1. Anne E. O’Duffy, MD Assistant Professor of Neurology Stroke Division Vanderbilt University Medical Center February 12, 2007 Stroke Prevention –What is New?

2. Vanderbilt Stroke News JCAHO certified primary stroke center, Nov. 2005JCAHO certified primary stroke center, Nov. 2005 4 members of the Vanderbilt Neurology Stroke Division are the only Board Certified Vascular Neurologists in the state of TN4 members of the Vanderbilt Neurology Stroke Division are the only Board Certified Vascular Neurologists in the state of TN

6. Stroke Mortality

7. Stroke Subtypes

11. 61 year-old man with history of HTN, afib, prior stroke 2001, abrupt onset right hemiparesis 6:50PM while at work, global aphasia, INR 1.661 year-old man with history of HTN, afib, prior stroke 2001, abrupt onset right hemiparesis 6:50PM while at work, global aphasia, INR 1.6 CT outside ER: hyperdense MCA signCT outside ER: hyperdense MCA sign

13. We (Still) Must Focus on PREVENTION!

14. Stroke Prevention Stroke, February, 2006. AHA/ASA/AAN guidelines on stroke prevention in patients with TIA and strokeStroke, February, 2006. AHA/ASA/AAN guidelines on stroke prevention in patients with TIA and stroke Summary with guidelines and levels of evidenceSummary with guidelines and levels of evidence Well-referenced, single sourceWell-referenced, single source

16. Stroke Risk and BP UK-TIA trial BMJ 313 (1996), p. 147

17. Hypertension Commonest stroke risk factor, 50 million Americans, undertreatedCommonest stroke risk factor, 50 million Americans, undertreated HOPE suggested that ACE-I ramipril reduced stroke, MI, vascular death by 22% greater than placebo (32% reduction in stroke)HOPE suggested that ACE-I ramipril reduced stroke, MI, vascular death by 22% greater than placebo (32% reduction in stroke) Yusef,et al NEJM 2000; 342: 145-153Yusef,et al NEJM 2000; 342: 145-153 LIFE 1° stroke prevention trial in high- risk pts losartin better than atenololLIFE 1° stroke prevention trial in high- risk pts losartin better than atenolol Dahlof et al Lancet 2002; 359: 995-1003Dahlof et al Lancet 2002; 359: 995-1003

18. Hypertension PROGRESS 2° stroke prevention in 6105 patients w/ hx stroke/TIA (irregardless of history of HTN) perindopril w/ or w/o indapamide vs placebo found 28% reduction in stroke in ‘active tx’ arm and 43% reduction w/combination therapyPROGRESS 2° stroke prevention in 6105 patients w/ hx stroke/TIA (irregardless of history of HTN) perindopril w/ or w/o indapamide vs placebo found 28% reduction in stroke in ‘active tx’ arm and 43% reduction w/combination therapy Lancet, Vol. 358: September 29,2001Lancet, Vol. 358: September 29,2001

19. PROGRESS Results:

20. BP BPchange Stroke reduction (95% CI) (95% CI) NNT for 1 yr 1 yr (mm/Hg) All Patients 9/4 9/4 28% (17, 38) 28% (17, 38) 115 115 Perindopril only 5/3 5/3 5% (-19, 23) 5% (-19, 23) - Both agents 12/5 12/5 43% (30, 54) 43% (30, 54) 70 70

21. Hypertension ALLHAT trial: 33,000 pts w/ HTN and 1 other vascular risk factor tx w/ chlorthalidone, lisinopril or amlodipineALLHAT trial: 33,000 pts w/ HTN and 1 other vascular risk factor tx w/ chlorthalidone, lisinopril or amlodipine No differences in 1° outcome measures of fatal or non-fatal MI, chlorthalidone was better than lisinopril in preventing stroke and combined vascular endpoint of stroke, MI, and PVDNo differences in 1° outcome measures of fatal or non-fatal MI, chlorthalidone was better than lisinopril in preventing stroke and combined vascular endpoint of stroke, MI, and PVD Nearly 30% pts were black and thus more likely to do better w/ diureticsNearly 30% pts were black and thus more likely to do better w/ diuretics JAMA, December 18,2002—Vol 288,no 23,2981-97JAMA, December 18,2002—Vol 288,no 23,2981-97

22. Hypertension Specific BP agent may be less important than BP lowering for stroke preventionSpecific BP agent may be less important than BP lowering for stroke prevention The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure—The JNC 7 ReportThe Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure—The JNC 7 Report JAMA, May 21, 2003—Vol 289, No. 19, 2560-72JAMA, May 21, 2003—Vol 289, No. 19, 2560-72

23. Lipid Lowering Statins very effective in stroke reduction in pts w/ CAD:Statins very effective in stroke reduction in pts w/ CAD: –4S, CARE, LIPID trials shown 19-28% reduction in stroke outcomes in CAD pts SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) 2° stroke prevention, NEJM 2006; 355:549-559SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) 2° stroke prevention, NEJM 2006; 355:549-559

24. SPARCL Results, Stroke

25. SPARCL 4731 pts. w/cerebrovascular disease, no known CAD were randomized to 80 mg atorvastatin vs. placebo4731 pts. w/cerebrovascular disease, no known CAD were randomized to 80 mg atorvastatin vs. placebo Mean f/up 4.9 yearsMean f/up 4.9 years 16% RRR of recurrent stroke16% RRR of recurrent stroke Absolute RR 2.2%Absolute RR 2.2%

26. Women’s Estrogen for Stroke Trial (WEST) Randomized, double-blind, placebo- controlled trial of estrogen therapy in 664 postmenopausal women who had recently had an ischemic stroke or TIA, mean follow-up of 2.8 yearsRandomized, double-blind, placebo- controlled trial of estrogen therapy in 664 postmenopausal women who had recently had an ischemic stroke or TIA, mean follow-up of 2.8 years Results: Estrogen therapy did not reduce the risk of death alone, or of nonfatal stroke:Results: Estrogen therapy did not reduce the risk of death alone, or of nonfatal stroke:

27. WEST Results

28. Women’s Health Initiative (WHI) Defining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal womenDefining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women 16,608 women, primary outcome was CHD16,608 women, primary outcome was CHD Study stopped early after mean follow-up of 5.2 years based on health risks that exceeded benefitsStudy stopped early after mean follow-up of 5.2 years based on health risks that exceeded benefits JAMA.2002;288:321-333 JAMA.2002;288:321-333

29. WHI Results for Stroke

30. WHI Results HR’s for CHD 1.29, breast cancer 1.26, stroke 1.41, PE 2.13, colorectal ca 0.63, endometrial ca 0.83, hip fractures 0.66, other deaths 0.92HR’s for CHD 1.29, breast cancer 1.26, stroke 1.41, PE 2.13, colorectal ca 0.63, endometrial ca 0.83, hip fractures 0.66, other deaths 0.92 Absolute excess risks per 10,000 person- yrs: 7 more CHD events, 8 more strokes (4800 total strokes/yr est.), 8 more PE’s, 8 more invasive breast ca’sAbsolute excess risks per 10,000 person- yrs: 7 more CHD events, 8 more strokes (4800 total strokes/yr est.), 8 more PE’s, 8 more invasive breast ca’s Absolute risk reductions: 6 fewer colorectal ca’s, 5 fewer hip fracturesAbsolute risk reductions: 6 fewer colorectal ca’s, 5 fewer hip fractures

31. Antithrombotic Therapy

34. Rate vs. Rhythm? AFFIRM:Atrial Fibrillation Follow-up Investigation of Rhythm ManagementAFFIRM:Atrial Fibrillation Follow-up Investigation of Rhythm Management >4000 high-risk patients w/afib>4000 high-risk patients w/afib Rhythm control just as likely to suffer ischemic stroke over 3.5 yrs. as those who receive rate control aloneRhythm control just as likely to suffer ischemic stroke over 3.5 yrs. as those who receive rate control alone Warfarin reduced stroke by 68%Warfarin reduced stroke by 68% –Presented at AAN, Honolulu, HI, PI Sherman,DG,

39. ESPRIT Lancet 2006;367:1665-1673Lancet 2006;367:1665-1673 2763 pts. w/TIA or minor stroke randomized to low dose aspirin (30- 325mg) with or w/out dipyridamole2763 pts. w/TIA or minor stroke randomized to low dose aspirin (30- 325mg) with or w/out dipyridamole Mean f/up 3.5 yearsMean f/up 3.5 years 20% RRR in vascular death, non-fatal stroke or MI20% RRR in vascular death, non-fatal stroke or MI 1% absolute RR per year1% absolute RR per year

40. ESPRIT Results

43. MATCH Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic strokeManagement of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke Plavix + aspirin vs Plavix alone in high-risk stroke/ TIA patients (MI, DM, PVD)Plavix + aspirin vs Plavix alone in high-risk stroke/ TIA patients (MI, DM, PVD) 7599 pts, 500+ centers, 28 countries7599 pts, 500+ centers, 28 countries 15.7% of patients taking clopidogrel + ASA had a further ischemic event vs 16.73% of patients taking clopidogrel + placebo (p=.244)15.7% of patients taking clopidogrel + ASA had a further ischemic event vs 16.73% of patients taking clopidogrel + placebo (p=.244)

44. MATCH Results

45. Endpoint Placebo + Plavix ASA + Plavix RRR (95% CI) P value Primary 636 (16.73%) 596 (15.7%) 6.4(-4.6,16.3)0.244 MI 62 (1.63%) 59 (1.55%) Ischemic stroke 319 (8.39%) 299 (7.87%) CV death 74 (1.95%) 69 (1.82%) Rehosp. 181 (4.76%) 169 (4.45%)

46. MATCH Results Life threatening bleeding 2.6 vs 1.3%Life threatening bleeding 2.6 vs 1.3% P < 0.001 Raises serious concern about use of combination anti-platelet agents in stroke patientsRaises serious concern about use of combination anti-platelet agents in stroke patients

47. CHARISMA NEJM 2006;354:1706-1717NEJM 2006;354:1706-1717 15,603 pts. with vascular disease (27% stroke) randomized to clopidogrel vs. placebo plus aspirin15,603 pts. with vascular disease (27% stroke) randomized to clopidogrel vs. placebo plus aspirin Clopidogrel no more effective than placebo in aspirin treated pts.Clopidogrel no more effective than placebo in aspirin treated pts. Increased bleeding complications with combinationIncreased bleeding complications with combination

48. CHARISMA Results

49. PRoFESS Prevention Regimen For Effectively avoiding Second StrokesPrevention Regimen For Effectively avoiding Second Strokes 2 x 2 factorial design: Aggrenox vs. clopidogrel with or w/out Micardis (telmesartan)2 x 2 factorial design: Aggrenox vs. clopidogrel with or w/out Micardis (telmesartan) N= 18,000N= 18,000 Adults, >55 yrs, ischemic stroke within 90 daysAdults, >55 yrs, ischemic stroke within 90 days Enrollment period 2 yrs, study duration 4 yrs.Enrollment period 2 yrs, study duration 4 yrs.

51. SPS3 (Secondary Prevention of Small Subcortical Strokes) Multicenter phase III randomized 2x2 controlled trialMulticenter phase III randomized 2x2 controlled trial 2500 patients2500 patients 325 mg aspirin vs aspirin + clopidogrel325 mg aspirin vs aspirin + clopidogrel Targeted BP control: usual (systolic 130- 149) vs. aggressive (systolic <130)Targeted BP control: usual (systolic 130- 149) vs. aggressive (systolic <130) Primary efficacy outcome: recurrent stroke during mean follow-up 3 yrs.Primary efficacy outcome: recurrent stroke during mean follow-up 3 yrs. Secondary outcomes: cognitive status, major vascular events, deathSecondary outcomes: cognitive status, major vascular events, death

52. IRIS (Insulin Resistance Intervention after Stroke) Patients with recent stroke/TIA who are found to be insulin resistant are treated with pioglitazone vs. placebo for 4 yearsPatients with recent stroke/TIA who are found to be insulin resistant are treated with pioglitazone vs. placebo for 4 years Enrolling pts. > 45 years old, no hx. CHFEnrolling pts. > 45 years old, no hx. CHF

53. “A strategy to reduce cardiovascular disease by more than 80%” Simultaneously reduce four CV risk factors (LDL cholesterol, BP, homocysteine, platelet function)Simultaneously reduce four CV risk factors (LDL cholesterol, BP, homocysteine, platelet function) 10mg atorvastatin or 40mg simvastatin, 3 BP meds at half-strength (thiazide, beta-blocker, ACE-I), 0.8mg folic acid, 75mg aspirin10mg atorvastatin or 40mg simvastatin, 3 BP meds at half-strength (thiazide, beta-blocker, ACE-I), 0.8mg folic acid, 75mg aspirin 1/3 people would benefit from “the Polypill”, gaining average of 11 yrs free from IHD or stroke1/3 people would benefit from “the Polypill”, gaining average of 11 yrs free from IHD or stroke –NJ Wald, MR Law, BMJ Vol 326: 28 June, 2003

54. Conclusions While acute stroke interventions capture our imagination, the most significant impact on reducing the devastation of stroke remains it’s prevention.While acute stroke interventions capture our imagination, the most significant impact on reducing the devastation of stroke remains it’s prevention. The data is convincing, and yet has not been fully disseminated to physicians and patients.The data is convincing, and yet has not been fully disseminated to physicians and patients.