1. Treating Acute Ischemic Stroke, Can We Open Up the Time Window？
David Wang, D.O.,FAHA, FAAN
Director, OSF/INI Stroke Network, CSC at OSF SFMC
Director, Stroke Fellowship
Clinical Professor of Neurology
UICOMP

2. Need to Understand This Graphic
Stages of impaired cerebral circulation
CBF indicates cerebral blood flow;
CBV, cerebral blood volume;
OEF, oxygen extraction fraction;
CMRO2, cerebral metabolic rate for oxygen;
CVR, cerebrovascular reserve. The stages are referenced to the changes in OEF.
Stage I, OEF is unchanged.
Stage II, OEF begins to increase. Whether the increase is linear is unknown.
Stage III, OEF declines again. Solid lines show changes that are known and dashed lines, those that are postulated.

3. Let Us Review the Concept of PENUMBRA

4. Persistent Penumbra?
Darby et al, 1999

5. IV tPA to all comers: Declining benefit over time.
Is It True？

6. Evidence-based Treatment Time Window for Acute Ischemic Stroke
< 3 hrs：
IV tPA 0.9mg/kg
3-4.5 hrs: IV tPA 0.9mg/kg+4contraindications, 0.6 mg/kg
< 6 hrs:
IV tPA 0.9 mg/kg + IA thrombectommy

7. Let us exam the treatment window of <4.5 hours first

8. IV tPA NNTB and NNTH within 3 hours and 3-4.5 hours
Saver et al Stroke 2009;40:
Number of Patients to be Benefited (NNTB) and or Harmed (NNTH) Per Patients Treated With Intravenous TPA in Different Time Windows
1–3 Hours –4.5 Hours
NINDS tPA Trials ECASS 3 Trial
Benefit per
Harm per
NNTB = 6.1
NNTH = 37.5 8

9. Treatment window of < 6 hours What can we do?

10. IV TPA plus IA Thrombectomy，<6 hour or <12 hour window

11. 7 bridging trials bring us these points
Patient selection is important and Use imaging to select pts
Treatment window <6hrs or <12 hrs
Treat FAST!
Control group: ALL had IV TPA
Treatment group: IV TPA+IA thrombectomy
IA thrombectomy used stent assisted clot retriever
Benefit: NNT: 1 in every 2-4 pts treated

12. Effectiveness of IV TPA+IA Thrombectomy Further Confirmed
Trials
90d mRS 0-2
Mortality
TICI 2b-3
Control IA
MR CLEAN
19%
33%
22％
21％
59%
ESCAPE
29%
53%
19％
10％
72%
EXTEND-IA
40%
71%
20％ 9％
86%
SWIFT PRIME
36%
60%
12％
88%
REVASCAT
28%
44%
16％
18％
66%
THERAPY
30.4%
38%
THRACE
42.1%
54.2%
13.1%
12.5%
EAST
28.6%
4.4%
8.3%
90.4%

13. Treated >5.5 hours in ESCAPE Trial
59/315 subjects (33 in the intervention group and 26 in the control group) were randomized in the ESCAPE trial 5.5 hours after last seen normal
Favorable outcome seen across all clinical outcomes in the extended time window (absolute risk difference of 19.3% for mRS 0-2 at 90 days).
There were more asymptomatic intracerebral hemorrhage events within the intervention arm (48.5% vs. 11.5% p=0.004) but no difference in symptomatic ICH.

14. Between 3-8 hrs, any other options?

15. Between 3-8 hrs, any other options?
Two mechanical devices have been approved by FDA to remove or retrieve thrombus in acute ischemic stroke: MERCI： Not used anymore Penumbra system: In use

23. IV TPA >8 hours?

24. Can IV TPA be given to patients with stroke upon waking up?
NIHSS≥6
Age:18－85
Onset to treatment <8 hours
ICA,MCA M1 M2 occlusion
mRS 0－2 prior to randomization
IV tPA allowed
Identifying Penumbra by DWI/PWI mismatch did not show better result with IA therapy
IA thrombectomy showed no additional benefit than IV T-PA

25. MR WITNESS
~15-30% of stroke pts awaken with deficits or have unclear onset times
DWI positive FLAIR negative pattern on MR

26. 80 pt enrolled with 71% wakeup stroke
Median NIHSS 7.5(IQR )

30. Beyond 12 hrs? Possible?

31. Persistent Penumbra?
Darby et al, 1999

32. Pre DAWN trial in 2009: Endovascular therapy in late presenting stroke patients (>8 h) is a safe therapy in wake up stroke
Occlusion sites were: M1 MCA (94/49%), M2 MCA (19/10%), ICA terminus (43/22%), tandem ICA origin/MCA (25/13%), tandem ICA origin/ ICA terminus (12/6%)
93 patients, mean age of 64.4 (median 67; range 19–91)
Mean NIHSS 15
Mean time to treatment was h (median 12.4; range 8–111).
Intra-arterial thrombolytics in 92/193 (48%), Merci Retriever in 110/193(57%) and other mechanical modalities in 56/193 (29%).
Successful (TIMI 2 or 3) recanalization was achieved in 141/193 (73%) cases.
90 day outcomes MRS 2-3in 69 (45.7%) and 92 (60.9%)
ICH was 20/193 (10.4%).
Mortality rate was 22.2% (42/189).
Age (OR 0.96; 95% CI 0.93 to 0.99, p ), time to treatment (OR 1.11; 95% CI 1.01 to 1.21, p ) and successful recanalization (OR 3.21; 95% CI 1.21 to 8.51, p ) were significantly associated with favorable outcomes.

33. An early end to patient enrollment in the DAWN trial Treating stroke 6 to 24 last known well
Stryker: preplanned interim review of data from the first 200 patients, which concluded that multiple prespecified stopping criteria were met. DSMC recommended stopping the trial.
500 patients planned
Mechanical thrombectomy with the Trevo Retriever plus medical management leads to superior clinical outcomes at 90 days as compared with medical management alone in acute stroke patients treated 6 to 24 hours after last seen well.

35. Conclusions
Under the imaging guidance, the future of acute ischemic treatment is likely to have longer windows and multiple treatment modalities used together: IV thrombolysis+ IA thrombectomy+ Anticoagulants+ hypothermia+ neuronal protecting agents

36. Conclusions Identify patient early
The earlier, the more options we have
Using imaging to identify those outside the window
Stronger and better thrombolytics may be used in evolving lacunar syndrome in an even later time