Interventional Stroke Treatment 2015

1. Interventional Stroke Treatment 2015 Sudipta Roychowdhury, MD Director of Interventional Neuroradiology Director of Magnetic Resonance Imaging Clinical Associate Professor of Radiology Rutgers-RWJ Medical School University Radiology Group

2. Stroke Therapy Timeline MR CLEAN SWIFT PRIMEEXTEND IA ESCAPE REVASCAT THERAPY Solitaire Penumbra Trevo PROACT II IA tPA Angioplasty Stenting Level I Evidence Bridging IV/IA IV tPA MERCI ACE IV tPA (4.5h) Generation 1 Generation 2 Generation 3 1995 2000 2005 2010 2015 FDA Approved - Yellow Off-label - Red

3. Ischemic Stroke Interventions

4. NINDS tPA Trial • NINDS tPA trial (1995) • IV tPA vs Placebo < 3hrs • Outcomes improved with all 4 outcomes Symptomatic hemorrhage 6.4% vs 0.6% • Mortality 17% vs 21% placebo at 3 months • Established IV tPA as gold standard < 3hrs • Better for small rather than large occlusions • Benefit still seen 3-4.5 hours NEJM 9/2008 European study

5. PROACT II • PROACT II (1998) • Dr. Irwin Keller NJ Investigator – IA Prourokinase < 6 hrs • Favorable outcome 40% vs 25% control • Recanalization 66% vs 13% control • Mortality 25% vs 27% control • Symptomatic hemorrhage 10% vs 2% control • IA Prourokinase and tPA not FDA approved

6. Case • 55 y/o M presents after 5 hours of onset of rapidly progressive quadriparesis, ataxia, and dysphagia. • Head CT was normal.

7. Basilar Artery Occlusion

8. Basilar Angioplasty and Thrombolysis IA t-PA

9. Excellent Recanalization and Excellent Outcome

10. Case 77 y/o F presents after 4 hours of onset of slurred speech and ataxia rapidly progressing to loss of consciousness Head CT was unremarkable.

11. Basilar Artery Occlusion

12. Basilar Angioplasty/Stent & Thrombolysis IA t-PA

13. Futile Recanalization

14. MERCI Device MERCI

15. MERCI Trial • MERCI (2005) – MERCI < 8 hrs; n=141; No control arm • Recanalization 46% (66% PROACT II) • Mortality 44% (25% PROACT II, 27% Control) • Symptomatic hemorrhage 7.8% • Primary outcome recanalization not outcome • Results worse than PROACT II • FDA approved but heavily criticized for approval before establishing efficacy

16. Multi-MERCI Trial • Multi- MERCI (2006) – MERCI +/- IV tPA < 8 hrs; n=164; No control • Recanalization 54% and 69% w IA tPA • Mortality 31%; Symptomatic hemorrhage 9% • Primary outcome recanalization not outcome • Results still worse than PROACT II • Still trying to establish efficacy after FDA approval!

17. Does the MERCI Device Work? • “In summary, the MERCI study does not provide any evidence of improved outcomes or greater recanalization rates…. In addition, both clinically significant complications and mortality are higher than the results of other interventional trials…. the results do not support the proposal that the Merci retrieval device works by any definition.” Wechsler, Lawrence R. MD, Donnan, Geoffrey A. MD, FRACP; Davis, Stephen M. MD, FRACP Stroke Volume 37(5), May 2006, pp 1341-1342

18. MERCI: Defended Why high recanalization but not better outcomes? Comparing MERCI to PROACT II Different pt selection – MERCI trials included pts with poor functional status unlike PROACT II If adjust for patient selection, similar mortality and outcome

19. Case 38 y/o F presents with acute left sided hemiplegia presents at 4 hours. History of atrial fibrillation. Head CT was unremarkable.

20. MERCI

21. Penumbra Device Suction catheter with separator wire which prevents thrombus from clogging the tip

22. Penumbra Trial • Penumbra – n=125; Recanalization 82% (PROACT II 66%) • Mortality 32% (25% PROACT II, 27% Control) • Symptomatic hemorrhage 11% • Primary outcome recanalization • 36% good outcome; No control arm • 510k FDA approval – “equivalent” to MERCI

23. Case 44 y/o M presents with mental status changes and left leg weakness at 6 hours. Head CT was unremarkable.

24. Penumbra ACA Infarct

25. Stent Retrievers • 3rd Generation endovascular stroke treatment • Immediate flow restoration • Trap thrombus within stent struts and retrieved • Removable device so no anti-platelets needed Solitaire Trevo

26. Solitaire

27. Solitaire – SWIFT Trial • SWIFT (SOLITAIRE With the Intention for Thrombectomy) • Solitaire (S) versus Merci (M) randomized trial 200 intended pts but stopped at 144 by safety board • Successful recanalization without symptomatic hemorrhage – occurred in 61% of the Solitaire group and 24% of the Merci group. Highly significant difference with a P value of .0001 • Symptomatic intracranial hemorrhage (2% S vs. 11% M). • All intracranial hemorrhage (17% S vs. 38% M). • Good 90-day neurologic outcome (58% S vs. 33% M). • 90-day mortality (17% S vs. 38% M). • Solitaire was significantly better than Merci

28. Case 65 y/o M presents acute left sided hemiplegia at 4 hours and was on Coumadin for atrial fibrillation. Head CT was unremarkable.

29. Solitaire

30. Trevo • Trevo 2 Trial : Trevo versus Merci retrievers for large vessel stroke • Randomized Trevo Retriever group 88 patients and Merci Retriever group 90 pts • 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device. p<0·0001). • Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0·1826). • Trevo was significantly better than Merci

31. Futile Recanalization Unfavorable outcome even with excellent endovascular recanalization

32. How do we select Stroke Patients to avoid Futile Recanalization? • Time versus Penumbra versus Core • Time • Less than 6 hours for IA tPA (Anterior) • Less than 8 hours for mechanical (Anterior) • Unknown time for posterior circulation • Penumbra – Potential stroke territory • CT perfusion – very controversial • Not accurate predictor of penumbra • High radiation dose • Fallen out of favor by MGH original CTP advocates • Delayed CTA images for collaterals

33. How do we select Interventional Ischemic Stroke Patients? • Core – Actual irreversibly infarcted brain tissue • If less than 1/3 of MCA territory has been infarcted, better chance for good outcome with recanalization • If the Core is smaller with larger penumbra, the patient may have good collaterals which will allow better outcome with recanalization. • ASPECTS criteria • MRI diffusion

34. ASPECTS Criteria • Alberta Stroke Program Early CT score (ASPECTS) is a 10-point CT scan score • ASPECTS predicts core of infarct • A normal CT scan receives ASPECTS of 10 points.  • To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions OF MCA territory • A score of 0 indicates diffuse involvement throughout the MCA territory  • Patients with ASPECTS score of 8-10 had better outcomes than patients with 7 or less at both shorter (less 5 hours ) and longer (greater than 5 hours) recanalization

35. ASPECTS Criteria • A normal CT scan receives ASPECTS of 10 points.  • To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions OF MCA territory

36. MR Diffusion Criteria • MR diffusion accurately predicts core of infarct • If less than 1/3 MCA territory or less than 70ml volume, better outcome endovascular treatment (Volume = ABC/2) • If brainstem infarcted in posterior circulation, poor outcome with basilar stroke. • Takes additional time to obtain MR diffusion Diffusion (Core) PWI (Penumbra)

37. TICI Criteria for M1 Occlusion • Grade 0 – No antegrade flow beyond occlusion • Grade 1 – Open beyond obstruction but not distal • Grade 2a – Less 50% MCA circulation • Grade 2b – Greater than 50% MCA circulation • Grade 3 – Entire MCA circulation open • Grade 2B and 3 – Best neurological outcomes

38. Case 6 76 y/o F noted to have left arm/leg weakness 2 days after pelvic surgery.

39. Core: MR Diffusion Head CT MR Diffusion CTA – R M1 occlusion MR Diffusion: less than 1/3 MCA core infarct

40. CT Perfusion and MR Diffusion CBF TTP (Penumbra) Diffusion (Core)

41. Penumbra Device

42. CT Perfusion after Penumbra Thrombectomy TTP TTP after thrombectomy Diffusion

43. IMS III (2008-2012) • Interventional Management of Stroke III • NEJM March 2013 results – IV tPA only vs IV + IA tPA / Mechanical • Trial stopped in 2012 as ongoing data could not show benefit of combined IV+ IA superior to IV tPA alone • No distinction between small and large vessel strokes • Large vessel occlusions did better with IA • Limited by older endovascular devices • No CTA, No ASPECTS criteria

44. SYNTHESIS Expansion Trials • NEJM March 2013 – IV tPA only <3 hrs vs Combined IV + IA tPA and/or Mechanical Device < 6hrs • Can we do better than IV tPA? • Endocvascular Tx: Catheter & wire, Merci and Penumbra, minimal Stent-Retrievers • Limited by older endovascular devices • No difference in outcomes • No distinction between large and small vessel strokes

45. Level I Interventional Evidence MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT (THERAPY)

46. MR CLEAN Study Details • Control – IV/Medical only versus Interventional arm - IA and IV • MR CLEAN demonstrated a 71% improvement in good neurological outcomes for Interventional compared to medical management/TPA (32.6% (76/233) vs. 19.1% (51/267)) • There was no safety difference in adverse events (47% vs. 42%) , ICH (7.8% vs. 6.4%) or 90 day mortality (21% vs 22%) between the two groups. • Lower absolute rates of 90day mRS 0-2 and higher complication rates seen in MR CLEAN vs. prior studies reflect the ‘real-world’ experience in the Netherlands, particularly the relatively high rate of ICA lesions vs. prior studies like IMS3 (26% vs. 15%) • Stent Retrievers used in 97% of interventions • There was a improved mRS shift for Interventional vs Control • First large scale study demonstrating interventional superiority

47. MR CLEAN mRS mRS (Modified Rankin Scale) 0 – No symptoms 1 – No significant disability 2 – Slight disability 3 – Moderate disability 4 – Moderate severe disability 5 – Severe disability 6 – Death

48. MR CLEAN Study Conclusion • In patients with acute ischemic stroke caused by a large arterial occlusion of the anterior circulation, intraarterial treatment within 6 hours was effective and safe • IA treatment leads to a clinically significant increase in the functional independence in daily life by 3 months, without an increase in mortality • Triggered stoppage of multiple other trials: ESCAPE, SWIFT PRIME, Extend IA, REVASCAT, and THERAPY O.A. Berkhemer et. al. A Randomized Trial for Intraarterial Treatment for Acute Ischemic Stroke. N Eng J Med December 2014.

50. What does this mean? • Interventional therapy (with IV tPA) may have become the gold standard for large vessel ischemic stroke in 2015. • MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, EXTEND-IA, THERAPY • However, the selection criteria for interventional stroke treatment is not uniform. • Head CT, ASPECTS, Diffusion MRI, CTA, Delayed CTA, CTP • Medicolegal Implications: Large vessel ischemic stroke patients may need to have rapid access to Interventional tx.