Acute Stroke Therapy with IV Thrombolysis Lawrence R. Wechsler, M.D. Professor and Chair, Department of Neurology Director, UPMC Stroke Institute

Disclosures Consultant: Abbott Vascular, NMT, Ferrer Steering committee: ACT I, CLOSURE DSMB: DIAS 3 / 4, SAPPHIRE WW Scientific Advisory Board and Stockholder: Neurointerventional Therapeutics

INTRAVENOUS TPA - < 3 Hrs NINDS - Outcome at 90 days NEJM 1995

IV tPA Results Dichotomized outcome (NINDS) NNT 8 NNH 17 Non-dichotomized (Saver Arch Neurol 2004) NNT 3 NNH 30

Minutes Stroke Onset To Start of Treatment Time Is Brain: Effects of tPA vs Time 8 7 6 5 Favorable Outcome Odds Ratio 4 3 2 Benefit for rt-PA 1 No Benefit for rt-PA m 60 70 80 90 100 110 120 130 140 150 160 170 180 Minutes Stroke Onset To Start of Treatment Marler et. al., Stroke 1999;30:244

SITS- MOST Observational safety study of IV tPA within 3 hrs – mandated by EU with approval in 2002 6483 pts recruited from 285 sites in 14 countries Symptomatic hemorrhage * – 1.7% at 24 hr * PH2 and decrease in NIHSS 4 or more SITS-MOST Pooled RCT SICH – NINDS def 7.3% 8.6% Mortality at 90 days 11.3% 17.3% mRS < 2 at 90 days 54.8% 49% Wahlgren et al. Lancet 2007

ECASS III Randomized double blind – IV tPA v. placebo 821 pts 3 - 4.5 hrs after stroke; 130 sites in 19 countries Median time to treatment 3 hrs 59 min Primary outcome – mRS 0-1 at 90 days tPA Placebo Odds Ratio p Value Pts 418 403 Median NIHSS 9 10 mRS 0-1 52.4% 45.2% 1.34 (1.02-1.76) 0.04 Sx Hem 2.4% 0.2% 9.85 (1.26-77.32) 0.008 Mortality 7.7% 8.4% 0.90 (0.54-1.49) 0.68 Hacke et al. NEJM 2008

ECASS Exclusions Age > 80 Severe stroke - NIHSS > 25 or CT hypodensity > 1/3 MCA territory Oral anticoagulant treatment Combination of previous stroke and diabetes Glucose > 400

ECASS III – Good and Bad Good Per protocol results better than intent to treat Multiple endpoints statistically significant Rankin distribution favors treatment group Hemorrhages similar to < 3 hr tPA Bad Imbalance in baseline NIHSS favoring treatment Exclusions of old, severe, diabetics Outcomes in placebo group better than expected

Limitations of IV Therapy 40-50 % good outcomes Less effective for large artery occlusion Early reocclusion in 20 – 30% Contraindications such as recent surgery or invasive procedure Single modality treatment

Improving Outcomes IV + IA IV+ Mechanical Ultrasound with IV tPA Penumbra imaging Addition of antiplatelet therapy

New Plasminogen Activators TNK Retevase Desmoteplase

Summary IV tPA only FDA approved therapy for treatment of acute ischemic stroke Effective < 3 hrs and benefit to 4.5 hrs in selected patients Adherence to protocol important to achieve optimal results New plasminogen activators not yet proven