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1

Of all strokes recurring within 90 days of the indexevent, 50% occur in the first 2 weeks.1 The risk ofstroke after a transient ischemic attack (TIA) is also highest

in the first days and weeks after the index event.2,3However,

there are few published studies of the risk and risk factors

for early recurrent stroke in the recent era of early inten-

sive secondary prevention. The identification of patients at

high risk of early stroke recurrence may guide the selec-

tion of intensified early secondary prevention measures

and thus reduce morbidity and mortality.4 For example,

these patients may benefit from immediate dual antiplatelet

therapy for 3 months, a question which has experienced a

renaissance after publication of the Clopidogrel in High-

Risk Patients With Acute Nondisabling Cerebrovascular

Events (CHANCE) study.5

We therefore aimed to assess the frequency and determi-

nants of stroke during hospitalization after an index ischemic

stroke or TIA in an observational study using a strict definition

of stroke recurrence to distinguish true stroke recurrence from

other causes of neurological deterioration.

Background and PurposeWe aimed to assess the risk of recurrent ischemic events during hospitalization for stroke or

transient ischemic attack (TIA) with optimal current management and to identify associated risk factors.

MethodsWe performed a retrospective analysis of all patients treated for acute ischemic stroke or TIA in 3 stroke units

between 2010 and 2013. Recurrent stroke was defined as new persisting (24 hours) neurological deficit occurring >24

hours after the index event and not attributable to other causes of neurological deterioration. Cox proportional hazard

regression identified risk factors associated with recurrent stroke.

ResultsThe study included 5106 patients. During a median length of stay of 5 days (interquartile range, 48), stroke

recurrence (or stroke after TIA) occurred in 40 patients (0.8%) and was independently associated with history of TIA,symptomatic carotid stenosis (70%), or other determined etiology. Patients with recurrent stroke and other determined

etiology had cervical arterial dissection (n=2), primary angiitis of the central nervous system (n=1), giant cell arteritis

(n=1), and lung cancer with nonbacterial thrombotic endocarditis (n=1). In patients with initial TIA or minor stroke

(National Institutes of Health Stroke Scale 5) recurrence was associated additionally with pneumonia after the inciting

ischemic event but before stroke recurrence. Patients with initial stroke and aphasia had a lower stroke recurrence rate and

there were no recurrences in patients with lacunar stroke. Recurrence was associated with significantly higher in-hospital

mortality (17.5% versus 3.1%; P

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2 Stroke April 2015

Methods

Study Population and Data AcquisitionWe performed a retrospective analysis of data from all patients treatedbetween January 2010 and June 2013 for acute (onset of symptoms3 days) ischemic stroke or TIA in 3 certified stroke units (CampusBenjamin Franklin, Campus Virchow, and Campus Mitte) of our tertiarycare center (Department of Neurology, Charit, Berlin). Data were de-

rived from the data collection mandated for quality assurance as part ofthe Berlin Stroke Register.6This predefined data set has been describedelsewhere and includes stroke recurrence during hospital stay as com-plication of an index TIA or stroke (further information on the BerlinStroke Register is available in the online-only Data Supplement).7

Diagnosis of the index ischemic stroke was confirmed by the at-tending neurologist according to the World Health Organization defi-nition and was based on history, clinical presentation, and findingsin neuroimaging (computed tomography [CT] or magnetic resonanceimaging [MRI]).8TIA was diagnosed using the time-based definition(symptoms lasting 24 hours) neurological deficit,

2. onset of the new neurological deficit >24 hours after the indexevent, and

3. not because of other systemic or neurological causes.

New ischemic events in the same vascular territory as the first eventwere considered as recurrent stroke when they were clearly associatedwith new neurological symptoms. Progressive or worsening strokeand neurological deterioration because of other causes such as hemor-rhage, brain edema, seizure, pneumonia, sepsis, heart failure, and re-spiratory failure were not considered to be stroke recurrence. Patientswith recurrent stroke as a complication of endovascular thrombectomyor carotid endarterectomy (CEA) were not included in the main analy-sis. Patients who had been recently discharged from our or anotherhospital after a first TIA or stroke and presented in our emergencydepartment because of a new stroke were not included in the analysis.

To ascertain the completeness of recurrent strokes, we addition-ally used a computer program based on clinical domain ontologies,

semantic search algorithms (including synonyms and syntactic

variants), and recognition of negated and coordinated phrases (seeMethods in the online-only Data Supplement for specifications).12

To perform sensitivity analyses, we developed a clinical- and imag-ing-based definition of stroke recurrence which required verificationof each initial and recurrent stroke in repeated neuroimaging (CT or

MRI) apposite to the respective neurological symptoms. In this strictimaging-assisted definition, only clinically silent strokes verified in

neuroimaging were not considered to be recurrences.13 Similarly,growth of the infarcted area was not considered as proof of new in-farction. Additional analyses were conducted in patients with initialsymptoms lasting for >24 hours and in patients with initial symp-

toms lasting 24 hours or minor stroke (defined as NIHSS 5 onadmission).

Data AnalysisThe MannWhitney Utest was used to test differences in continuousvariables. The 2 test was used for dichotomized variables in pro-

portions. Using a time to event approach, a Cox proportional hazardregression analysis was performed to calculate adjusted hazard ra-tios and corresponding 95% confidence intervals. Variables were in-

cluded in the multiple model if univariate comparisons suggested an

association with P

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Erdur et al In-Hospital Stroke Recurrence 3

79.9% with blood pressurelowering agents, 81.8% with

statins, 27.6% with anticoagulants, and 16.9% received

thrombolytic therapy. CEA or carotid angioplasty and stent-

ing (CAS) within 14 days was performed in 77.3% of patients

with stroke attributable to severe carotid disease and eligible

for CEA or CAS. There were no significant differences ofmeasures of process of care in patients with and without

stroke recurrence.

Frequency and Risk Factors of Recurrent Stroke

Forty patients (0.8%) had a recurrent stroke during hospi-

talization. In univariate analysis, the frequency of recurrent

stroke was significantly higher in patients with a previous

TIA, severe ICA stenosis, other determined etiology of the

index event, or pneumonia acquired in the hospital after the

inciting ischemic event but before the recurrent stroke. Other

determined etiology included dissection (n=2), primary angi-

itis of the central nervous system (n=1), giant cell arteritis

(n=1), and nonbacterial thrombotic endocarditis in a patient

with lung cancer (n=1). None of the patients with initial TIA

or stroke attributable to small vessel disease had a recurrent

stroke. Of 148 patients with stroke attributable to severe ICA

stenosis, 6 had an early recurrent stroke. Of these 6 patients,

3 were not eligible for CEA/CAS because of major stroke,

medical condition, pre-existing disability, or occlusion of theICA in the meantime. In the remaining 3 patients stroke recur-

rence occurred before scheduled CEA/CAS (stroke recurrence

occurred on days 2, 3, and 5, respectively).

In-hospital mortality was significantly higher in patients

with stroke recurrence than in patients without recurrence

(17.5% versus 3.1%; P

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4 Stroke April 2015

was no significant interaction of sex, age, or early (48

hours) antithrombotic therapy with the risk factors of the

final model (Table II in the online-only Data Supplement)

nor was there significant interaction of symptomatic carotid

stenosis with CEA/CAS when both were included in the

Cox regression model as interaction terms (Pinteraction

=0.54).

For 4214 observations and 40 events with the final model,

Nagelkerke R2 (using bootstrap) was 0.33 (95% confidence

interval, 0.150.63).

Additional AnalysesTo assess the robustness of our findings, we performed

sensitivity analyses (multiple Cox proportional hazard

regression models) with subgroups of our total cohort. The

subgroups comprised (a) patients with initial symptom

duration of 24 hours, (b) with initial symptom duration

of 24 hours and additional verification of each initial and

recurrent stroke in neuroimaging, (c) patients with initial

TIA or minor stroke, and (d) all 85 patients with recurrent

stroke (including those who did not fulfill our strict criteria

for stroke recurrence).

History of TIA, severe ICA stenosis, and other determined

etiology were significantly associated with stroke recurrence

in every subgroup. In patients with initial symptom dura-

tion of 24 hours (subgroup a), the presence of aphasia on

initial presentation was additionally significantly associated

with freedom from stroke recurrence. In patients with initial

TIA/minor stroke (subgroup c) pneumonia after the inciting

ischemic event was significantly associated with stroke recur-

rence, whereas aphasia on admission was not. Of note, apha-

sia had been transient or of minor severity in the majority of

these patients (NIHSS on admission 5). When all patients

with recurrent stroke (including those who did not fulfill our

strict criteria; subgroup d) were included, both aphasia and

pneumonia were additionally associated with stroke recur-

rence. Unadjusted and adjusted hazard ratios for all sub-

groups are detailed in Tables III to VI in the online-only Data

Supplement.

Table 3. Cox Proportional-Hazard Analysis: Unadjusted and Adjusted Hazard Ratios for In-Hospital Recurrent Stroke in All Patients(n=5106)

Unadjusted Hazard Ratio

(95% CI) PValue Adjusted Hazard Ratio (95% CI) PValue

History of TIA 3.80 (1.808.00)

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DiscussionIn-Hospital stroke recurrence was rare (0.8%) in our cohort

of patients with acute ischemic stroke or TIA. History of

TIA, symptomatic stenosis (70%) of the ICA, and other

determined etiology were consistently associated with

higher early stroke recurrence in the total cohort and in all

sensitivity analyses. As a novel finding, pneumonia afterthe first ischemic event but before the recurrent stroke was

associated with a higher risk of stroke recurrence in patients

with initial TIA or minor stroke. The rate of in-hospital

mortality was high (17.5%) in patients with stroke recur-

rence, emphasizing the impact of early recurrence. Of note,

in the group of patients with initial symptom duration of

>24 hours, aphasia was associated with a lower recurrence

rate, suggesting that clinical symptoms at presentation may

conceal new deficits.

In older studies reporting risk of stroke recurrence within 7

days, rates range from 1.0% to 6.2%.1,1522The comparison of

reported recurrence rates is partly hampered by different defi-

nitions of stroke recurrence, patient populations, and time andfrequency of secondary prevention measures.11,23The low rate

of stroke recurrence in our cohort may be attributable to our

strict definition of stroke recurrence and the high frequency

of early secondary prevention measures in our stroke unit.

These include mainly antithrombotic therapy, anticoagula-

tion, statins, blood pressurelowering agents, and early refer-

ral to endarterectomy in patients with symptomatic stenosis of

the ICA, respectively. As has been shown in the Early use of

Existing Preventive Strategies for Stroke (EXPRESS) study,

these measures can result in an 80% reduction of risk of stroke

recurrence.24

Although the frequency of stroke recurrence was low in ourstudy, we were able to identify several risk factors associated

with stroke recurrence. Our results confirmed the well-known

higher risk of early recurrent stroke in patients with severe

ICA stenosis and history of TIA.2,3,18 Severe ICA stenosis

was associated with early stroke recurrence although a large

proportion of eligible patients (77%) underwent early CEA/

CAS in our cohort. Patients with recurrent stroke attributable

to severe ICA stenosis were either not eligible for CEA/CAS

(because of major stroke, pre-existing disability, or occlusion

of the ICA in the meantime) or recurrence occurred early

before scheduled CEA/CAS.

The higher risk of patients with stroke attributable to other

determined etiology has been described by Ay et al1 andArsava et al.15In our cohort, the other causes in patients with

recurrent stroke were arterial dissection, primary angiitis of

the central nervous system, giant cell arteritis, and nonbac-

terial thrombotic endocarditis in a patient with lung cancer.

Although rare, these conditions pose an imminent risk of

stroke and stroke recurrence for patients, and early diagno-

sis may lead to subsequent-specific secondary prevention

measures. Furthermore, our results confirm that patients with

stroke attributable to small vessel disease have a low risk of

early stroke recurrence.18This finding may indicate that stroke

because of small vessel disease is the result of a more chronic

focal pathophysiology and therefore unlikely to recur at a dif-ferent site in the short term.

Of note, aphasia was associated with a lower recurrence rate

in patients with symptoms lasting >24 hours. Aphasic patients

may not be able to report new neurological deficits. Attending

physicians must be highly vigilant on stroke recurrence. Sacco

et al25already noticed in 1989 that stroke recurrence may be

concealed by the type of initial clinical presentation. Aphasia,

neuropsychological disorders, and disorders of conscious-

ness may impair the ability of the patient to cooperate in the

neurological examination and thus veil the onset of new neu-

rological deficits. Therefore, stroke recurrence may remain

undetected and the true incidence is probably higher in these

patients.

Interestingly, pneumonia acquired in the hospital after the

first ischemic event but before recurrent stroke was associated

with a higher risk of stroke recurrence in patients with TIA or

minor stroke but not in the overall population studied. Patients

with a first stroke are at higher risk to develop pneumonia as

a complication early after the index event.26 It has also been

shown that acute lower respiratory tract infection is a risk fac-

tor for the first occurrence of stroke or myocardial infarction,especially within the first days after infection.27,28Infection may

promote a higher risk of stroke by inducing hypercoagulability,

platelet activation, and impairing endothelial function.29,30Our

results indicate that pneumonia may raise the risk not only for

first occurrence of a stroke but also for early recurrence. This

association was seen in patients with TIA or minor stroke only.

New neurological symptoms may not be noticed as often in

severely affected patients as they are in patients with TIA or

minor stroke. Pneumonia itself, which is often accompanied by

impaired vigilance and a poor general condition, may veil new

neurological deficits. However, in patients with TIA or minor

stroke, new neurological deficits may often be noticed despite

pneumonia because the initial neurological symptoms have

remitted or are not severe. On the contrary, the veiling effect

of pneumonia may be more pronounced in severely affected

patients. Therefore, the true rate of stroke recurrence in patients

with moderate to severe stroke and concomitant pneumonia

may be higher. However, the association of pneumonia with

early stroke recurrence has to be confirmed by further research,

as the number of patients with TIA/minor stroke, pneumonia,

and stroke recurrence was small.

As we have shown previously in a smaller cohort, follow-up

neuroimaging with MRI within the first week after the index

stroke revealed an incidence of new apparently clinically silent

DWI lesions which was higher than the incidence of new clini-cally manifest strokes (26%).13New DWI lesions were associ-

ated with symptomatic carotid stenosis, vessel recanalization,

and multiple lesion pattern in the initial MRI.13Presumably,

the risk factors associated with early new clinically silent DWI

lesions are similar to those associated with early new clini-

cally manifest strokes. In line with this, our present study adds

complementary data confirming the higher risk of symptom-

atic carotid stenosis for early new clinically manifest strokes.

Furthermore, we provide additional data on further clinical

characteristics (history of TIA, other determined etiology,

and pneumonia) associated with early stroke recurrence. The

higher incidence of early clinically manifest recurrent strokesin our previous investigation (2%) may be explained mainly

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6 Stroke April 2015

by the different definition of stroke recurrence used in our pre-

vious study, which did not exclude patients with a temporal

deterioration, whereas our present study required a persisting

(>24 hours) new deficit.

This study has several strengths and limitations. Strengths

of our study include the large cohort of patients with stan-

dardized assessment of numerous risk factors, comorbidities,

clinical presentation, and therapeutic interventions. The main

baseline characteristics and therapeutic interventions of our

cohort are representative for an urban area.10High frequency

of (repeated) neuroimaging with CT and MRI has allowed

confirmation of brain infarction in a high number of patients.

This in turn has allowed additional usage of a more finely

tuned definition of stroke recurrence. We have been able to

exclude clinical deterioration attributable to intracranial hem-

orrhage, infarct growth, or to other systemic or neurological

causes. Confining our analysis to patients with the imaging

definition of recurrent stroke has not changed our main results.

The main limitation of our study is the retrospective design.

As the length of stay in our cohort was short, our results areconfined to the early phase after the inciting event. The distri-

bution of specific etiologies in the other etiology category may

be different in non-European cohorts, for example, the rate

of stroke attributable to Moyamoya disease is higher in Asian

populations than in European populations.31Furthermore, the

stroke recurrence risk may be different for specific etiologies

in the other etiology category. The heterogeneity of this group

and the overall low number of recurrent events did not allow

a comparison of specific etiologies. We may have missed

potential confounders. Specifically, we were not able to assess

pattern of infarction in neuroimaging.1,32 The diagnosis of

pneumonia relied on the clinical judgment of the treating phy-

sicians and there was no strict application of standardized cri-teria such as the Centers for Disease Control and Prevention

criteria for the diagnosis of clinically defined pneumonia.

Nevertheless, the rate of pneumonia in our cohort was similar

to reports in previous large studies,22,33thus making a signifi-

cant proportion of incorrect diagnoses improbable.10The low

number of primary end points is a limitation from a statistical

viewpoint. However, our main results were robust findings in

5 different analyses.

ConclusionsIn-Hospital stroke recurrence was low. This may be attributed

to specialized stroke unit care with early assessment of etiol-

ogy of the index event and high frequency of early specific

secondary prevention measures. Patients with previous TIAs,

severe ICA stenosis, other determined etiology, and patients

with TIA/minor stroke and pneumonia are at higher risk. This

should prompt special efforts.

AcknowledgmentsWe would like to thank Catherine Aubel for language revision andediting of the article.

DisclosuresDr Endres receives funding from the Deutsche Forschungsgemein-

schaft (DFG, M.E. receives funding from the DFG (Excellence clus-ter NeuroCure; SFB TR43, KFO 247, KFO 213), Bundesministerium

fr Bildung und Forschung (BMBF, Centre for Stroke ResearchBerlin), European Union (European Stroke Network, Wake-Up,

Counterstroke), Volkswagen Foundation (Lichtenberg Program);

has participated in advisory board meetings of Bayer, Boehringer

Ingelheim (BI), Bristol-Myers Squibb (BMS), MSD, Pfizer, and

Sanofi; and has received honoraria from Astra Zeneca, Bayer, BI,

Boston Scientific, BMS, Ever, Glaxo Smith Kline, MSD, Novartis,

Pfizer, Sanofi. Dr Nolte has served as a consultant for BMS and has

received speaker honoraria from BI, Pfizer, and Takeda Pharma. Theother authors report no conflicts.

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Peter M. Rothwell, Matthias Endres and Christian H. NolteHebun Erdur, Jan F. Scheitz, Martin Ebinger, Andrea Rocco, Ulrike Grittner, Andreas Meisel,

and Risk FactorsIn-Hospital Stroke Recurrence and Stroke After Transient Ischemic Attack: Frequency

Print ISSN: 0039-2499. Online ISSN: 1524-4628Copyright 2015 American Heart Association, Inc. All rights reserved.

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