Download Association of Hypertension With Stroke Recurrence Depends on

Association of Hypertension With Stroke Recurrence
Depends on Ischemic Stroke Subtype
Yilong Wang, MD, PhD*; Jie Xu, MD, PhD*; Xingquan Zhao, MD, PhD;
David Wang, DO, FAHA, FAAN; Chunxue Wang, MD, PhD; Liping Liu, MD, PhD;
Anxin Wang, MD; Xia Meng, MD, PhD; Hao Li, PhD; Yongjun Wang, MD
Downloaded from http://stroke.ahajournals.org/ by guest on August 9, 2017
Background and Purpose—The association between hypertension (HTN) and stroke recurrence is unclear, but may be
influenced by different subtypes of stroke. This study aims to explore whether HTN contributes to the recurrence of
certain subtypes of ischemic stroke (IS).
Methods—Data from the China National Stroke Registry was examined and 1-year follow-up data for stroke recurrence
was analyzed. Trial of Org 10172 in Acute Stroke Treatment criteria was used to classify the subtypes of all IS. HTN was
defined when resting blood pressure was ≥140/90 mm Hg on repeated measurements during hospitalization or a patient
had been on antihypertensive medication. Recurrent stroke was defined as a new neurological deficit compatible to IS or
intracerebral hemorrhage. The association between HTN and stroke recurrence in patients with different IS subtypes was
analyzed by using univariable and multivariable logistic regression models.
Results—Of 11 560 patients with IS, 8409 (72.7%) had HTN and 2050 (17.7%) experienced a recurrent stroke within 1 year.
Patients with HTN had an insignificantly higher stroke recurrence rate than those without (18.0% versus 17.0%; P=0.21).
After stratification by Trial of Org 10172 in Acute Stroke Treatment subtypes, multivariable analysis revealed a significant
association between HTN and stroke recurrence in small-artery occlusion subtype (odds ratio, 1.52; 95% confidence
interval, 1.03–2.31), but not in the other subtypes (large-artery atherosclerosis: odds ratio, 0.99; 95% confidence interval,
0.81–1.21; cardioembolic: odds ratio, 1.14; 95% confidence interval, 0.75–1.73; other: odds ratio, 0.88; 95% confidence
interval, 0.71–1.09).
Conclusions—Our results showed that HTN is specifically related to the recurrent strokes in patients with small-vessel
diseases, not other subtypes of IS. (Stroke. 2013;44:1232-1237.)
Key Words: hypertension
■
ischemic stroke
K
■
recurrent event
Methods
nown as a major risk factor contributing to the causes of
ischemic stroke (IS), hypertension (HTN) has not been
well studied as a risk factor for subsequent strokes.1–7 Because
of methodological differences, previously published studies
were vague on the association of HTN with the recurrence
of strokes.8 HTN therefore may not contribute to subsequent
strokes of different subtypes equally. This is because IS is
a heterogeneous disease with variable pathogenesis.9 Most
previous studies examined HTN as a potential risk factor
for recurrent stroke among IS patients without distinguishing the initial IS subtypes.1–7 The aim of the current study
was to assess the association between HTN and stroke recurrence in patients with different IS subtypes, as defined by
the Trial of Org 10172 in Acute Stroke Treatment (TOAST)
classification.10
China National Stroke Registry is a nationwide, hospital-based registry that enrolls consecutive stroke patients (≥18 years) within 14
days after stroke onset in 1 of 132 participating hospitals in China.11
Acute stroke included acute IS, intracerebral hemorrhage, and subarachnoid hemorrhage. The participating hospitals included 100
tertiary and 32 secondary urban hospitals, selected from 27 provinces and 4 municipalities in Mainland China. Detailed baseline data
were abstracted prospectively by using paper-based registry forms.
Patients or their authorized proxies were contacted at 3, 6, and 12
months after stroke onset by telephone for follow-up. The study
was approved by the central Institutional Review Board at Beijing
Tiantan Hospital, and all patients or their designated relatives provided informed consent.
The current analysis included all patients in the China National
Stroke Registry who had been diagnosed with acute IS according to
the World Health Organization criteria,12 and with confirmation by
Received November 28, 2012; final version accepted January 22, 2013.
From the Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (Y.W., J.X., X.Z., C.W., L.L., A.W., X.M.,
H.L., Y.W.); and INI Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria, IL (D.W.).
*Drs Wang and Xu contributed equally to this article.
The online-only Data Supplement is available for this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
111.000302/-/DC1.
Correspondence to Yongjun Wang, MD, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantanxili, Dongcheng
District, Beijing, China. E-mail [email protected]
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.000302
1232
Wang et al Hypertension, Stroke Subtypes, and Recurrence 1233
Downloaded from http://stroke.ahajournals.org/ by guest on August 9, 2017
brain computed tomography (CT) or MRI. All patients with acute IS
were further classified according to the TOAST criteria: large-artery
atherosclerosis (LAA), small-artery occlusion (SAO), cardioembolism (CE), stroke of other determined pathogenesis, and stroke of
undetermined pathogenesis.10 Subtype classification was based on
patient’s features combined with the results of 1 or more diagnostic
tests, including brain imaging (CT and MRI), EKG, echocardiography (transesophageal or transthoracic), imaging of extracranial and
intracranial arteries (carotid duplex, transcranial Doppler, CT angiography, magnetic resonance angiography, or digital subtraction angiography), and laboratory assessments for a prothrombotic state. At
least 2 study neurologists from each participating hospital reviewed
the clinical features and diagnostic tests results, and then gave the
subtype classifications. These neurologists were trained centrally
and the diagnostic criteria of subtype classifications were consistent
across all participating hospitals: (1) Patients with LAA had clinical
and brain imaging findings of either significant (≥50%) stenosis or
occlusion of a major brain artery or branch cortical artery. Clinical
findings included cerebral cortical impairment (eg, aphasia, neglect,
apraxia, anopia, restricted motor involvement) or brain stem or cerebellar dysfunction. Infarct areas were >1.5 cm in diameter on CT or
MRI. (2) Patients with SAO had one of the traditional clinical lacunar
syndromes (including pure motor stroke, pure sensorimotor stroke,
pure sensory stroke, ataxic hemiparesis, or clumsy hand dysarthria)
and did not have evidence of cerebral cortical dysfunction. Infarct
areas were <1.5 cm in diameter on CT or MRI. A history of HTN
or diabetes mellitus supports the clinical diagnosis. Evidence of cardiac sources of embolism was absent and large extracranial arteries
had a stenosis of <50% in an ipsilateral artery. (3) Patients with CE
had at least one cardiac source for an embolus, including rheumatic
mitral valve disease, nonvalvular atrial fibrillation, sick sinus syndrome, recent myocardial infarction (<4 weeks), cardiac thrombus,
valvular vegetation, akinetic left ventricular segment, atrial myxoma,
dilated cardiomyopathy, prosthetic mitral or aortic valve, and paradoxical emboli. Clinical and brain imaging findings are similar to
those described for LAA. The angiogram or ultrasonogram does not
show significant (≥50%) stenosis or ulcerated plaques in the proximal large-artery supply. (4) Patients with stroke of other determined
pathogenesis had rare causes of stroke, including nonatherosclerotic
vasculopathies, hypercoagulable states, or hematologic disorders. (5)
Stroke of undetermined pathogenesis was defined when any of the
following criteria were met: (a) no cause was found despite an extensive evaluation; (b) a most likely cause could not be determined
because >1 plausible cause was found; or (c) undetermined pathogenesis attributable to incomplete evaluation. As there were a few patients in the stroke of other determined pathogenesis subtype (1.6%),
these patients were combined with the stroke of undetermined pathogenesis subgroup and defined together as “Other.” Hence, patients
with IS in this study were classified into 4 subtypes (LAA, SAO, CE,
and “Other”).
HTN was defined when a patient’s blood pressure was ≥140/90
mm Hg on repeated measurements during the hospitalization or patient was on antihypertensive medication. Other risk factors were
defined as follows: history of stroke (defined as a medical chart-confirmed history of stroke, including IS, intracerebral hemorrhage, or
subarachnoid hemorrhage), coronary heart disease (a reported history
of myocardial infarction or cardiac surgery, or with a final diagnosis
of myocardial infarction at discharge), atrial fibrillation (a reported
history of atrial fibrillation, or diagnosed using the patient’s in-hospital EKG), diabetes mellitus (fasting blood glucose level ≥120 mg/dL,
or use of antidiabetic drugs), dyslipidemia (total cholesterol measurement ≥240 mg/dL, high-density lipoprotein measurement <35 mg/dL,
or use of lipid-lowering agents), current or previous smoking (defined
as an individual who smoked at the time of stroke or had quit smoking
within 1 year), and moderate or heavy drinking (≥2 standard alcoholic beverages consumed per day). Other clinical features included
severity of stroke on admission (National Institutes of Health Stroke
Scale score),13 and persistence with secondary prevention medication,
including antithrombotic (antiplatelet or anticoagulation) agents and
antihypertensive agents (included angiotensin-converting enzyme
Figure 1. Patient flow diagram. CE indicates cardioembolism; CNSR, China National Stroke Registry; HTN, hypertension; LAA, largeartery atherosclerosis; and SAO, small-artery occlusion.
1234 Stroke May 2013
inhibitors, angiotensin receptor blockers, calcium channel blockers,
diuretics, β-blockers, and other antihypertensives, including centrally
acting adrenergics, peripherally acting antiadrenergics, and vasodilators). Persistence was calculated as the cumulative duration of taking
medication divided by the length of the follow-up period. Persistence
of ≥75% was defined as high and <75% was defined as low. Patients
who did not take any medication during the follow-up period were
defined as untreated. The detailed definition of persistence can be
found in the online-only Data Supplement.
Recurrent stroke was defined as a new neurological deficit or a
deterioration of the previous deficit that fits the definitions for ischemic or hemorrhagic stroke,12 not considered to be because of edema,
hemorrhagic transformation, or intercurrent illness. At 3, 6, and 12
months after the incident stroke, patients or their relatives were asked
whether they had new symptoms and experienced rehospitalization
with a diagnosis of IS or intracerebral hemorrhage. Hospitals that admitted patients with recurrent strokes were contacted to verify the
diagnosis. All recurrent events were based on clear documentation
in medical records, and neurological deficits had lasted longer than
24 hours. If a patient died within the year of follow-up, the cause of
death was verified by examining the hospital medical records.
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Statistical Analyses
For descriptive analysis, proportions were used for categorical variables and means with standard deviations were used for continuous variables. Demographic and clinical variables among different
TOAST subtypes were compared by χ2 test for categorical and
analysis of variance test for continuous variables. The associations
between HTN and stroke recurrence were analyzed in multivariable
logistic regression models, after adjusting for potential confounders,
including age, sex, history of stroke, diabetes mellitus, atrial fibrillation, dyslipidemia, coronary heart disease, smoking, drinking, stroke
severity, and medication persistence during follow-up. Subanalyses
of the data by TOAST subtypes were prespecified. Unadjusted and
adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are
reported separately. Two-tailed probability values are reported, and a
probability value <0.05 was considered significant in univariable and
multivariable analyses. Data were analyzed using SAS version 9.1.3
statistical software (SAS Institute, Inc., Cary, NC).
Results
Characteristics of Patient Population
Of the 22 216 patients enrolled in the China National Stroke
Registry, 18 580 patients had complete baseline information
and agreed to participate in follow-up. Among them, 12 415
had an IS. Among these IS patients, 855 patients were lost to
follow-up during the first year, leaving 11 560 patients for the
final analysis. Among this group entered into the final analysis, 8409 (72.7%) had HTN (Figure 1). The clinical characteristics of the analyzed population (n=11 560), including the
prevalence of HTN (P=0.09) and the distribution of TOAST
subtypes (P=0.06), were generally similar to those of 855
patients who were lost to follow-up. However, patients who
Table 1. Baseline Characteristics Among Patients With Different Ischemic Stroke Subtypes
LAA
SAO
CE
Other
Variables
n=5237
n=1938
n=714
n=3671
Women
1915 (36.6%)
689 (35.6%)
414 (58.0%)
1424 (38.8%)
<0.0001
65.6±11.8
65.1±11.7
69.9±12.8
64.7±13.1
<0.0001
Hypertension
4028 (76.9%)
1477 (76.2%)
462 (64.7%)
2442 (66.5%)
<0.0001
Diabetes mellitus
1638 (31.3%)
584 (30.1%)
143 (20.0%)
884 (24.1%)
<0.0001
Atrial fibrillation
308 (5.9%)
68 (3.5%)
586 (82.1%)
292 (8.0%)
<0.0001
Dyslipidemia
3226 (61.6%)
1114 (57.5%)
312 (43.7%)
1596 (43.5%)
<0.0001
History of stroke
1860 (35.5%)
641 (33.1%)
235 (32.9%)
1231 (33.5%)
NS
<0.0001
Mean age, years (SD)
Coronary heart disease
P Value*
769 (14.7%)
246 (12.7%)
224 (31.4%)
495 (13.5%)
Current or previous smoker
2197 (41.6%)
776 (40.0%)
273 (38.2%)
1451 (39.5%)
NS
Moderate or heavy drinking
549 (10.5%)
179 (9.2%)
67 (9.4%)
319 (8.7%)
NS
<0.0001
NIHSS scores at admission
0–4
2445 (46.7%)
1295 (66.8%)
169 (23.7%)
1825 (49.7%)
5–14
2196 (41.9%)
593 (30.6%)
270 (37.8%)
1325 (36.1%)
≥15
596 (11.4%)
50 (2.6%)
275 (38.5%)
521 (14.2%)
Persistence with antithrombotic drugs during follow–up
High persistence (≥75%)†
2320 (44.3%)
769 (39.7%)
206 (28.8%)
1281 (34.9%)
Low persistence (<75%)†
2367 (45.2%)
933 (48.1%)
324 (45.4%)
1843 (50.2%)
550 (10.5%)
236 (12.2%)
184 (25.8%)
547 (14.9%)
Nontreated†
<0.0001
Persistence with antihypertensive drugs during follow-up‡
High persistence (≥75%)†
1321 (32.8%)
496 (33.6%)
110 (23.8%)
732 (30.0%)
Low persistence (<75%)†
2111 (52.4%)
743 (50.3%)
187 (40.5%)
1106 (45.3%)
596 (14.8%)
238 (16.1%)
165 (35.7%)
604 (24.7%)
Untreated†
<0.0001
CE indicates cardioembolism; LAA, large-artery atherosclerosis; NIHSS, National Institutes of Health Stroke Scale; and SAO, small-artery occlusion.
*The P values are related to comparison between 4 groups.
†Persistence was calculated as the cumulative duration of taking medication divided by the length of the follow-up period. Persistence of ≥75% was defined as high
and <75% was defined as low. Patients who did not take any medication during follow-up period were defined as untreated.
‡This analysis was limited in hypertensive patients.
Wang et al Hypertension, Stroke Subtypes, and Recurrence 1235
Table 2. Comparison of Recurrence Rate in Patients With and
Without Hypertension; Stratified by Ischemic Stroke Subtype
Association Between HTN and Stroke Recurrence
in Patients Stratified by IS Subtypes
Stroke Subtype
Table 2 shows the comparison of stroke recurrence rates at different time points between patients with or without HTN in
each IS subtype. For the entire study population (n=11 560), the
cumulative stroke recurrence rate was 17.7% (n=2050) at 1 year
after stroke onset. There was no statistically significant difference in stroke recurrence rates in patients with or without HTN
at either 3 months (13.0% versus 12.9%; P=0.89), 6 months
(16.2% versus 15.6%; P=0.48), or 1 year (18.0% versus 17.0%;
P=0.21) after stroke onset. However, once they were stratified
according to the IS subtypes, the stroke recurrence rate in the
SAO subgroup was significantly greater in patients with HTN
than in those without HTN (9.8% versus 6.3%, P=0.023 at 3
months; 12.3% versus 8.7%, P=0.031 at 6 months; 14.0% versus 9.3%, P=0.010 at 1 year). In contrast, there were no statistically significant differences between patients with and without
HTN in the LAA, CE, or “Other” subgroups. The stroke recurrence rates and probability values were listed in Table 2.
Furthermore, we used multivariable logistic regression
analyses to investigate the association between HTN and risk
of stroke recurrence. After adjusting for potential confounders,
HTN was associated with stroke recurrence in the SAO subtype
group at 3 months (OR, 1.77; 95% CI, 1.10–2.86), 6 months
(OR, 1.48; 95% CI, 1.06–2.37), or 1 year (OR, 1.52; 95% CI,
1.03–2.31) after stroke onset. This phenomenon was not seen
in the LAA, CE, or “Other” subtype groups. The unadjusted
and adjusted ORs with 95% CIs are shown in Figure 2.
All IS
Recurrence at 3 mo
All
HTN
Non-HTN
11 560
8409
3151
P Value*
1494 (12.9%) 1089 (13.0%) 405 (12.9%) 0.89
Recurrence at 6 mo
1848 (16.0%) 1357 (16.2%) 491 (15.6%) 0.48
Recurrence at 12 mo
2050 (17.7%) 1514 (18.0%) 536 (17.0%) 0.21
LAA
Recurrence at 3 mo
5237
4028
1209
671 (12.8%) 517 (12.8%) 154 (12.7%) 0.93
Recurrence at 6 mo
827 (15.8%) 647 (16.1%) 180 (14.9%) 0.34
Recurrence at 12 mo
920 (17.6%) 719 (17.9%) 201 (16.6%) 0.33
SAO
Recurrence at 3 mo
1938
1477
461
173 (8.9%)
144 (9.8%)
29 (6.3%)
0.023
Recurrence at 6 mo
222 (11.5%) 182 (12.3%)
40 (8.7%)
0.031
Recurrence at 12 mo
249 (12.9%) 206 (14.0%)
43 (9.3%)
0.010
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CE
Recurrence at 3 mo
714
462
158 (22.1%) 105 (22.7%)
252
53 (21.0%) 0.60
Recurrence at 6 mo
189 (26.5%) 125 (27.1%)
64 (25.5%) 0.64
Recurrence at 12 mo
206 (28.9%) 138 (29.9%)
68 (27.0%) 0.42
Other
Recurrence at 3 mo
3671
2442
1229
492 (13.4%) 323 (13.2%) 169 (13.8%) 0.66
Recurrence at 6 mo
610 (16.7%) 403 (16.5%) 207 (16.9%) 0.79
Recurrence at 12 mo
675 (18.4%) 451 (18.5%) 224 (18.2%) 0.86
CE indicates cardioembolism; HTN, hypertension; IS, ischemic stroke; LAA,
large-artery atherosclerosis; and SAO, small-artery occlusion.
*The P values are related to comparison between HTN and Non-HTN.
were lost follow-up seemed less likely to have had a history
of atrial fibrillation (P=0.027) or severe stroke (National
Institutes of Health Stroke Scale score ≥15 at admission;
P<0.0001), compared with the study population (online-only
Data Supplement Table I).
All 11 560 patients with IS (mean age 65.5 years [SD,
12.3]; 4442 [38.4%] women), had brain CT or MRI and
EKG. However, 2578 patients (22.3%) had a Holter monitor,
2230 (20.1%) had echocardiography (transthoracic or
transesophageal), 5257 patients (45.5%) had neurosonographic
evaluations (carotid ultrasonography or transcranial Doppler),
and 3564 patients (30.8%) had angiographic evaluations (CT
angiography, magnetic resonance angiography, or digital
subtraction angiography). The overall interrater agreement
for the TOAST classification was good, with a κ value of 0.73
(95% CI, 0.65–0.81). Each of the IS patients was classified
into a subtype: 5237 (45.3%) with LAA, 1938 (16.8%) with
SAO, 714 (6.2%) with CE, and 3671 (31.8%) with “Other”
(Figure 1).
Baseline characteristics according to stroke subtypes are
presented in Table 1. LAA and SAO subtype groups had a
similar rate of HTN and diabetes mellitus, whereas SAO subtype had a milder stroke symptom on presentation. Patients
with CE subtype were older and had a higher proportion of
women, atrial fibrillation, coronary heart disease, and higher
stroke severity scores on admission. This group was also
less persistent with the antithrombotic or antihypertensive
medications.
Other Risk Factors for Recurrent Stroke
in Each IS Subtype
Multivariable logistic analysis showed that diabetes mellitus,
atrial fibrillation, and history of stroke were independent risk
factors for recurrent stroke at 1 year in all IS subtypes, whereas
dyslipidemia, smoking, and drinking had no association.
Such as HTN, the impact of coronary heart disease on stroke
recurrence varied according to IS subtypes (Table 3). The
detailed ORs with 95% CIs of above risk factors are shown in
Table II in the online-only Data Supplement.
Discussion
To the best of our knowledge, this is the largest observational
study exploring HTN as a risk factor for stroke recurrence in
patients with different IS subtypes. We identified HTN as a risk
factor for stroke recurrence within 1 year in Chinese patients
with the SAO subtype of IS, but not in other subtype groups.
The results of previous studies concerning the association
between HTN and stroke recurrence have been inconsistent.
A positive association between HTN and stroke recurrence
was seen in the Stroke Data Bank study,1,2 the Lehigh Valley
study,3 the Northern Manhattan stroke study,4 and the Nanjing
Stroke Registry Program.5 In contrast, no association was found
in the Oxfordshire Community Stroke Project study6 or the
Rochester population study.7 These studies evaluated the association of HTN and recurrent stroke in all IS patients, regardless of the subtypes. It is clear now that racial-ethnic differences
would have different proportions of IS subtypes, as reported in
­different stroke registries.14 As both the underlying pathogenesis
1236 Stroke May 2013
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Figure 2. Association between hypertension and stroke recurrence in patients stratified by ischemic stroke subtypes. *Adjusted for
age, sex, history of stroke, diabetes mellitus, atrial fibrillation, dyslipidemia, coronary heart disease, smoking, drinking, stroke severity,
and medication persistence during follow-up. CE indicates cardioembolism; CI, confidence interval; LAA, large-artery atherosclerosis;
OR, odds ratio; and SAO, small-artery occlusion.
and the role of HTN would vary among different IS subtypes,
the results from these previous studies were nonconclusive.
In this study, the positive association between HTN and
stroke recurrence was only found in SAO subtype. This is
consistent with the results of 2 previous clinical trials,15,16
which showed that lacunar strokes have a greater response to
blood pressure-lowering strategy than other IS subtypes. As we
know, lacunar infarction is usually caused by occlusion of a
single, small, deep penetrating artery or one of its branches.
HTN is characterized by lipohyalinosis and fibrinoid necrosis,
particularly taking place in penetrating arteries.17 HTN-related
Table 3. Risk Factors for Recurrent Stroke in Each IS
Subtype
Risk Factors
LAA
SAO
CE
Other
Hypertension
–
+
–
–
Diabetes mellitus
+
+
+
+
Atrial fibrillation
+
+
+
+
Dyslipidemia
–
–
–
–
History of stroke
+
+
+
+
Coronary heart disease
+
–
–
–
Current or previous smoking
–
–
–
–
Moderate or heavy drinking
–
–
–
–
CE indicates cardioembolism; LAA, large-artery atherosclerosis; and SAO,
small-artery occlusion.
strokes are mainly lacunar infarctions or intracerebral hemor­
rhage because of rupture of resistance vessels affected by
those pathological processes.18 Russell was the first to propose
that treatment of HTN may prevent hemorrhagic and lacunar
strokes, but not those because of atherosclerosis.17 Observations
in a community blood pressure control study19 supported the
hypothesis, and showed that the strokes prevented by treating
HTN are mostly because of hypertensive small-vessel diseases.
To our knowledge, the PROGRESS study15 was the only trial
that examined the various subtypes of the outcomes of stroke
in a secondary prevention setting, although the initial strokes
were not subclassified. It showed that the risk of lacunar stroke
was reduced almost by one quarter with active antihypertensive
treatment. However, to date, no studies have answered the
question directly, whether the HTN contributes to stroke
recurrence in different subtypes of initial IS. In this large
observational study, our results imply that, among patients
with initial IS, the association of HTN with stroke recurrence
is related to the IS subtype. HTN plays an important role
for stroke recurrence within 1 year in patients with the SAO
subtype of IS, but not in LAA, CE, or “Other” subtype groups.
Besides HTN, in this study, we also investigated the impact
of other traditional risk factors on stroke recurrence in each IS
subtype. The factors that are most constantly associated with
recurrence among different subtypes are diabetes mellitus,
atrial fibrillation, and history of stroke. It is worth noting that
Wang et al Hypertension, Stroke Subtypes, and Recurrence 1237
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coronary heart disease was associated with stroke recurrence
in LAA other than SAO, CE, or “Other” subtypes. This may
be attributed to the same pathogenesis between myocardial
infarction and LAA.
Our study also demonstrated differences among subtypes
for recurrence rate, at 3 months, 6 months, or 1 year (Table 2).
The recurrence rate was highest for CE stroke, followed by
LAA stroke, and lowest for SAO stroke. Our result was different from Western population studies,20–22 in which a high
recurrence risk was confirmed for IS LAA, and a minimum
risk for lacunar stroke. The highest recurrence rate for patients
with CE subtype in our study may be attributable to the older
age, higher proportion of risk factors, and lower persistence
with secondary prevention medication after discharge, compared with those with the other stroke subtypes.
Our study had some limitations. First, our data came from
a hospital-based registry, which could have hospital selection
bias,23 including a greater number of patients with LAA or
CE stroke, who would experience more severe symptoms than
patients with an SAO stroke. Second, patients who were lost
to follow-up had milder stroke than study population, which
could also lead to selection bias. Third, blood pressure during
the follow-up period was not recorded in the registry, and we
could not evaluate the effect of blood pressure control and its
impact on stroke recurrence. However, we used the level of
persistence with antihypertensive medication during followup to reflect the control of blood pressure.24 Finally, although
we classified the subtypes of initial IS using the TOAST criteria, we could not classify the subtypes of recurrent stroke, as
this information was not collected in the registry. It is likely
that after the initial lacunar stroke, a recurrence is more likely
to be another lacunar stroke.25‍
Acknowledgments
The authors acknowledge the independent medical writing assistance
provided by Janelle Keys, PhD, and Karen Woolley, PhD, of ProScribe
Medical Communications, funded from an unrestricted financial grant
from Beijing Novartis Pharma Co., Ltd. ProScribe’s services complied
with international guidelines for Good Publication Practice (GPP2).
Sources of Funding
The China National Stroke Registry was funded by the Ministry of
Sciences and Technology and the Ministry of Health of the People’s
Republic of China (Grant no. 2006BA101A11, 2009CB521905, and
200902004) and the National Science Foundation (Grant no. 81071115).
The current analysis of the CNSR data were supported by Beijing
Novartis Pharma Co, Ltd. In compliance with the Uniform Requirements
for Manuscripts, established by the International Committee of Medical
Journal Editors, Novartis did not impose any impediment, directly or
indirectly, on the publication of the study’s results.
Disclosures
All authors participated in the interpretation of study results, and in
the drafting, critical revision, and approval of the final version of the
manuscript. Yilong Wang was responsible for study design, data analyses, and drafting/revising the manuscript; Jie Xu was responsible
for acquisition of data, data analyses, and drafting the manuscript;
Xingquan Zhao, David Wang, Chunxue Wang, and Liping Liu were
involved in revising the manuscript for important intellectual content; Hao Li, Anxin Wang, and Xia Meng conducted the statistical
analysis; and Yongjun Wang was responsible for the study concept or
design, technical, material support, administration, and supervision.
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Association of Hypertension With Stroke Recurrence Depends on Ischemic Stroke
Subtype
Yilong Wang, Jie Xu, Xingquan Zhao, David Wang, Chunxue Wang, Liping Liu, Anxin Wang,
Xia Meng, Hao Li and Yongjun Wang
Downloaded from http://stroke.ahajournals.org/ by guest on August 9, 2017
Stroke. 2013;44:1232-1237; originally published online February 26, 2013;
doi: 10.1161/STROKEAHA.111.000302
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SUPPLEMENTAL MATERIAL
Supplemental Methods
Assessment of medication compliance
In this study, the compliance levels of antihypertensive and antithrombotic agents were
calculated separately but used the same criteria. Compliance was defined as the overall
duration of medication therapy.1 Compliance with antihypertensive therapy was assessed
through the telephone interview. At the 3-, 6-, and 12-month intervals after initial stroke,
patients were asked whether they had taken antihypertensive therapy since their last follow
up. A ‘yes’ answer at the 3- month follow-up was defined as 3 months’ duration of therapy. A
‘yes’ answer at 6-month follow-up indicated that a patient had been taking medicine from
3-month to 6 month. A ‘yes’ answer at 12-month follow-up indicated that a patient had been
taking medicine from 6-month to 12 month.
Compliance was calculated as the ratio of the cumulative duration of antihypertensive
therapy and the duration of overall follow-up before the recurrence event. For example, if a
patient had a recurrent stroke at 12-month follow up, a ‘yes’ answer with antihypertensive
drugs used at 3-month follow up, a “no” answer at 6-month and a “yes” answer at 12-month,
the compliance level was calculated as (3+0+6)/12=75%. If a patient had a recurrent stroke at
6-month follow up, a ‘yes’ answer with antihypertensive drugs used at 3-month follow up,
but had a “no” answer at 6-month, the compliance level was calculated as (3+0)/6=50%. If a
patient had a recurrent stroke at 3-month follow up, and a ‘yes’ answer with antihypertensive
drugs used at 3-month follow up, the compliance level was calculated as 3/3=100%.
Compliance of ≥ 75% was defined as high and < 75% was defined as low. Patients who did
Page 1
not take any medication during follow-up period were defined as untreated.
Supplemental Tables
Supplemental Table e-1. Baseline characteristics of patients with acute ischemic stroke
who did or did not have 1-year follow-up data.
Patients with
Patients Lost to
Follow-up Data
Follow-up
(n = 11,560)
(n = 855)
P value
4,442 (38.4%)
315(36.8%)
0.36
18~45
721 (6.2%)
61(7.1%)
0.68
46~65
4,662 (40.3%)
351(41.1%)
66~75
3,567 (30.9%)
256(29.9%)
≥76
2,610 (22.6%)
187(21.9%)
3,967 (34.3%)
267(31.2%)
0.07
8409（72.7%）
599（70.1%）
0.09
Coronary heart disease
1,685(14.6%)
107(12.5%)
0.10
Atrial fibrillation
1,254 (10.9%)
72(8.4%)
0.032
Diabetes mellitus
3,249 (28.1%)
237(27.7%)
0.81
Dyslipidaemia
6,248 (54.1%)
478(55.9%)
0.29
Current smoking
3,166 (27.4%)
242 (28.3%)
0.33
Variable
Demographics variables
Female
Age
Vascular risk factors
History of stroke
Hypertension
Page 2
Patients with
Patients Lost to
Follow-up Data
Follow-up
Variable
(n = 11,560)
(n = 855)
P value
Moderate or heavy drinking
1,082 (9.4%)
89(10.4%)
0.31
0-4
5,734 (49.5%)
490(57.3%)
＜0.0001
5-14
4,384 (38.0%)
291(34.0%)
≥15
1,442 (12.5%)
74(8.7%)
LAA
5237 (45.3%)
350 (40.9%)
SAO
1938 (16.8%)
152 (17.8%)
714 (6.2%)
49 (5.7%)
3671 (31.8%)
304 (35.6%)
Other clinical features
NIHSS scores at admission
Ischemic stroke subtype
CE
others
0.06
Data shown are n (%).
Abbreviations: CE, cardioembolism; LAA, large-artery atherosclerosis; NIHSS, National
Institutes of Health Stroke Scale; SAO, small-artery occlusion.
Supplemental Table e-2. Risk factors for recurrent stroke in each ischemic stroke subtype.
Risk factors
LAA
SAO
CE
Other
Hypertension
0.99 (0.81-1.21)
1.52 (1.03-2.31)
1.14 (0.75-1.73)
0.88 (0.71-1.09)
Diabetes mellitus
1.18 (1.01-1.38)
1.14 (1.08-1.93)
1.21 (1.06-2.36)
1.25 (1.02-1.53)
Atrial fibrillation
1.77 (1.36-2.31)
2.14 (1.18-3.88)
1.25 (1.09-2.28)
1.80 (1.36-2.38)
Page 3
Dyslipidaemia
0.92 (0.75-1.13)
0.76 (0.49-1.17)
0.89 (0.55-1.42)
0.91 (0.71-1.16)
History of stroke
1.59 (1.37-1.85)
1.86 (1.41-2.47)
1.58 (1.11-2.26)
1.55 (1.29-1.86)
Coronary heart disease
1.35 (1.11-1.65)
1.24 (0.84-1.83)
1.07 (0.74-1.56)
1.03 (0.80-1.33)
Current smokers*
0.91 (0.73-1.12)
1.01 (0.69-1.48)
1.61 (0.91-2.85)
0.95 (0.74-1.24)
Moderate or heavy drinking
1.04 (0.79-1.36)
0.84 (0.49-1.44)
0.48 (0.17-1.31)
0.99 (0.69-1.41)
*Odds ratios for “current smokers” vs “never smoked”. Abbreviations: CE,
cardioembolism; LAA, large-artery atherosclerosis; SAO, small-artery occlusion.
Supplemental References
1.
Ho PM, Bryson CL, Rumsfeld JS. Medication adherence. Circulation 2009; 119: 3028
-3035.
Page 4