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

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.

Let Us Review the Concept of PENUMBRA

Persistent Penumbra? Darby et al, 1999

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

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

Let us exam the treatment window of <4.5 hours first

IV tPA NNTB and NNTH within 3 hours and 3-4.5 hours Saver et al Stroke 2009;40:2433-37 Number of Patients to be Benefited (NNTB) and or Harmed (NNTH) Per 100 Patients Treated With Intravenous TPA in Different Time Windows 1–3 Hours 3–4.5 Hours NINDS tPA Trials ECASS 3 Trial Benefit per 100 32.3 16.4 Harm per 100 3.3 2.7 NNTB = 6.1 NNTH = 37.5 8

Treatment window of < 6 hours What can we do?

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

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

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%

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.

Between 3-8 hrs, any other options?

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

IV TPA >8 hours?

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

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

80 pt enrolled with 71% wakeup stroke Median NIHSS 7.5(IQR 4.3-13.8)

Beyond 12 hrs? Possible?

Persistent Penumbra? Darby et al, 1999

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 16.3 613 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 50.026), time to treatment (OR 1.11; 95% CI 1.01 to 1.21, p 50.019) and successful recanalization (OR 3.21; 95% CI 1.21 to 8.51, p 50.018) were significantly associated with favorable outcomes.

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.

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

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