Acute Stroke Therapy with IV Thrombolysis Lawrence R
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 n Steering committee: ACT I, CLOSURE n DSMB: DIAS 3 / 4, SAPPHIRE WW n Scientific Advisory Board and Stockholder: Neurointerventional Therapeutics n
INTRAVENOUS TPA - < 3 Hrs NINDS - Outcome at 90 days NEJM 1995
IV t. PA Results Dichotomized outcome (NINDS) u NNT 8 u NNH 17 n Non-dichotomized (Saver Arch Neurol 2004) u NNT 3 u NNH 30 n
Time Is Brain: Effects of t. PA vs Time Odds Ratio Favorable Outcome 8 7 6 5 4 3 2 1 0 Benefit for rt-PA No Benefit for rt-PA 60 70 80 90 m 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 n n n Observational safety study of IV t. PA 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 * PH 2 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% m. RS < 2 at 90 days 54. 8% 49% Wahlgren et al. Lancet 2007
ECASS III n n Randomized double blind – IV t. PA 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 – m. RS 0 -1 at 90 days t. PA Placebo 418 403 9 10 m. RS 0 -1 52. 4% Sx Hem Mortality Pts Median NIHSS Odds Ratio p Value 45. 2% 1. 34 (1. 02 -1. 76) 0. 04 2. 4% 0. 2% 9. 85 (1. 26 -77. 32) 0. 008 7. 7% 8. 4% 0. 90 (0. 54 -1. 49) 0. 68 Hacke et al. NEJM 2008
ECASS Exclusions Age > 80 n Severe stroke - NIHSS > 25 or CT hypodensity > 1/3 MCA territory n Oral anticoagulant treatment n Combination of previous stroke and diabetes n Glucose > 400 n
ECASS III – Good and Bad Good u Per protocol results better than intent to treat u Multiple endpoints statistically significant u Rankin distribution favors treatment group u Hemorrhages similar to < 3 hr t. PA n Bad u Imbalance in baseline NIHSS favoring treatment u Exclusions of old, severe, diabetics u Outcomes in placebo group better than expected n
Limitations of IV Therapy 40 -50 % good outcomes n Less effective for large artery occlusion n Early reocclusion in 20 – 30% n Contraindications such as recent surgery or invasive procedure n Single modality treatment n
Improving Outcomes IV + IA n IV+ Mechanical n Ultrasound with IV t. PA n Penumbra imaging n Addition of antiplatelet therapy n
New Plasminogen Activators TNK n Retevase n Desmoteplase n
Summary IV t. PA only FDA approved therapy for treatment of acute ischemic stroke n Effective < 3 hrs and benefit to 4. 5 hrs in selected patients n Adherence to protocol important to achieve optimal results n New plasminogen activators not yet proven n
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