1. Acute Ischemic Stroke Treatments Patrick J. Ward, PA-S

2. PICO Question When do the risks and benefits of new treatment options outweigh the FDA’s current recommendations of tissue plasminogen activator, for reducing mortality and severe long-term neurological deficits in male and female ischemic stroke patients of all ages?

3. United States and Europe Acute Ischemic Stroke –Third leading cause of death –Major source of severe long-term disability Need for continued research – to increase the number of patients treated – decrease long term disability and death.

4. 1996 - Food and Drug Administration (FDA) Approved the use of recombinant tissue plasminogen activator (rt-PA) Only during the three-hour time window from onset of symptoms based on the National Institute of Neurological Trials (NINDS). Large percentages of ischemic stroke patients do not fit within this time window. It is estimated that only 2% of ischemic stroke patients receive treatment.

5. 2003 Cochran Review Several randomized studies Including 5727 ischemic stroke patients Overall decrease in the number of patients dead or dependent in activities of daily living Approximate 5% increase in deaths from intracranial hemorrhage when comparing TPA to a placebo

6. European Cooperative Acute Ischemic Stroke Study, ECASS III 3 – 4.5 hour time window from onset of symptoms rt-PA (Alteplase) had significant favorable outcomes (52.4% vs 45.2%; OR,1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04) The best time window remains at 1.5 hours from onset of symptoms(odds ratio of 2.81).

7. Alteplase 3 – 4.5 Hour Window

8. Physiology Two types of Ischemic stroke tissue –Core tissue– unsalvageable infarct tissue –Penumbra tissue– ischemic tissue salvageable by reperfusion Without treatment penumbra tissue will continue to infarct

9. Ischemic Stroke

10. Imaging Studies – a clinical view MRI studies remain the best –No radiation –Large availability Puerfusion Weighted Imaging – Diffusion Weighted Imaging Mismatch (PWI-DWI) mismatch views the potential perfuseable tissue

11. PWI-DWI Mismatch

12. MRI Feasibility Study No delay to treatment when comparing door to needle times with CT imaging in 88% of the patients. MRI remains within the three hour time window (2%)

13. Other Penumbra Imaging Studies Advantages - Disadvantages

14. DIFUSE Study MRA-DWI mismatch Comparable to PWI-DWI Non-perfusion in the patients without the mismatch during the 3 – 6 hours time window from onset of symptoms Criteria the MRA-DWI mismatch needs validated, allowing further research to continue

15. Conclusion The TPA - three-hour window - beneficial but limits TPA use Small percentage of patients still experience severe intracranial hemorrhage and death Majority of patients do not meet the three hour time window to receive treatment Strive for treatment in and outside the three-hour window with tissue plasminogen activator Evidence of penumbra PWI-DWI imaging studies should be treated with TPA outside the three-hour time window Decrease the long-term disabilities and death associated with acute ischemic stroke.

16. Application Follow the current recommendations - three-hour window from onset of symptoms should be treated as prescribe by the FDA with TPA/ rt-PA (Alteplase). PWI-DWI imaging for all acute ischemic stroke patients as they arrive to the trauma center. TPA / rt-PA Alteplase treatment should prevail for selected patients based on the presence of penumbra tissue beyond the three-hour window. Further cohort studies are necessary for the evaluation of this data and continued research.

17. References Clark, W.M., Wissman, S., Albers, G.W., Jhamandas, J.H., Madden, K.P., Hamilton, S. (2009). Recombinant tissue- type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The Atlantis Study: a randomized control trial. The Journal of the American Medicine Association, 282(21),2019-26 Ebinger, M., De Silva, D., Christensen, S., Parsons, M., Markus, R., Donnan, G., & Davis, S. (2009). Imaging the penumbra – strategies to detect tissue at risk after ischemic stroke. Journal of Clinical Neuroscience, 16(2), 178- 87. Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., Larrue, V., Lees, KR., Medeghri, Z., Machnig, T., Schneider, D., von Kummer, R., Wahlgren, N., Toni, D., & ECASS Investigators. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New England Journal of Medicine, 359, 1317-29. Hakimelahi, R., & Gonzalez, R. (2009). Neuroimaging of ischemic stroke with CT and MRI: Advancing towards physiology-based diagnosis and therapy. Expert Review Cardiovascular Therapy, 7(1), 29-48. Kakuda, W., & Abo, M. (2008). Intravenous administration of a tissue plasminogen activator beyond 3 hours of the onset of acute ischemic stroke--MRI-based decision making. Brain Nerve, 60, 1173-80. Lansberg, M.G., Thijs, V.N., Bammer, R., Olivot, J.M., Marks, M.P., Wechsler, L.R., Kemp, S., & Albers, G.W. (2008). The MRA-DWI mismatch identifies patients with stroke who are likely to benefit from reperfusion. Stroke, 39, 2491- 6. Solling, C., Ashkanian, M., Hjort, N., Gyldensted, C., Andersoen, G., & Ostergaad, L. (2008). Feasibility and logistics of MRI before thrombolytic treatment. Acta Neurologica Scandinavica. (no pages referenced) Wardlaw, J.M., del Zoppo, G.J., Yamaguchi, T., & Berge, E. (2003). Thrombolysis for acute ischaemic stroke. Cochran Database of Systematic Reviews,Issue 4. CD000213.