mean arterial pressure (MAP), or PP did not doi:10.1093/ajh/hpx121

Pulse pressure (PP) as a pulsatile component of blood these studies, BP within 24–72 hours after stroke onset was
pressure (BP), is a surrogate marker of arterial stiffness.1,2 commonly applied. However, an acute hypertensive response
Accumulating evidence has indicated that PP was superior occurs within 24 hours in up to 80% of patients with acute
to either systolic BP (SBP) or diastolic BP (DBP) in predict- stroke and spontaneously declines afterward within days
ing the risk of coronary heart disease (CHD).3–6 In prospec- to weeks.16,17 Thus, PP in the acute stage of stroke may not
tive cohorts, PP was associated with myocardial infarction be a proper measurement for investigating the association
(MI) and mortality in normotensive and hypertensive between arterial stiffness and stroke outcomes.
populations.7 PP has also been linked to incident stroke.8–11 Based on previous findings, we conducted a national,
A  recent meta-analysis summarizing 11 studies demon- multicenter, prospective, observational study. Patients hav-
strated an association between the increase in PP and the ing ischemic stroke were recruited, and BP levels were meas-
risk of stroke occurrence.11 ured. We aimed to investigate the relationship of PP within
Unlike the established role of PP as a risk factor for stroke, 3 months after stroke with long-term stoke outcomes.
the prognostic importance of PP in determining the outcome
after stroke is still unknown because most related studies
METHODS
focused on short-term outcomes and reported controversial
results.12–14 Aslanyan et al.13 reported that elevated PP during Study population
the first 60 hours of acute ischemic stroke was associated with
poor short-term functional outcome and mortality, while The Standard Medical Management in Secondary
Dawson et al.15 found that PP within 72 hours of ictus had Prevention of Ischemic Stroke in China (SMART) study
no prognostic impact on short-term death or dependence. In had revealed that a guideline-based structured program,

1Department of Neurology, Peking Union Medical College Hospital,


Correspondence: Li-Ying Cui (pumchcuily@sina.com).
Chinese Academy of Medical Sciences and Peking Union Medical College,
Initially submitted June 1, 2017; date of first revision June 16, 2017; Beijing 100730, China.
accepted for publication July 12, 2017.
*Both authors contributed equally to this work.
†Both authors contributed equally to this work.

© American Journal of Hypertension, Ltd 2017. All rights reserved.


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American Journal of Hypertension  1


Su et al.

combination of pharmaceutical treatment, lifestyle modifi- 2  years after recruitment to assess the clinical outcomes.
cation, and patient education could improve the adherence Follow-up evaluations were conducted at the medical center
to secondary prevention of ischemic stroke during 1-year or by telephone interviews.
follow-up in China.18,19 In order to implement SMART pro- The combined end-points were recurrent vascular events
gram in more patients with ischemic stroke, we performed and all-cause mortality. The recurrent vascular events were a
the SMART-II study in 91 medical centers in China. Patients composite of recurrence of ischemic or hemorrhagic stroke,
having ischemic stroke within 3  months, aged 18  years or transient ischemic stroke, acute coronary syndrome, or
older, and functionally independent before stroke (modi- peripheral vascular disease. A recurrent stroke was defined
fied Rankin scale < 3), were enrolled between July 2012 as new-onset focal neurologic deficits persisting longer than
and February 2014. Those with severe handicaps (modified 24 hours. The ST elevation MI, non-ST elevation MI, and
Rankin scale = 5) after stroke, severe comorbid illness, unsta- unstable angina were defined as acute coronary syndrome.
ble medical condition, such as congestive cardiac failure, The peripheral vascular disease was defined as new-onset
severe liver dysfunction, renal failure, or expected life span ischemic symptoms in the lower limbs. All-cause mortality
less than 2  years were excluded. All participants provided was also recorded.
their written informed consent to participate. The study was
approved by the central ethics committee of the principal Statistical analysis
study center at Peking Union Medical College Hospital and
by the ethics committees at the participating study sites. Demographic and clinical characteristics of the sample
A total of 4,487 patients of the SMART-II study with first- were compared among the PP quartiles, using the analysis of
ever ischemic stroke were enrolled in the current study. We variance for continuous variables and the chi-squared tests
excluded 24 patients with missing baseline BP measure- for categorical variables. Kaplan–Meier survival analysis
ments, and 268 patients lost to follow-up. Thus, the final with log–rank test was conducted to compare the survival
analysis of the present study was performed with 4,159 rates across the 4 PP quartiles.
patients. The baseline characteristics of all patients with first- The multivariable Cox proportional hazards regression
ever ischemic stroke, both included and not included in this model was used to assess the relations of combined end-
study, were comparable (Supplementary Table S1). points and recurrent stroke with BP components as continu-
ous variables. Hazards ratios (HRs) with 95% confidence
BP measurement and clinical assessments interval (CI) were estimated for 1-SD increment in each BP
component, adjusted for age, sex, current smoking, obesity
BP measurements were made using conventional meth- (body mass index ≥ 30), DM, hyperlipidemia, atrial fibril-
ods.20–22 The SBP and DBP were measured in the sitting lation, history of CHD, antihypertensive medication, anti-
position with a sphygmomanometer on the left arm of the platelet medication, and lipid-lowering medication. Single
patients after sitting for 5 minutes. The mean of the 3 record- BP components (SBP, DBP, MAP, PP) were initially entered
ings was used in the analysis. The mean arterial pressure in separate multivariable models. With results from the
(MAP) was calculated as two-thirds DBP plus one-third Framingham study that age-related changes of SBP and DBP
SBP.23 PP was calculated as SBP minus DBP. leading to steep rise of PP after the 6th decade,24 and find-
Baseline data on demographics, cardiovascular risk fac- ings from Costa Rican Study that wide PP was associated
tors, and medical history were collected through a struc- with higher risk of cardiovascular death in those aged 60
tured questionnaire by trained neurologists. Body mass or more years,25 while under age 60, PP became not predic-
index was calculated as weight in kilograms divided by the tive,26 as well as the lower age boundary of 60 years in sev-
height in meters squared. Cardiovascular risk factors were eral randomized clinical trials on antihypertensive treatment
defined as follows: (i) hypertension was defined as SBP in the elderly,27 we stratified our participants by 60 years of
≥140  mm Hg or DBP ≥90  mm Hg, self-reported hyper- age to explore the association between BP levels and out-
tension, or treatment with antihypertensive medication; come events in the respective age subgroups. Furthermore,
(ii) diabetes mellitus (DM) was defined as fasting serum in order to assess the independent relationships of PP with
glucose ≥7.0 mmol/l, self-reported diabetes, or use of oral other BP indices, the dual BP components of SBP + PP, DBP
blood sugar-lowering drugs or insulin; (iii) hyperlipidemia + PP, or MAP + PP were entered simultaneously in the same
was defined as total cholesterol >5.2  mmol/l or low-den- model to adjust for each other in each age subgroup. Similar
sity lipoprotein-cholesterol >2.58  mmol/l, or self-reported statistical method has been used in previous studies for
hyperlipidemia; (iv) atrial fibrillation was identified on community populations.3,8,10,28 A  2-sided P value of <0.05
electrocardiogram or continuous electrocardiographic indicated statistical significance. All statistical analyses were
recording; (v) CHD included any history of MI, angina, or performed using SAS version 9.4 (SAS Institute, Cary, NC).
asymptomatic MI; and (vi) current smoker was defined as
one who smoked at least one cigarette per day for more than
6 months before the stroke onset. RESULTS

Demographic and clinical characteristics


Follow-up process and outcomes assessment
A total of 4,195 patients with first-ever ischemic stroke
The registered patients were followed up at 3 months and were enrolled in the present study, of which 2,869 were
6  months after recruitment and then every half-year until men (68.4%). The mean age (SD) was 61.2  years (11.6),

2  American Journal of Hypertension


Association of PP With Stroke Outcome

with 1,847 (44.0%) patients younger than 60  years of age. of combined end-points and recurrent stroke than those in
Prevalent conditions at baseline included hypertension the lower PP quartiles (log–rank test, P = 0.008 and 0.035,
(82.4%), DM (33.0%), hyperlipidemia (65.2%), and atrial respectively; Figure 1a and b).
fibrillation (5.8%). Most of the patients with hypertension
(70.6%) were taking antihypertensive medications. Mean
(SD) BP parameters included SBP of 144.4 (20.4), DBP of Association of PP with long-term outcomes in single BP
85.7 (12.3), MAP of 105.2 (13.7), and PP of 58.7 (15.2) mm component models
Hg. The patients with high PP levels tended to be older at
The associations between PP and long-term stroke
inclusion, included a higher proportion of male and current
outcomes (combined end-points and recurrent stroke)
smoker participants, had histories of hypertension, hyper-
are summarized in Table  2. The multivariate Cox pro-
lipidemia, and DM, and received antihypertensive and anti-
portional-hazards model adjusted by age, sex, current
platelet treatment. In addition to the increased MAP values,
smoking, obesity, DM, hyperlipidemia, atrial fibrillation,
patients with high PP values also had higher SBP and DBP
history of CHD, antihypertensive medication, antiplatelet
values (P < 0.01; Table 1).
medication, and lipid-lowering medication showed that
every 1-SD increment in PP was associated with a 26%
Follow-up and outcomes increase in the risk of combined end-points (HR, 1.26;
95% CI, 1.12–1.41; P < 0.01) and 33% increase in the risk
The median follow-up time was 23.5 months (interquar- of recurrent stroke (HR, 1.33; 95% CI, 1.16–1.53; P < 0.01;
tile range, 16.8–25.6 months). During follow-up, 371 (8.8%) Table 2).
patients had combined end-points, of whom 302 (7.2%) In order to assess whether the association of stroke out-
experienced recurrent vascular events and 69 (1.6%) patients comes and BP components was influenced by age, the sample
died. Among those patients, 236 (5.6%) had a recurrent was then stratified by age (<60 years, ≥60 years). There were
stroke. Patients having the highest quartile of PP had a com- no associations between BP components (SBP, DBP, MAP,
bined end-point rate of 11% and a recurrent stroke rate of or PP) and the combined end-points or recurrent stroke in
6.8%, compared to 7.2% and 4.2%, respectively, in the lowest the group <60 years of age (Table 2). In the group ≥60 years
category (Table 1). Figure 1 shows the Kaplan–Meier curves of age, PP was significantly associated with combined end-
for each point. Analysis of the survival curves demonstrated points (HR, 1.35; 95% CI, 1.18–1.54; P < 0.01) and recurrent
that patients in the higher PP quartiles were at a higher risk stroke (HR, 1.46; 95% CI, 1.24–1.72; P < 0.01; Table 2).

Table 1.  Demographic and clinical characteristics of whole sample and subgroups by quartiles of pulse pressure

Quartiles of pulse pressure

<50 mm Hg 50–58 mm Hg 59–69 mm Hg >69 mm Hg


Characteristic Overall (n = 4,195) (n = 881) (n = 1,204) (n = 1,039) (n = 1,071) P value

Age, years, mean (SD) 61.2 (11.6) 57.5 (11.9) 59.5 (11.2) 62.6 (11.1) 64.9 (11.0) <0.01
Male, n (%) 2,869 (68.4) 632 (71.7) 856 (71.1) 706 (67.9) 675 (63.0) <0.01
Current smoker, n (%) 1,578 (37.6) 375 (42.6) 473 (39.3) 358 (34.5) 372 (34.7) <0.01
Obesity (BMI ≥ 30), n (%) 266 (6.5) 47 (5.5) 78 (6.6) 70 (6.9) 71 (6.8) 0.59
Blood pressure, mean (SD)
  SBP (mm Hg) 144.4 (20.4) 124.9 (13.2) 136.2 (10.9) 147.4 (12.1) 166.5 (17.9) <0.01
  DBP (mm Hg) 85.7 (12.3) 84.5 (12.4) 84.6 (10.8) 86.1 (11.9) 87.5 (13.7) <0.01
  MAP (mm Hg) 105.2 (13.7) 98.0 (12.4) 101.8 (10.8) 106.5 (11.9) 113.8 (14.4) <0.01
  PP (mm Hg) 58.7 (15.2) 40.5 (5.3) 51.6 (2.5) 61.4 (2.6) 79.0 (10.8)
Hypertension, n (%) 3,456 (82.4) 539 (61.2) 894 (74.3) 962 (92.6) 1,061 (99.1) <0.01
Diabetes mellitus, n (%) 1,384 (33.0) 256 (29.1) 376 (31.2) 363 (34.9) 389 (36.3) <0.01
Hyperlipidemia, n (%) 2,733 (65.2) 535 (60.8) 801 (66.5) 686 (66.0) 711 (66.4) 0.02
Atrial fibrillation, n (%) 243 (5.8) 58 (6.6) 66 (5.5) 62 (6.0) 57 (5.3) 0.63
Outcome events, n (%)
  Combined end-pointsa 371 (8.8) 63 (7.2) 94 (7.8) 96 (9.2) 118 (11.0) 0.01
  Recurrent stroke 236 (5.6) 37 (4.2) 60 (5.0) 66 (6.4) 73 (6.8) 0.04

Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; MAP, mean arterial blood pressure; PP, pulse pressure; SBP, systolic
blood pressure.
aCombined end-points include new-onset ischemic and hemorrhagic stroke, transient ischemic stroke, acute coronary syndrome, peripheral

vascular disease, and all-cause mortality.

American Journal of Hypertension  3


Su et al.

Figure 1.  Kaplan–Meier curves of long-term outcomes by quartiles of pulse pressure. Kaplan–Meier curves of the cumulative risk for combined end-
points (a) and recurrent stroke (b) in patients with first-ever ischemic stroke stratified into quartiles of pulse pressure. The P values were calculated with
the log–rank test.

Table 2.  Association of single blood pressure component with combined end-points and recurrent stroke

Combined end-points Recurrent stroke

BP components/per SD increment HRa (95% CI) P value HRa (95% CI) P value

Total patients (n = 4,195) (n = 371, 8.8%) (n = 236, 5.6%)


 SBP 1.24 (1.11, 1.40) <0.01 1.34 (1.16, 1.54) <0.01
 DBP 1.07 (0.94, 1.21) 0.31 1.14 (0.98, 1.33) 0.08
 MAP 1.16 (1.03, 1.31) 0.02 1.26 (1.09, 1.45) <0.01
 PP 1.26 (1.12, 1.41) <0.01 1.33 (1.16, 1.53) <0.01
Age <60 years (n = 1,847) (n = 120, 6.5%) (n = 76, 4.1%)
 SBP 1.05 (0.86, 1.29) 0.61 1.08 (0.84, 1.38) 0.54
 DBP 0.97 (0.79, 1.20) 0.81 1.04 (0.81, 1.34) 0.76
 MAP 1.01 (0.83, 1.23) 0.92 1.06 (0.83, 1.36) 0.64
 PP 1.11 (0.90, 1.37) 0.34 1.09 (0.83, 1.43) 0.53
Age ≥60 years (n = 2,348) (n = 251, 10.7%) (n = 160, 6.9%)
 SBP 1.36 (1.18, 1.57) <0.01 1.49 (1.26, 1.76) <0.01
 DBP 1.11 (0.95, 1.29) 0.19 1.18 (0.98, 1.42) 0.09
 MAP 1.25 (1.08, 1.46) <0.01 1.36 (1.14, 1.64) <0.01
 PP 1.35 (1.18, 1.54) <0.01 1.46 (1.24, 1.72) <0.01

SBP, DBP, MAP, and PP entered in separate model, adjusted for age, sex, current smoking, obesity (BMI ≥ 30), diabetes mellitus, hyperlipi-
demia, atrial fibrillation, history of coronary heart disease, antihypertensive medication, antiplatelet medication, and lipid-lowering medication.
Abbreviations: BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HR, hazards ratio; MAP, mean arterial blood pres-
sure; PP, pulse pressure; SBP, systolic blood pressure.
aHR was calculated by 1-SD increase in corresponding blood pressure component.

Association of PP with long-term outcomes in dual BP dual BP components of SBP + PP, DBP + PP, MAP + PP were
component models analyzed separately using the same model. Neither of these
BP components showed an association with combined end-
We further addressed the relative importance of PP, SBP, points or recurrent stroke (Table 3). When SBP and PP were
DBP, and MAP in predicting stroke outcomes using the mul- examined in the same model in the group ≥60 years of age,
tivariate Cox proportional-hazards model to examine the BP PP, but not SBP, was significantly associated with combined
parameters in combination. In the group <60 years of age, end-points (HR, 1.29; 95% CI, 1.02–1.64; P  =  0.03) and

4  American Journal of Hypertension


Association of PP With Stroke Outcome

Table 3.  Association of dual blood pressure components with combined end-points and recurrent stroke stratified

Combined end-points Recurrent stroke

BP components/per SD increment HRa (95% CI) P value HRa (95% CI) P value

Age <60 years (n = 1,847)


  SBP and PP
  SBP 0.91 (0.64, 1.28) 0.58 1.02 (0.67, 1.56) 0.92
  PP 1.22 (0.85, 1.77) 0.28 1.08 (0.68, 1.71) 0.75
  DBP and PP
  DBP 0.94 (0.77, 1.16) 0.58 1.01 (0.78, 1.31) 0.92
  PP 1.14 (0.92, 1.41) 0.25 1.09 (0.83, 1.44) 0.52
  MAP and PP
  MAP 0.94 (0.74, 1.18) 0.58 1.01 (0.76, 1.35) 0.92
  PP 1.16 (0.91, 1.49) 0.23 1.09 (0.80, 1.49) 0.59
Age ≥60 years (n = 2,348)
  SBP and PP
  SBP 1.09 (0.85, 1.40) 0.50 1.18 (0.87, 1.59) 0.29
  PP 1.29 (1.02, 1.64) 0.03 1.32 (0.99, 1.75) 0.06
  DBP and PP
  DBP 1.05 (0.91, 1.22) 0.50 1.10 (0.92, 1.32) 0.29
  PP 1.38 (1.20, 1.58) <0.01 1.48 (1.26, 1.75) <0.01
  MAP and PP
  MAP 1.06 (0.90, 1.25) 0.50 1.11 (0.91, 1.36) 0.29
  PP 1.35 (1.16, 1.57) <0.01 1.43 (1.18, 1.71) <0.01

Dual BP measurements entered in the same model, additionally adjusted for age, sex, current smoking, obesity (BMI ≥ 30), diabetes mel-
litus, hyperlipidemia, atrial fibrillation, history of coronary heart disease, antihypertensive medication, antiplatelet medication, and lipid-lowering
medication. Abbreviations: BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HR, hazards ratio; MAP, mean arterial
blood pressure; PP, pulse pressure; SBP, systolic blood pressure.
aHR was calculated by 1-SD increase in corresponding blood pressure component.

marginally associated with recurrent stroke. In a separate plausible mechanism that explains the link between raised PP
multivariate model of DBP and PP, the effect of PP on com- and cardiac risk has been described. However, the association
bined end-points (HR, 1.38; 95% CI, 1.20–1.58, P  <  0.01) between PP and stroke risk or prognosis is less understood.
and recurrent stroke (HR, 1.48; 95% CI, 1.26–1.75, P < 0.01) A  study with 198 patients with acute stroke demonstrated
was independent of DBP. Similarly, the effect of PP on com- that for every 10-mm Hg increase of PP, mortality at 1-year
bined end-points (HR, 1.35; 95% CI, 1.16–1.57; P  <  0.01) post-stroke increased by 40%.29 Another study with 219
and recurrent stroke (HR, 1.43; 95% CI, 1.18–1.71, P < 0.01) patients with acute stroke reported no association between
was independent of MAP (Table 3). PP and mortality at 2.5 years post-stroke.30 The present find-
ings indicated that PP within 3 months after ischemic stroke
DISCUSSION was positively related to 2-year post-stroke recurrence and
death rates. This may offer further evidence of large artery
The present study investigated the association of PP with stiffness contributing to poor outcomes of cerebral vascular
long-term stroke outcomes in 4,195 patients with ischemic diseases. Unlike in our study, most previous studies assessing
stroke in a multicenter prospective cohort study. We found the predicting value of BP parameters for stroke outcomes
that PP within 3-month after ischemic stroke was associ- initiated the BP measurement 24 hours of ictus. Since BP
ated with 2-year-outcomes of combined end-points and increases following acute stroke and spontaneously decreases
recurrent stroke, and that this association was prominent in over a period of days to weeks, studies on BP measures in
patients older than 60 years of age. For every 1-SD increase this period may be influenced by stress response and disease
in PP, there was a 35% increase in the risk of recurrent vascu- severity. Hence, we investigated BP within 3  months after
lar events and all-cause mortality and a 46% increase in the stroke in order to eliminate the acute phase response.
risk of recurrent stroke. In this study, the predictive effect of PP was prominent in
The superiority of PP as a cardiac risk predictor in hyper- the stroke population aged 60 years or older, thus manifesting
tension has been well-established. Moreover, a physiologically a possible modification of PP effect by age. This is consistent

American Journal of Hypertension  5


Su et al.

with previous evidence demonstrating that, with advancing


age, the predictor of CHD shifts from DBP to SBP and then ACKNOWLEDGMENTS
to PP as a consequence.8 This may be because the large vessel
stiffness is a dominant risk factor of CHD in the aging popula- This study was supported by the 11th and 12th Five-Year
tion, whereas the resistance of peripheral arteries is dominant National Science and Technology Support Program (grant
in the younger population. Indeed, the changing patterns of number: 2006BAI01A10, 2011BAI08B03), and the National
BP with increasing age have been widely accepted. SBP con- Natural Science Foundation of China (grant number:
tinues to rise throughout life in comparison to DBP, which 81173663).
rises until 50 years of age, levels off over the next decade, and
remains constant or falls after 60  years of age. In line with
recent findings that PP dose not substantially contribute to the DISCLOSURE
cardiovascular risk stratification below the age of 60 years,31,32
The authors declared no conflict of interest.
our study further indicated that this age difference might also
be true in predicting the stroke outcomes. Further investiga-
tion is warranted to study the relationship of age-modified PP
effects with long-term outcomes in patients with stroke.
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