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Risks of Intracranial Hemorrhage among Patients with Acute Ischemic Stroke Receiving Warfarin and Treated with Intravenous Tissue Plasminogen Activator.

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Presentation on theme: "Risks of Intracranial Hemorrhage among Patients with Acute Ischemic Stroke Receiving Warfarin and Treated with Intravenous Tissue Plasminogen Activator."— Presentation transcript:

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,% 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,% (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,% (0.93-1.29)0.30 In-hospital mortality,%* (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

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