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“As it pertains to CME, I have the following relationships to disclose”

Verbal Disclosure Statement. “As it pertains to CME, I have the following relationships to disclose”. 2010 UPDATE: Stroke Treatment and Prevention. Souvik Sen MD, MS, MPH, FAHA, Professor and Chair, USC Neurology, Columbia, South Carolina. Financial Disclosures:.

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“As it pertains to CME, I have the following relationships to disclose”

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  1. Verbal Disclosure Statement “As it pertains to CME, I have the following relationships to disclose”

  2. 2010 UPDATE:Stroke Treatment and Prevention. Souvik Sen MD, MS, MPH, FAHA, Professor and Chair, USC Neurology, Columbia, South Carolina

  3. Financial Disclosures: Salary and Research Support: American Heart Association University of South Carolina South Carolina Center of Economic Excellence Additional income from honoraria as speaker: Bristol Myers Squibbs/Sanofi-Aventis BoehringerIngelheim Additional income from consultancy: Coaxia Inc. FDA unapproved drug or device will not be discussed

  4. American Heart AssociationLevels of Evidence(Stroke 2007; 38:1655-1711) Level A Multiple randomized trials positive and low false-negative errors Level B Single Randomized trial or non- randomized studies Level C Consensus of experts

  5. Early Management of Ischemic Stroke:Level A Consistent Evidence (Stroke 2007; 38:1655-1711) • Benefit • Imaging (CT) prior to treatment • IV rt-PA < 3 hrs (3-4.5 hrs) • Aspirin within 24-48 hrs (IV tPA after 24 hrs) • Stroke unit care • Subcutaneous anticoagulation for DVT prophylaxis • No Benefit • Anticoagulation • Intravenous streptokinase • Hemodilution • Pentoxifylline • Neuroprotection

  6. Pooled analysis of ATLANTIS, ECAS I & II, and NINDS t-PA trials(Lancet 2004; 363: 768-74) Odds of favorable outcome at 3 mos t-PA vs control

  7. NINDS vs ECASS III NEJM 1995; 333:1581-1587, NEJM 2008; 359:1317-1329

  8. Aspirin for Acute Ischemic StrokeInternational Stroke Trial Lancet 1997; 349:1569-1581 Chinese Acute Stroke Trial Lancet 1997; 349:1641-1649 Aspirin within the first 48 hours prevents 10 deaths or recurrent strokes per 1000 patients during the first 2-4 weeks Level A Evidence for Efficacy

  9. Prevention of Deep Venous Thrombosis in Patients with Acute Ischemic Stroke P Sandercock, C Counsell, SL Stobbs: Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke.Cochrane Database of Systematic Reviews 2006 Issue 4 • Low-molecular-weight heparin (LMWH) or heparinoid was associated with a significant reduction in DVT (OR 0.52, 95% CI 0.35 to 0.79, 2p = 0.002). • There were too few Pulmonary Emboli to provide reliable evidence on whether or not the observed trend in favor of LMWH or heparinoid (OR 0.53, 95% CI 0.20 to 1.39) was merely due to the play of chance. • However, if a larger trial confirmed these results, the absolute benefits might be substantial: PE might be avoided in about an extra 20 patients per 1000 patients treated with danaparoid or LMWH. Level A Evidence for Efficacy

  10. Stroke Unit • A disease-specific service provided by a discrete stroke ward or stroke team working exclusively in the care of stroke patients. • The service can be based in a geographically discrete ward or comprise a peripatetic team.

  11. Organized inpatient stroke unit care for acute stroke Cochrane Database Syst Rev 2007 Oct 17; CD000197. Thirty-one trials, involving 6936 participants, compared stroke unit care with an alternative service Stroke unit care showed reductions in the odds of death recorded at median one year follow up (OR 0.86, p = 0.02), death or institutional care (OR 0.82, p = 0.0006) death or dependency (OR 0.82, p = 0.001). Level A Evidence for Efficacy

  12. Mortality reduction occurs in 1st two weeks Stroke Unit Trialists' Collaboration. Stroke. 1997;28:2139-2144

  13. COMPARATIVE EFFECTIVENESS Gilligan AK, Thrift AG, Sturm JW, Dewey HM, Macdonell RA, Donnan GA: Stroke units, tissue plasminogen activator, aspirin and neuroprotection: which stroke intervention could provide the greatest community benefit? Cerebrovasc Dis 2005; 20:239–44.

  14. Level I evidence from multiple randomized controlled trials of over 20,000 heterogeneous patients with ischemic stroke have provided definitive, unequivocal evidence that Acute anticoagulation with heparin, low molecular weight heparin or heparinoids DOES TRIPLE THE RISK OF MAJOR EXTRACRANIAL HEMORRHAGE Cochrane Database Syst Rev 2004; CD000024.

  15. Other Management Issues for which there is less Evidence (Stroke 2007; 38:1655-1711) • General Management • Swallowing/Aspiration • Supplemental Oxygen • Temperature • Cardiac Monitoring • Blood Pressure • Blood Glucose • Cerebral Edema • Acute Interventions • Intravenous Thrombolysis after 4.5 hours • Intra-arterial Thrombolysis • Mechanical Thrombectomy

  16. Intra-arterial ThrombolysisPROACT IIJAMA 1999; 282:2003-2011 • Randomized, open label trial of 9 mg intra-arterial recombinant prourokinase (r-proUK) plus heparin vs heparin alone • Acute stroke < 6 hours duration caused by arteriographically documented MCA stem occlusion

  17. PROACT IIJAMA 1999; 282:2003-2011 • Intent-to-Treat Analysis - Primary endpoint • 40% of r-proUK+heparin vs 25% heparin only achieved good outcome (mRS < at 90 days, p=.04) • On Treatment Analysis – Primary Endpoint • 42% of r-proUK+heparin vs 27% heparin only achieved good outcome (mRS < at 90 days, p=.053) • Secondary endpoints • None of 6 achieved p< .15 uncorrected

  18. Intra-arterial Therapies for Acute Ischemic StrokeNeurology 2007; 68:2132-2139. Data from 27 reports of outcomes in 1117 treated patients compared to predicted outcomes based on model derived from placebo arms of 16 randomized trials Compared to predicted, treated patients had Fewer deaths by 0.25 +/- 3.5 % More bad outcome by 0.15 +/- 2.7%% In other words, there was no significant difference between the treated and untreated patients when adjusted for age and stroke severity (NIHSS)

  19. Mechanical Embolectomy in Acute Ischemic Stroke within 8 Hours Results of the Uncontrolled MERCI Trial Stroke 2005; 36: 1432-1438 MERCI vs. PROACT II Controls RecanalizationDeathSymptomatic ICH MERCI 46% 33% 7.8% PROACT 18% 27% 2% Controls

  20. The Penumbra System™ Intracranial Large Vessel Revascularization within 8 hours - An uncontrolled Trial

  21. Related Trial Comparisons*90 Day Mortality 1 2 3 PROACT II Controls (n=59) 4 1. Stroke 2005;36:1432. 2. AJNR 2006;27:1177. 3. JAMA1999;282:2003. 4. N. Eng J M 2004;351:2170 * Population observation rates, and 95% Exact Binomial Confidence Intervals

  22. Related Trial Comparisons*mRS ≤ 2 at 90 Days 1 2 3 PROACT II Controls (n=59) 4 1. Stroke 2005;36:1432. 2. AJNR 2006;27:1177. 3. JAMA1999;282:2003. 4. N. Eng J M 2004;351:2170 * Population observation rates, and 95% Exact Binomial Confidence Intervals

  23. Early Management of Ischemic Stroke:Level A Consistent Evidence • Benefit • rt-PA (< 4.5 hours) • Aspirin • DVT Prophylaxis • Stroke unit care • No Benefit • Anticoagulation • Intravenous streptokinase • Hemodilution • Pentoxifylline • Neuroprotection

  24. PREVENTION

  25. Secondary Stroke Prevention:Level A Consistent Evidence (Stroke 2006; 37:577-617) Benefit Antiplatelet therapy Warfarin for (Atrial Fibrillation) Target INR 2.0-3.0 Aspirin 325 mg/day (if Warfarin contraindicated) Antihypertensive treatment (Diuretic or ACEI) Statins (independent of LDL) Smoking cessation Endarterectomy for symptomatic moderate carotid stenosis (50-99%)

  26. STROKE EPIDEMIOLOGY National  South Carolina 

  27. STROKE AND TIA • STROKE: SUDDEN ONSET neurological deficit of presumed VASCULAR ORIGIN > 24 hrs duration. • TIA: <24 hrs duration. Most TIAs last <20 minutes but may last up to 1 hour.

  28. Transient Ischemic Attack (TIA) 1707 patients with TIA identified by emergency department physicians 1.0 Stroke 10.5% .9 Probability of Survival Free From Stroke and Adverse Events .8 Adverse events 25.1% (stroke, cardiovascular hospitalization, death, or recurrent TIA) .7 .6 0 7 30 90 60 Days After TIA Johnston SC et al. JAMA. 2000;284:2901-2906.

  29. TIA risk stratification • Age (≥ 60 years = 1) • Blood Pressure (>140 and/or ≥90 = 1) • Clinical features: (Weakness = 2) (Slurred speech = 1) • Duration: (≥60 min = 2) (10-59 min = 1) 7-day risk of stroke: <5: 0.4% 5: 12.1% 6: 31.4% Lancet 2005; 366:29-36

  30. Recurrent Vascular EventsSummary of Preventing Vascular Events After Stroke over 5 Years1. For implementing diet, exercise, aspirin, statins & antihypertensive therapy: A. Cumulative Risk Reduction= 80%B. NNT= 52. For implementing an intensifiedapproachwith diet, exercise, modified-release aspirin/dipyridamole, high-dose statins, and aggressive blood pressure control: A. Cumulative Risk Reduction= 90%B. NNT= 5Source: Hackam KG, Spence DJ. Stroke 2007; 38: 1881-85NNT= number-needed-to-treat to save 1 major vascular event

  31. Stroke Subtypes Hemorrhagic Stroke (20%) Ischemic Stroke (80%) Atherothrombotic large vessel (20%) Intracerebral Hemorrhage (60%) Cryptogenic (15%) Others (20%) Cardiac Embolism (20%) Subarachnoid Hemorrhage (40%) Lacunar (25%) Small vessel disease Albers GW, et al. Chest. 1998;114:683S-698S. Rosamond WD, et al. Stroke. 1999;30:736-743.

  32. ~68% ~17% • Noncardioembolic or TIA • Atherothrombotic • Lacunar • Unknown High-risk Cardioembolic Antiplatelet Anticoagulant Stroke Classification Albers GW, et al. Chest. 2004;126:483S­512S.

  33. CAPRIE: Clopidogrel vs Aspirin (MI, Stroke, or Vascular Death) 8.7%* Aspirin 16 Overall Relative RiskReduction2 Aspirin 5.83%1 Clopidogrel 12 Cumulative Risk (%) P=.045 8 5.32%1 Clopidogrel 4 0 36 0 3 6 9 12 15 18 21 24 27 30 33 Time After Randomization (months) • *ITT analysis. • CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

  34. CAPRIE: Subpopulations Stroke 7.3 MI -3.7 PAD 23.8 All 8.7 Relative Risk Reduction (%) -40 40 Clopidogrel better Aspirin better A test of heterogeneity was statistically significant (p= 0.042) Reprinted with permission from Elsevier (TheLancet. 1996;348:1329-1339).

  35. ESPS-2: Treatment Arms N=6602 Placebo (n=1649) ASA 25 mg bid (n=1649) ER-DP 200 mg bid (n=1654) ASA/ER-DP 25 mg ASA/200 mg ER-DP bid (n=1650) Diener HC, et al. J Neurol Sci. 1996;143:1-13.

  36. ESPS 2: Primary Outcome 40 30 20 10 0 Prevention of Fatal and Nonfatal Stroke 37.0% p<0.001 23.1% p=0.006 18.1% p=0.013 16.3% p=0.039 Relative Risk Reductions (%) ER-DP vs. Placebo ASA vs. Placebo ASA/ER-DP vs. ASA ASA/ER-DP vs. Placebo ESPS 2 Group. J Neurol Sci 1997;151(suppl):S1-S77.

  37. MATCH: Primary Endpoint IS, MI, VD, Rehospitalization for Acute Ischemic Event 0.20 Placebo + clopidogrel Overall Risk Reduction RRR: 6.4% P=0.244 0.16 ASA + clopidogrel Cumulative Event Rate 0.12 0.08 N=7,599 0.04 0.00 0 3 6 9 12 15 18 Months of Follow-up Adapted from Diener HC, et al. Lancet. 2004;364:331-337.

  38. MATCH: Safety Clopidogrel (n=3,781) Clopidogrel + ASA (n=3,759) Bleeding Complications 289 300 7.7% 169 200 4.5% Number of patients with events 110 120 96 73 2.9% 71 100 3.2% 2.6% 49 1.9% 39 1.9% 22 1.3% 1.0% 0.6% 0 Minor Major Life- threatening Major + Life-threatening All p<0.0001 for all hemorrhagic complications categories. Diener HC et al. Lancet. 2004;364: 331-337.

  39. PRoFESS Study Group (Sacco RL et al). Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238-51

  40. Clopidogrel PRoFESS Study Group (Sacco RL et al). Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238-51

  41. Atrial Fibrillation and Stroke:Summary of Randomized Studies Warfarin Aspirin Placebo 67% 8 % decrease in events 42% 72% 7 6 79% 26% 7.4% 5 6.3% 5.5% % Stroke/Year 86% 5.5% 4 4.5% 4.3% 3 3.6% 3.0% 2.9% 2 2.3% 1 0.9% 0.8% 0.4% 0 AFASAK SPAF1 SPAF2 BAATAF CAFS SPINAF Morley J, et al. Am J Card. 1996;77:38A-44A.

  42. CHADS2 Stroke Risk Stratification for Patients With Nonvalvular AF Relationship between CHADS2 score and annual risk of stroke Stroke Rate (%) CHADS2 Score Hersi A and Wyse DG. Curr Probl Cardiol. 2005;30:175–234.

  43. ACTIVE-W *stroke, non-CNS systemic embolism, myocardial infarction, or vascular death ** includes severe and fatal hemorrhage Conclusion: Warfarin is superior to the combination of clopidogrel and ASA for prevention of vascular events in patients with atrial fibrillation at high risk of stroke Connolly SJ et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial. Lancet. 2006; 367:1903-12.

  44. ACTIVE-A *stroke, non-CNS systemic embolism, myocardial infarction, or vascular death ** includes severe and fatal hemorrhage Conclusion:Addition of Clopidogrel to ASA reduced the risk of vascular events (specially stroke) but increased the risk of hemorrhage Connolly SJ et al. Effect of Clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360.

  45. AFFIRM Trial Design: AFFIRM was a multi-center randomized trial of rhythm control (n=2,033) vs rate control (n=2,027) in patients with atrial fibrillation and a high risk of stroke or death. Patients were followed for 5 years. The primary endpoint was all-cause mortality. • Results • All cause mortality did not differ between the rate and rhythm control arms • Hospitalization rate was higher in the rhythm control arm (80% vs 73%, P<0.001) • Conclusion • There is no survival benefit to the strategy of rhythm control in elderly patients with atrial fibrilation • Limitations • Trial enrolled high-risk elderly patients; extrapolation of results to other subgroups may not be appropriate *Composite of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest. N Engl J Med. 2002;347:1825-1833.

  46. STATINS IN STROKE PREVENTION WOSCOPS ALLHAT AFCAPS/ TexCAPS CARDS Primary Prevention No Prior Stroke/TIA Secondary Prevention Prior Stroke/TIA 4S TNT LIPID Secondary Prevention Prior CHD IDEAL CARE MIRACL GREACE PROSPER HPS SPARCL Primary Prevention No Prior CHD ASCOT

  47. JUPITER TRIAL • N=17,802 • LDL <130 mg /dL • hs-CRP ≥2.0 mg /L • Rosuvastatin 20 mg Ridker et al, N Engl J Med. 2008 Nov 20;359(21):2195-207

  48. Cardiac disorders in stroke • EKG, Holter and event monitoring • Echocardiography Transesophageal echo • ACAD: Stress testing  Catheterization

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