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Introduction to Biostatistics


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Introduction to Biostatistics

  1. 1. Acute Medical Stroke Therapy Gregory W. Albers, MD Professor of Neurology and Neurological Sciences Director, Stanford Stroke Center
  2. 2. Acute Medical Treatment of Stroke <ul><li>Restore Blood Flow </li></ul><ul><ul><li>Thrombolytics </li></ul></ul><ul><ul><li>Mechanical devices </li></ul></ul><ul><li> Stroke progression or recurrent thromboembolism </li></ul><ul><ul><li>Anticoagulants </li></ul></ul><ul><ul><li>Antiplatelet agents </li></ul></ul>
  3. 3. How would you treat this patient? <ul><li>If he presents at 2 hours? </li></ul><ul><li>If he presents at 5 hours? </li></ul>72 yo male with aphasia and right hemiparesis NIH =18
  4. 4. <ul><li>Size of ischemic core? </li></ul><ul><li>Size of penumbra? </li></ul><ul><li>Location of vessel occlusion? </li></ul>How would you treat this patient? 72 yo male with aphasia and right hemiparesis NIH =18
  5. 5. NINDS tPA Stroke Trial tPA tPA Placebo Placebo 31 20 9 8 20 1 NIHSS Excellent Recovery (%) Total Death Rate (%) Hemorrhage p < .05 New England Journal, 1995
  6. 6. Large Randomized Trials of IV tPA for Treatment of Acute Stroke <ul><li>Study N Dose Time Window </li></ul><ul><li>ECASS I 650 1.1 0 – 6 </li></ul><ul><li>NINDS 624 0.9 0 – 3 </li></ul><ul><li>ECASS II 800 0.9 0 – 6 </li></ul><ul><li>ATLANTIS A 142 0.9 0 – 6 </li></ul><ul><li>ATLANTIS B 619 0.9 3 – 5 </li></ul>
  7. 7. Pooled Analysis <ul><li>Odds Ratios for Favorable Outcome </li></ul><ul><li>Time Odds Ratio 95% (CI) Interval </li></ul><ul><li>0-90 2.8 1.8 - 4.5 </li></ul><ul><li>91-180 1.5 1.1 - 2.1 </li></ul><ul><li>181-270 1.4 1.1 - 1.9 </li></ul><ul><li>271-360 1.2 0.9 - 1.5 </li></ul>
  8. 8. NINDS tPA Trial Any EIC 194 (31) Loss of GWMD 164 (27) Presence of hypodensity 54 (9) Compression of CSF spaces 89 (14) Loss of GWMD >1/3 MCA 77 (13) Hypodensity >1/3 MCA 14 (2) Compression of CSF > 1/3 MCA 54 (9) Extent of EIC  1/3 MCA 84 (14)  1/3 MCA 110 (18) None 422 (69) Type of EIC, No. (%) Distribution of Early Ischemic Changes (EIC) on CT Scans at Baseline (N=616) Patel SC, et al. JAMA . 2001;286:2830-2838
  9. 9. Stroke Code <ul><li>Who is eligible for tPA? </li></ul><ul><li>What needs to be checked before starting the tPA infusion? </li></ul><ul><li>Common errors to avoid </li></ul>
  10. 10. Early Infarct Signs: Guidelines for Patients with Clearly Established Stroke Onset and Treatment Within 3 hrs <ul><li>tPA eligible </li></ul><ul><li>not predictive of an unfavorable response to tPA </li></ul><ul><li>insufficient data </li></ul><ul><li>withholding tPA recommended (Level C data ) </li></ul>Subtle early infarct signs (regardless of size) Extensive and clearly identifiable hypodensity (>1/3 MCA territory)
  11. 11. Stroke Code <ul><li>Who is eligible for tPA? </li></ul><ul><li>What needs to be checked before starting the tPA infusion? </li></ul><ul><li>Common errors to avoid </li></ul>
  12. 12. Stroke Code <ul><li>Nursing – if patient is found to have symptoms of a stroke </li></ul><ul><ul><li>Confirm symptoms with resource RN immediately </li></ul></ul><ul><ul><li>Resource RN calls primary team </li></ul></ul><ul><ul><li>Pt’s RN calls Page Operator to initiate Stroke Code </li></ul></ul><ul><ul><li>Then gather: </li></ul></ul><ul><ul><ul><li>Brief history </li></ul></ul></ul><ul><ul><ul><li>Reason for thinking patient had a stroke </li></ul></ul></ul><ul><ul><ul><li>Last time patient seen normal </li></ul></ul></ul><ul><ul><ul><li>Current vital signs </li></ul></ul></ul>
  13. 13. Stroke Code <ul><li>Neurology Resident – will be paged by page operator on stroke code pager with text message : “Stroke Code: Room xxxx” </li></ul><ul><li>Must respond to bedside within 5 minutes </li></ul><ul><li>If patient is thought to be having a stroke then: </li></ul><ul><ul><li>Activate Brain Attack Team (BAT) Code Immediately </li></ul></ul>
  14. 14. Stroke Code <ul><li>Brain Attack Team consists of: </li></ul><ul><ul><li>Critical Care Crisis RN </li></ul></ul><ul><ul><li>CT Tech </li></ul></ul><ul><ul><li>Transport </li></ul></ul><ul><ul><li>Nursing Supervisor </li></ul></ul><ul><ul><li>Stroke Fellow/Attending (specify) </li></ul></ul>
  15. 15. Stroke Code <ul><li>Neurology Resident </li></ul><ul><li>Carries “stroke code” pager </li></ul><ul><li>Responds to Stroke Code immediately </li></ul><ul><li>Determines if Brain Attack Team (BAT) needs to be activated </li></ul><ul><li>If yes: </li></ul><ul><ul><li>Orders labs </li></ul></ul><ul><ul><li>Orders CT or MRI </li></ul></ul><ul><ul><li>EKG if needed </li></ul></ul><ul><ul><li>NIHSS </li></ul></ul>
  16. 16. Stroke Code <ul><li>Stroke Fellow/Attending </li></ul><ul><li>CT or MRI scan evaluation </li></ul><ul><li>Determines if tPA criteria is met or if Neurosurgery/Neuroradiology needs to be consulted </li></ul><ul><li>Confirms NIHSS </li></ul><ul><li>Writes tPA orders if appropriate </li></ul><ul><li>Family communication and consent </li></ul>
  17. 17. How Often Should Full Dose Anticoagulation Be Used for Treatment of Acute Stroke? <ul><li>A. Often used for multiple stroke subtypes </li></ul><ul><li>B. Rarely used, except for cardioembolic </li></ul><ul><li>C. Rarely used for any stroke subtype </li></ul>
  18. 18. Guidelines for Anticoagulant Therapy <ul><li>Urgent administration of anticoagulants has not yet been associated with lessening the risk of early recurrent stroke or improving outcomes. Because it can increase the risk of brain hemorrhage, routine use cannot be recommended . </li></ul>American Heart Association, 2003
  19. 19. Guidelines for Anticoagulant Therapy <ul><li>Anticoagulants are not recommended for any subgroup of patients with acute stroke based on any presumed mechanism or location (e.g., cardioembolic, large vessel atherosclerotic, vertebrobasilar, or “progressing” stroke) because data are insufficient . </li></ul>American Academy of Neurology / AHA, 2003
  20. 20. Anticoagulation for Acute Stroke <ul><li>Heparin in Acute Stable Stroke (n=212) </li></ul><ul><li> Stroke progression Improvement </li></ul><ul><li>Placebo 20% 24% </li></ul><ul><li>Heparin 17% 27% </li></ul>Duke, Ann Int Med 1986
  21. 21. International Stroke Trial Recurrent Stroke Within 14 Days (N = 19,435)
  22. 22. Nadroparin (Fraxiparin) Stroke Studies
  23. 23. TOAST Study
  24. 24. TOAST Study
  25. 25. Treatment of Acute Cardioembolic Stroke
  26. 26. Recent Trial Results <ul><li>Trial Recurrent Stroke (%) </li></ul><ul><li>IST (AF subgroup) Heparin 2.8 </li></ul><ul><li>(N = 3169) No heparin 4.9 </li></ul><ul><li>TOAST (cardioembolism) Danaparoid 0 </li></ul><ul><li>(N = 266) Placebo 1.6 </li></ul><ul><li>HAEST (all with AF) Dalteparin 8.5 </li></ul><ul><li>(N = 449) Aspirin 7.5 </li></ul><ul><li>TAIST* HD Tinzaparin 3.3 </li></ul><ul><li>(N = 1484) LD Tinzaparin 4.7 </li></ul><ul><li>Aspirin 3.1 </li></ul>* no benefit in cardioembolism subgroup
  27. 27. <ul><li>Risk of Early Stroke Recurrence </li></ul><ul><li>Multiple recent emboli </li></ul><ul><li>Mechanical heart valve </li></ul><ul><li>Atrial fibrillation + high risk features </li></ul><ul><li>Established intra-cardiac thrombus </li></ul>Treatment of Acute Cardioembolic Stroke
  28. 28. <ul><li>Risk of Hemorrhagic Complications </li></ul><ul><li>Anticoagulation increases the risk of extracranial hemorrhage by about 2% </li></ul><ul><li>Spontaneous hemorrhagic transformation is common and usually asymptomatic </li></ul><ul><li>Anticoagulation increases the risk of symptomatic ICH by about 2% </li></ul>Treatment of Acute Cardioembolic Stroke
  29. 29. <ul><li>Risk Factors for Symptomatic ICH </li></ul><ul><li>Infarct size </li></ul><ul><li>Timing of reperfusion (12 - 48 hours) </li></ul><ul><li>Excesssive anticoagulation / tPA </li></ul><ul><li>Heparin bolus? </li></ul><ul><li>Severe hypertension? </li></ul>Treatment of Acute Cardioembolic Stroke
  30. 30. Aspirin for Treatment of Acute Stroke <ul><li>International Stroke Trial (IST, N = 19,435) </li></ul><ul><li>Chinese Acute Stroke Trial (CAST N = 21,106) </li></ul>
  31. 31. International Stroke Trial Recurrent Stroke Within 14 Days
  32. 32. International Stroke Trial
  33. 33. Guidelines for Aspirin Therapy <ul><li>Early aspirin therapy (160-325 mg/day) is recommended Grade 1A </li></ul><ul><li>Delay aspirin for at least 24 hours after tPA </li></ul><ul><li>Aspirin can be used safely in combination with low doses of subcutaneous heparin </li></ul>Acute Ischemic Stroke
  34. 34. Guidelines for Acute Stroke Therapy <ul><li>tPA is recommended for eligible patients within 3 hours of stroke onset Grade 1A </li></ul><ul><li>Aspirin is recommended for non-tPA eligible patients Grade 1A </li></ul><ul><li>Use of full-dose anticoagulation with intravenous, subcutaneous, or low molecular weight heparins or heparinoids should be avoided Grade 2B </li></ul>ACCP, 2004