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

Objectives n Prevention u What are the most effective stroke prevention strategies? n Management of Symptomatic Patients u endarterectomy u warfarin u antiplatelet drugs

How common is stroke?

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

Stroke Prevention The Modifiable Risk Factors

The Asymptomatic Patient

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

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

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

Diabetes n Progression of risk by severity n stroke risk stratified by HgA1C n goal is normoglycemia

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

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

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

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

The Symptomatic Patient TIA or completed stroke

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

Symptomatic Carotid Stenosis n 70-99% - surgery n 50-69% - ? n <50% - no surgery

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

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

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

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

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

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

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

Antiplatelet Trialists’ Collaboration s Meta-analysis of 145 trials s 70,000 high-risk patients s Antiplatelet drugs reduced risk of composite outcome of ischemic stroke, MI, or vascular death by 27% in high-risk patients s 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

Antiplatelet Trialists’ Collaboration Antiplatelet Trialists’ Collaboration. BMJ 1994;308: Prior stroke/TIA Acute MI Patients with stroke, MI, or vascular death (%) Antiplatelet therapy Control Prior MIOther high risk All high risk 22% odds reduction 29% odds reduction 25% odds reduction 32% odds reduction 27% odds reduction

Aspirin n rapid onset of action n 30 mg sufficient for antiplatelet effect in lab n Optimal dose controversial n Low dose ( mg) now recommended for stroke prevention by FDA

Taylor DW, et al. Lancet 1999;353: ACE Trial Prevention of Vascular Events Following Carotid Endarterectomy Stroke or death at 3 months Stroke, MI, or death at 3 months Low-dose (N=1,395) (81 or 325 mg) High-dose (N=1,409) (650 or 1,300 mg) Event rate (%) 5.7% 6.2% 7.1% 8.4% p=0.030 p=0.120

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

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

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

Clopidogrel: Primary Analysis Treatment group Stroke Non- fatal Fatal MI Non- fatal Fatal Other vascular death Total first events Event rate/ year Clopidogrel % ASA , % RRR 8.7% (p=0.043) intent-to-treat analysis RRR 9.4% on-treatment analysis CAPRIE Steering Committee. Lancet 1996;348:

Clopidogrel: RRR by Qualifying Condition* * Qualifying condition at entry PAD = peripheral arterial disease ASA betterClopidogrel better Relative-risk reduction (%) All events Stroke MI PAD CAPRIE Steering Committee. Lancet 1996;348:

Incidence (%) Clopidogrel: Clinically Important* Adverse Events Clopidogrel 75 mg/day (n=9,599) ASA 325 mg/day (n=9,586) Indigestion/nausea/ vomiting Gastrointestinal hemorrhage Rash Diarrhea Any bleeding disorder Intracranial hemorrhage ASA Clopidogrel = = Adapted from CAPRIE Steering Committee. Lancet 1996;348: * Severe = Statistically significant (p<0.05)

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