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Risks of Intracranial Hemorrhage among
Patients with Acute Ischemic Stroke
Receiving Warfarin and Treated with
Intravenous Tissue Plasminogen Activator
Ying Xian, MD, PhD; Li Liang, PhD; Eric E. Smith, MD, MPH; Lee
H. Schwamm, MD; Mathew J. Reeves, PhD; DaiWai M. Olson,
PhD, RN; Adrian F. Hernandez, MD, MHS; Gregg C. Fonarow,
MD; Eric D. Peterson, MD, MPH
Presenter Disclosure Information
Y Xian, L Liang, MJ Reeves: None
EE Smith: Unpaid volunteer for AHA GWTG, Advisory Board to Genentech (2010, <$10,000).
LH Schwamm: Dr Schwamm serves as chair of the American Heart Association (AHA) Get With The
Guidelines (GWTG) Steering Committee, is a consultant to the Massachusetts Department of Public
Health, and provided expert medical opinions in malpractice lawsuits regarding stroke treatment and
prevention.
DM Olson: Dr Olson reports in the past 2 years receiving no research support, consulting fees, or
speaking fees from pharmaceutical companies. He serves as a member of the Duke Clinical
Research Institute, which serves as the AHA GWTG data coordinating center.
AF Hernandez: Dr Hernandez receives research grant from Johnson & Johnson, Amylin, Proventys
and serves as a consultant to Corthera.
GC Fonarow: Dr Fonarow receives research support from the National Institutes of Health and
previously had served as a consultant to Pfizer, Merck, Schering Plough, Bristol Myers Squibb, and
Sanofi-Aventis; previously received speaker honoraria from Pfizer, Merck, Schering Plough, Bristol
Myers Squibb, and Sanofi-Aventis, and is an employee of the University of California, which holds a
patent on retriever devices for stroke.
ED Peterson: Dr Peterson receives research grant from Johnson & Johnson, Eli Lilly and serves as a
consultant to Boehringer Ingelheim, Johnson & Johnson, Medscape, Merck, Novartis, Ortho-McNeilJanssen, Pfizer, Westat, Cardiovascular Research Foundation, WebMD, and United Healthcare.
DISCLOSURE INFORMATION:
Background
• Intravenous tissue plasminogen activator
(IV tPA)
– The most effective medical treatment to improve
outcomes for acute ischemic stroke
• Symptomatic intracranial hemorrhage
(sICH)
– A potential life-threatening complication
– Incidence: 2.4-8.8% in clinical trials
Adams et al, 2007; del Zoppo et al, 2009
Safety of IV tPA in Patients on Warfarin
• High prevalence of warfarin use with
subtherapeutic INR among ischemic stroke patients
• The AHA/ASA stroke guidelines
– Patients not taking an oral anticoagulant
– If anticoagulant being taken, INR≤1.7
• Lack of safety data of IV tPA in warfarin patients
– Excluded from major tPA trials
– Few observational studies
u Small sample: <250 patients in total
u Inconsistent results: odds ratio from 0.29 to 14.7
Adams et al, 2007; Prabhakaran et al, 2010, Meretoja et al, 2010; Kim et al, 2010; Seet et al, 2011; Vergouwen et al, 2011
Objectives
• Aim 1: Determine whether warfarin-treated patients
were at an increased risk of sICH following IV tPA
for acute ischemic stroke.
• Aim 2: Examine the association between INR and
sICH in warfarin-treated patients.
• Aim 3: Estimate the percentage of warfarin-treated
patients in current clinical practice who were
otherwise eligible to receive tPA treatment, but did
not get treated
Methods
• Study population
– Get With The Guidelines-Stroke (GWTG) registry between April
2009-June 2011
u 1/4 of U.S. hospitals
u >30% all ischemic stroke cases in the U.S.
– 23,437 ischemic stroke patients treated with IV tPA (INR≤1.7)
– 1,803 (7.7%) on warfarin
• Variables of interest
– Warfarin treatment: patient taking warfarin within 7 days of the
index stroke admission
– Baseline INR: first measurement after presentation to the hospital
Outcome Measures
• Primary: symptomatic intracranial
hemorrhage
– Documented ICH by CT or MRI within 36 hours and the
treating physician’s notes indicating clinical deterioration,
due to hemorrhage
• Secondary endpoints
– Life-threatening or serious systemic hemorrhage within 36
hours
– Any tPA complications within 36 hours
– In-hospital mortality
Statistical Analysis
• Multivariable logistic regression model
accounting for within-hospital clustering
with GEE approach
– Bleeding model: age, gender, race, baseline National
Institutes of Health Stroke Scale (NIHSS), systolic blood
pressure, and blood glucose
– Mortality model: age, gender, arrival mode, medical history
of atrial fibrillation, coronary artery disease, prior stroke or
transient ischemic attack (TIA), diabetes mellitus,
dyslipidemia, and NIHSS
– Multiple imputation for 9.9% NIHSS missing data
Menon et al, 2012; Smith et al, 2010
Baseline Characteristics
Warfarin
(N=1,802)
No Warfarin
(N=21,635)
p value
77 (68-84)
71 (59-82)
<.001
Female,%
54.2
50.5
.003
Hx of atrial fibrillation,%
69.2
19.0
<.001
Hx of stroke/TIA,%
36.2
26.1
<.001
Hx of CAD/prior MI,%
37.1
27.8
<.001
Hx of heart failure,%
18.0
8.9
<.001
NIHSS, median (IQR)
14 (8-20)
11 (6-17)
<.001
1.20 (1.07-1.40)
1.00 (1.00-1.10)
<.001
148 (120-174)
145 (115-175)
0.28
53.6
54.9
0.20
Age, median (IQR)
INR, median (IQR)
Time from symptom onset to IV
tPA, median (IQR)
Teaching hospital,%
Aim 1. Warfarin and Outcomes
Endpoints
Warfarin
(N=1,802)
No Warfarin
(N=21,635)
Adjusted OR
(95% CI)
p
value
sICH,%
5.7
4.6
1.01 (0.82-1.25)
0.94
Life-threatening or
serious systemic
hemorrhage,%
0.9
0.9
0.78 (0.49-1.24)
0.29
Any t-PA
complications,%
10.6
8.4
1.09 (0.93-1.29)
0.30
In-hospital
mortality,%*
11.4
7.9
0.91 (0.79-1.13)
0.50
* Transfer-out excluded. N=1,772 for warfarin and 21,304 for no warfarin patients
Aim 1. Warfarin and sICH, Sensitivity Analysis
Main analysis
Age<75 years
Age 75 years
Male
Female
NIHSS 14
NIHSS>14
Adjustment for antiplatelet
Subgroup analysis INR 1.5-1.7
0.0
1.01 (0.82-1.25)
1.12 (0.77-1.62)
0.96 (0.74-1.25)
1.17 (0.87-1.59)
0.89 (0.66-1.19)
1.20 (0.86-1.69)
0.94 (0.70-1.26)
1.04 (0.84-1.29)
1.32 (0.85-2.04)
0.5
1.0
1.5
2.0
Adjusted OR and 95% CI
2.5
Aim 2. INR and sICH in Warfarin Patients (N=1,802)
Adjusted OR=1.10, 95% CI (1.00-1.20) for each 0.1
unit increase in INR, p=0.06
Aim 3. Eligible Warfarin Patients Not Receiving IV tPA
• 443,916 acute ischemic stroke patients in the GWTG-Stroke Registry Apr 2009-Jun 2011
• 25,762 taking warfarin with INR≤1.7
• 2,489 arrived within 2 hrs w/o contraindication (potentially eligible for 0-3 hr window)
• 1,065 arrived between 2-3.5 hrs w/o contraindication (3-4.5 hr window)
• 0-3 hr window: 32.1% (799) failed to receive IV tPA
• 3-4.5 hr window: 87.3% (930) failed to receive IV tPA
• Collectively, 48.6% (1,729/3,554) patients on warfarin who were otherwise eligible were
not treated with IV tPA
Limitations
• Retrospective observational analysis
• Potential treatment selection
• Lack of long-term outcomes
• Generalizability
Conclusions
• Use of IV tPA among warfarin-treated stroke
patients (INR≤1.7) is not associated with increased
risks of sICH
• While the risk of sICH increases marginally with
higher INR, these findings provide empirical
support of current AHA/ASA guidelines
• Substantial undertreatment among eligible warfarin
patients
Acknowledgement
•
•
•
•
Mentor: Eric Peterson
Coauthors: Li Liang, Eric Smith, Lee Schwamm, Mathew Reeves,
DaiWai Olson, Adrian Hernandez, Gregg Fonarow
American Heart Association Pharmaceutical Roundtable and David
and Stevie Spina
The Get With The Guidelines®–Stroke (GWTG-Stroke) program is
provided by the American Heart Association/American Stroke
Association. The GWTG-Stroke program is currently supported in
part by a charitable contribution from Janssen Pharmaceutical
Companies of Johnson & Johnson. GWTG-Stroke has been funded
in the past through support from Boeringher-Ingelheim, Merck,
Bristol-Myers Squib/Sanofi Pharmaceutical Partnership and the
AHA Pharmaceutical Roundtable.
16
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