Clinical Overview Gregory W. Albers, MD Director, Stanford Stroke Center Stanford University Palo Alto, California
Ischemic Stroke • 85% of strokes are ischemic • 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
The Most Frequent Sites of Arterial and Cardiac Abnormalities Causing Ischemic Stroke IntracranialAtherosclerosis PenetratingArtery Disease Carotid Plaque WithArteriogenic Emboli Flow ReducingCarotid Stenosis Aortic ArchPlaque Atrial Fibrillation Valve Disease CardiogenicEmboli Left VentricularThrombi Albers et al, Chest, 1998.
Transient Ischemic Attack • Transient occlusion of an intracranial arterydue to thromboembolism • Symptoms resolve following rapid fragmentation and dissolution of the microemboli/thrombus
Stroke Morbidity and Mortality • Leading cause of serious, long-term disability • Third leading cause of death in the U.S.;second leading cause worldwide • Accounts for >50% of all hospitalizationsfor acute neurologic disease
Stroke Incidence • >700,000 new or recurrent strokes per year • ~ 4 million Americans are living with neurologic deficits due to stroke
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.
Secondary Preventionof Ischemic Stroke • Carotid endarterectomy: >50% stenosis • Anticoagulation therapy: Cardioembolic stroke • Antiplatelet therapy: Most common therapy
Antiplatelet Agentsfor Stroke Prevention • Aspirin • Ticlopidine • Clopidogrel • Dipyridamole
Efficacy of Antiplatelet Agentsfor Prevention of Stroke, MI,or Vascular Death Risk Reductions Patient Relative Risk Odds Population Therapy Reduction (%) Reduction (%) All Vascular All antiplatelet 22 27Diseases regimens Stroke/TIA All antiplatelet 17 22 regimens Stroke/TIA Aspirin 13 16 Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.
Efficacy of Antiplatelet Agents vs Placebo for Prevention of Stroke, MI, or Vascular Death in Stroke/TIA Patients Relative Risk Antiplatelet Agent No. of Studies Reduction (%) Aspirin (all doses) 10 13 Ticlopidine 1 23 Dipyridamole + ASA 4 30 All Antiplatelet Agents 18 17 Source: Algra and Van Gijn 1996; Gent et al.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.
Relative Risk Reductions for VascularDeath, Stroke, MI from ASA Trials vs Placebo in Stroke/TIA Patients ASA 100 mg (2 Studies) RR = 13% ASA 300 mg (1 Study) RR = 9% RR = 14% ASA 900 mg (7 Studies) Low vs Med: P = 0.75Low vs High: P = 0.99Med vs High: P = 0.71 ALL (10 Studies) RR = 13% 0.4 60% 0.6 40% 0.8 20% 1 0% 1.2 -20% 1.4 -40% 1.6 -60% RR and 95% CI Algra and van Gijn (1996) J Neurol Neurosurg Psychiatr 60:197–199.
ACE TRIALAspirin Efficacy by DosePrevention of Vascular Events Following Carotid Endarterectomy 10 P = 0.030 P = 0.120 9 8.4% 8 Low-Dose (N = 1395) (81 or 325 mg) 7.1% 7 6.2% 5.7% 6 High-Dose (N = 1409) (650 or 1300 mg) Event Rate (%) 5 4 3 2 1 0 Stroke or Death at 3 Months Stroke, MI, or Death at 3 Months 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.
FDA RecommendsLow-Dose Aspirin • FDA reviewed trials of aspirin vs placebo • The “positive findings at lower dosagesare sufficient reason to lower the dosageof aspirin...for subjects with TIAand ischemic stroke.” • For “ischemic stroke and TIA: 50 to 325 mg [aspirin] once a day. Continue therapy indefinitely.” FDA, Federal Register. 1998.63:56802–56819.
New Aspirin Dosing Guidelines for Secondary Stroke Prevention • FDA • 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 • American Heart Association • [50–325 mg/day proposed]
Available Antiplatelet Agents • Ticlopidine • Advantages • Proven efficacy in patients having sufferedan ischemic stroke (compared with placebo) • Proven efficacy in patients having suffered a TIAor minor stroke (compared with high-dose ASA) • Disadvantages • Risk of neutropenia • Risk of thrombotic thrombocytopenic purpura (TTP) • Require CBC monitoring • Diarrhea/Rash
Available Antiplatelet Agents (Cont’d) • Clopidogrel • Advantages • Proven efficacy compared with ASA in patients with stroke, MI, or PAD • Well-tolerated • Disadvantages • Efficacy for TIA not proven • Not more efficacious than ASA in the stroke and myocardial infarction subgroups
Efficacy of Antiplatelet Agents in Patients With Cerebrovascular Disease Relative Risk Reduction vs Aspirin 25 23%* 22%* 20 21%* Relative RiskReduction (%) 15 10 9% 8% 7% 5 0 Stroke Stroke/MI/Vascular Death† Clopidogrel (CAPRIE, N = 6431) Ticlopidine (TASS, N = 3069) ER-DP + ASA (ESPS-2, N = 3299) * Statistically significant. † Represents stroke/MI/Sudden Death for ESPS-2.
ACCP Antiplatelet Guidelines • “Every patient who has experienced a [non-cardioembolic] stroke or TIA...should receive an antiplatelet agent.…” • “Aspirin, clopidogrel...ticlopidine..., and the combinationof 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.” • “The combination of dipyridamole and aspirin b.i.d. may be more effective than clopidogrel and has a similarly favorable adverse effect profile.” Albers GW et al. Chest. 1998;114:683S–698S.
Summary and Conclusions • Antiplatelet agents are effective in the secondary prevention of non-fatal stroke and death • Currently approved antiplatelet regimens providea modest reduction in risk • More effective and safe treatment options for stroke prevention and its devastating consequences are needed