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

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

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

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

5. 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

6. 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

7. ECASS III Randomized double blind – IV tPA v. placebo
821 pts 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 ( )
0.04
Sx Hem
2.4%
0.2%
9.85 ( )
0.008
Mortality
7.7%
8.4%
0.90 ( )
0.68
Hacke et al. NEJM 2008

8. 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

9. 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

10. 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

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

12. New Plasminogen Activators
TNK
Retevase
Desmoteplase

13. 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