1. ACUTE TREATMENT OF STROKE: RECENT ADVANCES AND PERFORMANCE AT CAMPBELLTOWN ALEX BUTTFIELD ED STAFF SPECIALIST

2. CASE PRESENTATION CS, 49 year old male: Woke at 0600, normal interaction with wife Onset at 0630 (after waking with no symptoms): – Collapse – Dense right-sided weakness – Aphasia Arrived at Campbelltown ED at 0725 – Stroke call notification prior to arrival by CDA at 0715 Background: – HT on lercanidipine/enalapril – Hypercholesterolaemia on rosuvastatin – Prior TIA 2007 (lost to follow up)

3. EXAMINATION: – Obs T36.4C, HR 72, BP 150/100, Sats 100%. BSL 8 – Aphasic, obtunded – GCS E3, V1, M6 – Dense right hemiparesis – Upgoing plantars (right)

7. Period of hypertension (up to 170/110) treated prior to administration of thrombolysis with hydralazine and GTN patch Thrombolytics (alteplase) administered 0926 “In view of large area of cerebral involvement, dense right hemiplegia, aphasia and early presentation (<3 hours from onset), patient is for transfer to Liverpool hospital” Arrived LDH at 1020 and transferred to interventional radiology – Needle-to-groin at 11am (~4.5 hours post symptom onset)

11. Long-segment of internal carotid artery dissection  stented Successful embolectomy of M1 However, carotid artery stent subsequently thrombosed Returned to ICU ventilated Extubated on day two

12. PROGRESS CT ON DAY TWO

16. PROGRESS Remained aphasic with right arm paralysis Received empirical treatment for aspiration pneumonia after developing fever and focal CXR changes Returned to Campbelltown for ongoing management on day 7 Carotid doppler on day 9 confirmed ongoing complete occlusion of left ICA

17. Transferred to Camden rehab on day 15. Last review 16/3/15: – Able to mow lawn, ongoing significant expressive dysphasia. – Normal power in both upper and lower limbs – Normal gait but right UL incoordination. – Ongoing physiotherapy through Camden hospital

18. STROKE TREATMENT: A VERY BRIEF HISTORY

19. ISSUES WITH THROMBOLYSIS Strict time restrictions – Most benefit in those treated earliest (especially within the first 90 minutes from symptom onset) – Not given beyond 4.5 hours Unable to administer to those with absolute contraindications to thrombolysis Limited efficacy in large, proximal clots – Only about one third demonstrate early recanalisation after IV t-PA in patients with occlusion of the ICA terminus – Prognosis in such patients without recanalisation is poor (Lima et al, JAMA 2014)

21. EARLY TRIALS IN ENDOVASCULAR THERAPY

22. PROACT I & II Aimed to determine the clinical efficacy and safety of IA pro-urokinase in patients with acute stroke (<6 hours onset) with proven MCA occlusion Randomised to receive either heparin plus 6mg of pro- UK (PROACT I) or 9mg pro-UK (PROACT II) vs heparin alone. Both showed a benefit in terms of greater proportion of functional independence (MRS ≤ 2) and recanalisation rates HOWEVER  not applicable to our patients as neither study controlled against IV t-PA

23. EARLY TRIALS IN ENDOVASCULAR THERAPY

24. None of these three studies showed a benefit for endovascular therapy vs standard care Concerns with these studies: – Long interval before intraarterial treatment after randomisation – Absence of pretreatment vascular imaging to confirm proximal intracranial occlusion – Limited use of more advanced thrombectomy devices (such as retrievable stents)

25. RECENT DEVELOPMENTS

26. MR CLEAN Multi-centre, open-label, RCT where eligible patients were randomly assigned to: – Intra-arterial treatment plus usual care (IV thrombolytics) – Usual care alone Eligible patients had proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intra-arterially within 6 hours Primary outcome was Modified Rankin Score at 90 days

30. 500 patients randomised. Mean age 65 The absolute between group difference in the proportion of patients who were functionally independent (MRS ≤ 2) was 13.5% (32.6% vs 19.1%) No difference in mortality or rates of clinically significant ICH

31. Issues with MR CLEAN: – Slight imbalance resulting more patients in the control group – Reperfusion rates relatively low compared with other case series (58.7%) – 9% of patients in intervention arm had embolisation in to new vascular territory – Relatively low proportion of patients in control group with MRS ≤2

32. Because of MR CLEAN, four ongoing trials had interim analyses performed and were all stopped due to evidence of efficacy

34. EXTEND IA Multi-centre, prospective, open-label, blinded end-point RCT performed in Australia and New Zealand Eligible patients randomly assigned either: – Undergo endovascular thrombectomy with Solitaire Retrievable Stent after thrombolysis (alteplase 0.9mg/kg) – Continue alteplase alone Eligible patients: – Ischaemic stroke, receiving TPA within 4.5 hours from symptom onset – Occlusion of ICA or MCA – Evidence of salvageable brain tissue on perfusion CT – Ischaemic core less than 70mL Primary outcome reperfusion at 24 hours and early neurological improvement – Secondary outcomes included functional score on MRS at 90 days

39. In patients with acute ischaemic stroke with major vessel occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy is beneficial – Improved reperfusion – Early neurologic recovery – Improved functional outcome

40. EXTEND IA PITFALLS Small study population Very few patients will meet the strict criteria to see the magnitude of benefit demonstrated in this trial – The study group screened 7,798 stroke patients over two years to come up with 70 patients Campbelltown at this time does not have CT perfusion scanning

42. Multi-centre, prospective, open-label, blinded outcome assessment RCT Eligible patients assigned to receive: – Standard care – Standard care plus endovascular treatment with the use of available thrombectomy devices Eligible patients: – Up to 12 hours post onset of symptoms – Occluded proximal artery – Moderate-to-good collateral circulation – Small infarct core (6-10 on ASPECTS score) Primary outcome: – Modified Rankin Score at 90 days

45. RESULTS 22 centres worldwide 316 patients enrolled 238 received thrombolytics (120 intervention, 118 control) Median time from study CT to first reperfusion was 84 minutes Rate of functional independence (MRS 0-2) increased in intervention (53% vs 29.3%, p<0.001) Median MRS in intervention was 2, vs 4 in control (p<0.001)

46. ESCAPE PITFALLS Did not obtain screening logs, so no way of knowing how many patients were excluded on the basis of imaging criteria A majority of patients were enrolled at selected endovascular centres that were capable of implementing efficient workflow Very tight time-targets (60 minutes from CT to groin puncture, first reperfusion of 90 minutes or less) Industry-funded

48. International, multicentre, prospective randomised, open clinical trial Compared IV t-PA followed by thrombectomy with retrievable Solitaire stent vs t-PA alone within six hours of symptom onset All patients had confirmed occlusion of the intracranial ICA, M1 or both on vessel imaging and absence of large ischemic-core lesions Primary outcome was MRS at 90 days

49. RESULTS 39 centres, 196 patients recruited Median time from qualifying imaging to groin puncture was 57 minutes Intervention reduced disability at 90 days over the entire range of scores on MRS (p<0.001) Rate of functional independence (MRS 0-2) was higher in intervention group 60% vs 35%, P<0.001) No difference in mortality

50. SWIFT PRIME PITFALLS Industry-funded Did not study those ineligible for IV t-PA Very tight time-targets

52. Multicentre, prospective, randomised, open label. Blinded evaluation Compared thrombectomy with medical therapy alone in eligible patients who had received IV alteplase within 4.5 hours after onset of symptoms Eligible patients: – 18-80 – Occlusion of proximal anterior circulation – Able to be treated within 8 hours from onset – Premorbid MRS 0-1 Exclusion: – Large ischemic core (ASPECTS <7)

53. 206 patients randomised Thrombectomy reduced severity of disability over the range of the MRS – Higher rates of functional independence (43.7% vs 28.2%) – No difference in ICH rates – No difference in mortality

55. HOW ARE WE GOING AT CAMPBELLTOWN?

58. DOOR-TO-NEEDLE

63. CONCLUSION Those patients with ischaemic stroke and proven proximal occlusion (either distal ICA or proximal MCA) have improved functional outcomes with endovascular therapy after TPA