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