Stroke: The Year in Acute Stroke What did we learn in the ...

1 Stroke : The Year in Acute Stroke What did we learn in the last year? Ischemic Is IV t- t- PA safe in community practice? Hemicraniectomy for large hemispheric J. Claude Hemphill III, MD, MAS infarction? Associate Professor of Clinical Neurology and Rethinking TIA. Neurological Surgery Minocycline as neuroprotectant? neuroprotectant? University of California, San Francisco Director, Neurocritical Care San Francisco General Hospital Intracerebral hemorrhage Does recombinant fVIIa improve outcome in non- non-warfarin ICH? Disclosures UCSF Do statins increase risk of ICH? Research Support: NIH/NINDS, Novo Nordisk Consulting: Astra Zeneca, Novo Nordisk, Innercool Therapies NEUROCRITICAL. Stock options: Cardium Therapeutics (Innercool Therapies) CARE PROGRAM. Stroke Facts Ischemic Stroke - Timeline 0 min Embolus Blocks Vessel No Symptoms 700,000 strokes/year in the Clinical Symptoms Begin 70% of patients survive an Acute Stroke 4-10 min Electrical Failure of Neurons Excitotoxins Released 3,000,000 Stroke survivors in the 4 min- Neuronal Death Membrane Breakdown hours Penumbra at Risk 3rd leading cause of death hours- Penumbral Region Symptoms Peak 72 hrs Leading cause of adult disability weeks Compensates Rapid Clinical Recovery 2 weeks Surviving Neurons & Other Logarithmic Recovery 6 months Hemisphere Compensate Page 1.

2 Acute Ischemic Stroke Treatment IV t- t-PA in ischemic Stroke Inclusion Criteria Exclusion Criteria Reperfusion Age 18 complete hemiplegia Reopening arterial occlusion Clinical diagnosis of (very large Stroke ). Improving collateral blood flow Acute Stroke BP > 185/110 (sustained). Can initiate treatment glucose > 400 or < 50. within 3 hours of onset of Neuroprotection Stroke platelets <100,000. Stalling ischemic cascade INR > head CT without hemorrhage recent Stroke , trauma, or surgery Salvage Therapy More than minor Stroke deficit seizure at onset of Stroke Managing complications of large Stroke NEJM 333: 1581-1587, 1995. IV t- t-PA in Acute ischemic Stroke IV t- t-PA in ischemic Stroke Outcome About 1 1/2 times as many patients treated with tPA. dose - mg/kg IV (maximum 90 mg) were normal at 3 months compared to placebo 10% as bolus, remainder infused over 1 hour Rankin Scale functional outcome {t- {t- PA 39% vs.}}

3 Placebo 26%}. Mortality must begin treatment w/in 3 hrs of symptom onset No difference between groups at 3 months t-PA 17% vs. placebo 21%. avoid heparin, ASA, or clopidogrel for 24 hours Hemorrhage of t- t- PA patients suffered a symptomatic intracranial hemorrhage Admit to ICU, keep BP < 185/110 for 24 hours of t- t- PA patients died because of intracranial hemorrhage NEJM 333: 1581-1587, 1995. Page 2. Barriers to Adoption SITS- SITS-MOST. Patients presenting outside time window Safe Implementation of Thrombolysis in Stroke Most common reason for exclusion Monitoring Monitoring Study Study (Lancet 2007). Safety in community practice Observational study of IV t- t-PA within 3 hours Major barrier to adoption by ED physicians, of Acute ischemic Stroke (2002- (2002-2006).)

4 General neurologists 6483 patients Addressed by 285 centers (50% w/o sig Stroke thrombolysis exp). Certifying Primary Stroke Centers (JCAHO). Studying safety and outcome in community Required by European Union regulators settings SITS- SITS-MOST SITS- SITS-MOST. Functional outcome as good or better than randomized trials Hemorrhage rate 24 hours - 7 days (consistent with in pooled randomized trials). Mortality 3 months - Consistent with in randomized trials Conclusion Trial results can be replicated in community practice Stop making excuses (my conclusion). Page 3. Large Hemispheric Infarction Options? Case 43 yo man with Acute 1. Let him go complete L MCA. ischemic Stroke 2. ICP monitoring Received IV t- t-PA Mannitol, Mannitol, etc w/in 3 hours of onset 3. Hypothermia 12 hours later, 4.

5 Decompressive deteriorated to deep coma hemicraniectomy Evidence? Decompresive Hemicraniectomy Hemicraniectomy Considered in Allow herniation Malignant MCA infarction outwards, not Traumatic brain injury inwards ICH, SAH, CSVT. Salvage therapy not designed to Difficult to assess efficacy improve deficit from Small trials original Stroke Sick population Ethical issues Page 4. Outcome European Pooled Trial Results Prospective pooled analysis of 3. ongoing (at the time) trials of decompressive surgery in malignant MCA infarction Vahedi et al. Lancet Neurology March 2007. DECIMAL, DESTINY, HAMLET. Patient criteria Age 18- 18-60. Rx w/in 48 hrs of Stroke onset Randomized to surgery or conservative Rx 93 patients Number Needed to Treat (NNT). Large Hemispheric Infarction Alive but unable to walk NNT=2 Hemicraniectomy works Major effect with very low NNT.

6 Alive, disabled but able to walk Caveats NNT=4 Save lives to a disabled state Many patients & families accept this Side of Stroke Study was done on age < 60. ( dominant Don't bias decision based on aphasia ( Stroke side). hemisphere didn't Must do wide decompression & durotomy matter). Page 5. Rethinking TIA Stroke Risk after TIA. risk of Stroke w/in 90 days Transient Ischemic Attack Half of strokes occurred within 2 days Focal neurological deficit presumably due to ischemia and resolving completely within 24. hours of onset ABCD2 score (points). 2 day ABCD2. Age > 60 (1) Stroke risk score BP > 140/90 (1). Old way Unilateral weakness (2) 0- 3 Go home and work up expeditiously (often Speech impairment within a week or so) without weakness (1) 4- 5 Duration > 60 min (2). or 10- 10-59 min (1).

7 6- 7 New way Diabetes (1). Treat as unstable angina of the brain Johnston JAMA 2000. Johnston Lancet 2007. Early Evaluation of TIA EXPRESS. EXPRESS study - UK What was done differently? (Rothwell et al. Lancet Oct 9, 2007). Before/after study of immediate or referral TIA or minor Stroke evaluation TIA clinic with evaluation and urgent treatment (rather than referral to primary care). 90 day Stroke rates Before (clinic referral) After (immediate) Page 6. Early Evaluation of TIA SOS- SOS-TIA. SOS- SOS-TIA study France (Lavall . Lavall e et al. Lancet Oct 9, 2007). 24 hour TIA clinic (seen w/in 4 hrs of presentation). CT or MRI. Carotid U/S and or TCD. Urgent TTE or TEE if indicated Labs Urgent TIA evaluation led to ~1/5 of patients did not have cerebral ischemia as judged by vascular neurologist 90 day Stroke rate of ABCD2 predicted rate of New Acute Stroke Trials Minocycline in Acute Ischemic Stroke Minocycline Anti- Anti-inflammatory Ischemic Stroke Matrix metalloproteinase inhibitor Minocycline as neuroprotectant Inhibits apoptosis?

8 Clopidogrel loading Open- Open-label, evaluator blinded study Intracerebral Hemorrhage 152 patients Recombinant factor VIIa to reduce hematoma 74 minocycline 200 mg/d orally for 5 days expansion Starting 6- 6-24 hours after Stroke 77 placebo Lampl Neurology 2007. Page 7. Minocycline in Acute Ischemic Stroke FASTER. Fast Assessment of Stroke and Transient ischaemic attack to prevent Early Recurrence Randomized factorial pilot trial 392 TIA patients w/in 24 h of symptom onset Clopidogrel 300 mg loading dose then 75 mg daily (v. placebo). Simvastatin 40 mg daily (v. placebo). Kennedy et al. Lancet Neurology Nov 2007. FASTER - results Hematoma Expansion in ICH. Trial stopped early due to failure to recruit because of increased use of statins 90 day Stroke rates Clopidogrel Placebo risk ratio [95% CI ].

9 Simvastatin Placebo risk ratio [95% CI ]. The interaction between clopidogrel and simvastatin was not significant (p= ). Initial CT 10 hours later Page 8. F7 ICH-1371 Trial design: Ultra-Early Hemostatic Multi-center, randomized, double-blind, Therapy for ICH parallel group, placebo-controlled trial <3 hours 60 mins 24 hours 90 days GOAL: to limit ongoing bleeding and Placebo N = 100 Clinical outcome Mortality reduce ICH volume in a substantial mRS. Barthel Index rFVIIa E-GOS. proportion of patients 40 g/kg NIHSS. GCS. N = 100 Efficacy Euro-QOL. N = 400. Use as the emergency room counterpart patients randomized Baseline CT scan rFVIIa Percent Change in ICH volume at 24 hours Safety 80 g/kg Adverse events of t-PA for Acute ischemic Stroke N = 100 until discharge Serious adverse events Trial agent: Recombinant factor VIIa CTs performed rFVIIa 160 g/kg until day 90.

10 At baseline, 24 N = 100. and 72 hours NovoSeven ICH Trial NovoSeven ICH Trial Mayer SA, NEJM 2005. Estimated Mean Percent Change in Survival at 90 Days According to Study Group ICH Volume at 24 Hours Bars represent confidence Percent intervals Change in ICH RR = relative reduction Volume by Treatment 70 70. 65 65. 60 60. 55 55. 50 50. 45 45. 40 40. 35 35. 30 30. 25. 29% 25. 20 20. 15 15. 10. 16% 14%. 10. 5. 11% 5. 0 0. -5 -5. -10 -10. -15 -15. -20 -20. Placebo 40 ug/kg rFVIIa 80 ug/kg rFVIIa 160 ug/kg rFVIIa 45% RR 52% RR 62% RR. NovoSeven ICH Trial Mayer, S. et al. N Engl J Med 2005;352:777-785. Mayer SA, NEJM 2005. Page 9. Modified Rankin Scale at Day 90. FAST Trial 160 g/kg Phase III Trial of rFVIIa in Acute ICH. FAST trial under way globally since May 2005;. 80 g/kg mRS 0-1 completed in November 2006.