1. 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

2. Presenter Disclosure Information 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-McNeil- Janssen, Pfizer, Westat, Cardiovascular Research Foundation, WebMD, and United Healthcare.

3. 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

4. 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  Small sample: <250 patients in total  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

5. 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

6. Methods Study population –Get With The Guidelines-Stroke (GWTG) registry between April 2009-June 2011  1/4 of U.S. hospitals  >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

7. 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

8. 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

9. Baseline Characteristics Warfarin (N=1,802) No Warfarin (N=21,635) p value Age, median (IQR)77 (68-84)71 (59-82)<.001 Female,%54.250.5.003 Hx of atrial fibrillation,%69.219.0<.001 Hx of stroke/TIA,%36.226.1<.001 Hx of CAD/prior MI,%37.127.8<.001 Hx of heart failure,%18.08.9<.001 NIHSS, median (IQR)14 (8-20)11 (6-17)<.001 INR, median (IQR)1.20 (1.07-1.40)1.00 (1.00-1.10)<.001 Time from symptom onset to IV tPA, median (IQR) 148 (120-174)145 (115-175)0.28 Teaching hospital,%53.654.90.20

10. Aim 1. Warfarin and Outcomes EndpointsWarfarin (N=1,802) No Warfarin (N=21,635) Adjusted OR (95% CI) p value sICH,%5.74.61.01 (0.82-1.25)0.94 Life-threatening or serious systemic hemorrhage,% 0.9 0.78 (0.49-1.24)0.29 Any t-PA complications,% 10.68.41.09 (0.93-1.29)0.30 In-hospital mortality,%* 11.47.90.91 (0.79-1.13)0.50 * Transfer-out excluded. N=1,772 for warfarin and 21,304 for no warfarin patients

11. Aim 1. Warfarin and sICH, Sensitivity Analysis 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)

12. 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

13. Aim 3. Eligible Warfarin Patients Not Receiving IV tPA 443,916 acute ischemic stroke patients in the GWTG-Stroke Registry Apr 2009-Jun 201125,762 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

14. Limitations Retrospective observational analysis Potential treatment selection Lack of long-term outcomes Generalizability

15. 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

16. 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