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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