Acute Stroke Care: the Nuts and Bolts of it. ECASS I and II ATLANTIS. Chris V. Fanale, MD Colorado Neurological Institute Swedish Medical Center

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1 Acute Stroke Care: the Nuts and Bolts of it Chris V. Fanale, MD Colorado Neurological Institute Swedish Medical Center ECASS I and II tpa for patients presenting <6hr from symptom onset Negative Studies Showed benefit if tpa at dose of 0.9mg/kg given to patients <3 hours from onset ATLANTIS protocol similar to NINDS trial using tpa in a 3- to 5-hour window Negative Study

2 tpa and the Era of Acute Stroke Treatment No disability, TPA advantage: P = ~30% RRR, ~12% ARR, NNT~8 (Symptomatic ICH 6.4% vs 0.6%) r-tpa 50% 16% 17% 17% Placebo 38% 23% 18% 21% No Disability Mod Disability Severe Disability Death Adapted from NEJM: 1995, 333: (Barthel Index Scores) Concerns About the NINDS Study Imbalance in baseline stroke severity between the two treatment groups biased the results in favor of tpa treatment Generalizability of results Community <> Academic centers Feasibility of treatment in specified time frame Risk of intracerebral hemorrhage Other thrombolytic trials negative Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic StrokeTreatment Trial Timothy John Ingall MB, BS, PhD; William Michael O Fallon, PhD; Kjell Asplund, MD, PhD; Lewis Robert Goldfrank, MD; Vicki S. Hertzberg, PhD; Thomas Arthur Louis, PhD; Teresa J. Hengy Christianson, BS Results A clinically important and statistically significant benefit of t-pa therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-pa treated patients. Conclusions These findings support the use of t-pa to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-pa trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-pa in acute ischemic stroke patients. (Stroke. 2004;35: )

3 Can Acute Stroke Treatment be Done Outside of a Trial? 3948 stroke patients in Cleveland Area 1.8% iv-tpa Treatment Rate 15.7% Symptomatic ICH Rate STARS Study Assess safety and clinical outcomes in patients treated with intravenous tpa for acute stroke in clinical practice 57 medical centers in the United States (24 academic and 33 community)

4 STARS Study Symptomatic ICH in 3.3% of the pts with protocol violations tpa for Stroke: Importance of the System of Care Many hospitals do not have the infrastructure or the organization required to treat patients with stroke as it should be treated today. Brain Attack Coalition, JAMA, 2000; 283: It has `become clear that the use of intravenous fibrinolytics requires well-developed systems in order to maximize benefit and to minimize risk. Policy statement on ACEP Website, 2005

5 Wall Street Journal, May, 2005 Stroke Victims Are Often Taken To Wrong Hospital Too often, stroke victims are taken to the closest hospital rather than one with the ability to treat stroke effectively. Far too many stroke victims, get inadequate care thanks to deficient medical training and outdated ambulance rules that don't send patients to the best stroke hospitals. "There are still very parochial interests by hospitals and physicians to keep patients locally even if they're not equipped to handle them. "Some hospitals are resisting losing stroke business," he says. "We have the same political crap as in most communities. Paramedics still take people to the local ER." Stroke experts aren't proposing that every hospital needs to specialize in stroke care but instead that in every population center there should be at least one that does. "Trauma patients go to trauma centers, not the nearest hospital," he says. "Stroke victims, too, require a real specialized sort of care." Colorado tpa Use in Ischemic Stroke* (Primary Diagnosis) Year N tpa Ischemic Strokes Treated with tpa % % % * Ischemic Stroke = ICD , ; tpa = ICD9 Proc Code 99.10

6 The Impetus for Stroke Centers Stroke is common and serious Approved, effective treatment since 1996 Improves odds of good outcome by 30% Treatment is underutilized < 3% receive stroke-reversing treatment Like trauma: stroke requires complex set of urgent actions, coordinated among many individuals *Recommendations for the Establishment of Primary Stroke Centers. JAMA 2000; 283: Re-engineering Stroke Care Elements of a Primary Stroke Center Acute Stroke Teams Center Director Educational Programs Emergency Department Emergency Medical Services Laboratory Services Neuroimaging Neurosurgical Services Organizational Support and Commitment Outcome and Quality Improvement Stroke Unit Written Care Protocols Recommendations for the Establishment of Primary Stroke Centers JAMA, June 21, 2000 Vol 283, Effect of SMC Stroke Center: Treatment of Ischemic Strokes w/ Lytics* Yes 2% Yes 25% No 98% No 75% *Includes all ischemic strokes in database, not just stroke alerts

7 Intra-arterial Therapy: PROACT II 180 patients within 6 hrs of AIS caused by angiographically proven occlusion of the MCA Intervention: Patients were randomized to receive 9 mg of IA r-prouk plus heparin (n = 121) or heparin only (n = 59). Primary outcome: modified Rankin score of 2 or less at 90 days The Results Recanalization Rates

8 Acute Stroke: Extending the Window? ECASS = European Cooperative Acute Stroke Study ECASS-3: 19 European countries Industry-sponsored double blind RCT 821 pts: alteplase (418), 0.9 mg/kg, max 90mg placebo (403) Inclusion Criteria yo Clinical dx of acute ischemic stroke Able to receive tx 3-4 (4.5) hrs after onset CT excludes ICH and major infarction Symptoms for >=30 min w/o significant improvement before treatment

9 Exclusion Criteria Intracranial hemorrhage Onset time unknown Minor or rapidly improving symptoms Severe stroke (NIHSS score >25) or >1/3 MCA on image Seizure at onset Stroke or serious head trauma within 3 months Combination of previous stroke and diabetes mellitus Heparin in 48 h, with elevated PTT Platelets < 100,000 Systolic >185, diastolic >110; or aggressive treatment to target Glucose <50 or > 400 Symptoms suggestive of SAH Oral anticoagulant treatment Major surgery or severe trauma in 3 months Other major disorders associated with an increased risk of bleeding Endpoints Primary Disability at 90 d, dichotomized: MR 0-1 vs 2-6 Secondary Global four neurologic/disability scores combined (MR, Barthel, NIHSS, GOS) Safety Death Symptomatic ICH Other serious adverse events Results Alteplase Placebo OR (CI) P-value Good OC-MR 52.4% 45.2% 1.34( ) 0.04 adjusted analysis* 1.42( ) 0.04 (*adjusted for NIHSS and time to treatment) Good OC-Global 1.28(1-1.65) <0.05 Any ICH 27.0% 17.6% 1.73( ) Sx ICH** 7.9% 3.5% 2.38( ) (**per NINDS def) Mortality 7.7% 8.4% 0.90 ( ) 0.68 Median time for the administration of alteplase was 3 hours 59 minutes *NNT = 14

10 3-Mo MR: NINDS and ECASS-3 NINDS ECASS-3 TPA (312) 39% 21% 23% 17% tpa (418) 52% 23% 17% 7% Plcbo (312) 26% 25% 27% 21% p (403) 45% 28% 19% 8% 0-1 (No Disability) 2-3 (Mod Disability) 4-5 (Severe Disability) 6 (Death) 0-1 (No Disability) 2-3 (Mod Disability) 4-5 (Severe Disability) 6 (Death) Comparison of Trials Initial NIHSS (Median) Time To Tx (min) SICH (%) DM (%) AFIB (%) NINDS (0-3hr) 14 N/A ATLANTIS (3-5hr) ECASS 3 (3-4.5hr) Conclusions intravenous alteplase given 3 to 4.5 hours (median, 3 hours 59 minutes) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of symptomatic intracranial hemorrhage than that reported previously among patients treated within 3 hours. Although our findings suggest that treatment with alteplase may be effective in patients who present 3 to 4.5 hours after the onset of stroke symptoms, patients should be treated with alteplase as early as possible to maximize the benefit. Having more time does not mean we Should be allowed to take more time.

11 Pooled Analysis of Major Trials Hacke, Lancet: 2004: 9411: % 80% 60% 40% 45.3% 0_60 min 38.1% 20% 0% 100% 80% 60% 40% 20% 0% 100% 13.7% 2.2% 0.7% 0.0% None IVs IVs_IAs IAs IVo IVo_IAs 58.7% 61_120 min 25.3% 10.7% 2.7% 2.7% 0.0% None IVs IVs_IAs IAs IVo IVo_IAs 80% # = 49 pts 60% 40% 20% 0% 100% 80% 60% 40% 50.0% 121_180 min 22.6% 12.9% 4.8% 6.5% 3.2% None IVs IVs_IAs IAs IVo IVo_IAs 47.1% 181_270 min 37.5% # = 6 pts 20% 0% 8.7% 5.8% 1.0% 0.0% None IVs IVs_IAs IAs IVo IVo_IAs Thoughts on the 3-4.5hr Window Milder strokes better? Case By Case Determination Use the Trial Criterion Stroke with Diabetes, Age>80, NIHSS>25 Trial was published 13 years after NINDS We have learned hopefully Family Consent Needed Still an Emergent Patient

12 Future Studies Further Studies may involve Functional Studies MR RESCUE DIAS-2: Negative EPITHET: Negative Intra-arterial Modalities Measuring Reperfusion/Racanalization Rates Treatment Paradigm: SMC Stroke Center 0-3hrs: iv-tpa; Standard of Care Options of IMS3 or TNK study For non-qualified lytic patients: 3CT perfusion mismatch for consideration of IA mechanical thrombectomy 3-4.5hrs: WRITTEN CONSENT NEEDED CT perfusion demonstrates either no perfusion defect or matched defect lean towards iv-tpa CT perfusion demonstrates mismatch lean towards IA treatment >4.5 and <8hrs: WRITTEN CONSENT NEEDED large vessel occlusion and mismatch of 3CT, offer IA (no lytics) Pooled Analysis of Major Trials Hacke, Lancet: 2004: 9411: