Post on 13-Jan-2016
Daniel I. Simon, M.D.
Associate Director, Interventional Cardiology
Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA USA
ASA Resistance andASA Resistance andClinical OutcomesClinical Outcomes
ASA Resistance: Key QuestionsASA Resistance: Key Questions
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?
Established Platelet Function TestsEstablished Platelet Function Tests
Harrison P. Br J Hematology 2000;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 variabilityLabor intensive & non-physiological
Insensitive
Semi-quantitative
Specialized equipment
Measures clot properties only, insensitive to ASARequires blood counter
Prone to artifact
Plt Function TestPlt Function Test DisadvantagesDisadvantagesAdvantagesAdvantagesAssayAssay
Newer Platelet Function TestsNewer Platelet Function Tests
(PFA)-100 Whole blood + Primary Limited range-most ptshemostasis 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 Hematology 2000;111:733-744Mukherjee D & Moliterno DJ. Clin Pharmacokinet 2000;39(6): 445-458
Flow cytometry Whole blood - Platelet GP, Flexible & powerful. Requires activation markers, specialized operator. ExpensivePlatelet function
AssayAssay Substrate BedsideSubstrate Bedside PrinciplePrinciple Comments Comments
Prevalence of ASA Resistance Prevalence of ASA Resistance
Gum PA et al. Am J Cardiol 2001;88:230-235
ASA-R: mean aggregation ASA-R: mean aggregation ≥70% with µM 10 ADP & ≥70% with µM 10 ADP & ≥20% with 0.5 mg/ml AA ≥20% 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
Wang JC et al. Amer J Cardiol 2003;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 Aspirin Resistance Prevalence of Aspirin Resistance
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
Clinical StudiesClinical Studies
ASA Resistance: Long-term Clinical StudiesASA Resistance: Long-term Clinical 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/ 1.8 times
HOPE4 TX B2 CVDeath higher risk in (n=967) upper vs. lower quartileCVD5 325 mg Optical platelet 679±185 Death/MI/CVA
24% 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; 71:397-4032. Mueller MR, et al. Thromb Haemost 1997; 78:1003-10073. Grundmann K, et al. J Neurol 2003; 250: 63-664. Eikelboom JW, et al. Circulation 2002; 105:1650-16555. Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965
PtsPts ASA doseASA dose TestTest F/UF/U End-pointEnd-point Results Results
ASA Resistance and Clinical ASA Resistance and Clinical Outcome in CAD PatientsOutcome 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 Resistance and Clinical ASA Resistance and Clinical Outcome in CVD PatientsOutcome in CVD Patients
Gum PA, et al. J Am Coll Cardiol 2003; 41:961-965
ASA-R: mean aggregation ≥70% with 10 µM ADP & ≥20% with 0.5 mg/ml AA
326 CVD patients on ASA 325 mg 326 CVD patients on ASA 325 mg >> 7 days 7 days
p=0.03
ASA Resistance and Clinical ASA Resistance and Clinical Outcome in PVD PatientsOutcome in PVD Patients
Mueller MR et al. Thromb Haemost 1997; 78:1003-1007
ASA Resistance and Clinical ASA Resistance and Clinical Outcome in Stroke PatientsOutcome in Stroke Patients
Grotemeyer KH et al. Thromb Res 1993; 71:397-403
ASA Resistance and Clinical ASA Resistance and Clinical Outcome in Stroke PatientsOutcome in Stroke Patients
Grundmann K et al. J Neurol 2003; 250: 63-66
53 CVA pts on ASA 100 mg for secondary prevention > 60 months
Chen et al. J Amer Coll Cardiol 2004;43:1122-6
ASA Resistance in PCIASA Resistance in PCI
RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant
Oral Antiplatelet AgentsOral Antiplatelet Agents
CollagenCollagenThrombinThrombin
TXATXA22
Aspirin
ADPADP
(Fibrinogen(FibrinogenReceptor)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 Med 1996;101:199–209.
CClopidogrel in lopidogrel in UUnstable Angina to nstable Angina to Prevent Prevent RRecurrent Ischemic ecurrent Ischemic EEventsvents
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Aspirin 75-325mgAspirin 75-325mg
Aspirin 75-325mgAspirin 75-325mg
Plac
ebo
Plac
ebo
Clopid
ogrel
Clopid
ogrel
300m
g
300m
g
load
ing d
ose
load
ing d
ose
Patients withPatients withNon-ST elevationNon-ST elevation
Acute CoronaryAcute Coronary
SyndromeSyndromeRR
1 3 61 3 6 9 12 9 12 MonthsMonths
3 months 3 months double-blind treatment double-blind treatment 12 months 12 months3 months 3 months double-blind treatment double-blind treatment 12 months 12 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 + ASA Placebo + ASA 75-325 mg q.d.*75-325 mg q.d.*(6303 patients)(6303 patients)
* 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
Cu
mu
lati
ve H
azar
d R
ate
Cu
mu
lati
ve H
azar
d R
ate
Clopidogrel Clopidogrel + ASA*+ ASA*
33 66 99
Placebo Placebo + ASA*+ ASA*
Months of Follow-UpMonths of Follow-Up
11.4%11.4%
9.3%9.3%
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
00 1212
Primary Endpoint: MI/Stroke/CV Primary Endpoint: MI/Stroke/CV DeathDeath
PCI
PLACEBOPLACEBO + ASA *+ ASA *
CLOPIDOGRELCLOPIDOGREL300 mg300 mg
3-24h pre-PCI3-24h pre-PCI+ ASA *+ ASA *
30 days post PCI
End of follow-upUp to 12 months
after randomization
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
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%
Aspirin Resistant Patient ManagementAspirin Resistant Patient Management
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
Conclusions Conclusions
ASA use associated with 23% reduction in the odds of vascular events
Beneficial anti-thrombotic effect of ASA mediated by irreversible acetylation of COX-1
ASA resistance 5-60% ASA resistance associated with increased risk
of major adverse cardiovascular events