Anticoagulation in Acute Ischemic Stroke

1. Anticoagulation in Acute Ischemic Stroke

2. TPA: Tissue Plasminogen Activator 1995: NINDS study of TPA administration Design: randomized, double blind placebo-controlled study. N=624 Dosing: 0.9mg/kg (10% bolus, 90% given over 60 minutes) Outcomes: At 12 months tpa patients were 30% more likely to have minimal or no disability. 1996: FDA approved TPA for acute stroke management. Additional Studies: ECASS I/II and Atlantis: Concluded the earlier the better (< 3hrs) and there is improved outcome if no significant infarct on CT.

3. TPA: Tissue Plasminogen Activator • Inclusion criteria: **Clinical diagnosis of stroke with measurable deficit. ** Time: < 3 hours (based on the last time patient was seen normal) ** Previously independent functional status.

4. TPA: Tissue Plasminogen Activator • Absolute Exclusion criteria **History: 1. CVA or head trauma 3 months prior 2. Cerebral Aneurysm or known AVM. 3. MI in the 3 months prior 4. Any history of intracranial hemorrhage **Clinical: 1. spontaneously clearing stroke symptoms 2. BP >185 or diastolic >110. **Labs: 1. Platelets <100,000 2. INR >1.7 on oral anticoagulants **Radiology:Evidence of multi-lobar infarction with >33% cerebral involvement or hemorrhage or mass on CT

5. TPA: Tissue Plasminogen Activator • Relative Exclusion criteria **History: 1. Major surgery <14 days prior 2. GI or GU bleeding <21 days prior 3. LP <7 days prior. 4. Arterial puncture at non-compressible site <7 day prior. **Labs: Glucose <50 or >400

6. Aspirin Therapy • Aspirin: Only therapy that has been evaluated with RCTs. • Aspirin therapy given within 48 hours of onset of acute ischemic stroke symptoms leads to a significant reduction in the risk of early stroke recurrence/mortality, and leads to improved long-term outcome (IST and CAST). • Recommended dose: Initial 325mg, thereafter 150mg -325mg/day. It may be used in assoc. with DVT prophylaxis. • Contraindications: Receiving TPA, IV heparin, or oral anticoagulants. • Alternatives: clopidogrel, ticlopidine, aggrenox.

7. IST ( International Stroke Trial) • Design: Unblinded, randomized control trial. • N= 19,435; 467 hospitals in 36 countries. • Treatment arms: 1. no treatment 2. ASA 300mg 3. heparin 5000 units SQ BID 4. Heparin 5000 U SQ BID + ASA 300mg 5. Heparin 12,500 U SQ BID + ASA 300mg 6. Heparin 12, 500U SQ

8. IST ( International Stroke Trial) • Conclusions regarding ASA therapy : >ASA led to significantly fewer recurrent ischemic stroke. >ASA led to decreased death and dependence at 6 months. >ASA was NOT associated with an excess of hemorrhagic strokes. • Combined analyst of the IST and CAST trial: Of 1000 patients, 9 deaths/recurrent stroke are prevented with ASA therapy in the first few weeks. 13 deaths/recurrent strokes are prevented at 6 months.

9. Full anticoagulation with IV heparin and LMWH. • Use is not recommended by AHA/ASA and ACCP due to limited evidence of efficacy and increased risk of bleeding complications. • No clinical trial has yet to adequately evaluate full dose-anticoagulation in acute stroke.

10. Resources: • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator foracute ischemic stroke. N Engl J Med 1995; 333:1581–1587. • International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet 1997; 349:1569–1581. • ACP medicine Dale and Federman et Al. 2007 2206-2212 • Anti-thrombotic and Thrombolytic Therapy for Ischemic Stroke: Chest 2001;119;300S-320S