STROKE PREVENTION- A REALITY IN THIS MILLENNIUM

1. STROKE PREVENTION- A REALITY IN THIS MILLENNIUM Prof. A.V. SRINIVASAN, MD, DM, Ph.D, F.A.A.N, F.I.A.N. Emeritus Professor The Tamilnadu Dr. M.G.R. Medical University Former Head Institute of Neurology, Madras Medical College 21-08-10

2. Is survival a mere stroke of Luck? Cerebrovascular Prevention “My Opinions are founded on knowledge but modified by experience”

3. INTRODUCTION • Perceptual Sense (Observation) • Word Sense (Recording) • Common Sense (Thinking) • Will lead you to get - Clinical Sense “ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy

4. Cerebrovascular disease – Mind boggling facts • World wide incidence: 2/1000 population/annum1 • Incidence in people aged 45 – 84 years: about 4/10001 • Incidence in India: was 36/100,000 for the year 1998-19993 in a study in Calcutta • Incidence of mortality due to stroke (India: WHO study): 73/100,000 per year2 CVD is the most disabling of all neurologic diseases. 50% of survivors have a residual neurologic deficit. Greater than 25% require chronic care. 1.A practical approach to management of stroke patients; 1996; 360-384 2. Epidemology of cerebrovascular disorders in India; 1999; 4-19 3. Neuroepidemiology 2001;20:201-207 If you think you can or you can’t You are always right

5. Annual risk CVD, MI, vascular death following TIA, minor CVD • CVD 6.7 % • MI 2.5 % • Death 7.2 % • CVD, MI, Vascular death 8.6 % • CVD, MI, Death 10.3 % Experience can be defined as yesterday’s answer to today’s problems

6. Common Stroke Mimics • Hypoglycemia • Post ictal state • Drug overdose • Concussion with neck injury • Migrainous accompaniment • Encephalopathies with focal signs • Hyponatremia • Subdural hematoma, Empyema • Focal Encephalitis: Herpes Being ignorant is not so much a shame as being unwilling to learn

7. Drugs used for stroke prevention… ACE inhibitors Lipid lowering agent Anti-platelets

8. Prevention of Cerebrovascular Events with Perindopril: New Evidence

9. Why ACE inhibitors in stroke prevention ? • Blood pressure lowering effect • Prevention of endothelial dysfunction • Prevention of progression of atherosclerosis • Favourable alteration of the fibrinolytic balance • Prevention of cardiac remodelling Clinical evidence…

10. Objective of PROGRESS Whether in patients with… Stroke TIA OR Perindopril + Indapamide Risk of stroke & vascular events WHO – ISH initiated the study PROGRESS collaborative group. Lancet 2001;358:1033-41.

11. Patient selection criteria Evidence of Stroke / TIA > 2 weeks and < 5 years of event …but without a definite indication / contraindication to treatment with an ACE inhibitor PROGRESS collaborative group. Lancet 2001;358:1033-41.

12. Patient selection criteria Young Diabetic Non-diabetic Included Normotensive Hypertensive Old PROGRESS collaborative group. Lancet 2001;358:1033-41.

13. Baseline characteristics Perindopril + indapamide N = 3051 Placebo N = 3054 Characteristic Mean age (yrs) Females (%) Stroke history • Ischaemic stroke (%) • Haemorrhagic stroke (%) • TIA (%) • Duration since event (months) Diabetes (%) CAD (%) Mean BP (mmHg) Hypertension (%) Antihypertensive therapy (%) 64 30 71 11 22 8 13 16 147/86 48 50 64 30 71 11 22 8 12 16 147/86 48 51 PROGRESS collaborative group. Lancet 2001;358:1033-41.

14. Total stroke 28% risk reduction Placebo group Risk reduction (%) 38% Active group 0 1 2 3 4 Years PROGRESS collaborative group. Lancet 2001;358:1033-41.

15. Stroke subtype (1) Fatal / disabling stroke Non fatal / disabling stroke 24 33 Risk reduction (%) PROGRESS collaborative group. Lancet 2001;358:1033-41.

16. Stroke subtype (2) Ischaemic stroke Haemorrhagic stroke 24 50 Risk reduction (%) PROGRESS collaborative group. Lancet 2001;358:1033-41.

17. Hypertensives / normotensives Stroke Hypertensives Normotensives 27 32 Risk reduction (%) PROGRESS collaborative group. Lancet 2001;358:1033-41.

18. Treatment acceptability Active group Placebo 23 Causes of withdrawal (%) 21 8 8 2 2 0.9 0.4 All causes Voluntary Cough Hypotension PROGRESS collaborative group. Lancet 2001;358:1033-41.

19. PROGRESS results showed… • Perindopril + indapamide substantially reduced risk of secondary stroke and other vascular events Irrespective of • Age • Blood pressure level • Other diseases • Background medication PROGRESS collaborative group. Lancet 2001;358:1033-41.

20. Summarise… • ACE inhibitors are beneficial in the prevention of stroke • All stroke patients, hypertensive as well as normotensives should receive an ACE inhibitor • All CAD patients, diabetic patients, who are at-risk of developing stroke should receive an ACE inhibitor Which ACE inhibitor ?

21. Which ACE inhibitor ? Perindopril-based therapy Treatment Number-needed-to-treat 23 to prevent 1 stroke in 5 years 67 to prevent 1 stroke in 5 years Ramipril-based therapy JNC – 7 reference only to perindopril Stroke 2002;33:862-875. JNC-7, JAMA May 2003 – Vol.289; No.19: 2560-2571.

22. Statins: Stroke Prevention and Survival Benefits

23. Primary Prevention of Ischemic StrokeA Guideline From the American Heart Association/American StrokeAssociation Stroke Council It is recommended that patients with known CAD and high-risk hypertensive patients even with normal LDL cholesterol levels be treated with lifestyle measures and a statin (Class I, Level of Evidence A). Stroke 2006;37;1583-1633

24. JUPITER & STROKE JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C hsCRP predicts cardiovascular disease independent of LDL-C levels

25. JUPITER Trial Design JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) 4-week run-in Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:2292-2297.

26. JUPITER: Results No. of patients with any stroke 48% Reduction * n=8901 n=8901 Circulation 2010;121:143-150 * p< 0.002 vs. placebo

27. JUPITER: Results No. of patients with non-fatal stroke 48% Reduction * n=8901 n=8901 Circulation 2010;121:143-150 * p< 0.003 vs. placebo

28. JUPITER: Results 50% Reduction No. of patients with fatal stroke 6 6 5 4 3 3 2 1 0 Rosuvastatin Placebo n=8901 n=8901 Circulation 2010;121:143-150

29. JUPITER: Results 47 50 45 51% 48% Reduction 40 35 30 23 25 20 15 10 5 0 Rosuvastatin Placebo No. of patients with ischemic stroke * n=8901 n=8901 Circulation 2010;121:143-150 * p< 0.004 vs. placebo

30. Primary Prevention of Stroke: What do the previous statins trials suggest?

31. WOSCOPS STUDY: Statin: Pravastatin 40 mg n=6595 Results: Stroke 11% MEGA STUDY: Statin: Pravastatin 10-20 mg n=7730 Results: Stroke 17% AFCAPS/TexCAPS STUDY: Statin: Lovastatin 10-40 mg n=6605 Results: Stroke 18% JUPITER STUDY: Statin: Rosuvastatin 20 mg n=17802 Results: Stroke 48% Circulation 2010;121:143-150

32. A meta-analysis of WOSCOPS+AFCAPS/TexCAPS+MEGA • Stroke reduction by 14% (statistically non-significant) • A meta-analysis of these 3 trials along with JUPITER • Stroke reduction by 25% (statistically significant) Analysis of JUPITER only: Stroke reduction by 48% (statistically non-significant)

33. Summary Stroke is one of the leading cause of death worldwide. Guidelines recommends the use of statins for primary as well as secondary prevention of stroke. JUPITER trial has established that rosuvastatin is the most effective statin in preventing stroke in high risk population.

34. Symptomatic Carotid Endarterectomy ASA 2006 Secondary Stroke Recs • Ipsilateral severe (70% to 99%) carotid stenosis, CEA is recommended (Class I, Evidence A). • Ipsilateral moderate (50% to 69%) carotid stenosis, CEA is recommended depending on age, gender, comorbidities, and the severity of symptoms (Class I, Evidence A). • Stenosis <50%, there is no indication for CEA (Class III, Evidence A).

35. Urgent Endarterectomy Surgery within 2 weeks is suggested rather than delaying surgery (Class IIa, Evidence B). Rothwell PM. Lancet 2004;363(9413):915-24

36. Carotid Angioplasty and StentingASA 2006 Secondary Stroke Recs • CAS may be considered (Class IIb, Evidence B). • - Stenosis (>70%) difficult to access surgically • - Medical conditions that greatly increase the risk for surgery, or • - When other circumstances exist such as radiation-induced stenosis or restenosis after CEA. • CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).

37. Atrial FibrillationASA 2006 Recommendations • For patients with ischemic stroke or TIA with persistent or paroxysmal (intermittent) AF, anticoagulation with adjusted-dose warfarin (target INR 2.5, range 2.0 to 3.0) is recommended (Class I, Evidence A). • For patients unable to take oral anticoagulants, aspirin 325 mg per day is recommended (Class I, Evidence A).

38. Stroke Prevention: Non-cardioembolic ASA 2006 Recommendations For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents are recommended rather than oral anticoagulation to reduce the risk of recurrent stroke and other cardiovascular events (Class I, Evidence A).

39. Stroke Prevention: Non-cardioembolic ASA 2006 Recommendations • Acceptable options for initial therapy • (Class IIa, Evidence A). • - aspirin (50-325 mg qd) • - the combination of aspirin and extended- release dipyridamole (25/200 mg bid) • - clopidogrel (75 mg qd)

40. Antiplatelet TherapyASA 2006 Recommendations • Compared to aspirin alone, both the combination of aspirin and extended-release dipyridamole and clopidogrel are safe. • The combination of aspirin and extended-release dipyridamole is suggested instead of aspirin alone (Class IIa, Level A). • Clopidogrel is suggested instead of aspirin alone based on direct comparison trials • (Class IIb, Level B).

41. Secondary Stroke PreventionASA 2006 Recommendations • Insufficient data are available to make evidence-based recommendations regarding choices between antiplatelet options other than aspirin. Selection of an antiplatelet agent should be individualized based on patient risk factor profiles, tolerance, and other clinical characteristics.

42. Secondary Stroke PreventionASA 2006 Recommendations • The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely recommended for stroke or TIA patients (Class III, Evidence A). • For patients allergic to aspirin, clopidogrel is recommended (Class IIa, Evidence B).

43. MATCH: Safety Outcomes • Excess life-threatening bleeding events with combination versus clopidogrel monotherapy: • 96 (2.6%) vs. 49 (1.3%); p<0.0001 • Excess minor bleeds with combination therapy versus clopidogrel alone: • 120 (3.2%) vs. 39 (1.0%); p<0.0001 Diener H-C et al. Lancet 2004;364:331-7

44. Secondary Stroke PreventionASA 2006 Recommendations • For patients who have an ischemic cerebrovascular event while taking aspirin, there is no reliable evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered for these patients, no single agent or combination has been specifically evaluated in patients who have had an event while receiving aspirin.

45. Stroke and Pregnancy ASA 2006 Secondary Stroke Recs • High-risk thromboembolic conditions consider: • - adjusted-dose UFH throughout pregnancy, • - adjusted-dose LMWH with Factor Xa monitoring • - UFH or LMWH until week 13, followed by warfarin until mid-3rd trimester, then UFH or LMWH in last trimester (Class IIb, Evidence C). • Lower risk conditions • - UFH or LMWH in the first trimester followed by - low-dose aspirin for the remainder of the pregnancy (Class IIb, Evidence C).

46. Postmenopausal Hormones ASA 2006 Secondary Stroke Recs For women with ischemic stroke or TIA, postmenopausal hormone therapy (with estrogen with or without a progestin) is not recommended (Class III, Evidence A).

47. Women’s Health Initiative • 16,608 postmenopausal women, 50-79 years, with an intact uterus at baseline were recruited by 40 U.S. clinical centers for the period 1993-1998. • Received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). • After a mean of 5.2 years of follow-up, the trial was stopped because of high rates of invasive breast cancer and the global index statistic supported risks exceeding benefits. Rossouw et al. JAMA 2002;288(3):321-33

48. Other CircumstancesASA 2006 Secondary Stroke Recs • Dissections • PFO and hyperhomocysteinemia • Hypercoagulable states • Sickle cell disease • Cerebral venous thrombosis • Anticoagulation after cerebral hemorrhage

49. Level A Recommendations • Antihypertensive treatment • Glucose control to reduce microvascular complications of diabetes • Statins to reduce LDL to <100 or <70 for high-risk patients (sympt CHD or athero) • CEA for sympt 50-99% • NO CEA for <50% sympt stenosis • Warfarin at INR 2.5 for Afib. (ASA if unable) • Antiplatelet for noncardioembolic • NO combination clopidogrel and ASA

50. Carotid Angioplasty and StentingASA 2006 Secondary Stroke Recs • CAS may be considered (Class IIb, Evidence B). • - Stenosis (>70%) difficult to access surgically • - Medical conditions that greatly increase the risk for surgery, or • - When other circumstances exist such as radiation-induced stenosis or restenosis after CEA. • CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).