Is there even a time window?

Transcription

1 Is there even a time window? A brief summary of key 2018 trials: DAWN and DEFUSE-3 For Neurosciences Update Conference, February 22, 2018 Maxim D. Hammer, M.D.

2 Executive Summary Based on DAWN and DEFUSE-3, we now have proof that some patients with large vessel occlusion will benefit from endovascular therapy well beyond 6 hours. The patients who are proven to benefit are those with small core infarction and large area of tissue at risk. From 0-6 hours, we should maintain our focus on rapid treatment with IVtPA and endovascular therapy. From 6-24 hours, we can now treat selected patients who meet clinical and imaging criteria. Cleveland Clinic Abu Dhabi 2

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4 Terminology LVO: Large vessel occlusion. Refers to occlusion of a major vessel of the Circle of Willis, such as ICA (intracranial), MCA, BA CIM: Clinical Imaging Mismatch. Refers to the discrepancy between a neurological examination that shows malfunction of a large region of the brain and imaging that shows only partial infarction of that region. Suggests potentially reversible ischemia. IM: Imaging mismatch Refers to a significant discrepancy between the size of the core infarction and size of the tissue at risk, as determined by perfusion imaging. RAPID: Rapid Processing of Perfusion and Diffusion. Refers to imaging software (CT and MR) that automatically calculates brain tissue core infarction versus tissue at risk using consensus-derived, medically validated standards. Cleveland Clinic Abu Dhabi 4

5 Example of RAPID

6 DAWN DEFUSE 3 N Engl J Med Jan 4;378(1):11-21 N Engl J Med Jan 24

7 Trial Designs DAWN Multicenter Prospective Randomized Blinded end points Sponsored by Stryker Neurovascular Halted early (prespecified interim analysis) DEFUSE-3 Multicenter Prospective Randomized Blinded end points Sponsored by NIH (StrokeNet) Halted early (prespecified interim analysis) Cleveland Clinic Abu Dhabi 7

8 Inclusion criteria, abbreviated Trial DAWN DEFUSE-3 Time 6-24 hours 6-16 hours NIHSS 10 6 mrs IVtPA Allowed Allowed LVO Intracranial ICA and/or MCA Intracranial ICA and/or MCA CIM Target 3 strata: Core 0-21cc, NIHSS 10, age 80 Core 0-31cc, NIHSS 10, age<80 Core 31-51cc, NIHSS 20, age<80 Small core infarct Large CIM 1 stratum, fulfilling: Core <70cc Mismatch ratio >1.8 Mismatch volume 15cc Accept larger core, Large IM Cleveland Clinic Abu Dhabi 8

9 Endpoints, abbreviated Trial DAWN DEFUSE-3 Primary utility-weighted mrs at day 90 Functional independence (mrs 0-2) Secondary mrs at day 90 Functional independence (mrs 0-2) Cleveland Clinic Abu Dhabi 9

10 The mrs vs utility-weighted mrs mrs 0 No symptoms 1 No significant disability Able to carry out all usual activities despite some symptoms. 2 Slight disability Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 Moderate disability Requires some help, but able to walk unassisted. 4 Moderately severe disability Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 Severe disability Requires constant nursing care and attention, bedridden, incontinent. 6 Dead Cleveland Clinic Abu Dhabi 10

11 The mrs vs utility-weighted mrs mrs 0 No symptoms 1 No significant disability 2 Slight disability 3 Moderate disability 4 Moderately severe disability 5 Severe disability 6 Dead Cleveland Clinic Abu Dhabi 11

12 The mrs vs utility-weighted mrs mrs Utility weighted mrs 0 No symptoms 10 1 No significant disability Slight disability Moderate disability Moderately severe disability Severe disability 0 6 Dead 0 Cleveland Clinic Abu Dhabi 12

13 Endpoints, abbreviated Trial DAWN DEFUSE-3 Primary utility-weighted mrs at day 90 Functional independence (mrs 0-2) mrs at day 90 Secondary * Functional independence (mrs 0-2) Cleveland Clinic Abu Dhabi 13

14 Baseline characteristics DAWN DEFUSE-3

15 Key Baseline Features: CIM comparison median NIHSS T/E Control DAWN DEFUSE Core cc T/E Control 7.6 ( ) 8.9 ( ) 9.4 ( ) 10.1 ( ) 15

16 DAWN - Efficacy

17 DAWN

18 DAWN

19 DEFUSE-3

20 DEFUSE-3

21 DEFUSE-3

22 Outcomes comparison DAWN DEFUSE-3 mrs Treatment Control mrs 0-2 Functional outcome Treatment Control Number Needed to Treat= Utility weighted 5.5 (+/-3.8) 3.4 (+/- 3.1) 52 (49%) 13 (13%) 2.8 mrs 3 (1-4) 4 (3-6) 41(45%) 15(17%) 3.6 Infarct growth at 24h (median, cc) 1(0-28) 13(0-42) 23(10-75) 33(18-75) Cleveland Clinic Abu Dhabi 22

23 DAWN: Safety

24 DEFUSE-3 - Safety

25 Safety Comparison DAWN DEFUSE-3 Death at 90 days n(%) 17(16) 18 (18) Tx Cx 13(14) 23(26) Early sich n(%) 20(19) 18(18) Tx Cx 6(7) 4(4) Early Neurological Deterioration n(%) 6(6) 3(3) Tx Cx 8(9) 1(12) Cleveland Clinic Abu Dhabi 25

26 Clinical-Imaging Mismatch (CIM) vs Imaging Mismatch (IM) Within a late time window: DAWN aimed for CIM DEFUSE aimed for IM They ended up with similar patients: Small Core CIM and IM CIM = IM! Cleveland Clinic Abu Dhabi 26

27 Executive Summary Based on DAWN and DEFUSE-3, we now have proof that some patients with large vessel occlusion will benefit from endovascular therapy well beyond 6 hours. The patients who are proven to benefit are those with small core infarction and large area of tissue at risk, which are definable using advanced imaging techniques. Core can be defined using RAPID software for CT or MRI Tissue at risk can be defined by RAPID or by CIM From 0-6 hours, we should maintain our focus on rapid treatment with IV-tPA and endovascular therapy. From 6-24 hours, we can now treat selected patients who meet clinical and imaging criteria. Cleveland Clinic Abu Dhabi 27