Lessons Learned from IMS III: Implications for the Future

Transcription

1 Lessons Learned from IMS III: Implications for the Future Pooja Khatri, MD, MSc Professor, Dept of Neurology Director of Acute Stroke, UC Stroke Team University of Cincinnati

2 Disclosures Univ of Cincinnati Dept of Neurology receives research support from the following for my research efforts: NIH (Co-PI NCC, PI RCC, CTSA) Genentech, Inc (Lead PI of PRISMS trial) Penumbra, Inc (Neuro PI of THERAPY trial) Biogen, Inc. (DSMB member)

3 Overview Lessons learned from IMS III Considerations for future positive trials

4 Lessons from IMS III Faster times to reperfusion?

5 Time Phenomenon Validated in IMS III ICAT, M1, and M2 Cases with Reperfusion with 95% confidence bands (p=0.0045) ICAT, M1, and M2 Cases without Reperfusion (10%; 95% CI ) Khatri, Lancet Neurology, 2014

6 Time Phenomenon Validated in IMS III ICAT, M1, and M2 Cases with Reperfusion with 95% confidence bands (p=0.0045) Every 30 minute delay in reperfusion is a 10% relative reduction in probability of good clinical outcome (mrs 0-2) in adjusted analysis. ICAT, M1, and M2 Cases without Reperfusion (10%; 95% CI ) Khatri, Lancet Neurology, 2014

7 Modeling from IMS III Data

8 Modeling from IMS III Data Time to Reperfusion 223 min if 76% TICI 2-3 Time to Reperfusion 255 min if 86% TICI 2-3

9 IMS III Time Intervals Mean Onset to Groin: 209 minutes Mean Onset to Start of IA Therapy: 249 minutes Mean Onset to Angio Reperfusion: 325 minutes

10 Further Analyses No Modification of Time Effect by ASPECTS, NIHSS Strata TICI 2b/3, Exclusion of M2s Similar time effects between ASPECTS groups (p=0.91) ASPECTS 0-4: RR (95% CI , ) ASPECTS 5-7: RR (95% CI , ) ASPECTS 8-10: RR (95% CI , ) Similar time effects between NIHSS strata (p=0.69) NIHSS 8-19: RR (95% CI , ) NIHSS 20+: RR (95% CI , ) Change reperfusion to TICI 2b/3 (from 2a/2b/3) (p=0.01) RR 0.89 (95% CI , ) Change occlusions to ICAT/M1 (from ICAT, M1, M2) (p=0.002) RR 0.82 (95% CI , ) Khatri, Lancet Neurology, 2014

11 Lessons from IMS III Faster times to reperfusion? Better devices/revascularization?

12 Revascularization Rates Overall TICI %; TICI 2b-3 38% By Device (ICAT and M1 only) (n=4) (n=39) (n=77) (n=14) (n=51)

13 Good Outcome By TICI Score n=55 n=29 n=108 n=119 n=7

14 Lessons from IMS III Faster times to reperfusion? Better devices/revascularization? More clinically severe strokes?

15 NIHSS Strata IMS III Prespecified Secondary Analysis NIHSS 8-19 IV/ Endo IV rtpa Only NIHSS >/=20 IV/Endo IV rtpa Only mrs 0-2 (%) 146 (48.3%) 74 (49.3%) mrs 0-2 (%) 31 (23.5%) 12 (16.7%) -1.0% 7.2% Breslow Day p-value 0.27 (no evidence of heterogeneity of treatment effects between NIHSS strata) Broderick, NEJM, 2013

16 Lessons from IMS III Faster times to reperfusion? Better devices/revascularization? More clinically severe strokes? Baseline CTA+ only? Worst clots only?

17 Baseline CTA Subset Only n=306 (47%) ANY OCCLUSION ICA, M1, or BA OCCLUSION NO OCCLUSION IV/Endo IV Only n mrs 0-2 n mrs (44.7%) 62 (41.3%) 17 (81%) (38%) 27 (38.6%) 2 (66.7%) Demchuk, Radiology, 2014

18 90-Day mrs Distribution, ICAT, Basilar, M1s on Baseline CTA Prespecified Secondary Analysis p-value 0.11

19 Outcome by Occlusion Site (CTA Subset Only)

20 Outcome by Occlusion Site (CTA Subset Only)

21 Lessons from IMS III Faster times to reperfusion? Better devices/revascularization? More clinically severe strokes? Baseline CTA+ only? Worst clots only? Core imaging selection?

22 No Treatment Effect Modification by Baseline ASPECTS ASPECTS 8-10 ASPECTS 0-7 ITT population IV/Endo N=247 IV Only N=131 RR (99% CI) IV/Endo N=187 IV Only N=91 RR (99% CI) Pooled RR (99% CI) P (heterogeneity) mrs % 47% 1.1 ( ) 28% 26% 1.1 ( ) 1.1 ( ) ITT, Onset-IV time 120 min N=129 N=73 N=97 N=46 mrs % 45% 1.2 ( ) 33% 22% 1.5 ( ) Onset-IV tpa time 120 min AND baseline ICA and/or MCA occlusion (M1-M4) on CTA N=43 N=33 N=53 N= ( ) mrs % 52% 1.3 ( ) 36% 19% 1.9 ( ) 1.4 ( ) Hill, Stroke, 2013

23 ASPECTS in IMS III: Graded Prognosis ASPECTS 8-10 (Good scan) ASPECTS 5-7 (Fair scan) ASPECTS 0-4 (Poor scan) IV-endo (n=247) IV tpa (n=131) IV-endo (n=130) IV tpa (n=56) IV-endo (n=57) IV tpa (n=35) mrs 0-2 at 90d 51% 47% 32% 29% 19% 23% Hill, Stroke, 2014

24 ASPECTS in IMS III: Graded Prognosis ASPECTS 8-10 (Good scan) ASPECTS 5-7 (Fair scan) ASPECTS 0-4 (Poor scan) IV-endo (n=247) IV tpa (n=131) IV-endo (n=130) IV tpa (n=56) IV-endo (n=57) IV tpa (n=35) mrs 0-2 at 90d 51% 47% 32% 29% 19% 23% Reasonable to exclude but may not enhance treatment effect Hill, Stroke, 2013

25 Possible Recipe for a Positive Trial Based on IMS III Exploratory Analyses Faster times to reperfusion Better devices/revascularization More clinically severe strokes Baseline CTA+ only, and with worst clots Core imaging selection

26 MR CLEAN Eligibility Was Broader NIHSS </=2 Vs IMS III NIHSS >/= 10 A1, A2, M1, M2, ICA Vs IMS III no thrombus criteria Start IA tx by 6 hours Vs IMS III by 5 hours No upper age limit Vs IMS III <83 yo No imaging core exclusions Vs IMS III <1/3 clear hypodensity **Grey principle (vs IMS III explanatory)

27 MR CLEAN But Who Was Enrolled? Faster procedure times? IMS III onset to groin 209 minutes vs? Better devices/revascularization? IMS III 2b/3 40%, % vs? More clinically severe strokes? IMS III 17/16 vs? IMS III age 69/68 vs? Baseline CTA+ only? Worst clots? IMS III ~20% with no occlusion vs? IMS III ~20% intracranial ICA occlusions vs? Core imaging selection? Or penumbra? IMS III had ~15% ASPECTS 0-4 vs? BROADER ELIGIBILITY BUT NARROWER ENROLLMENT?

28 ESCAPE Eligibility NIHSS >/=5 ICA, M1, or M1 equivalent Onset to randomization <12 hrs CT to groin <60 min No upper age limit ASPECTS 6-10 Adequate perfusion/collaterals Clinicaltrials.gov

29 MR CLEAN, ESCAPE, EXTEND IA Details Pending

30 Thank You