(Stroke. 1998;29:2491-2500.)
© 1998 American Heart Association, Inc.
Original Contributions |
From the Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Western Australia (G.J.H., E.G.S-W.); Departments of Public Health (K.J., R.J.B., S.F.) and Psychiatry and Behavioral Science (P.W.B.), University of Western Australia, Perth; and Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand (C.S.A.).
Correspondence to Dr Graeme J Hankey, Stroke Unit, Department of Neurology, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6001, Australia. E-mail gjhankey{at}cyllene.uwa.edu.au
| Abstract |
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MethodsBetween February 1989 and August 1990, all people with a suspected acute stroke or transient ischemic attack of the brain who were resident in a geographically defined region of Perth, Western Australia, with a population of 138 708 people, were registered prospectively and assessed according to standardized diagnostic criteria. Patients were followed up prospectively at 4 months, 12 months, and 5 years after the index event.
ResultsThree hundred seventy patients with a first-ever stroke were registered, of whom 351 survived >2 days. Data were available for 98% of the cohort at 5 years, by which time 199 patients (58%) had died and 52 (15%) had experienced a recurrent stroke, 12 (23%) of which were fatal within 28 days. The 5-year cumulative risk of first recurrent stroke was 22.5% (95% confidence limits [CL], 16.8%, 28.1%). The risk of recurrent stroke was greatest in the first 6 months after stroke, at 8.8% (95% CL, 5.4%, 12.1%). After adjustment for age and sex, the prognostic factors for recurrent stroke were advanced, but not extreme, age (75 to 84 years) (hazard ratio [HR], 2.6; 95% CL, 1.1, 6.2), hemorrhagic index stroke (HR, 2.1; 95% CL, 0.98, 4.4), and diabetes mellitus (HR, 2.1; 95% CL, 0.95, 4.4).
ConclusionsApproximately 1 in 6 survivors (15%) of a first-ever stroke experience a recurrent stroke over the next 5 years, of which 25% are fatal within 28 days. The pathological subtype of the recurrent stroke is the same as that of the index stroke in 88% of cases. The predictors of first recurrent stroke in this study were advanced age, hemorrhagic index stroke, and diabetes mellitus, but numbers of recurrent events were modest. Because the risk of recurrent stroke is highest (8.8%) in the first 6 months after stroke, strategies for secondary prevention should be initiated as soon as possible after the index event.
Key Words: Australia prognosis recurrence stroke outcome
| Introduction |
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The factors reported to have been associated with an increased risk of recurrent stroke in community-based and hospital-based series include increasing age,2 5 9 male sex,6 female sex,15 clinical stroke syndrome (partial anterior and posterior circulation syndromes 4.9% and 4.8% within the first 30 days, compared with lacunar syndrome 0.3% in the first 30 days13 ), history of transient cerebral ischemic attack,10 14 hypertension,6 10 11 12 14 16 17 initial elevated blood pressure,11 17 low blood pressure,18 cigarette smoking,13 alcohol abuse,7 diabetes mellitus,5 10 16 17 elevated blood glucose,7 16 history of coronary heart disease,6 9 15 atrial fibrillation,12 14 valvular heart disease and congestive heart failure,15 19 peripheral vascular disease, abnormal initial cranial CT scan,17 ECG evidence of left ventricular hypertrophy, echocardiographic evidence of atherosclerotic disease of the aortic arch,20 severity of carotid artery stenosis,21 22 and the occurrence of dementia after stroke.15 A reduced risk of recurrent stroke has been associated with a low diastolic blood pressure, no history of stroke, no history of diabetes, and an infarct of unknown cause.17 However, no independent factor has consistently been associated with an increased or decreased risk of recurrence.
We conducted a prospective community-based study of a cohort of patients with stroke followed over 5 years to document their outcome in the long term and to identify the factors present at baseline that predicted a first recurrent stroke.
| Subjects and Methods |
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Baseline Assessment
All cases meeting the clinical criteria for inclusion (resident
in the PCSS geographic area and suffering a stroke, as defined below,
between February 20, 1989, and August 19, 1990) underwent a
standardized neurological assessment. Information obtained at baseline
included data on associated illnesses, risk factors for
cardiovascular disease, and patterns of disability and
social activity in the immediate premorbid period.23 24
The physical signs recorded for each patient at the onset of stroke
included an assessment of the level of consciousness, the severity of
limb paresis, and the presence or absence of urinary incontinence,
cardiac failure, and atrial fibrillation. Level of consciousness at the
time of presentation was measured by means of the Glasgow
Coma Scale;25 a score of 3 to 9 was defined as comatose,
10 to 14 as drowsy, and the top score of 15 as normal. The severity of
limb paresis was only measured in patients assessed within 2 weeks of
onset of the stroke. Severe paresis was defined as Motricity Index
score of 0 to 50, moderate paresis 51 to 95, and normal or minimal
paresis 96 to 100.26 Patients were classified as
incontinent if they had accidents, needed help, or needed an indwelling
catheter during admission to hospital. Atrial fibrillation must have
been confirmed on ECG within 1 month after the onset of stroke.
Premorbid and baseline levels of disability were assessed with the
modified scale of the Barthel Index of activities of daily
living.27 28 Patients were defined as independent if they
had a score of 20 and as having some measure of dependency if they had
a score of <20.
Follow-Up
Surviving patients were followed up prospectively at 4 months,
12 months, and 5 years, with vital status at the latter point initially
being ascertained by electronic linkage of the study records to
mortality data supplied by the Registrar General of Births, Marriages,
and Deaths for Western Australia. Admissions to the hospital for stroke
during the period of follow-up were identified by an equivalent linkage
to the Hospital Morbidity Data System, a computerized, name-identified
register of all admissions to hospitals in Western Australia that is
maintained by the State Health Department.
Survivors at the time of the 5-year follow-up study were asked to participate in a structured interview and assessment at home by the study research nurse. The interview schedule included questions aimed at detecting a new stroke or other vascular event that had occurred during the period of follow-up.
For patients who had died or were suspected of having had a recurrent stroke or other vascular event, we independently reviewed all of the available clinical information and results of investigations obtained from records held by hospitals and physicians in private practice, and we reviewed the findings at necropsy (if one was performed) for patients whose death certificates indicated that the cause of death was vascular disease. We classified these events using standardized diagnostic criteria (see below).29 The physician (G.J.H.) assessing whether a recurrent stroke had occurred and, if so, its type was blind to the pathological and etiologic nature of the initial stroke.
Definitions
Stroke was defined according to the World Health Organization
criteria as "rapidly developing symptoms and/or signs of focal, and
at times global, loss of cerebral function, with symptoms lasting more
than 24 hours or leading to death with no apparent cause other than
that of vascular origin."30 The term "global" refers
mainly to subarachnoid hemorrhage.
Like others,8 13 we defined a recurrent stroke as a stroke, using the above definition,30 in which (1) there was clinical evidence of the sudden onset of a new focal neurological deficit with no apparent cause other than that of vascular origin (ie, the deficit could not be ascribed to an intercurrent acute illness, epileptic seizure, or toxic effect) occurring at any time after the index stroke; or (2) there was clinical evidence of the sudden onset of an exacerbation of a previous focal neurological deficit with no apparent cause other than that of vascular origin occurring >21 days after the index stroke.
Each recurrent stroke was classified as ischemic, hemorrhagic, or of undetermined nature on the basis of a CT or MRI scan performed within 28 days of recurrence or autopsy examination of the brain. Etiologic subtypes of ischemic stroke were defined according to standardized criteria.24
Statistical Analysis
Crude associations between the occurrence of recurrent stroke
outcome events and each of 26 independent categorical variables
recorded at baseline were assessed by preliminary cross-tabulations
with the
2 test and SAS
software.31 The Kaplan-Meier product-limit technique
was used to generate survival probabilities and survival curves. In
addition, we compared the cumulative incidence of first recurrent
strokes over 5 years of follow-up with the expected incidence of
strokes in the general population, derived from the age- and
sex-specific rates of first-ever stroke from the PCSS23
using statistical techniques developed at the Mayo
Clinic32 and calculated using the SAS macro
Survexp.31 Confidence limits (CL) for the ratio of
the observed to the expected frequency were calculated from the Poisson
distribution.33 Multiple regression with the use of Cox
proportional hazards analysis modeling and EGRET
software34 was used to develop statistical models
predicting occurrence of a new stroke within 5 years of a first stroke.
The 26 independent variables were screened by
univariate associations; after adjustment for age and sex,
each variable was considered individually. When a variable was
significant at the 0.1 level, it was chosen to contribute to the
multivariate model. When a most parsimonious model was
obtained by backward elimination, each variable was entered
separately into the model to look for further effects.
Ethical Considerations
The protocol for the study was approved by the Committee for
Human Rights at the University of Western Australia and by the
Confidentiality of Health Information Committee of the Health
Department of Western Australia. Patients or their next of kin gave
permission for review of medical records pertaining to suspected
vascular events occurring during follow-up.
| Results |
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One in 5 patients was managed entirely outside the hospital during the acute phase (19%; 95% CL, 15%, 23%). The pathology of the index stroke was identified in 87% of index events. Cerebral infarction accounted for 73% of all strokes (95% CL, 68%, 78%), primary intracerebral hemorrhage (PICH) 10.5% (95% CL, 7%, 14%), and subarachnoid hemorrhage 3.8% (95% CL, 2%, 6%). Surviving patients contributed a minimum of 3.8 years and a maximum of 5.3 years of follow-up time.
Outcome at 5 Years
Five years after a first stroke, 199 patients (58%) had died and
52 (15%) had suffered a first recurrent stroke, of which 12 (23%)
were fatal within 28 days. There were 164 patients who were censored
because of death (ie, death occurred before a recurrent stroke) of the
total of 199 deaths. Thirty-two of the 52 recurrent strokes were
registered during the 19891990 incidence study, in which patients
were recruited over 18 months and then followed up at 4 months and 12
months. The other 20 recurrent strokes were recorded at the time of
the follow-up study in 19941995. Forty-three of the 52 recurrent
strokes were detected by review of autopsy and medical records (all
32 in 19891990 and 11 in 19941995), and 9 were detected by the
structured interview in 19941995.
Pathological Subtype of Recurrent Stroke
The majority (n=37, 71%) of recurrent strokes were due to
cerebral infarction, and 89% (33/37) of new ischemic strokes
occurred in patients with cerebral infarction as the index stroke.
Among the 4 patients with new PICH, 3 occurred in patients with prior
PICH (Table 1
). In 88% (36) of
the 41 patients in whom the pathological basis of both the index and
recurrent event was known, these were identical.
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Risk of Recurrent Stroke
The 5-year cumulative risk of first recurrent stroke was 22.5%
(95% CL, 16.8%, 28.1%). The risk of recurrent stroke was greatest in
the first 6 months after stroke, at 8.8% (95% CL, 5.4 to 12.1%)
(Table 2
and Figure 1
). The 5-year cumulative risk of
surviving free of recurrent stroke was 77.6% (95% CL, 71.9%,
83.2%), as shown in Figure 1
.
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Table 3
shows the number of first
recurrent strokes in each calendar year after the index stroke compared
with the expected number of strokes in the general population of the
same age and sex.
|
Predictors of First Recurrent Stroke Over 5 Years
Table 4
shows the
associations of baseline prognostic variables with recurrent stroke
in the 343 patients with a first-ever stroke. When all index
hemorrhagic strokes, that is, cases of PICH plus those of
subarachnoid hemorrhage, were considered as a single
group, none of the relationships examined was statistically significant
at the 5% level.
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Figures 2
, 3
, and
4 show Kaplan-Meier survival curves for
first recurrent stroke, stratified by the age of the patient, clinical
syndrome, and pathology of the first stroke, respectively.
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The multivariate prediction model for first recurrent
stroke was based on 47 events in 337 patients (Table 5
). After adjustment for sex, the
prognostic factors for recurrent stroke were an index stroke that was
hemorrhagic (hazard ratio [HR], 2.1; 95% CL, 0.98, 4.4) and diabetes
mellitus (HR, 2.1; 95% CL, 0.95, 4.4), although neither of these was
statistically significant at the 5% level. Patients aged 75 to 84
years at the time of their index stroke were significantly more likely
than those aged <65 years to suffer a recurrent stroke.
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| Discussion |
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9% (8.8%
in PCSS and 8.6% in OCSP), and after 1 year it was
13% (12.5% in
PCSS and 13.2% in OCSP).13 The risk of another stroke
occurring in the 12 months after a first stroke was 8.5 (95% CL, 5.4,
11.6) times greater than the risk of first stroke in the general
population of the same age and sex, an estimate that is significantly
less than the figure of 15.4 (95% CL, 12.1, 19.0) reported in the
OCSP.13 The reasons for this difference are unclear, but
the 2 studies were conducted almost a decade apart, during which time
it became much clearer that low-dose aspirin is a simple, inexpensive,
and safe treatment for the secondary prevention of
stroke.35 We collected data concerning secondary
prevention treatments at registration (baseline) and at follow-up at 4
and 12 months but not at discharge from hospital. Thus, we do not have
a complete picture of medical management after the index stroke and
cannot judge whether this might explain the different relative
survivals observed in the PCSS and the OCSP.
After the first year, the average annual risk of recurrent stroke
for the next 4 years fell to
3%, which is again lower than the
figures of 4% to 6% reported in most other population-based
studies.2 3 4 8 13 This is mainly because of the low
frequency of stroke in the second year after an index event (1.0%),
which is inconsistent with other years in our study (and other
studies) and may reflect some incompleteness of ascertainment of
recurrent events. Our patients were not followed up between 12 months
and 5 years after their index events. Rather, recurrent strokes treated
in the hospital were ascertained by linking identifying information
from the inception cohort to the Hospital Morbidity Data System, an
electronic file that includes all inpatient separations in Western
Australia, while fatal recurrent strokes were detected by linkage of
the cohort to the official death register. Our vulnerable area is
therefore recurrent strokes occurring in patients who survived these
events and were not treated in the hospital. We suspect that the recall
of patients surviving to 5 years of the occurrence, up to 3 years
earlier, of nonfatal, nondisabling recurrent strokes that were not
severe enough to require admission to the hospital may have been
incomplete. Similarly, it was impossible for us to detect mild events
of this kind in patients who subsequently died of other causes.
The high rate of a recurrent stroke within the first year, and
particularly the first few months, of first stroke is well recognized
and consistent with the hypothesis that atheroma
(the cause of most strokes) is an acute-on-chronic disease, causing
recurrent episodes of thromboembolism before settling down as the
endothelium of the ulcerated plaque heals. In the OCSP,
the cumulative incidence of recurrent stroke over the year after
cerebral infarction varied among the 4 clinical subtypes of cerebral
infarction: from 6% in total anterior circulation infarction, 9% in
lacunar infarction, 17% in partial anterior circulation infarction, to
20% in posterior circulation infarction.36 There were 3
different patterns of recurrence: patients with partial
anterior circulation infarction have a high risk of early
recurrence (suggesting an active source of recurrent embolism);
patients with posterior circulation infarction have a moderately high
risk early, with further episodes throughout the first year; and those
with lacunar infarction have a low and fairly constant rate of
recurrence, supporting the notion that lacunar infarcts occur
as a result of occlusion of a single perforating artery and are not
usually due to an active source of recurrent embolism.37
Our results are consistent with these findings in that partial
anterior circulation infarction was associated with the highest rate of
recurrent stroke, although the association was not statistically
significant (Table 4
).
We were unable to classify recurrent strokes into clinical
subtypes. Previous studies provide some evidence that recurrent
infarcts in patients with lacunar infarction are predominantly lacunar,
supporting the hypothesis that lacunar infarctions are usually caused
by intracranial obstruction of small vessels, but other studies have
found that recurrent lacunar infarctions account for no more than
25% of recurrences (which is similar to the proportion of
patients with first-ever ischemic stroke who are found to have
a lacunar infarction).38 39 40
Factors that increase the risk of a first-ever stroke may not necessarily be as important in predicting a recurrent stroke. We identified advanced (but not extreme) age, hemorrhagic stroke, and diabetes mellitus as the independent predictors of recurrent stroke. We were surprised to identify diabetes as the single most important modifiable risk factor for recurrence (ahead of hypertension and heart disease, for example), but we note that several other studies, including the Rochester population study,5 the Lehigh Valley study,10 and the Stroke Data Bank,16 also found diabetes to be an independent predictor of recurrence.5 10 16 17 Although our statistical model is unstable because of the modest number of recurrent strokes on which it is based, these studies collectively support the increasing body of evidence that diabetes has widespread effects on vascular, hemorheologic, and coagulation systems. Furthermore, they emphasize that diabetes should be recognized as an important risk factor for recurrent stroke that is amenable to intervention. Similarly, patients with hemorrhagic stroke should also be considered at increased risk of recurrent stroke and investigated to identify an underlying treatable cause, such as poorly controlled hypertension or an arteriovenous malformation. Among populations with reasonable blood pressure control, lobar hemorrhages in particular appear to confer an increased risk of recurrent hemorrhagic stroke, presumably because they reflect a persistent underlying cause such as a small angioma (which tends to cause recurrent hemorrhage in the same site) or cerebral amyloid angiopathy (which tends to cause recurrent lobar hemorrhage in different sites).40
The high rate of early stroke recurrence that we and others
have identified emphasizes the importance of early secondary prevention
for those at increased risk. There is now evidence from the
International Stroke Trial and Chinese Aspirin Stroke Trial that early
treatment with aspirin, within 48 hours of onset of acute
ischemic stroke, prevents
5 recurrent strokes (7 fewer
recurrent ischemic strokes but 2 more hemorrhagic strokes) and
9 nonfatal strokes or deaths in the first few weeks per 1000 patients
treated (2P<0.001).41 42 Early aspirin therapy
is also associated with
13 (SD 5) fewer patients who are dead or
dependent after some weeks or months of follow-up per 1000 treated
(2P<0.01).41 42 There have been no long-term
prognostic studies beyond 5 years to indicate whether risks of stroke
recurrence and the need for long-term treatments continue.
Conclusions
In conclusion,
1 in 6 survivors (15%) of a first-ever stroke
experience a recurrent stroke over the next 5 years, and
25% of
these first recurrent strokes are fatal within 28 days. The risk of
recurrent stroke is highest (9%) in the first 6 months after the index
stroke. The pathological subtype of the recurrent stroke is the same as
that of the index stroke in 88% of cases. The predictors of recurrent
stroke are advanced age, hemorrhagic stroke, and diabetes mellitus.
Although diabetes is increasingly recognized as an important risk
factor that is amenable to therapy, there is no single factor that has
consistently been associated with an increased or decreased
risk of recurrence in the literature. This may reflect
differences between reports in the types of recurrent strokes studied
(eg, first or multiple recurrence; pathological subtype
[ischemic or hemorrhagic], etiologic subtype, severity
[fatal, disabling, nondisabling], and timing [early or late]) but
more probably reflects the interplay of several factors in determining
the risk of recurrent stroke and the statistical instability of the
prediction models because of the small numbers of recurrent strokes
included. Larger community-based studies of recurrent stroke are
required to resolve these uncertainties and to determine unambiguously
the balance of benefits and risks associated with use of various
secondary preventive treatments in particular subsets of patients.
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| Acknowledgments |
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Received May 21, 1998; revision received September 28, 1998; accepted September 28, 1998.
| References |
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