Aspirin Resistance Uchil

8/14/2019 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



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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


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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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.

Documents

Aspirin Resistance Uchil