Subtherapeutic warfarin is not associated with increased hemorrhage rates in ischemic strokes treated with tissue plasminogen activator.

Abstract

Concern exists that preadmission warfarin use may be associated with an increased risk of intracerebral hemorrhage in patients with ischemic stroke receiving intravenous tissue plasminogen activator, even in those with an international normalized ratio <1.7. However, evidence to date has been derived from a small single-center cohort of patients.
We used data from Phase 3 of the Registry of the Canadian Stroke Network. We compared the rates of post-tissue plasminogen activator hemorrhage, including any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and gastrointestinal hemorrhage in patients with and without preadmission warfarin use. For those receiving warfarin, we restricted the analysis to patients with an international normalized ratio <1.7 on presentation. Secondary outcomes included functional status and mortality. Multivariate analyses were performed to adjust for other prognostic factors.
Our cohort included 1739 patients with acute ischemic stroke treated with intravenous tissue plasminogen activator of whom 125 (7.2%) were receiving warfarin before admission and had an international normalized ratio <1.7. Preadmission warfarin use was not associated with any secondary intracerebral hemorrhage (OR, 1.2; 95% CI, 0.7 to 2.2), symptomatic intracerebral hemorrhage (OR, 1.1; 95% CI, 0.5 to 2.3), or gastrointestinal hemorrhage (OR, 1.1; 95% CI, 0.2 to 5.6). Multivariate analysis showed that preadmission warfarin use was independently associated with a reduced risk of poor functional outcome (OR, 0.6; 95 CI, 0.3 to 0.9), but not with in-hospital mortality (OR, 0.6; 95% CI, 0.3 to 1.0).
The results from the present study suggest that tissue plasminogen activator treatment appears to be safe in patients with acute ischemic stroke taking warfarin with an international normalized ratio <1.7 and may reduce the risk of poor functional outcome.

Full text

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Stamplecoski, Moira K. Kapral and Frank L. Silver
Mervyn D.I. Vergouwen, Leanne K. Casaubon, Richard H. Swartz, Jiming Fang, Melissa
Ischemic Strokes Treated With Tissue Plasminogen Activator
Subtherapeutic Warfarin Is Not Associated With Increased Hemorrhage Rates in
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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doi: 10.1161/STROKEAHA.110.599183
2011;42:1041-1045; originally published online February 24, 2011;
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Subtherapeutic Warfarin Is Not Associated With Increased
Hemorrhage Rates in Ischemic Strokes Treated With Tissue
Plasminogen Activator
Mervyn D.I. Vergouwen, MD, PhD; Leanne K. Casaubon, MD, MSc; Richard H. Swartz, MD, PhD;
Jiming Fang, PhD; Melissa Stamplecoski, BSc; Moira K. Kapral, MD, MSc; Frank L. Silver, MD; on
behalf of the Investigators of the Registry of the Canadian Stroke Network
Background and Purpose—Concern exists that preadmission warfarin use may be associated with an increased risk of
intracerebral hemorrhage in patients with ischemic stroke receiving intravenous tissue plasminogen activator, even in
those with an international normalized ratio ?1.7. However, evidence to date has been derived from a small
single-center cohort of patients.
Methods—We used data from Phase 3 of the Registry of the Canadian Stroke Network. We compared the rates of
post-tissue plasminogen activator hemorrhage, including any intracerebral hemorrhage, symptomatic intracerebral
hemorrhage, and gastrointestinal hemorrhage in patients with and without preadmission warfarin use. For those
receiving warfarin, we restricted the analysis to patients with an international normalized ratio ?1.7 on presentation.
Secondary outcomes included functional status and mortality. Multivariate analyses were performed to adjust for other
prognostic factors.
Results—Our cohort included 1739 patients with acute ischemic stroke treated with intravenous tissue plasminogen
activator of whom 125 (7.2%) were receiving warfarin before admission and had an international normalized ratio ?1.7.
Preadmission warfarin use was not associated with any secondary intracerebral hemorrhage (OR, 1.2; 95% CI, 0.7 to
2.2), symptomatic intracerebral hemorrhage (OR, 1.1; 95% CI, 0.5 to 2.3), or gastrointestinal hemorrhage (OR, 1.1; 95%
CI, 0.2 to 5.6). Multivariate analysis showed that preadmission warfarin use was independently associated with a
reduced risk of poor functional outcome (OR, 0.6; 95 CI, 0.3 to 0.9), but not with in-hospital mortality (OR, 0.6; 95%
CI, 0.3 to 1.0).
Conclusions—The results from the present study suggest that tissue plasminogen activator treatment appears to be safe in
patients with acute ischemic stroke taking warfarin with an international normalized ratio ?1.7 and may reduce the risk
of poor functional outcome. (Stroke. 2011;42:1041-1045.)
Key Words: cerebral infarct ? hemorrhage ? mortality ? outcome ? thrombolysis ? warfarin
T
mic stroke is secondary intracerebral hemorrhage. Because
patients using anticoagulant drugs may have an increased risk
of secondary hemorrhage, the National Institute of Neurolog-
ical Disorders and Stroke tPA study excluded patients who
were taking anticoagulants or who had received heparin
within the 48 hours preceding the onset of stroke and had an
elevated partial thromboplastin time as were those with
prothrombin times ?15 seconds.1All 3 European Coopera-
tive Acute Stroke Study trials excluded patients treated with
he most significant complication of intravenous tissue
plasminogen activator (tPA) in patients with acute ische-
warfarin irrespective of the international normalized ratio
(INR).2–4Nevertheless, current guidelines permit intravenous
tPA use in patients taking anticoagulant drugs when the INR
is ?1.7.5
Recently, it was suggested that there is a 10-fold increased
risk of symptomatic intracerebral hemorrhage (ICH) in pa-
tients on warfarin treated with intravenous tPA, even if the
INR is ?1.7.6This single-center study of a cohort of 107
tPA-treated patients included only 13 patients on warfarin
limiting its validity and generalizability. The aim of the
present study was to investigate the risk of secondary hem-
Received August 5, 2010; final revision received November 4, 2010; accepted November 5, 2010.
From the Department of Medicine, Division of Neurology (M.D.I.V., L.K.C., F.L.S.) and the Division of General Internal Medicine and Clinical
Epidemiology and Women’s Health Program (M.K.K.), University Health Network, University of Toronto, Toronto, Canada; the Department of
Experimental Vascular Medicine (M.D.I.V.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; the Division of
Neurology (R.H.S.), Sunnybrook Hospital, University of Toronto, Toronto, Canada; the Department of Health Policy, Management and Evaluation
(M.K.K.), University of Toronto, Toronto, Canada; the Institute for Clinical Evaluative Sciences (J.F., M.S., M.K.K., F.L.S.), Toronto, Canada; and the
Canadian Stroke Network (M.K.K., F.L.S.).
Correspondence Mervyn D.I. Vergouwen, MD, PhD, University of Toronto, Toronto Western Hospital, Department of Medicine, Division of
Neurology, 399 Bathurst Street, 5th Floor, West Wing, room 443, Toronto, Ontario M5T 2S8, Canada. E-mail m.d.vergouwen@amc.uva.nl
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.orgDOI: 10.1161/STROKEAHA.110.599183
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orrhage in a large, multicenter cohort of patients with acute
ischemic stroke on warfarin and treated with tPA. We
hypothesized that the risk of secondary intracerebral hemor-
rhage is not increased in patients who receive warfarin and
have an INR ?1.7.
Methods
We used data from Phase 3 of the Registry of the Canadian Stroke
Network (RCSN), which is a hospital-based registry of consecutive
patients presenting with acute stroke to 11 regional stroke hospitals
in Ontario and 1 hospital in Halifax, Nova Scotia, Canada.7,8
Approval for the RCSN was obtained from the Research and Ethics
Board at each of the participating centers. Patients in this registry
were identified prospectively and data were abstracted systematically
during their hospital stay and after hospital discharge by trained
research nurses using a standardized case report form and custom
electronic data entry software to increase data quality.7For the
current analysis, a research protocol with a statistical analysis plan
was developed and submitted to the RCSN Publication Committee
for approval. We identified all patients admitted to the hospital with
acute ischemic stroke who received treatment with intravenous tPA
between July 1, 2003, and March 31, 2008. Patients with missing
INR levels, an INR ?1.7, and those who received intra-arterial
treatment were excluded.
At baseline, the following variables were abstracted: age, gender,
atrial fibrillation, hypertension, diabetes mellitus, previous stroke,
preadmission antiplatelets use, preadmission warfarin use, INR level,
systolic and diastolic blood pressure, glucose level, National Insti-
tutes of Health Stroke Scale (NIHSS) score, and stroke onset (when
the patient was last known to be normal) to start of tPA infusion
time.
Primary outcomes were the incidence of any ICH, symptomatic
ICH, and gastrointestinal hemorrhage during hospitalization. Sec-
ondary outcomes were poor functional outcome (predefined as a
modified Rankin Scale score of 3 to 6) at discharge, death during
hospitalization, discharge home, and length of stay. Any ICH was
defined as the presence of any intracerebral hemorrhage on CT or
MRI within 36 hours of tPA administration, and symptomatic
ICH was defined as the presence of any ICH and documented
clinical evidence of neurological worsening within 36 hours of
tPA administration.
Statistical Analyses
All statistical analyses were performed using a commercially avail-
able software package (SAS Version 9.1.3 statistical software; SAS
Institute Inc, Cary, NC). Baseline characteristics were summarized
using descriptive statistics and comparisons were made between
patients with and without preadmission warfarin use. Categorical
variables were analyzed using the ?2test. A probability value ?0.05
was considered statistically significant. Mean values were presented
with SD and median values with interquartile range (IQR). No
comparisons were made when a cell value was ?5 to protect the
privacy of individuals in the database. A multivariate logistic
regression model was performed to investigate whether warfarin use
was independently associated with (1) any ICH; (2) symptomatic
ICH; (3) gastrointestinal hemorrhage; (4) poor functional outcome
(modified Rankin Scale 3 to 6); (5) death during hospitalization; and
(6) discharge home. Adjustments were made for age (as a continuous
variable), gender, NIHSS score (as a categorical variable, according
to previously described categories9), presence of atrial fibrillation,
and INR (as a categorical variable). For patients with missing NIHSS
scores (in 325 patients [18.7% of all patients]), we used a recently
described and validated formula to convert Canadian Neurological
Scale scores to NIHSS scores.10Results of multivariate logistic
regression analyses were presented as ORs with 95% CIs. In another
analysis, we compared the incidence of any ICH, symptomatic ICH,
and gastrointestinal ICH in patients on warfarin in 3 groups of
patients with an INR ?1.11, INR 1.11 to 1.40, and INR 1.41 to 1.70,
respectively.
Results
In total, 1739 patients were included. Baseline characteristics
are described in Table 1. The median age of the cohort was 75
years (IQR, 64 to 82), 48.7% of the patients were female, and
125 patients (7.2%) had preadmission warfarin use. Patients
using warfarin were older (P?0.0003), more often had atrial
fibrillation (P?0.0001) and hypertension (P?0.0004), higher
INR levels (P?0.0001), and more severe strokes (P?0.0002)
and less often had preadmission use of antiplatelets
(P?0.0001).
Although a trend was observed toward a higher incidence
of any ICH (P?0.054) in patients using warfarin, the inci-
dence of symptomatic ICH was similar in both groups
(P?0.29; Table 2). Also, the incidence of gastrointestinal
hemorrhage was similar in both groups (P?0.57). Regarding
the secondary outcomes, no differences were observed in the
incidence of poor functional outcome, mortality, and dis-
charge to home or rehabilitation institution (Table 2). Patients
with preadmission warfarin use had an increased length of
stay compared with patients who did not use warfarin on
admission (P?0.02).
In the multivariate analysis, warfarin use was not associ-
ated with either any ICH (OR, 1.2; 95% CI, 0.7 to 2.2; Figure
A), symptomatic ICH (OR, 1.1; 95% CI, 0.5 to 2.3), or
gastrointestinal hemorrhage (OR, 1.1; 95% CI, 0.2 to 5.6). In
the multivariate analysis, preadmission warfarin use was
independently associated with a decreased risk of poor
functional outcome (OR, 0.6; 95% CI, 0.3 to 0.9; Figure 1B),
but not with death (OR, 0.6; 95% CI, 0.3 to 1.0) and discharge
home (OR, 1.3; 95% CI, 0.8 to 2.2).
Of the warfarin-treated patients, 50 patients had an INR
?1.11, 58 patients an INR 1.11 to 1.40, and 17 patients an
INR of 1.41 to 1.70. In all 3 groups of patients in the INR
categories, median age was similar (P?0.78) and so was the
number of males (P?0.87). However, a trend was noted
toward more severe strokes in the group of patients with INR
1.41 to 1.70 (P?0.13). No difference was observed in the
incidence of any ICH (P?0.23), symptomatic ICH (P?0.67),
and gastrointestinal hemorrhage (P?0.85) among these 3
groups of patients. However, there were more deaths in the
groups of patients with INR levels 1.11 to 1.40 and INR 1.41
to 1.70 (P?0.03), but not more patients with poor functional
outcome (P?0.22).
Discussion
Our results suggest that tPA treatment is not associated with
an increased risk of secondary ICH or gastrointestinal hem-
orrhage in patients with acute ischemic stroke taking warfarin
with an INR ?1.7. Furthermore, the results of our multivar-
iate analysis showed that preadmission warfarin use is inde-
pendently associated with a decreased risk of poor functional
outcome.
Only 1 previous study has investigated the effect of
preadmission warfarin use in patients with acute ischemic
stroke treated with tPA.6In that study, only 13 of 107 patients
used warfarin. A 10-fold increased risk of symptomatic ICH
was observed in the group of patients on warfarin compared
with nonwarfarin users. In an exploratory logistic regression
model that adjusted for age, NIHSS score, atrial fibrillation,
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and initial INR, baseline warfarin use remained strongly
associated with symptomatic ICH. The authors did not report
multivariate analyses describing whether baseline warfarin
use was independently associated with functional outcome or
mortality. The authors concluded that their results should be
considered hypothesis-generating and that larger cohort stud-
ies are required for confirmation.
In our large multicenter cohort, we could not confirm the
previous observation that preadmission warfarin use was
associated with hemorrhagic complications after tPA. There-
fore, it suggests that tPA is safe in this group of patients with
an INR ?1.7. Furthermore, it was shown that preadmission
warfarin use might beneficially affect functional outcome
despite having more severe strokes on admission. Although
patients on warfarin in our study were older and had more
severe strokes on admission, multivariate analysis showed
reduced mortality and improved functional outcome in pa-
tients taking warfarin before receiving tPA. Other observa-
tional studies have demonstrated that the presence of warfa-
rin, even at subtherapeutic INR levels, will reduce the initial
stroke severity and improve the outcomes of patients with
ischemic stroke secondary to atrial fibrillation in comparison
to patients on no antithrombotic or on antiplatelet therapy
alone.11,12Another possible explanation is that warfarin
reduces the risk of reocclusion after tPA-induced recanaliza-
tion. Previous studies showed that reocclusion occurs in 20%
to 34% of patients receiving tPA.13,14Reocclusion may
account for two thirds of clinical deterioration after initial
improvement after tPA administration and is highly predic-
tive of poor functional outcome.13–15By preventing reocclu-
Table 1.Baseline Characteristics
Variable
All Patients
(N?1739)
No Preadmission
Warfarin Use
(N?1614)
Preadmission
Warfarin Use
(N?125)P
Age, years (median?IQR) (no.)
No. of females (n/N ?%?)
Atrial fibrillation (n/N ?%?)
Hypertension (n/N ?%?)
Diabetes mellitus (n/N ?%?)
Previous stroke (n/N ?%?)
Preadmission antiplatelets use (n/N ?%?)
INR on admission (median?IQR) (no.)
INR ?1.10 (n/N ?%?)
INR 1.11–1.40 (n/N ?%?)
INR 1.41–1.70 (n/N ?%?)
Systolic blood pressure on admission
(mean?SD) (no.)
Diastolic blood pressure on admission
(mean?SD) (no.)
Glucose level on admission (median ?IQR?) (no.)
NIHSS score on admission (median?IQR) (no.)
NIHSS 0–6 (n/N ?%?)
NIHSS 7–15 (n/N ?%?)
NIHSS ?16 (n/N ?%?)
Last seen normal time to start tPA treatment
in minutes (median?IQR) (no.N)
75 (64–82) (1739)
847/1739 (48.7)
458/1739 (26.3)
1155/1739 (66.4)
358/1739 (20.6)
286/1739 (16.4)
712/1739 (40.9)
(1.0–1.1) (1739)
1467/1739 (84.4)
252/1739 (14.5)
20/1739 (1.2)
157.8?28.9 (1733)
74 (64–82) (1614)
777/1614 (48.1)
357/1614 (22.1)
1054/1614 (65.3)
334/1614 (20.7)
259/1614 (16.0)
689/1614 (42.7)
1.0 (1.0–1.1) (1614)
1417/1614 (87.8)
194/1614 (12.0)
3/1614 (0.2)
157.8?28.7 (1608)
79 (72–84) (125)
70/125 (56.0)
101/125 (80.8)
101/125 (80.8)
24/125 (19.2)
27/125 (21.6)
23/125 (18.4)
1.2 (1.1–1.3) (125)
50/125 (40.0)
58/125 (46.4)
17/125 (13.6)
157.6?31.4 (125)
0.0003
0.09
?0.0001
0.0004
0.69
0.11
?0.0001
?0.0001
?0.0001
0.93
83.4?16.9 (1726)83.4?16.8 (1602)83.2?18.1 (124)0.88
6.8 (5.8–8.3) (1727)
12 (8–17) (1728)
276/1728 (16.0)
864/1728 (50)
588/1728 (34.0)
145 (120–175) (1738)
6.8 (5.8–8.3) (1604)
12 (8–17) (1603)
267/1603 (16.7)
803/1603 (50.1)
533/1603 (33.3)
146 (120–175) (1613)
6.8 (6.0–8.3) (123)
14 (10–18) (125)
9/125 (7.2)
61/125 (48.8)
55/125 (44.0)
145 (117–170) (125)
0.46
0.0002
0.005
0.50
Table 2.Outcome Characteristics
Variable
All Patients
(N?1739)
No Preadmission Warfarin Use
(N?1614)
Preadmission Warfarin Use
(N?125)P
Intracerebral hemorrhage
Any (n/N ?%?)
Symptomatic (n/N ?%?)
Gastrointestinal hemorrhage (n/N ?%?)
Poor functional outcome at discharge (n/N ?%?)
Mortality (n/N ?%?)
Discharge to home (n/N ?%?)
Length of stay in days (median?IQR) (no.)
200/1739 (11.5)
102/1739 (5.9)
19/1739 (1.1)
1195/1731 (69.0)
284/1739 (16.3)
537/1739 (30.9)
9 (5–18) (1738)
179/1614 (11.1)
92/1614 (5.7)
17/1614 (1.1)
1105/1608 (68.7)
260/1614 (16.1)
506/1614 (31.4)
8 (4–18) (1613)
21/125 (16.8)
10/125 (8.0)
2/125 (1.6)
90/123 (73.2)
24/125 (19.2)
31/125 (24.8)
12 (5–24)
0.054
0.29
0.57
0.30
0.37
0.13
0.02
Vergouwen et al Warfarin and Thrombolysis in Acute Ischemic Stroke
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sion, functional outcome after tPA might improve. An ongo-
ing multicenter placebo-controlled randomized trial is
currently underway to determine whether intravenous aspirin
further may improve clinical outcome in tPA-treated patients
with ischemic stroke by preventing reocclusion.16
Our study has some limitations. The results of our primary
analysis, in which the incidence of several types of hemor-
rhagic complications was analyzed, can be limited by ascer-
tainment and interobserver bias. Our data are collected by
chart review and only complications that are documented in
the chart are captured. To improve the reliability of the data,
all variables in the RCSN are predefined in the case record
form manual and the study nurses were all trained and
evaluated by completing standard test charts. Also, because
this was a retrospective analysis of prospectively collected
data, we were not able to systematically measure recanaliza-
tion rates to prove our hypothesis that preadmission warfarin
use may prevent reocclusion. Finally, the external validity of
our study is still in question. Little data were available on
those subjects that were screened and otherwise eligible but
rejected because their INR was too high. Only a randomized
controlled trial can answer the question if tPA treatment is
safe and effective in this group of patients.
In conclusion, the results from the present study suggest
that tPA treatment appears to be safe in patients with acute
ischemic stroke taking warfarin with an INR ?1.7. There is
no increased risk of bleeding, and there may even be a
reduced risk of poor functional outcome and mortality.
Therefore, tPA treatment should not be discouraged in the
group of patients taking warfarin with INR ?1.7.
Sources of Funding
This work was funded by an operating grant from the Canadian
Stroke Network. The Registry of the Canadian Stroke Network is
funded by an operating grant from the Ontario Ministry of Health
and Long-Term Care. The results and conclusions are those of the
authors and should not be attributed to any of the sponsoring or
funding agencies. The funding agencies had no role in the design or
conduct of the study or the collection, management, analysis,
or interpretation of the data. The article was reviewed and approved
by the publications committee of the Registry of the Canadian Stroke
Network. The Institute for Clinical Evaluative Sciences is supported
by an operating grant from the Ontario Ministry of Health and
Long-Term Care. M.D.I.V. is financially supported by an unre-
stricted grant from the Niels Stensen Foundation, The Netherlands.
M.K.K. is supported by a New Investigator Award from the
Canadian Institutes for Health Research (CIHR) as well as career
support from the Canadian Stroke Network and the University
Health Network Women’s Health Program. F.L.S. receives salary
support from the Canadian Stroke Network.
Disclosures
None.
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Abstract 7
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