Resistance to Anti-Platelet Therapy in CAD

Resistance to Anti-Platelet Therapy in CADResistance to Anti-Platelet Therapy in CAD

Rabih R. Azar, MD, MSc, FACCRabih R. Azar, MD, MSc, FACC

Associate Professor of MedicineAssociate Professor of Medicine

Director of Cardiovascular ResearchDirector of Cardiovascular Research

Division of CardiologyDivision of Cardiology

Hotel Dieu de France HospitalHotel Dieu de France Hospital


1.1. Role of platelets in coronary artery diseaseRole of platelets in coronary artery disease

2.2. Aspirin resistanceAspirin resistance

3.3. Clopidogrel resistanceClopidogrel resistance

4.4. New anti-platelet drugsNew anti-platelet drugs

5.5. How to detect resistance to anti-platelet agentsHow to detect resistance to anti-platelet agents

6.6. How to manage resistant patientsHow to manage resistant patients

Role of the Platelets in ThrombosisRole of the Platelets in ThrombosisRole of the Platelets in ThrombosisRole of the Platelets in Thrombosis

UA/NQMI:Partially-occlusive thrombus

(primarily platelets)

Intra-plaque thrombus (platelet

dominated)

Plaque core

ST MI:occlusive thrombus (platelets,

red blood cells, and fibrin)

Intra-plaque thrombus (platelet dominated)

Plaque core

SUDDEN DEATHAdapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

Aspirin is as important as streptokinase in AMI

ISIS 2: Lancet ISIS 2: Lancet 1988;2:3491988;2:349

Aspirin in Primary and Secondary Prevention TrialsAspirin in Primary and Secondary Prevention Trials

Currently Available Antiplatelet Agents

11Antiplatelet Trialists’ Collaboration. Antiplatelet Trialists’ Collaboration. BMJ.BMJ. 1994;308:81–106. 1994;308:81–106.

22Diener HC et al. Diener HC et al. J Neurol Sci. J Neurol Sci. 1996;143:1–13. 1996;143:1–13. 33Schafer AI. In: Smith TW, ed. Schafer AI. In: Smith TW, ed. Cardiovascular Therapeutics. Cardiovascular Therapeutics. Philadelphia, PA: WB Saunders; 1996:chap 27.Philadelphia, PA: WB Saunders; 1996:chap 27.44Schafer AI. Schafer AI. Am J Med. Am J Med. 1996;101:199–209.1996;101:199–209.

AspirinAspirin

Ticlopidine/Ticlopidine/

clopidogrelclopidogrel

DipyridamoleDipyridamole

MechanismMechanismof Actionof Action

TXATXA22

ADP binding ADP binding to receptorto receptor

cAMPcAMP

EfficacyEfficacy

25%25%11

33%33%11

16%16%22

Significant Significant Side EffectsSide Effects

GI bleeding,GI bleeding,

GI intoleranceGI intolerance33

Severe neutropenia,Severe neutropenia,

rash, diarrhearash, diarrhea44

GI distress, GI distress, headacheheadache44

CAPRIE StudyMI, Ischemic Stroke, or Vascular Death

Months of Follow-UpMonths of Follow-Up

Cu

mu

lati

ve

Ev

en

t R

ate

, %

Cu

mu

lati

ve

Ev

en

t R

ate

, %

00

44

88

1212

1616

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

5.83%5.83%

ClopidogrelClopidogrel

AspirinAspirin

5.33%5.33%

Overall Overall RiskRisk

ReductionReduction

8.7%8.7%

Event Rate per YearEvent Rate per Year

P P = 0.045= 0.045

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cum

ula

tive

Haz

ard 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

* In combination with standard therapy

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURE Study: Clopidogrel on the top of aspirinPrimary End Point - MI/Stroke/CV Death

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

Aspirin Usage In the US

Percentage of Use

37.6

23.3

13.812.2

14.1

0

10%

20%

30%

40%

Heart Disease

Arthritis Headache Body Ache

Other

26,000,000 Americans receive chronic aspirin therapy for

cardioprotection.

26,000,000 Americans receive chronic aspirin therapy for

cardioprotection.

Definitions of Aspirin and Clopidogrel Definitions of Aspirin and Clopidogrel ResistanceResistance

• Clinical:– Failure to prevent clinical events

• Biological:– Failure to adequately inhibit platelet aggregation

– Aspirin:• Aggregation > 70% on 5 µmol/L ADP• Aggregation > 70% on 10 µmol/L ADP• Aggregation > 20% on 0.5mg/mL arachidonic acid

– Clopidogrel:• Baseline – post-treatment ADP aggregation < 10% • ADP aggregation < 14% (Plateletworks)

J Am Coll Cardiol 2006;47:27-33

ASA Resistance and Clinical Outcome 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

Chen et al. J Amer Coll Cardiol 2004;43:1122-6

ASA Resistance in PCI

RPFA-ASA, ASA/clopidogrel (n=151), 19.2% ASA resistant

Possible Mechanisms for Variability in Response to Aspirin

• Decreased bioavailability

– Non-compliance

– Concomitant NSAIDs

• Platelet function

– Accelerated platelet turnover

– Increased platelet COX-2

• Platelet Receptor Polymorphisms

• Other factors

DeGaetano G. J Thromb Haemost 2003;1:2048-50

Metabolic Pathways of Arachidonic Acid

Membrane Phospholipids

ARACHIDONIC ACID

Prostaglandin H2

COX-1

Thromboxane A2 Platelet Aggregation

- Vasoconstriction

Prostacyclin Platelet Aggregation

- Vasodilitation

12-Lipoxygenase

12-HETE, 12-HPETE- Platelet Adhesivity

Non-EnzymaticLipid Peroxidation Catalyzed by Free

Radicals

Isoprostanes- Amplifies platelet response to other agonists. - Vasoconstrictor- Plasma levels 1-2 orders of magnitude > COX -derived metabolites.

Aspirin

ACC/AHA Guidelines (2005)ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Percutaneous Coronary Interventions:

Oral Antiplatelet TherapyOral Antiplatelet Therapy

Prevalence of inadequate response to Prevalence of inadequate response to clopidogrel 4% to 30%clopidogrel 4% to 30%

Nguyen et al. J Am Coll Cardiol 2005;45:1157-64Nguyen et al. J Am Coll Cardiol 2005;45:1157-64

Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment

% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)

97.597.5

92.592.5

87.587.5

82.582.5

77.577.5

72.572.5

67.567.5

62.562.5

57.557.5

52.552.5

47.547.5

42.542.5

37.537.5

32.532.5

27.527.5

22.522.5

17.517.5

12.512.5

7.57.5

2.52.5

2020

1515

1010

55

00

Nu

mb

er

Nu

mb

er o

f o

f Pati

en

tsP

ati

en

ts

Bleeding riskBleeding risk Ischemic riskIschemic risk

Clinical RelevanceFunctional ParameterN

Post-PCI ischemic events (30 days)

↑ platelet aggregation292Cuisset et al.JACC 2006


Post-PCI ischemic events (3 months)

Post-PCI ischemic events (12 months)

↑ platelet aggregation (3rd & 4th quartiles)

↓ platelet inhibition

↑ platelet aggregation

802

379

100

Hocholzer et al.JACC 2006

Geisler et al.Eur Heart J 2006

Bliden et al.JACC 2007

Post PCI-myonecrosis↑ clopidogrel/aspirin-resistant patients120Lev et al.JACC 2006


↑ platelet aggregation106Cuisset et al.J Thromb Haemost2006

Myonecrosis and inflammation marker release

↑ periprocedrual platelet aggregation 120Gurbel et al.Circulation 2005

Post-PCI ischemic events(6 months)

↑ periprocedrual platelet aggregation 192Gurbel et al.JACC 2005

Post-primary PCI ischemic events (6 months)

↑ platelet aggregation (4th quartile)60Matezky et al.Circulation 2004

Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

PostPost-- Stent Ischemic Events and Stent Ischemic Events and PeriproceduralPeriprocedural InfarctionInfarction

Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness

Importance of clopidogrel resistance in ST elevation MI

• Patients with ST elevation MI were divided in 4 quartile according to their response to clopidogrel compared to baseline

• First quartile = Poor responder

• 4th quartile = Excellent responder

• Cardiovascular event rate was higher in the first quartile

Clopidogrel resistance is associated with increased recurrent atherothrombotic events in patient with acute MI

(Circulation 2004;109:3171-3175)

69

58

33

0

10

20

30

40

50

60

70

80

90

100

1st Qtr 2nd Qtr 3rd Qtr 4th Qtr

40

6.7

0 00

5

10

15

20

25

30

35

40

45

1st Qtr 2nd Qtr 3rd Qtr 4th Qtr

% %

Quartiles of mean platelet aggregation Recurrent cardiovascular events

as compared to baseline

Cellular FactorsCellular Factors• Accelerated platelet turnoverAccelerated platelet turnover

•• Reduced CYP3A metabolic activityReduced CYP3A metabolic activity•• Increased ADP exposure Increased ADP exposure •• UpUp--regulation of the P2Yregulation of the P2Y1212 pathwaypathway•• UpUp--regulation of the P2Yregulation of the P2Y11 pathway pathway •• UpUp--regulation of P2Yregulation of P2Y––independent pathwaysindependent pathways

(collagen, epinephrine, TXA(collagen, epinephrine, TXA22, thrombin), thrombin)

Clinical FactorsClinical Factors• Failure to prescribe/poor complianceFailure to prescribe/poor compliance

•• UnderUnder--dosing dosing •• Poor absorptionPoor absorption•• DrugDrug--drug interactions involving CYP3A4drug interactions involving CYP3A4•• Acute coronary syndromeAcute coronary syndrome•• Diabetes mellitus/insulin resistanceDiabetes mellitus/insulin resistance•• Elevated body mass indexElevated body mass index

Genetic FactorsGenetic Factors• Polymorphisms of CYPPolymorphisms of CYP

•• Polymorphisms of Polymorphisms of GPIaGPIa•• Polymorphisms of P2YPolymorphisms of P2Y1212

•• Polymorphisms of Polymorphisms of GPIIIaGPIIIa

Clopidogrel Response VariabilityClopidogrel Response Variability

Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .

Clopidogrel MetabolismClopidogrel Metabolism

• Clopidogrel is a prodrug

• It requires oxidation by the hepatic cytochrome P450 to generate the active metabolite

• Only a small proportion of clopidogrel undergoes metabolism by CYP450

• Clopidogrel is mostly hydrolyzed by esterases to an inactive carboxylic acid derivative that accounts for 85% of clopidogrel-related circulating compounds

• Any drugs that affects CYP450 may affect the efficacy of clopidogrel

≈≈ 95% 95% (few minutes)(few minutes)

≈≈ 95% 95% (2(2--4 hours)4 hours)

≈≈ 70% 70% (<1 hour) (<1 hour)

Mean Platelet Mean Platelet InhibitionInhibition

((Time RequiredTime Required))

CHAMPIONCHAMPION

PLATOPLATO

TRITONTRITON

TrialsTrials(Phase III)(Phase III)DoseDoseActionActionRouteRouteTypeTypeDrugDrug

4 4 μμg/kg/ming/kg/minCompetitive Competitive bindingbindingParenteral Parenteral ATP analogue ATP analogue ––

Direct inhibition Direct inhibition CangrelorCangrelor(ARC(ARC--669931MX)669931MX)

90 mg bid90 mg bidCompetitive Competitive bindingbinding

OralOral

CyclopetylCyclopetyl--triazolopytriazolopy--rimidinerimidine ––

Direct inhibitionDirect inhibitionAZD6140AZD6140

60 mg 60 mg loading loading

dose, 10 mg dose, 10 mg maintenance maintenance

dosedose

Irreversible Irreversible bindingbindingOralOral

Thienopyridine Thienopyridine (3(3rdrd gengen) ) ––

requires hepatic requires hepatic conversion to conversion to

active metabolite active metabolite

PrasugrelPrasugrel(CS(CS--747)747)

Novel P2YNovel P2Y1212 ADP Receptor AntagonistADP Receptor Antagonist

More potent and less variability!!More potent and less variability!!

Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .

Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment

% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)

97.597.5

92.592.5

87.587.5

82.582.5

77.577.5

72.572.5

67.567.5

62.562.5

57.557.5

52.552.5

47.547.5

42.542.5

37.537.5

32.532.5

27.527.5

22.522.5

17.517.5

12.512.5

7.57.5

2.52.5

2020

1515

1010

55

00

Nu

mb

er

Nu

mb

er o

f o

f Pati

en

tsP

ati

en

ts

Bleeding riskBleeding risk Ischemic riskIschemic risk

Sanofi-aventis-BMS Confidential- For Internal Purposes Only- Not for Further Copying or Distribution

TRITON: Primary Efficacy and Safety Endpoints TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Monthsin Entire ACS Cohort at 15 Months

Wiviott SD, et al. N Engl J Med 2007;357:2001-15

0

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

Prasugrel

Clopidogrel1.82.4

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

HR 0.81(0.73-0.90)

P<0.001

138events

NNT = 46

HR 1.32(1.03-1.68)

P=0.03

35events

NNH = 167

How to Measure Platelets Aggregation?

• Platelets function is measured in vitro by light transmission aggregometry

• This method is considered the gold standard

• Disadvantages:

– Limited reproducibility

– Complex sample preparation

– Cannot be routinely performed

WHAT ARE THE ALTERNATIVES WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION TO LIGHT TRANSMISSION

AGGREGOMETRY?AGGREGOMETRY?

Newer 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 useAnalyzer 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

Plateletworks: Kit for measurement of Plateletworks: Kit for measurement of platelets aggregationplatelets aggregation

Photo-optical (turbidometric) platelet Photo-optical (turbidometric) platelet aggregometryaggregometry

Excellent Correlation Between Light Transmission Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test Aggregometry and Plateletworks Test ((Cathet Cardiovasc Intervent Cathet Cardiovasc Intervent

2001;53:346-351)2001;53:346-351)

PlateletWorks: Values in Healthy Patients*

Agonist % aggregation % inhibtion

Collagen > 70% < 30%

ADP > 86% < 14%

Arach. Acid > 60% < 40%Healthy patients = patients with normal platelets and not on anti-platelet therapy

How to Manage Aspirin Resistant Patients

• Assess compliance with treatment

• Eliminate drugs that interfere with aspirin (NSAID)

• Increase the dose of aspirin?– May increase toxicity without improving response

• Add clopidogrel

How to Manage Clopidogrel Resistant Patients

• Assess compliance with treatment

• Eliminate drugs that interfere with the metabolism of clopidogrel (Cytochrome P 450 inhibitors)

• Increase the dose of clopidogrel

*ASA=250-500 mg on admission, then 100 mg/day plus other standard care

Randomized, multicenter, open-label trial with blind centralized laboratory assessment in patients aged 18 85 years with NSTE-ACS (onset < 48 h)

n=35

LMWH and ASA*

Clopidogrel 300 mg LD then 75 mg qd

Clinical follow-upat 30 days

R



n=34

n=34

D2

D2

D2

0 2 3 4 5 6 2411/2

Sampling Time

Hours post-LD

LD

Variability of response: dose, Variability of response: dose, 300, 600 vs 900300, 600 vs 900

G. Montalescot et al. JACC 2006

P < 0.05 vs. 300 mg LD

A Faster Onset of Action Was Seen with Higher Clopidogrel Loading Regimens

A Faster Onset of Action Was Seen with Higher A Faster Onset of Action Was Seen with Higher ClopidogrelClopidogrel Loading RegimensLoading Regimens

The ALBION trial

0

10

20

30

40

50

1 2 3 4 5 6

300 mg LD600 mg LD900 mg LD

Maximum Inhibition of Platelet Aggregation (5 µM ADP)

Time (h)

(%) Inhibition

Shortened time to reach the highest level of inhibition of the 300 mg LD

Montalescot G et al. J Am Coll Cardiol 2006;48:931-8

Dual Resistance to Aspirin and Clopidogrel in Dual Resistance to Aspirin and Clopidogrel in Patients Undergoing PCIPatients Undergoing PCI

• 150 patients referred for elective PCI

• All were on aspirin 81 to 325 mg/day for > 1 week

• Clopidogrel was given immediately following PCI

• The response to clopidogrel was tested at 24 hours post loading dose

• 12.7% resistant to aspirin

• 24% resistant to clopidogrel

• 47% of aspirin resistant patients were also resistant to clopidogrel

J Am Coll Cardiol 2006;47:27-33

ACC/AHA Guidelines (2005)ACC/AHA Guidelines (2005)Percutaneous Coronary Interventions: Oral Antiplatelet Percutaneous Coronary Interventions: Oral Antiplatelet

TherapyTherapy

CLASS I:CLASS I:

- After the PCI procedure, in patients with neither - After the PCI procedure, in patients with neither aspirin resistanceaspirin resistance, , allergy, nor increased risk of bleeding, aspirin 325 mg daily should be allergy, nor increased risk of bleeding, aspirin 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after given for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which daily chronic aspirin use should eluting stent implantation, after which daily chronic aspirin use should be continued indefinitely at a dose of 75 to 162 mg.be continued indefinitely at a dose of 75 to 162 mg.

CLASS IIb:CLASS IIb:

- In patients in whom subacute thrombosis may be catastrophic or - In patients in whom subacute thrombosis may be catastrophic or lethal, lethal, platelet aggregation studiesplatelet aggregation studies may be considered and the dose of may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.platelet aggregation is demonstrated.

Aspirin and Clopidogrel Effects Should Be Aspirin and Clopidogrel Effects Should Be MonitoredMonitored

• 75 year old male

• HTN, treated with ramipril BP: 120/70 mm Hg

• Diabetes, treated with insuline HbA1c: 6.8%

• Hyperlipidemia, treated with atorvastatin LDL: 88 mg/dL

• S/P stent, aspirin and clopidogrel ????????????

Do you want to be sure that aspirin and clopidogrel are working?

Resistance to Anti-Platelet Therapy in CAD

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