1. Stroke : To Lyse or Not to Lyse ? Understand the Literature and Decide : What is best for your practice environment ?

2. General Considerations for Use of Thrombolytics for Stroke Most studies have shown increased mortality and / or morbidity in patients treated with thrombolytics compared to placebo Only the 1995 NINDS study allegedly showed benefit –Treated patients 12% more likely to have minimal or no disability at 3 months –NO improvement in mortality however –Follow-on studies from community hospitals show low enrollment and poorer outcomes than reported in this study at academic centers only

3. Why Has there Been Such a Push by the A.H.A. for Thrombolytic Treatment for Stroke ? Labeled as a "Class 1" recommendation Clinicians frustrated with lack of effective treatments for stroke Stroke is leading cause of long term disability in adults Companies producing thrombolytic agents stand to make a lot of money if this recommendation becomes more widespread

4. Features of the NINDS Study Reported in 1995 Conducted by the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group Randomized controlled trial Univ. of Cincinatti was lead center for study (8 academic centers enrolled patients) 624 patients enrolled from January 1991 to October 1994 in 2 part sequential study Alteplase (Activase, recombinant tPA) used in treatment arm at dose of 0.9 mg/kg (90 mg max.)

5. Inclusion Patient Selection Criteria for the NINDS Study Ischemic stroke with : –Clearly defined time of onset –Measureable deficit on the National Institutes of Health Stroke Scale (NIHSS) –No evidence of hemorrhage on CT scan Had to start to receive thrombolytic within 3 hours (180 minutes) since onset of Sx No anticoagulants or antiplatelet agents given for 24 hours after Rx

6. Exclusion Criteria for the NINDS r-tPA Study Prior stroke or head trauma within 3 months Major surgery within 14 days History of intracranial hemorrhage Rapidly improving or minor symptoms Symptoms suggestive of SAH GI or urinary tract hemorrhage within 21 days Arterial puncture at noncompressible site within 7 days Seizure at onset of stroke Anticaogulants or heparin within 48 hours High PTT, PT > 15 sec., Platelets< 100,000 Serum glucose 400 mg/dl BP > 185 systolic or > 110 diastolic, or "if aggressive Rx required to reduce BP to these limits"

7. Results of the NINDS r-tPA Study No significant differences in functional outcome in Part 1 of study (333 patients) Overall 3 month mortality 21 % in placebo and 17 % in tPA group (p=NS) In Part 2 patients treated in 91 to 180 minutes, improvement was 40% in placebo group and 35 % in tPA group NIHSS score was significantly different (favoring tPA) only in Part 2 patients treated within 90 minutes, and in the combined Parts 1 and 2 patients treated within 90 minutes, but not in other subgroups

8. Adverse Bleeding Results in the r-tPA Treated Patients in the NINDS Study Symptomatic intracranial hemorrhage occurred in 7 % of tPA and <1% of placebo patients in first 36 hours – 4 more tPA and 2 more placebo patients had symptomatic bleeds in next 3 months –61 % of patients with symptomatic bleeds died in 3 months "Serious" systemic bleeds occurred in 5 tPA patients and zero placebo patients Minor bleeding occurred in 23 % of tPA patients and 3 % of placebo patients

9. Precautions About Overextrapolation of the NINDS Study Results No improvement in overall mortality Only 12 % absolute (30% relative) improvement in function Results are from academic centers with strong interests in the study & dedicated stroke response teams Only applies to small % of total stroke patients Requires strict adherence to protocols

10. Interpretation of NIH Stroke Scale Numbers Scale range is from zero (normal) to max. of 42 Those with minor deficits (scale <4) are not candidates for thrombolysis –Exceptions may be severe aphasia (scale = 3), or hemianopsia (scale = 2 or 3) Those with severe deficits (scale > 22) are at increased risk for hemorrhage, & so are also not thrombolytic candidates

11. 3 Cautionary Studies Related to Use of Thrombolytics for Stroke Schriger et al. 1998: showed CT scans to physicians : –67% correct by emergency physicians, 83% correct by neurologists, 83% correct by radiologists –"Physicians in this study did not identify cerebral hemorrhage sufficiently to permit safe selection of candidates for thrombolytic therapy" Engelstein et al. 2000 –Set up NINDS criteria stroke protocol but had no eligible candidates for 3 years in a busy E.D. Katzan et al. 2000 –Only 1.8% of stroke patients received tPA –tPA group mortality was 15.7% versus 5.1% nontreated

12. Another Cautionary Study Use of TPA in acute stroke patients identified by Los Angeles paramedics Prospective, multicenter 3 year study Reported as abstract in AEM May 2001 Overall mortality was 15.4 % for TPA patients, and was 11.6% for non-TPA patients

13. Other Stroke Thrombolytic Trials With Worse Outcomes in the Thrombolytic Group ECASS-1 (1995, used tPA) ECASS-2 (1998, used tPA) MAST-I (1995, used streptokinase) MAST-E (1996, used streptokinase) ASK (1996, used streptokinase) ATLANTIS (1999, used tPA at 3 to 5 hours)

14. Study of Danaparoid Treatment of Acute Stroke Reported in JAMA 1998 TOAST Trial ("Trial of ORG 10172 in Acute Stroke Treatment") Used danaparoid (ORG 10172), a low molecular weight heparinoid, bolus then infusion for 7 days Randomized, double blind, placebo controlled trial Eligible if stroke Sx between 1 and 24 hours Enrollment of 1281 patients 1990 to 1996 No significant outcome improvement at 3 months 15 intracranial bleeds in ORG group versus 5 in placebo group

15. The PROACT 2 Study of Prourokinase for Stroke JAMA Dec. 1999 Prolyse in Acute Cerebral Thromboembolism trial (PROACT) for strokes < 6 hours symptom duration Used intraarterial prourokinase (Prolyse) for MCA clots 12,323 stroke patients screened & 474 (4%) had angiography, and 180 of these were randomized (121 to Rx group & 59 to control group) No difference in overall mortality Improved functional scores in treated patients Intracranial hemorrhage "with neurological deterioration" in 10% of treated & 2% of control patients

16. The STARS Study of tPA for Stroke JAMA March 2000 Standard Treatment with Alteplase to Reverse Stroke (STARS) 57 centers, 389 patients from 1997 to 1998 No control group Patients refusing tPA not reported Protocol violations in 32 % 3.3 % had symptomatic ICH, 8.2 % had asymptomatic ICH 35% had good outcome (Rankin score 0 to1) at 30 days

17. The STAT Study for Treatment of Stroke JAMA May 2000 Stroke Treatment with Ancrod (STAT) trial Used defibrinogenating agent Ancrod from Malaysian pit viper 72 hour infusion, begun within 3 hours of stroke onset Followup doses at 96 and 120 hours Mortality 25% in both treated & placebo groups Improved favorable functional status in Ancrod group (42 % versus 34 %) Symptomatic ICH 5 % vs. 2 %, asymptomatic ICH 19 % vs. 11 % (both higher in Ancrod group)

18. Neuroprotective Agents Reported Out as Not Effective for Stroke Barbiturates Selfotel Cerostat Tirilizad Lubeluzole Citocholine Aptiganel Gavestinel Several chelators & anti- oxidants still in trials

19. Follow-on Studies to the NINDS Trial Several studies have been reported reworking some of the NINDS trial data One indicated that there was minimal association of bleeding problems with mild ischemic abnormalities noted on the initial CT scan However this reworking of the NINDS data suffers from the same small subgroup numbers that affect the original study

20. Relevance to EMS Systems of the Controversy Over Stroke Management No need yet for designation of "Stroke Centers" with required EMS referral of cases Prehospital administration of thrombolytics not indicated Extended prehospital neuro exams not indicated (simple Cincinatti Prehospital Stroke Scale is most applicable)

21. Other Considerations If You Believe in the NINDS Report Most stroke patients are still not eligible Re-exam of the patient after they return from CT should always precede consideration of administration of TPA (their deficits may resolve or lessen enough to no longer benefit from thrombolysis) Don't forget to routinely screen "up front" for hypoglycemia, hypoxia, +/- carbon monoxide intoxication

22. My Beliefs Regarding the Thrombolytic Issue Thrombolysis for acute stroke is currently unproven and unsafe Thrombolysis for acute stroke should currently only be attempted in research centers and all treated patients reported More research needs to be done to find a truly effective treatment for this terrible clinical problem (such as testing other thrombolytic agents and other regimens)

23. To Lyse or Not to Lyse Summary The weight of literature meta-analysis is against thrombolytic treatment at this time If however you believe in the NINDS study, before undertaking thrombolytic treatment, you must make certain your facility has the resources to follow the same strict protocol Any cases you treat should be recorded and tracked More research on this is needed