1. Stroke: Year in Review 2007 South Carolina Society of Health-System Pharmacists Spring Symposium April D. Miller, PharmD South Carolina College of Pharmacy- USC Campus

2. True or False Warfarin therapy is generally contraindicated in atrial fibrillation patients greater than 75 years of age due to fall and bleeding risk

3. Which of the following agents can be used for DVT prophylaxis in patients with ischemic stroke? A: Enoxaparin B: Unfractionated heparin C: Fondaparinux D: Abciximab

4. Objectives Discuss new evidence for antiplatelet and anticoagulant therapy for stroke prevention Present evidence on the use of DVT prophylaxis in stroke patients Explain recent studies on non- pharmacologic issues in stroke care

5. Epidemiology of Stroke 3 rd leading cause of death in United States Approximately 550,000 cases per year Leading cause of disability National Vital Statistics Reports 2007

6. Disability Due to Stroke % of Stroke Survivors 31% 20% 71% Heart and Stroke Facts: 1996 Statistical Supplement

7. Antithrombotics and Primary Stroke Prevention Guidelines “Antithrombotic therapy (warfarin or aspirin) is recommended to prevent stroke in patients with non-valvular atrial fibrillation according to assessment of their absolute stroke risk, estimated bleeding risk, patient preferences, and access to high quality anticoagulation monitoring.” (Class I, Level A evidence) Stroke 2006;37:1583-1633

8. Majority of elderly patients do not receive warfarin therapy Study aim: Determine risk versus benefit of warfarin in an elderly population Lancet 2007;370:493-503

9. BAFTA Study design: prospective, randomized, open-label with blind endpoint assessment Primary objective is compare frequency: –Fatal and non-fatal hemorrhagic or ischemic stroke –Intracranial hemorrhage –Clinically significant arterial embolism Lancet 2007;370:493-503

10. BAFTA Patients –Inclusion criteria: Age > 75 (mean age 81.5 years) Atrial fibrillation diagnosed by ECG within 2 years –Exclusion criteria Rheumatic heart disease Major, non-traumatic hemorrhage or ICH within 5 years Peptic ulcer disease or esophageal varices BP > 180/110 Lancet 2007;370:493-503

11. BAFTA Interventions: Aspirin 75mg (n= 488) daily versus warfarin (n= 485) with target INR 2-3 x 5.5 years –Frequency or method of INR monitoring not altered by study Results: –Ischemic stroke: Warfarin 1.6% versus Aspirin 3.4% RR: 0.46, ARR: 1.8%, NNT: 56, P=0.003 –Major hemorrhage: Warfarin 1.9% versus Aspirin 2%, P=0.74 Lancet 2007;370:493-503

12. BAFTA Discussion: –Selection bias for low-risk stroke patients –Patients potentially at lower risk for bleeding Conclusion: –Warfarin is effective and safe for stroke prevention in elderly patients with atrial fibrillation Lancet 2007;370:493-503

13. Background: Up to 75% of patients with hemiplegia post-stroke develop DVT and 20% develop PE –Unfractionated Heparin and Low Molecular Weight Heparin (LMWH) are shown to be beneficial –Optimal agent unknown Lancet 2007;369:1347-55

14. PREVAIL: DVT Prophylaxis Study design: Prospective, randomized, open-label trial –Randomization stratified based on stroke severity (severe- NIHSS > 14, less severe NIHSS 14, less severe NIHSS < 14) Primary endpoint: cumulative occurrence of confirmed venous thromboembolism Secondary endpoints: ICH, thrombocytopenia, adverse events Lancet 2007;369:1347-55

15. PREVAIL: DVT Prophylaxis Interventions initiated within 48 hours of stroke symptoms and continued ~10days: –Enoxaparin 40mg SC daily (n=604) OR –Unfractionated heparin 5000 units SC q12h (n=609) Results –Frequency of VTE at day 14 Enoxaparin 10% versus UFH 18% P= 0.0001, RRR= 43%, ARR= 8%, NNT= 13 Lancet 2007;369:1347-55

16. PREVAIL: DVT Prophylaxis

17. Results –Bleeding at end of treatment + 48h Enoxaparin and UFH = 8% –Extracranial hemorrhage incidence slightly increased in enoxaparin group (1% n= 7 versus 0) Lancet 2007;369:1347-55

18. PREVAIL: DVT Prophylaxis Important considerations –95% of DVTs detected were asymptomatic and detected routine venography –Comparison with BID unfractionated heparin Conclusions –Enoxaparin more effective for DVT prophylaxis in ischemic stroke –Increased incidence of clinically significant bleeding with enoxaparin Lancet 2007;369:1347-55

19. NEJM 2007;357:2262-8

20. Pooled analysis of 3 prior studies (93 patients total) –DECIMAL –DESTINY –HAMLET Lancet Neurol 2007;6:215-22

21. Patient Outcomes Surgery Conservative Lancet Neurol 2007;6:215-22

22. Stroke 2008;39:30-35 Northern Manhattan Study Metabolic Syndrome and Ischemic Stroke Risk

23. Upcoming Studies FASTER: Fast Assessment of Stroke and TIA to prevent Early Recurence –Use of clopidogrel, aspirin and simvastatin to reduce subsequent stroke in patients presenting with TIA SELESTIAL: Trial of insulin to control blood sugar after acute stroke using MRI endpoints http://www.clinicaltrials.gov

24. Upcoming Studies PRoFESS: Prevention Regimen for Effectively avoiding Second Strokes –Aspirin/dipyridamole versus clopidogrel CLEAR stroke: Combined approach to Lysis utilizing eptifibatide and rt-TPA in acute ischemic stroke http://www.clinicaltrials.gov

25. True or False Warfarin therapy is generally contraindicated in atrial fibrillation patients greater than 75 years of age due to fall and bleeding risk

26. Which of the following agents can be used for DVT prophylaxis in patients with ischemic stroke? A: Enoxaparin B: Unfractionated Heparin C: Fondaparinux D: Abciximab

27. References Minino AM, Heron MP, Murphy SL, et al. Deaths: Final data for 2004. National Vital Statistics Reports; 55 (19). Hyattsville, MD: National Center for Health Statistics 2007. Heart and Stroke Facts: 1996 Statistical supplement. Dallas: American Heart Association 1996. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke. Stroke 2006;37:1583-1633. Mant J, Hobbs R, Fletcher K et al. Warfarin versus aspirin for stroke prevention with atrial fibrillation (BAFTA): a randomised controlled trial. Lancet 2007;370: 493-503 Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of VTE after acute ischemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55 Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Eng J Med 2007;357:2262-8 Vahedi K, Hofmejer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the MCA: a pooled analysis of three randomised trials. Lancet Neurol 2007;6:215-22. Boden-Albala B, Sacco RL, Lee HS. Metabolic syndrome and ischemic stroke risk. Stroke 2008;39:30-35

28. Stroke: Year in Review 2007 South Carolina Society of Health-System Pharmacists Spring Symposium April D. Miller, PharmD South Carolina College of Pharmacy- USC Campus