Medical Prevention of Stroke November 17, 2000

1. Medical Prevention of Stroke November 17, 2000 Ash Singhal University of Toronto

2. Objectives • Prevention • What are the most effective stroke prevention strategies? • Management of Symptomatic Patients • endarterectomy • warfarin • antiplatelet drugs

3. How common is stroke?

4. Important Stroke Stats to Remember • A stroke occurs every minute • Leading cause of adult neurological disability • 4th leading cause of death • Longest length of hospital stay • Leading cause of transfer to long-term care

5. Stroke Prevention The Modifiable Risk Factors

6. The Asymptomatic Patient

7. Encourage Risk Factor Modification • Hypertension (increases stroke risk 4x) • Smoking (increases stroke risk 1.5x) • Diabetes • Physical inactivity, obesity • Serum cholesterol • ?Homocysteine

8. Hypertension • Strongest link as a risk factor • 42% risk reduction • benefit seen within 12 months • optimal SBP/DBP unknown • recommendation: <140/85

9. Smoking • 50% increase in stroke risk • rates normalize after only 2-4 years • this is regardless of age/pack years

10. Diabetes • Progression of risk by severity • stroke risk stratified by HgA1C • goal is normoglycemia

11. Alcohol I’ll have a double rye n’ coke...

12. Physical Activity • Lesser impact risk factor • Even modest activity beneficial • 20 minutes 3 times/week • Graded benefit with more activity • Little/no effect for women

13. Cholesterol • Well documented factor for M.I. • Less clear in stroke • Statins reduce risk up to 20%

14. Homocysteine • Circulating amino acid • 1997: JAMA, NEJ articles • under 60, top quintile • adjusted OR 1.2 • folic acid, B6, B12 reduce serum levels • VISP trial

15. The Symptomatic Patient TIA or completed stroke

16. Etiology Determines Treatment • Need to search for underlying cause(s) • Carotid Endarterectomy for high-grade symptomatic stenosis • Anticoagulation for cardioembolic events • Antiplatelet therapy for large and small vessel arteriosclerosis

17. Symptomatic Carotid Stenosis • 70-99% - surgery • 50-69% - ? • <50% - no surgery

18. Carotid Endarterectomy is Extremely Effective • NASCET Study • 2-year stroke risk: 26% with medical Rx vs. 9% with carotid surgery • RRR 65% • NNT = 6 to prevent one stroke in 2 years

19. Carotid Angioplasty and Stenting: An Emerging Treatment • 2 RCTs to begin this year: • CREST (n=2400) • SAPHIRE (n=600, only high risk pts)

20. Cardioembolic Events • Atrial fibrillation most important factor • others include: • recent anterior MI • artificial heart valves • severe dyskinetic sections (on Echocardiography) • PFO

21. Atrial Fibrillation • Most important cardiac factor • 6 large clinical trials • 3-16%/year risk of stroke • best estimate: 5%/year • stratification important

22. Rat Poison • SPAF SPAF SPAF • 70% RR for Warfarin (INR=2-3) • 20% RR for ASA • 1%/year risk major bleeding • increases by 1%/INR point

23. Antiplatelet Therapy • ASA • Ticlopidine (Ticlid) • Clopidogrel (Plavix) • Dipyridamole • Dipyridamole + ASA (Aggrenox) • Other combinations? • MATCH trial: ASA 75mg + Plavix 75mg vs.Plavix 75mg

24. New Recommendations • American College of Chest Physicians 2001: • ASA or Plavix or Aggrenox can be first line agents for secondary stroke prevention

25. Antiplatelet Trialists’ Collaboration • Meta-analysis of 145 trials • 70,000 high-risk patients • Antiplatelet drugs reduced risk of composite outcome of ischemic stroke, MI, or vascular death by 27% in high-risk patients • Relative odds reduction was consistent: • Over a wide range of clinical manifestations (CAD, CVD, PVD) • Across subsets of patients at varying risks within specific clinical disorders Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106

26. Antiplatelet Trialists’ Collaboration Antiplatelet therapyControl 25 22% odds reduction 20 25% oddsreduction 29% oddsreduction 27% oddsreduction 15 Patients with stroke, MI, orvascular death (%) 32% oddsreduction 10 5 0 Priorstroke/TIA Acute MI Prior MI Otherhigh risk Allhigh risk Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106

27. Aspirin • rapid onset of action • 30 mg sufficient for antiplatelet effect in lab • Optimal dose controversial • Low dose (50-325 mg) now recommended for stroke prevention by FDA

28. ACE TrialPrevention of Vascular Events Following Carotid Endarterectomy 10 p=0.030 p=0.120 9 8.4% 8 Low-dose (N=1,395) (81 or 325 mg) 7.1% 7 6.2% 5.7% 6 High-dose (N=1,409) (650 or 1,300 mg) Event rate (%) 5 4 3 2 1 0 Stroke or death at 3 months Stroke, MI, or death at 3 months Taylor DW, et al. Lancet 1999;353:2179-2184

29. Advantages and Disadvantages of ASA Advantages • Proven efficacy in patients having suffered a TIA or minor stroke (when compared with placebo) • Cost of daily treatment • Generally well tolerated • Efficacy can be increased if combined with other antiplatelet drugs Disadvantages • Gastrointestinal discomfort • Bleeding • Low relative risk reduction Unanswered questions • Does the beneficial effect of aspirin persist after longer follow-up and should aspirin be prescribed for life?

30. Advantages and Disadvantages of Ticlopidine Advantages • Modest superiority over ASA • No GI ulceration Disadvantages • Onset of action 48 hrs, max 8–11 days • 1% risk of neutropenia, small risk TTP • Requires monitoring for the first 3 months • 10% incidence of diarrhea, rash, dyspepsia Dose • 250 mg bid with meals

31. Clopidogrel in the Secondary Prevention of Stroke Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) • Clopidogrel 75 mg/day versus ASA 325 mg/day • >19,000 patients divided equally into three groups according to qualifying condition • Ischemic stroke • MI • Peripheral arterial disease • 1–3 year follow-up CAPRIE Steering Committee. Lancet 1996;348:1329-1339

32. Clopidogrel: Primary Analysis RRR 8.7% (p=0.043) intent-to-treat analysis RRR 9.4% on-treatment analysis Stroke MI Othervasculardeath Totalfirstevents Eventrate/year Non-fatal Fatal Non-fatal Fatal Treatmentgroup Clopidogrel 405 33 226 49 226 939 5.32% ASA 430 32 270 63 226 1,021 5.83% CAPRIE Steering Committee. Lancet 1996;348:1329-1339

33. 8.7 7.3 - 3.7 23.8 Clopidogrel: RRR byQualifying Condition* * Qualifying condition at entry PAD = peripheral arterial disease All events Stroke MI PAD - 40 - 30 - 20 - 10 0 10 20 30 40 ASA better Clopidogrel better Relative-risk reduction (%) CAPRIE Steering Committee. Lancet 1996;348:1329-1339

34. = = Clopidogrel: Clinically Important*Adverse Events ASA Rash Clopidogrel Clopidogrel 75 mg/day (n=9,599) ASA 325 mg/day (n=9,586) Diarrhea Indigestion/nausea/ vomiting Any bleeding disorder Intracranial hemorrhage * Severe = Statistically significant (p<0.05) Gastrointestinal hemorrhage 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Incidence (%) Adapted from CAPRIE Steering Committee. Lancet 1996;348:1329-1339

35. Advantages and Disadvantages of Clopidogrel Advantages • Proven efficacy “modest” compared with ASA in patients with stroke, MI or PAD • Well tolerated Disadvantages • Cost of daily treatment Unanswered questions • Is the combination of clopidogrel plus ASA superior to ASA alone? • Is clopidogrel more efficacious than ASA in stroke and myocardial infarction subgroups? • Is clopidogrel associated with thrombocytopenic purpura?