Late Breaking Trials: An update….

2. Late Breaking Trials: An update…. Michael D. Hill Calgary Stroke Program

3. Disclosure Slide • In the last 5 years: • I have been funded by CIHR, HSF Alberta/NWT/Nunavut, CSN, AHFMR, NINDS (NIH) • I have received speaker fees/honouraria from Hoffmann-La Roche Canada Ltd., Sanofi Canada, Boehringer-Ingelheim Canada, Novo-Nordisk Canada • I have been an advisor to NovoNordisk Canada, Genentech Ltd, Stem Cell Therapeutics, Vernalis Group Ltd., Sanofi Canada, Portola Therapeutics. • I hold no stock or direct investment in any pharmaceutical or device company (except those possibly in mutual funds) • I believe you/we should “give the juice” (ie. tPA) far more often that we do

5. Outline - Focus on RCTs • ECASS-3 • Hemicraniectomy • Telestroke • FASTER • PROFESS • ONTARGET, TRANSCEND, HYVET

6. ECASS-3

9. RR Outcome • . csi 219 182 199 221, exact • | Exposed Unexposed | Total • -----------------+------------------------+---------- • Cases | 219 182 | 401 • Noncases | 199 221 | 420 • -----------------+------------------------+---------- • Total | 418 403 | 821 • | | • Risk | .5239234 .4516129 | .4884287 • | | • | Point estimate | [95% Conf. Interval] • |------------------------+---------------------- • Risk difference | .0723105 | .0040978 .1405233 • Risk ratio | 1.160116 | 1.007389 1.335997 • Attr. frac. ex. | .1380174 | .0073352 .2514956 • Attr. frac. pop | .0753761 | • +----------------------------------------------- • 1-sided Fisher's exact P = 0.0226 • 2-sided Fisher's exact P = 0.0428

10. RR outcome • 7.2% Absolute risk benefit • NNT = 14 (13.8) • Treat 14 patients in the 3-4.5 window and get 7 excellent functional outcomes at 90d instead of 6, OR one additional excellent functional outcome (mRS 0-1) • This includes an increased risk of ICH and no difference in mortality

12. 0–90 min, n=311; 91–180 min, n=618; 181–270 min, n=801; 270–360 min, n=1046. Values do not equal 100% because of rounding. Time is an effect modifier The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Lancet 2004; 363 (9411): 768-774.

13. Results – Pooled Analysis • Odds Ratios for Favorable Outcome • TimeOdds Ratio95% Conf. Interval • 0-90 2.8 1.8, 4.5 • 91-180 1.5 1.1, 2.1 • 181-270 1.4 1.1, 1.9 • 271-360 1.2 0.9, 1.5

14. Adverse Events

15. For each 10 minute delay in ER arrival, treatment was 18 minutes faster! Human Nature?

16. SITS-ISTR Lancet 2008; on-line. N=664 patients

17. What’s new in 2008? 2008: • 8 new trials (n=+1477, total: n=7152) • Drugs: 3 rt-PA; 2 UK; 3 desmoteplase • Route: 2 intra-arterial, 6 intravenous • Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs • Imaging pre randomisation: • CT: 5 • MR: 3 (+1) DWI/PWI mismatch • Age over 80: ≈42

18. rt-PA 2008- OR and events per 1000 treated rt-PA Effect per 1000 Symptomatic ICH : <3 hrs +70 3-6 hrs +60 Death by three months : <3 hrs 0 +20 3-6 hrs Dead or Dependent : <3 hours -110 - 40 3-6 hours 0.1 0.66 0.84 1.0 1.333.37 10 OR better thrombolysis worse CDSR 2008

19. 0.1 0.2 0.5 1 2 5 10 favours treatment favours control Death or dependency: subgroups OR (95% CI) n Trials n patients Latest time to treatment, all drugs (hours) 3 1 624 4.5 2 1161 6 9 3463 9 3 325 0.62 (0.45, 0.85) 0.85 (0.68, 1.07 0.84 (0.73, 0.96) 0.85 (0.52, 1.39) Treatment time rt-PA (hours) 0.64 (0.5. 0.8) 0.83 (0.7, 0.9) 0-3 5 930 3-6 6 2766

20. Conclusion, Update 2008 • Heterogeneity still confounds interpretation • ECASS 3 consistent with existing rt-PA meta-analysis. • Potential for benefit to at least six hours • Limited new knowledge on latest time windows. • Almost complete lack of data on older patients; antithrombotic use; stroke severity/subtype, diabetes • Outcome following selection on MR mismatch not apparently different to CT. • No material change in main outcomes since 2003.

21. Proposed CSS BPR • 3.5.1 All patients with disabling acute ischemic stroke who present to a hospital capable of administering thrombolytic therapy within a 4.5 hour treatment window* should be evaluated without delay to determine their eligibility for treatment with intravenous tissue-plasminogen activator (tPA). *Note:  In Canada, tPA is currently approved by the Health Canada Food and Drug Administration Regulations for administration  within 3 hours of stroke symptom onset, unless special compensation has been granted to individual practitioners or institutions, for example within the context of a clinical research trial.

22. Hemicraniectomy: Evidence

23. Enrolled <48h Age limit at 60

29. Telestroke

30. Study Profile

31. Outcomes: Correct decision with telestroke…

32. Fast Assessment of Stroke and TIA to Prevent Early Recurrence

33. Eligibility Criteria • Patients with TIA or minor acute ischaemic stroke (NIHSS  3) • Within 24h of symptom onset • Patients with: • weakness at time of TIA/minor stroke and/or language disturbance at time of TIA/minor stroke; • and duration of neurological deficit (TIA)  5 minutes • Age greater than 40

34. FASTER Study Design All patients within 24 hours of qualifying event All patients on Aspirin Simvastatin Placebo Clopidogrel Placebo

35. Trial Flowchart

36. Clopidogrel Flowchart

37. Simvastatin Flowchart

38. Primary Outcome Interaction Ratio 1.39 (0.36-5.24) p=0.64

39. Primary Outcome

40. Conclusions • Feasibility • Increased indications and uptake of statins hampered patient enrolment • Safety • Haemorrhagic Complications of Clopidogrel in keeping with MATCH • Efficacy • The addition of clopidogrel to aspirin may be associated with a reduction of stroke following TIA/ minor stroke • Appears unlikely that there is a significant effect of early statin use

41. Clopidogrel 300mg loadingdose Clopidogrel 75mg o.d. PLAVIX - FASTER 2Study Design Standard of care Within 12 hours symptom onset R Double-blind treatment up to 21 days • >40 yrs • Weakness/ speech deficit • TIA/ minor stroke (NIHSS <3) Standard of care Primary Endpoint: all stroke Placebo loading dose Placebo dose Day 2 to 21 Within 12 hours

42. Age-specific acute vascular event rates in the general population Data from Oxfordshire, UK, 2002-05. Lancet 2005;366:1773-83

43. PROFESS

44. Cerebrovascular Endpoints p-value heterogeneity Stroke With Stenosis 0.1245 Without Stenosis Fatal Stroke With Stenosis 0.9770 Without Stenosis Non-Fatal Stroke With Stenosis 0.4245 Without Stenosis Stroke or TIA With Stenosis 0.2592 Without Stenosis 0.4 0.7 1.0 1.3 1.6 2.2 Hazard Ratio (95% CI) Atorvastatin better Placebo better Sillesen H, Amarenco P, Hennerici MG, et al. Stroke

45. TRANSCEND • Patients intolerant of ACEi • -cough (88%) • -symptomatic hypotension (4.1%), angioedema (1.3%) and other • -hypertension requiring treatment • -primary prevention trial

46. Exclusions • CHF, cardiac outflow/AoV obstruction, constrictive pericarditis, complex congenital heart dx, unexplained syncope, planned or recent cardiac surgery, SBP > 160 mmHg, heart transplant, SAH, RAS, creatinine > 265 umol/L, proteinuria, heaptic dysfunction

47. Outcomes • 1. Composite of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure • 2. Composite of cardiovascular death, myocardial infarction or stroke (HOPE primary outcome)