1. Clinical Overview Director, Stanford Stroke Center Stanford University Palo Alto, California Gregory W. Albers, MD

2. Ischemic Stroke 85% of strokes are ischemic 85% of strokes are ischemic Most ischemic strokes caused by atherosclerosis of extracranial or intracranial arteries Most ischemic strokes caused by atherosclerosis of extracranial or intracranial arteries –Embolic or thrombotic occlusion of cerebral blood vessels by aggregated platelets, fibrin, and debris from atheromatous plaques

3. The Most Frequent Sites of Arterial and Cardiac Abnormalities Causing Ischemic Stroke Intracranial Atherosclerosis Carotid Plaque With Arteriogenic Emboli Aortic Arch Plaque Cardiogenic Emboli Penetrating Artery Disease Flow Reducing Carotid Stenosis Atrial Fibrillation Valve Disease Left Ventricular Thrombi Albers et al, Chest, 1998.

4. Transient Ischemic Attack Transient occlusion of an intracranial artery due to thromboembolism Transient occlusion of an intracranial artery due to thromboembolism Symptoms resolve following rapid fragmentation and dissolution of the microemboli/thrombus Symptoms resolve following rapid fragmentation and dissolution of the microemboli/thrombus

5. Stroke Morbidity and Mortality Leading cause of serious, long-term disability Leading cause of serious, long-term disability Third leading cause of death in the U.S.; second leading cause worldwide Third leading cause of death in the U.S.; second leading cause worldwide Accounts for >50% of all hospitalizations for acute neurologic disease Accounts for >50% of all hospitalizations for acute neurologic disease

6. Stroke Incidence >700,000 new or recurrent strokes per year >700,000 new or recurrent strokes per year ~ 4 million Americans are living with neurologic deficits due to stroke ~ 4 million Americans are living with neurologic deficits due to stroke

7. The High Cost of Stroke Annual Total 1998 Per Event* Direct Costs$28B$38,714 (care and treatment) Indirect Costs$15B$20,520 (lost productivity) Total$43B$59,234 *Based on 731,000 strokes/yr American Heart Association. 1998 Heart and Stroke Statistical Update. Dallas, TX:AHA, 1997. Broderick J et al. Stroke. 1998;29:415–421.

8. Secondary Prevention of Ischemic Stroke Carotid endarterectomy: >50% stenosis Carotid endarterectomy: >50% stenosis Anticoagulation therapy: Cardioembolic stroke Anticoagulation therapy: Cardioembolic stroke Antiplatelet therapy: Most common therapy Antiplatelet therapy: Most common therapy

9. Antiplatelet Agents for Stroke Prevention Aspirin Aspirin Ticlopidine Ticlopidine Clopidogrel Clopidogrel Dipyridamole Dipyridamole

10. PatientRelative RiskOdds PopulationTherapyReduction (%) Reduction (%) Efficacy of Antiplatelet Agents for Prevention of Stroke, MI, or Vascular Death All VascularAll antiplatelet2227 Diseasesregimens Stroke/TIAAll antiplatelet1722 regimens Stroke/TIAAspirin1316 Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996. Risk Reductions

11. Efficacy of Antiplatelet Agents vs Placebo for Prevention of Stroke, MI, or Vascular Death in Stroke/TIA Patients Aspirin (all doses)1013 Ticlopidine123 Dipyridamole + ASA430 All Antiplatelet Agents1817 Relative Risk Antiplatelet AgentNo. of Studies Reduction (%) Source: Algra and Van Gijn 1996; Gent et al. 1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.

12. Algra and van Gijn (1996) J Neurol Neurosurg Psychiatr 60:197–199. 0.460%0.640%0.820%10%1.2-20%1.4-40%1.6-60% RR and 95% CI ASA  100 mg (2 Studies) ASA  900 mg (7 Studies) ASA 300 mg (1 Study) ALL (10 Studies) RR = 13% RR = 9% RR = 14% RR = 13% Low vs Med:P = 0.75 Low vs High:P = 0.99 Med vs High:P = 0.71 Relative Risk Reductions for Vascular Death, Stroke, MI from ASA Trials vs Placebo in Stroke/TIA Patients

13. Stroke or Death at 3 Months Stroke, MI, or Death at 3 Months 0 1 2 3 4 5 6 7 8 9 10 Low-Dose (N = 1395) (81 or 325 mg) High-Dose (N = 1409) (650 or 1300 mg) Event Rate (%) 5.7% 6.2% 7.1% 8.4% P = 0.030 P = 0.120 Taylor DW, Thorpe KE, for the ACE Trial Study Group. Presented at The Challenge of Stroke; The Lancet Conference; October 15–16, 1998. Montreal, Quebec, Canada; 1998. ACE TRIAL Aspirin Efficacy by Dose Prevention of Vascular Events Following Carotid Endarterectomy

14. FDA Recommends Low-Dose Aspirin FDA reviewed trials of aspirin vs placebo FDA reviewed trials of aspirin vs placebo The “positive findings at lower dosages are sufficient reason to lower the dosage of aspirin...for subjects with TIA and ischemic stroke.” The “positive findings at lower dosages are sufficient reason to lower the dosage of aspirin...for subjects with TIA and ischemic stroke.” For “ischemic stroke and TIA: 50 to 325 mg [aspirin] once a day. Continue therapy indefinitely.” For “ischemic stroke and TIA: 50 to 325 mg [aspirin] once a day. Continue therapy indefinitely.” FDA, Federal Register. 1998.63:56802–56819.

15. New Aspirin Dosing Guidelines for Secondary Stroke Prevention FDA New professional labeling for aspirin recommends 50 to 325 mg/day New professional labeling for aspirin recommends 50 to 325 mg/day American College of Chest Physicians Aspirin at 50 to 325 mg/day as an initial choice Aspirin at 50 to 325 mg/day as an initial choice American Heart Association [50–325 mg/day proposed] [50–325 mg/day proposed]

16. Available Antiplatelet Agents Ticlopidine Advantages Advantages –Proven efficacy in patients having suffered an ischemic stroke (compared with placebo) –Proven efficacy in patients having suffered a TIA or minor stroke (compared with high-dose ASA) Disadvantages Disadvantages –Risk of neutropenia –Risk of thrombotic thrombocytopenic purpura (TTP) –Require CBC monitoring –Diarrhea/Rash

17. Available Antiplatelet Agents ( Cont’d ) Clopidogrel Advantages Advantages –Proven efficacy compared with ASA in patients with stroke, MI, or PAD –Well-tolerated Disadvantages Disadvantages –Efficacy for TIA not proven –Not more efficacious than ASA in the stroke and myocardial infarction subgroups

18. Relative Risk Reduction vs Aspirin 7% 21%* 9% 23%* 22%* 8% 0 5 10 15 20 25 Stroke Stroke/MI/Vascular Death † Relative Risk Reduction (%) Clopidogrel (CAPRIE, N = 6431) Ticlopidine (TASS, N = 3069) ER-DP + ASA (ESPS-2, N = 3299) Efficacy of Antiplatelet Agents in Patients With Cerebrovascular Disease * Statistically significant. † Represents stroke/MI/Sudden Death for ESPS-2.

19. Albers GW et al. Chest. 1998;114:683S–698S. ACCP Antiplatelet Guidelines “Every patient who has experienced a [non-cardioembolic] stroke or TIA...should receive an antiplatelet agent.…” “Every patient who has experienced a [non-cardioembolic] stroke or TIA...should receive an antiplatelet agent.…” “Aspirin, clopidogrel...ticlopidine..., and the combination of aspirin and dipyridamole are all acceptable options for initial therapy.” “Aspirin, clopidogrel...ticlopidine..., and the combination of aspirin and dipyridamole are all acceptable options for initial therapy.” “Clopidogrel is recommended in favor of ticlopidine because it has a lower incidence of significant adverse effects.” “Clopidogrel is recommended in favor of ticlopidine because it has a lower incidence of significant adverse effects.” “The combination of dipyridamole and aspirin b.i.d. may be more effective than clopidogrel and has a similarly favorable adverse effect profile.” “The combination of dipyridamole and aspirin b.i.d. may be more effective than clopidogrel and has a similarly favorable adverse effect profile.”

20. Summary and Conclusions Antiplatelet agents are effective in the secondary prevention of non-fatal stroke and death Antiplatelet agents are effective in the secondary prevention of non-fatal stroke and death Currently approved antiplatelet regimens provide a modest reduction in risk Currently approved antiplatelet regimens provide a modest reduction in risk More effective and safe treatment options for stroke prevention and its devastating consequences are needed More effective and safe treatment options for stroke prevention and its devastating consequences are needed

22. Risk Reductions Relative Risk: Relative Risk: Rate of events on drug A Rate of events on drug B Odds Ratio: Odds Ratio:# of pts with event on drug A# of pts with event on drug B # of pts without event on drug A # of pts without event on drug B 100 patients treated for 1 year: 5 strokes on drug A, 10 strokes on drug B Relative Risk:5%=.50Relative Risk = 50% 10%Reduction (1-relative risk) Odds Ratio:510 =.47Odds Reduction=53% 9590(1-odds ratio)  