Clinical OverviewClinical Overview

Director, Stanford Stroke Center Director, Stanford Stroke Center Stanford UniversityStanford UniversityPalo Alto, CaliforniaPalo Alto, California

Gregory W. Albers, MDGregory W. Albers, MD

Ischemic StrokeIschemic Stroke

85% of strokes are ischemic85% of strokes are ischemic

Most ischemic strokes caused by atherosclerosis Most ischemic strokes caused by atherosclerosis of extracranial or intracranial arteriesof extracranial or intracranial arteries– Embolic or thrombotic occlusion of cerebral Embolic or thrombotic occlusion of cerebral

blood vessels by aggregated platelets, fibrin, blood vessels by aggregated platelets, fibrin, and debris from atheromatous plaquesand debris from atheromatous plaques

The Most Frequent Sites of Arterial and The Most Frequent Sites of Arterial and Cardiac Abnormalities Causing Ischemic Cardiac Abnormalities Causing Ischemic StrokeStroke

IntracranialIntracranialAtherosclerosisAtherosclerosis

Carotid Plaque WithCarotid Plaque WithArteriogenic EmboliArteriogenic Emboli

Aortic ArchAortic ArchPlaquePlaque

CardiogenicCardiogenicEmboliEmboli

PenetratingPenetratingArtery DiseaseArtery Disease

Flow ReducingFlow ReducingCarotid StenosisCarotid Stenosis

Atrial FibrillationAtrial Fibrillation

Valve DiseaseValve Disease

Left VentricularLeft VentricularThrombiThrombi

Albers et al, Albers et al, Chest,Chest, 1998. 1998.

Transient Ischemic AttackTransient Ischemic Attack

Transient occlusion of an intracranial arteryTransient occlusion of an intracranial arterydue to thromboembolismdue to thromboembolism

Symptoms resolve following rapid fragmentation Symptoms resolve following rapid fragmentation and dissolution of the microemboli/thrombusand dissolution of the microemboli/thrombus

Stroke Morbidity and MortalityStroke Morbidity and Mortality

Leading cause of serious, long-term disabilityLeading cause of serious, long-term disability

Third leading cause of death in the U.S.;Third leading cause of death in the U.S.;second leading cause worldwidesecond leading cause worldwide

Accounts for >50% of all hospitalizationsAccounts for >50% of all hospitalizationsfor acute neurologic diseasefor acute neurologic disease

Stroke IncidenceStroke Incidence

>700,000 new or recurrent strokes per year>700,000 new or recurrent strokes per year

~ 4 million Americans are living with neurologic ~ 4 million Americans are living with neurologic deficits due to strokedeficits due to stroke

The High Cost of StrokeThe High Cost of Stroke

Annual TotalAnnual Total

19981998 Per Event*Per Event*

Direct CostsDirect Costs $28B$28B $38,714$38,714(care and treatment)(care and treatment)

Indirect CostsIndirect Costs $15B$15B $20,520$20,520(lost productivity)(lost productivity)

TotalTotal $43B$43B $59,234$59,234

*Based on 731,000 strokes/yr*Based on 731,000 strokes/yr

American Heart Association. American Heart Association. 1998 Heart and Stroke Statistical Update1998 Heart and Stroke Statistical Update. Dallas, TX:AHA, 1997. . Dallas, TX:AHA, 1997. Broderick J et al. Broderick J et al. Stroke.Stroke. 1998;29:415–421. 1998;29:415–421.

Secondary PreventionSecondary Preventionof Ischemic Strokeof Ischemic Stroke

Carotid endarterectomy: >50% stenosisCarotid endarterectomy: >50% stenosis

Anticoagulation therapy: Cardioembolic strokeAnticoagulation therapy: Cardioembolic stroke

Antiplatelet therapy: Most common therapyAntiplatelet therapy: Most common therapy

Antiplatelet AgentsAntiplatelet Agentsfor Stroke Preventionfor Stroke Prevention

AspirinAspirin

TiclopidineTiclopidine

ClopidogrelClopidogrel

DipyridamoleDipyridamole

PatientPatient Relative RiskRelative Risk OddsOddsPopulationPopulation TherapyTherapy Reduction (%)Reduction (%) Reduction (%) Reduction (%)

Efficacy of Antiplatelet AgentsEfficacy of Antiplatelet Agentsfor Prevention of Stroke, MI,for Prevention of Stroke, MI,or Vascular Deathor Vascular Death

All VascularAll Vascular All antiplateletAll antiplatelet 2222 2727DiseasesDiseases regimensregimens

Stroke/TIAStroke/TIA All antiplateletAll antiplatelet 1717 2222regimensregimens

Stroke/TIAStroke/TIA AspirinAspirin 1313 1616

Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.Source: Antiplatelet Trialists’ Collaboration, 1994: Algra and Van Gijn 1996.

Risk ReductionsRisk Reductions

Efficacy of Antiplatelet Agents vs Placebo for Efficacy of Antiplatelet Agents vs Placebo for Prevention of Stroke, MI, or Vascular Death in Prevention of Stroke, MI, or Vascular Death in Stroke/TIA PatientsStroke/TIA Patients

Aspirin (all doses)Aspirin (all doses) 1010 1313

TiclopidineTiclopidine 11 2323

Dipyridamole + ASADipyridamole + ASA 44 3030

All Antiplatelet AgentsAll Antiplatelet Agents 1818 1717

Relative RiskRelative Risk Antiplatelet Agent Antiplatelet Agent No. of Studies No. of Studies Reduction (%)Reduction (%)

Source: Algra and Van Gijn 1996; Gent et al.Source: Algra and Van Gijn 1996; Gent et al.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.1989; Tijssen, 1998; Antiplatelet Trialists’ Collaboration, 1994.

Algra and van Gijn (1996) Algra and van Gijn (1996) J Neurol Neurosurg PsychiatrJ Neurol Neurosurg Psychiatr 60:197–199. 60:197–199.

0.40.460%60%

0.60.640%40%

0.80.820%20%

110%0%

1.21.2-20%-20%

1.41.4-40%-40%

1.61.6-60%-60%

RR and 95% CIRR and 95% CI

ASA ASA 100 mg 100 mg(2 Studies)(2 Studies)

ASA ASA 900 mg 900 mg(7 Studies)(7 Studies)

ASA 300 mgASA 300 mg(1 Study)(1 Study)

ALLALL(10 Studies)(10 Studies)

RR = 13%RR = 13%

RR = 9%RR = 9%

RR = 14%RR = 14%

RR = 13%RR = 13%Low vs Med:Low vs Med: P P = 0.75= 0.75Low vs High:Low vs High: P P = 0.99= 0.99Med vs High:Med vs High: P P = 0.71= 0.71

Relative Risk Reductions for VascularRelative Risk Reductions for VascularDeath, Stroke, MI from ASA Trials vs Placebo Death, Stroke, MI from ASA Trials vs Placebo in Stroke/TIA Patientsin Stroke/TIA Patients

Stroke or DeathStroke or Deathat 3 Monthsat 3 Months

Stroke, MI, or Death Stroke, MI, or Death at 3 Monthsat 3 Months

00112233445566778899

1010

Low-Dose (N = 1395)Low-Dose (N = 1395)(81 or 325 mg)(81 or 325 mg)

High-Dose (N = 1409)High-Dose (N = 1409)(650 or 1300 mg)(650 or 1300 mg)

Eve

nt

Rat

e (%

)E

ven

t R

ate

(%)

5.7%6.2%

7.1%

8.4%P = 0.030P = 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 TRIALACE TRIAL

Aspirin Efficacy by DoseAspirin Efficacy by DosePrevention of Vascular Events Following Carotid EndarterectomyPrevention of Vascular Events Following Carotid Endarterectomy

FDA RecommendsFDA RecommendsLow-Dose AspirinLow-Dose Aspirin FDA reviewed trials of aspirin vs placeboFDA reviewed trials of aspirin vs placebo

The The “positive findings at lower dosages“positive findings at lower dosagesare sufficient reason to lower the dosageare sufficient reason to lower the dosageof aspirin...for subjects with TIAof aspirin...for subjects with TIAand ischemic stroke.”and ischemic stroke.”

For For “ischemic stroke and TIA: 50 to 325 mg“ischemic stroke and TIA: 50 to 325 mg [aspirin] once a day. Continue therapy indefinitely.”[aspirin] once a day. Continue therapy indefinitely.”

FDA, Federal Register. 1998.63:56802–56819.FDA, Federal Register. 1998.63:56802–56819.

New Aspirin Dosing Guidelines New Aspirin Dosing Guidelines for Secondary Stroke Preventionfor Secondary Stroke Prevention

FDA FDA

New professional labeling for aspirin New professional labeling for aspirin recommends 50 to 325 mg/dayrecommends 50 to 325 mg/day

American College of Chest Physicians American College of Chest Physicians

Aspirin at 50 to 325 mg/day as an initial choiceAspirin at 50 to 325 mg/day as an initial choice

American Heart AssociationAmerican Heart Association

[50–325 mg/day proposed][50–325 mg/day proposed]

Available Antiplatelet AgentsAvailable Antiplatelet Agents

TiclopidineTiclopidine

AdvantagesAdvantages– Proven efficacy in patients having sufferedProven efficacy in patients having suffered

an ischemic stroke (compared with placebo)an ischemic stroke (compared with placebo)– Proven efficacy in patients having suffered a TIAProven efficacy in patients having suffered a TIA

or minor stroke (compared with high-dose ASA)or minor stroke (compared with high-dose ASA)

DisadvantagesDisadvantages– Risk of neutropeniaRisk of neutropenia– Risk of thrombotic thrombocytopenic purpura (TTP)Risk of thrombotic thrombocytopenic purpura (TTP)– Require CBC monitoringRequire CBC monitoring– Diarrhea/RashDiarrhea/Rash

Available Antiplatelet Agents (Available Antiplatelet Agents (Cont’dCont’d))

ClopidogrelClopidogrel

AdvantagesAdvantages– Proven efficacy compared with ASA in patients Proven efficacy compared with ASA in patients

with stroke, MI, or PADwith stroke, MI, or PAD– Well-toleratedWell-tolerated

DisadvantagesDisadvantages– Efficacy for TIA not provenEfficacy for TIA not proven– Not more efficacious than ASA in the stroke Not more efficacious than ASA in the stroke

and myocardial infarction subgroupsand myocardial infarction subgroups

Relative Risk Reduction vs AspirinRelative Risk Reduction vs Aspirin

7%

21%*

9%

23%* 22%*

8%

00

55

1010

1515

2020

2525

StrokeStroke Stroke/MI/Vascular DeathStroke/MI/Vascular Death††

Rel

ativ

e R

isk

Rel

ativ

e R

isk

Red

uct

ion

(%

)R

edu

ctio

n (

%)

Clopidogrel (CAPRIE, N = 6431)Clopidogrel (CAPRIE, N = 6431)

Ticlopidine (TASS, N = 3069)Ticlopidine (TASS, N = 3069)

ER-DP + ASA (ESPS-2, N = 3299)ER-DP + ASA (ESPS-2, N = 3299)

Efficacy of Antiplatelet Agents Efficacy of Antiplatelet Agents in Patients With Cerebrovascular Diseasein Patients With Cerebrovascular Disease

* Statistically significant.* Statistically significant.†† Represents stroke/MI/Sudden Death for ESPS-2.Represents stroke/MI/Sudden Death for ESPS-2.

Albers GW et al. Albers GW et al. ChestChest. 1998;114:683S–698S.. 1998;114:683S–698S.

ACCP Antiplatelet GuidelinesACCP Antiplatelet Guidelines

““Every patient who has experienced a [non-cardioembolic] Every patient who has experienced a [non-cardioembolic] stroke or TIA...should receive an antiplatelet agent.…”stroke or TIA...should receive an antiplatelet agent.…”

““Aspirin, clopidogrel...ticlopidine..., and the combinationAspirin, clopidogrel...ticlopidine..., and the combinationof aspirin and dipyridamole are all acceptable options for of aspirin and dipyridamole are all acceptable options for initial therapy.”initial therapy.”

““Clopidogrel is recommended in favor of ticlopidine Clopidogrel is recommended in favor of ticlopidine because it has a lower incidence of significant adverse because it has a lower incidence of significant adverse effects.”effects.”

““The combination of dipyridamole and aspirin b.i.d. may The combination of dipyridamole and aspirin b.i.d. may be more effective than clopidogrel and has a similarly be more effective than clopidogrel and has a similarly favorable adverse effect profile.”favorable adverse effect profile.”

Summary and ConclusionsSummary and Conclusions

Antiplatelet agents are effective in the secondary Antiplatelet agents are effective in the secondary prevention of non-fatal stroke and deathprevention of non-fatal stroke and death

Currently approved antiplatelet regimens provideCurrently approved antiplatelet regimens providea modest reduction in riska modest reduction in risk

More effective and safe treatment options for stroke More effective and safe treatment options for stroke prevention and its devastating consequences are prevention and its devastating consequences are neededneeded