1. Disclosures: Maximo C. Kiok, M.D. Medical Director of Stroke Program Trinity Health System

2. Therapy Options for Acute Ischemic Stroke Trinity Stroke Nursing Symposium Feb 18, 2012 By Maximo C. Kiok, M.D.

3. Overview of Treatment Options IV thrombolytic therapy (0-3 hrs) IV thrombolytic therapy (3-4.5 hrs) IA thrombolytic therapy Endovascular mechanical thrombectomy (Merci, Penumbra, Solitaire, etc.) Balloon angioplasty with stenting Anti-platelet agents for non-thrombolytic Rx Anticoagulants for atrial fibrillation

4. IV Thrombolytic Therapy NINDS Stroke Trial (1995): 0-3 hrs window. – Benefit at 90 days – Risk of symptomatic cerebral hemorrhage within first 36 hours – Mortality Rate at 90 days – Exclusion criteria for administration of I.V. t-PA

5. References: Adams H P Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke 2007; 38:1655-1711. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.

6. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. No benefit found for IV t-PA. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS. Benefit found! The trial had two parts.

7. As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. BENEFIT of IV t-PA Treatment at 0-3 Hours

8. Risk of Symptomatic Intracerebral Hemorrhage (sICH) within 36 hours after the onset of stroke

9. Mortality Rate at 3 Months After Onset of Stroke

10. Exclusion criteria Historical Any past medical history of intracranial hemorrhage Stroke or head trauma in the previous 3 months Myocardial infarction in the previous 3 months Gastrointestinal or urinary tract bleeding in the previous 21 days Major surgery in the previous 14 days Arterial puncture at a noncompressible site in the previous 7 days The use of dabigatran within 48 hours prior to stroke onset is a relative contraindication

11. Exclusion criteria Clinical Symptoms of stroke suggestive of subarachnoid hemorrhage (such as severe headaches and nausea, vomiting, photophobia, nuchal rigidity or obtundation). Caution should be exercised in treating a patient with major deficits (NIHSS >22). Seizure at the onset of stroke is an exclusion if the residual impairments are due to postictal phenomenon; seizure is not an exclusion if the clinician is convinced that residual impairments are due to stroke and not to postictal phenomenon Spontaneously clearing stroke symptoms Only minor and isolated neurologic signs (NIHSS <4) Persistent blood pressure elevation (systolic ≥185 mmHg, diastolic ≥110 mmHg) Active bleeding or acute trauma (fracture) on examination

12. Exclusion criteria Laboratory Platelets <100,000/mm3* International normalized ratio (INR) >1.7 if on warfarin*; the use of dabigatran within 48 hours of stroke onset is a relative contraindication Serum glucose <50 mg/dL (<2.7 mmol/L) Elevated partial thromboplastin time (aPTT) if on heparin*

13. Exclusion criteria Head CT scan Evidence of hemorrhage Evidence of a multilobar infarction with hypodensity involving >33 percent of the cerebral hemisphere

14. PATIENT'S NAME ___________________________________ DATE & TIME OF ONSET___/___/____ ____:____:____ CATEGORYYESNOtPA EXCLUSION CRITERIA History of Present Illness Onset > 3 Hours Onset > 3 hours Age < 18 years Seizure Seizure at onset of stroke symptoms. Subarachnoid Hemorrhage Subarachnoid hemorrhage (severe HA, nausea/vomiting, neck stiffness, anisocoria, obtundation, retinal hemorrhage, high BP) Head Trauma Serious head trauma at onset of stroke. Past Medical History Pregnancy Pregnant <=48 hours Heparin/Enoxaparin within the last 48 hours and has elevated PTT. <= 7 days Arterial puncture at noncompressible site within the last 7 days. <=14 days Major surgery within the last 14 days. <= 21 days Hemorrhage in gastrointestinal or urinary tract within the last 21 days. <= 3 months Recent stroke or serious head trauma within the past 3 months. Any time in the past Intracranial hemorrhage

15. CT BRAIN Large middle cerebral artery (MCA) territory infarction (sulcal effacement or blurring of gray- white junction in greater than 1/3 of MCA territory), or shows hemorrhage or tumor. LABS PT is >15 seconds (or INR > 1.7) PTT is elevated and patient had been on heparin in the past 48 hours. Platelet count is <100,000/uL. Glucose 400 mg/dL. Troponin-I elevated Pregnancy Test (if female in child-bearing age) is positive. EKG ST-elevation or T-inversion BP Systolic blood pressure >185 mmHg. Diastolic blood pressure >110 mmHg. Neuro Exam NIH Stroke Scale score >22. Symptoms rapidly improving. NIHSS < 4 Note: If any of above criteria has "Yes", then patient is excluded from receiving IV t-pa. Signed: ________________________________ Name of Physician ________________________________

17. IV Thrombolytic Therapy European Cooperative Acute Stroke Study III (ECASS-III) 2008: 3-4.5 hrs window. – Benefit at 90 days – Risk of symptomatic cerebral hemorrhage within first 36 hours – Mortality Rate at 90 days – Additional exclusion criteria for administration of I.V. t- PA

18. References: Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317 (ECASS-III) Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945.

19. As compared with patients given placebo, patients treated with t-PA were 16 percent more likely to have minimal or no disability at three months on the assessment scales. Absolute improvement of 7.2% only. BENEFIT of IV t-PA Treatment at 3-4.5 Hours In the alteplase group, 52.4% had a favorable outcome (defined as a score of 0 or 1 on the modified Rankin scale), compared to the placebo group (45.2%), representing an absolute improvement of 7.2 percentage points (odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; relative risk, 1.16; 95% CI, 1.01 to 1.34; P=0.04).

20. Risk of Symptomatic Intracerebral Hemorrhage (sICH) within 36 hours after the onset of stroke There were more cases of intracranial hemorrhage in the alteplase group than in the placebo group (27.0% vs. 17.6%, P=0.001).

21. In the ECASS III protocol, symptomatic intracranial hemorrhage was defined as: 1.Any extravascular blood in the brain or within the cranium 2.Identified as the cause of any neurologic deterioration, and 3.With a magnitude of a.4 points or more in the NIHSS, or b.That led to death. Definition of Symptomatic Intracranial Hemorrhage

22. Mortality Rate at 3 Months After Onset of Stroke

23. Additional exclusion criteria for 3-4.5 hour use of IV tPA Historical Age >80 years History of both diabetes and previous stroke Current use of any anticoagulant (e.g. warfarin, enoxaparin) Clinical NIHSS >25

30. Thank you!