Aspirin Resistance Uchil
Transcript of Aspirin Resistance Uchil
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Aspirin HistoryAspirin History
First synthesized in pure formby Felix Hoffman of Friedr.
Bayer & Co. in 1897.
(From the German(From the German aacetylcetylspirspirsaure + chemical suffix saure + chemical suffix inin))
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Aspirin HistoryAspirin History
Due to problems with the original Aspirin powder beingcounterfeited, it became the first pharmaceutical
agent ever sold in pill form in early 1900s.
First pill in USA was 5 grains (~325 mg).
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Aspirin Resistance Or Aspirin
Failure?
Aspirin Resistance Or Aspirin
Failure?
Dr. Lalit M. Uchil MD
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Educational ObjectivesEducational Objectives
Define Aspirin Resistance, Incidence and
Prevalence in the Population
Describe the Mechanisms for Aspirin
Resistance and Reduced Platelet Inhibition
Understand the Importance of Aspirin
Resistance Testing, Methods of Detection
Understand Clinical Implication and ClinicalDecisions in Aspirin Resistant Patients
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Vascular Disease in the U.S.Vascular Disease in the U.S.
1. American Heart Association. 2004 Heart Disease and Stroke Statistics.2. Brown et al. Amer. Stroke Assoc. 25th Int. Stroke Conference. 2000.
3. National Stroke Association Press Release. April 25, 2000.4. Hirsch AT et al. JAMA. 2001;286:11:1317-1324.
TIA = transient ischemic attack. ACS = acute coronary syndrome.PAD = peripheral arterial disease.
AnnualIncidence(Millions)
Prevalence(Millions)
Stroke 0.701
4.71
TIA 0.502
4.93
ACS 1.71* 14.2
1
PAD 8124
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0
5
10
15
20
25
30
1970 1980 1990 2000 2010 2020 2030 2040 2050
Number of
Patients
(Millions)
ACC/AHA Guidelines 2001, NHLBI Chartbook 2000 and Foot et al (JACC 2000)
12.4
24.6
U.S. Heart Disease Doublesin the Next Half Century
U.S. Heart Disease Doublesin the Next Half Century
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Costs of CardiovascularDiseases and Stroke
Costs of Cardiovascular
Diseases and Stroke
$214
$111.8
$49.4 $47.2$23.2
$329.2
0
$50
$100
$150
$200
$250
$300
$350
Heart disease CoronaryHeart
disease
Stroke Hypertensivedisease
Congestiveheart failure
Total CVD3
Billions
2
1 2002 estimates (USA)
2 American Heart Association. 2002 Heart and Stroke Statistical Update. 20013 CVD = cardiovascular disease
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Aspirin Usage In the US
Percentage of Use
37.6
23.3
13.812.2
14.1
0
10%
20%
30%
40%
HeartDisease
Arthritis Headache BodyAche
Other
26,000,000 Americans receivechronic aspirin therapy for
cardioprotection.
26,000,000 Americans receivechronic aspirin therapy for
cardioprotection.
A tith b ti T i li t C ll b tiA tith b ti T i li t C ll b ti
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Antithrombotic Trialists Collaboration(ATC): Efficacy of Antiplatelet Therapy
on Vascular Events
Antithrombotic Trialists Collaboration(ATC): Efficacy of Antiplatelet Therapy
on Vascular Events
Antithrombotic Trialists Collaboration. BMJ2002; 324: 7186.
*Vascular events = myocardial infarction, stroke or vascular death
Category % Odds Reduction
Acute myocardial infarction
Acute stroke
Prior myocardial infarction
Prior stroke/transient ischemic attackOther high risk
Coronary artery disease
(e.g. unstable angina, heart failure)
Peripheral arterial disease
(e.g. intermittent claudication)High risk of embolism (e.g. atrial fibrillation)
Other (e.g. diabetes mellitus)
All trials
1.00.50.0 1.5 2.0Control betterAntiplatelet better
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17.1
6.5
Plac. ASA0
5
10
15
20
%
ofPatients
UnstableAngina
25
11
Plac. ASA0
10
20
30
3.3
1.9
Plac. ASA0
1
2
3
4
11.8
9.4
Plac. ASA0
5
10
15
Acute Myocardial Infarction
RISC Group. Lancet
1990;336:827-30.
Roux etal. JACC
1992;19:671-7.
ISIS-2. Lancet
1988;2:349-60.
ISIS-2. Lancet
1988;2:349-60.
Aspirin in Acute CoronarySyndromes
Aspirin in Acute CoronarySyndromes
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Aspirin in Acute CoronarySyndromes
Aspirin in Acute CoronarySyndromes
12.9
3.9
Plac. ASA0
5
10
15
11.9
3.3
Plac. ASA0
5
10
15
12.9
6.2
Plac. ASA0
5
10
15
2.2
1.3
Plac. ASA0
0.5
1
1.5
2
2.5
%
ofPatients
Unstable AnginaPrimaryPrevention
StableAngina
PHS. NEJM1989;321:129-35
Ridker etal. AJC1991;114:835-9.
Theroux, etal. NEJM1988;319:1105-11.
Cairns, etal. NEJM1985;313:1369-75.
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on Vascular Events in High-RiskPatients
on Vascular Events in High-Risk
Patients
* Odds reduction.
Treatment effect P
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Clopidogrel+ ASA
(N=6259)
ASA
(N=6303)
ASA Dose:
200 mg (N=2301) 3.7% 4.9%
Major Bleeding at 1 year byASA Dose
Major Bleeding at 1 year byASA Dose
CURE
P-Value
Peters RJG, et al. Circulation2003;108:1682-1687
BRAVO Bl di B ASABRAVO Bl di B ASA
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BRAVO: Bleeding By ASAdose
BRAVO: Bleeding By ASAdose
Topol EJ, et al. Circulation. 2003;108:399-406.
Outcomes by Aspirin Dose in Placebo Study Drug Patients
Low Dose,75-162 mg/d
(n=2410)
Higher Dose,162-326 mg/d
(n=2179)
Primary end point 16.4 18.6
Death, MI, stroke 6.2 6.1
Death 2.8 1.7
MI 2.0 2.1
Stroke 2.1 2.8
Internal bleeding 2.4 3.3Any bleeding 11.1 15.4
Transfusion 1.0 2.0
C di lC di l
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CardiovascularDisease
CardiovascularDisease
Aspirin is proven to reduce death, MI, stroke inpatients with all types of cardiovascular disease
Inexpensive, widely available
Dosing now focused on low-dose (75-81 mg) foroptimal efficacy / safety balance
However Does one dose fit all?
Is there Aspirin resistance? Are there clinical consequences of Aspirin
resistance?
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ASA Resistance: KeyQuestions
ASA Resistance: KeyQuestions
Does a standardized definition exist?
Are there reliable tests to diagnose this
phenomenon?What are the possible mechanisms and
future implications?
Does it have any clinical significance?How do we manage patients with
Aspirin resistance?
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Established PlateletFunction Tests
Established PlateletFunction Tests
Harrison P. Br J Hematology2000;111:733-744
Platelet Function Test
Bleeding time
Aggregometry-turbidometric
methods
Aggregometry-impedance
methods
Aggregometry &
luminescence
Adenine nucleotides
Thromboelastography (TEG)
Glass filterometer
Platelet release markers
In Vivo screening test
Responsiveness to panel agonists
Responsiveness to panel agonists
Combined aggregation and ADP
release
Stored and released ADP
Global Hemostasis
High shear platelet function
In vivo platelet activation markers
Advantages
Physiological
Diagnostic
Whole blood test
More information
Sensitive
Predicts bleeding
Simple
Simple, systemic
measure of platelet
activation
Disadvantages
Insensitive, invasive & high
variability
Labor intensive & non-
physiological
Insensitive
Semi-quantitative
Specialized equipment
Measures clot properties
only, insensitive to ASA
Requires blood counter
Prone to artifact
Plt Function TestPlt Function Test DisadvantagesDisadvantagesAdvantagesAdvantagesAssayAssay
l l il l i
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Newer Platelet FunctionTests
Newer Platelet FunctionTests
(PFA)-100 Whole blood + Primary Limited range-most pts
hemostasis after GP IIb/IIIa inhibitors have
(high shear closure times >300 sec, so
may
adhes/aggreg) not be able to discern diff. Used
to assay ADP antagonist
Clot Signature Whole blood + Adhesion, Large instrument for routine use
Analyzer aggregation and interpretation of results is
complex
Rapid platelet Whole blood + Aggregation GP IIb/IIa: baseline sample req.
function assay Clinical outcome data (GOLD)Aspirin: AA-like agonist
Harrison P. Br J Hematology2000;111:733-744Mukherjee D & Moliterno DJ. Clin Pharmacokinet2000;39(6): 445-458
Flow cytometry Whole blood - Platelet GP, Flexible & powerful. Requiresactivation markers, specialized operator. Expensive
Platelet function
AssayAssay Substrate BedsideSubstrate Bedside PrinciplePrinciple CommentsComments
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Prevalence of ASAResistance
Prevalence of ASAResistance
Gum PA et al.Am J Cardiol2001;88:230-235
ASA-R: mean aggregationASA-R: mean aggregation 70% with M 10 ADP &70% with M 10 ADP & 20% with 0.5 mg/ml AA20% with 0.5 mg/ml AA
325 patients with stable CVD taking ASA 325 mg >7days325 patients with stable CVD taking ASA 325 mg >7days
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Wang JC et al. Amer J Cardiol2003;92:1492-4
422 patients presenting to cardiac cath lab on ASA 81-325 mg >7d422 patients presenting to cardiac cath lab on ASA 81-325 mg >7d
Prevalence of AspirinResistance
Prevalence of AspirinResistance
23.4% Aspirin non-responsive
Accumetrics VerifyNow Aspirin
Definition: ARU > 550
Multivariate analysis: history of CAD associated
with twice the odds of being ASA non-responder
(odds ratio 2.09, 95% CI 1.189-3.411, p=0.009)
No association with gender, DM, smoking, ASA
dose
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Clinical StudiesClinical Studies
ASA Resistance: Long termASA Resistance: Long term
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ASA Resistance: Long-termClinical Studies
ASA Resistance: Long-termClinical Studies
Stroke1 1500 mg Plt Reactivity 24 m Stroke/MI/ 10-fold lower(n=180) Vascular death risk in ASA
respondersPVD2 100 mg Whole blood 18 m Arterial 87% higher risk(n=100) aggregometry Occlusion in ASA-R
CVD/CVA3 100 mg PFA-10 >60 m Recurrent CVA/Recurrent CVA 34%(n=53) TIA TIA ASA-R vs. 0% no
recurrent eventsSubgroup 75-325 mg Urinary 11-dehydro 5 yrs MI/Stroke/ 1.8times
HOPE4 TX B2 CVDeath higher risk in
(n=967) uppervs. lower quartileCVD5 325 mg Optical platelet 679185 Death/MI/CVA24% ASA-R vs.
(n=326) aggregation days 10%ASA-S [HR 3.12(95% CI 1.1- 8.9,p=0.03)
1. Grotemeyer KH, et al. Thromb Res 1993; 71:397-403
2. Mueller MR, et al. Thromb Haemost 1997; 78:1003-1007
3. Grundmann K, et al. J Neurol2003; 250: 63-66
4. Eikelboom JW, et al. Circulation 2002; 105:1650-16555. Gum PA, et al. J Am Coll Cardiol2003; 41:961-965
PtsPts ASA doseASA dose TestTest F/UF/U End-pointEnd-point ResultsResults
ASA R i t d Cli i lASA R i t d Cli i l
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ASA Resistance and ClinicalOutcome in CAD Patients
ASA Resistance and ClinicalOutcome in CAD Patients
Eikelboom JW, et al. Circulation 2002; 105:1650-1655
HOPE Trial Substudy: ASA 75-325 mgHOPE Trial Substudy: ASA 75-325 mg
ASA R i t d Cli i lASA Resistance and Clinical
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ASA Resistance and ClinicalOutcome in CVD Patients
ASA Resistance and ClinicalOutcome in CVD Patients
Gum PA, et al. J Am Coll Cardiol2003; 41:961-965
ASA-R: mean aggregation 70% with 10 M ADP & 20% with 0.5 mg/ml AA
326 CVD patients on ASA 325 mg326 CVD patients on ASA 325 mg >> 7 days7 days
p=0.03
S i d Cli i lASA R i d Cli i l
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ASA Resistance and ClinicalOutcome in PVD Patients
ASA Resistance and ClinicalOutcome in PVD Patients
Mueller MR et al. Thromb Haemost1997; 78:1003-1007
Clinical Outcome inClinical Outcome in
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Clinical Outcome inStroke Patients
Clinical Outcome inStroke Patients
Grotemeyer KH et al. Thromb Res 1993; 71:397-403
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Chen et al. J Amer Coll Cardiol2004;43:1122-6
ASA Resistance in PCI
RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant
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Oral Antiplatelet AgentsOral Antiplatelet Agents
CollagenCollagen
ThrombinThrombin
TXATXA22
Aspirin
ADPADP
(Fibrinogen(Fibrinogen
Receptor)Receptor)
clopidogrel bisulfateclopidogrel bisulfate
TXATXA22
ADPADP
DipyridamoleDipyridamole
PhosphodiesterasePhosphodiesterase
ADPADP
Gp IIb/IIIa ActivationActivation
COXCOX
ticlopidine HClticlopidine HCl
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Schafer AI.Am J Med1996;101:199209.
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Clopidogrel in UnstableAngina to Prevent Recurrent
Ischemic Events
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Aspirin 75-325mgAspirin 75-325mg
Aspirin 75-325mgAspirin 75-325mg
Pla
ceb
o
Pla
ceb
o
Clo
pido
grel
Clo
pido
grel
300m
g
300m
g
loadin
gdo
se
loadin
gdo
se
Patients withPatients withNon-ST elevationNon-ST elevation
Acute CoronaryAcute Coronary
SyndromeSyndrome
RR
1 3 61 3 6 9 129 12MonthsMonths
3 months3 months double-blind treatmentdouble-blind treatment 12 months12 months3 months3 months double-blind treatmentdouble-blind treatment 12 months12 months
Clopidogrel 75mg q.d.Clopidogrel 75mg q.d.+ ASA 75-325 mg q.d.*+ ASA 75-325 mg q.d.*
(6259 patients)(6259 patients)
Placebo + ASAPlacebo + ASA75-325 mg q.d.*75-325 mg q.d.*(6303 patients)(6303 patients)
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* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
0.140.14
0.000.00
0.020.02
0.040.04
0.060.06
0.080.08
0.100.10
0.120.12
Cumula
tiveHa z
ardRate
Cumula
tiveHazardRa
te
ClopidogrelClopidogrel
+ ASA*+ ASA*
33 66 99
PlaceboPlacebo
+ ASA*+ ASA*
Months of Follow-UpMonths of Follow-Up
11.4%11.4%
9.3%9.3%
20% RRR20% RRR
PP< 0.001< 0.001N = 12,562N = 12,562
00 1212
Primary Endpoint:MI/Stroke/CV DeathPrimary Endpoint:
MI/Stroke/CV Death
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PCI
PLACEBOPLACEBO+ ASA *+ ASA *
CLOPIDOGRELCLOPIDOGREL300 mg300 mg
3-24h pre-PCI3-24h pre-PCI+ ASA *+ ASA *
30 days postPCI
End of follow-upUp to 12 months
afterrandomization
Clopidogrel 75 QDClopidogrel 75 QD
PretreatmentPretreatment
Clopidogrel 75 QDClopidogrel 75 QD
PretreatmentPretreatment
N = 2,116 patients undergoing elective PCIN = 2,116 patients undergoing elective PCI
* In combination with standard therapy* In combination with standard therapy
N = 1345
N = 1313N = 1313
RR
CREDOCREDO
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Steinhubl et al. JAMA 2002
CREDO: Primary EndpointCREDO: Primary Endpoint
26.9% relative risk reduction
(CI 3.9-44.4%; P=0.02)
Absolute reduction = 3%
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Aspirin Resistant PatientManagement
Aspirin Resistant PatientManagement
Eliminate interfering substances (ibuprofen)
Increase aspirin dose
Use other anti-platelet medications such as
clopidogrel to prevent recurrent ischemic
events
Educate patient on importance of compliance
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ConclusionsConclusions
ASA use associated with 23% reduction in theodds of vascular events
Beneficial anti-thrombotic effect of ASAmediated by irreversible acetylation of COX-1
ASA resistance 5-60%
ASA resistance associated with increased risk ofmajor adverse cardiovascular events
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Metabolic Pathways ofArachadonic Acid
Metabolic Pathways ofArachadonic Acid
Membrane Phospholipids
ARACHIDONIC ACID
Prostaglandin H2
COX-1
Thromboxane A2Platelet Aggregation
- Vasoconstriction
ProstacyclinPlatelet Aggregation
- Vasodilitation
AspirinAspirin
Aspirin in the Treatment ofAspirin in the Treatment of
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Aspirin in the Treatment ofACS
Aspirin in the Treatment ofACS
Wallentin LC, et al. JACC 1991;18:1587-93.
0.00
0.05
0.10
0.15
0.20
0.25
0 3 6 9 12
Months
Probab il
ity
ofDeatho
rM
I
Placebo
Aspirin 75 mg
Risk ratio 0.5295% CL 0.37-0.72
A i i i A t M di lA i i i A t M di l
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Aspirin in Acute MyocardialInfarction: ISIS-2
Aspirin in Acute MyocardialInfarction: ISIS-2
100
200
300
400
500
600
0 7 14 21 28 35
Placebo alone:568/4300 (13.2%)
Aspirin alone:461/4295 (10.7%)
Streptokinase alone:448/4300 (10.4%)
Streptokinase plus aspirin:343/4292 (8.0%)
Cumula
tive
Number
ofVas
cularD
eaths
Days From Randomization
R d i d T i l f A i iR d i d T i l f A i i
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Randomized Trials of Aspirinin PTCA
Randomized Trials of Aspirinin PTCA
Schwartz, N Engl J Med 1988;318:1714 White, Coronary Artery Disease 1991;2:757
0
4
8
12
Schwartz et alN=376
White et alN=337
% Major IschemicComplications
6.9
12.6
Heparin 10,000 units
2.4
Ticlopidine + Heparin
1.6
ASA / Dipyridamole + Heparin
77%
P=0.0113 3.2
75%
P
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What is AspirinResistance?
What is AspirinResistance?
Inability of ASA to prevent treated patients
from having thrombotic events.
Inability of ASA therapy to prolong bleeding
time.
Inability of treatment with ASA to prevent
thromboxane biosynthesis.
Inability of ASA to achieve a pre-definedeffect on an ex vivo or in vitro measure of
platelet function.
Patrono C. J Thromb Haemost 2003;1:1710-3
A i i R Bl diA i i R Bl di
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Aspirin Response - BleedingTime
Aspirin Response - BleedingTime
Aspirin, 325 mg daily in 40 CABG patients
Buchanan,Can J Cardiol 1995;11(3):221
100 300 500 700 900
100
300
500
700
900
Bleeding Time, Pre-ASA
BleedingTime
Post-ASA
Responders
(58%)Mean BT 58 + 10 %
Non-responders(42%)Mean BT 2 + 4 %
A i i R i dAspirin Responsi eness and
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Aspirin Responsiveness andClinical Outcome
Aspirin Responsiveness andClinical Outcome
181 patients, following CVA. Aspirin 500 mg TID.Followed-up for 24 months.
100
75
50
6 12 18 24
% of Patients Without Event
Months of Observation
Aspirin RespondersN=114
Aspirin Non-responders
N=60
60%
95%
P
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Thromboxane Biosynthesison Aspirin and CV Events
Thromboxane Biosynthesison Aspirin and CV Events
1.0
1.3 1.4
1.8
0
1
2
< 15.1 15.1 - 21.8 21.9 - 33.8 > 33.8
Uninary 11-dehydro thromboxane B2(ng/mmole creatinine)
Odds Ratio for MI, Stroke or CV Death
Eikelboom Circ 2002;105:1650 HOPE Trial N=488, with 5 yr f/u
Aspirin Responsiveness ByAspirin Responsiveness By
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Aspirin Responsiveness ByPFA-100 and AggregometryAspirin Responsiveness ByPFA-100 and Aggregometry
23.8%
5.5%
70.7%Aspirin Sensitive
Resistant
Partial
Responders
9.5%
90.5%Aspirin Sensitive
325 patients with stable ASCAD
Aggregometry
Response to ADP and AAPFA-100
Gum P. Am J Cardiol 2001;88:230-235
Clinical Outcomes: AspirinClinical Outcomes: Aspirin
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Clinical Outcomes: AspirinResponsive-ness by
Aggregometry And PFA-100
Clinical Outcomes: AspirinResponsive-ness by
Aggregometry And PFA-100
0
20
40
00 200200 400400 600600 800800
Days after Treatment
Not Aspirin Resistant, N = 309
Aspirin Resistant, N = 17
% Death, MI, CVA% Death, MI, CVA
Log rankLog rank 22=5.05,=5.05,p=0.03p=0.03
Gum, P. JACC 2003;41:961-5
0
5
10
15
20
ASAResponder
N=294
ASA Non-Responder
N=32
12.9
15.1
% Death, MI, CVA% Death, MI, CVA
P=0.4
Clinical Outcomes based onPFA-100 Results
Variability in Response toVariability in Response to
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Variability in Response toAspirin
Variability in Response toAspirin
Decreased bioavailability
Non-compliance
Concomitant NSAIDsPlatelet function
Accelerated platelet turnover
Increased platelet COX-2Platelet Receptor Polymorphisms
Other factors
DeGaetano G. J Thromb Haemost 2003;1:2048-50
M t b li P th fM t b li P th f
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Metabolic Pathways ofArachadonic Acid
Metabolic Pathways ofArachadonic Acid
Membrane Phospholipids
ARACHIDONIC ACID
Prostaglandin H2
COX-1
Thromboxane A2Platelet Aggregation
- Vasoconstriction
ProstacyclinPlatelet Aggregation
- Vasodilitation
12-Lipoxygenase
12-HETE, 12-HPETE- Platelet Adhesivity
Non-EnzymaticLipid PeroxidationCatalyzed by Free
Radicals
Isoprostanes- Amplifies platelet response
to other agonists.
- Vasoconstrictor- Plasma levels 1-2 orders
of magnitude > COX
-derived metabolites.
Aspirin
PlA2 Polymorphism andPlA2 Polymorphism and
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PlA2 Polymorphism andAspirin Resistance
PlA2 Polymorphism andAspirin Resistance
0
20
40
60
80
0.1 1 10 100
% Aggregation
Aspirin mol/L
P=0.02
P=0.01
PlA1/A1
PlA1/A2
Cooke, Lancet 1998;351:
PlA2 Polymorphism
Single nucleotide
polymorphism -Proline for a leucineat position 33 of 3subunit.
~25% of individualsof N. Europeanancestry are PlA2 +.
Aspirin Resistance: Role ofAspirin Resistance: Role of
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Aspirin Resistance: Role ofCOX-2 ?
Aspirin Resistance: Role ofCOX-2 ?
Weber A-A Lancet 1999;353:900
Aspirin is 170-fold morepotent inhibitor of COX-1 thanCOX-2.
Platelets from 20 differentdonors were COX-2 positive.
COX-2 expression in plateletsincreased 16-fold in 9 post-CABG patients. (Zimmermann AHA1999)
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ConclusionsConclusions
Every study that has ever evaluated individual
responsiveness to ASA has found marked variability.
Most studies have been able to correlate this variability
with a clinically significant increase in thrombotic events.
The ability to identify the substantial proportion of patients
who are unable to achieve an adequate response to ASA
has the potential to dramatically improve their
antithrombotic regimen and with it, long-term outcomes.