Anti-Platelet Therapy in Primary Coronary Intervention

Paul Gordon, MDDirector

Cardiac Catheterization LaboratoryThe Miriam Hospital

Discosures: research/grant support:Eli LillySanofiAccumetricsBristol Meyers

Treatment of STEMITreatment of STEMITreatment of STEMI

Primary PCI with stenting is the preferred treatment to establish reperfusion and improve outcomeDrug eluting stents are safe and have improved late outcomes c/w bare metal stents (mainly lower TVR and TVF)

ANTITHROMBOTIC DRUGS USED IN STEMI

I. ANTIPLATELET DRUGS

II. ANTICOAGULANT DRUGS

• COX-1 inhibitor (aspirin)• ADP P2Y12 receptor inhibitors (ticlopidine; clopidogrel; prasugrel) • Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban)

• Anti-Factor II (anti-thrombins) - Indirect Thrombin Inhibitors (UFH & LMWH)- Direct Thrombin Inhibitors (Bivalirudin)

ORAL

Options for Transport of Patients With STEMI and Initial Reperfusion Treatment

EMS Transport

Onset of symptoms of

STEMI

9-1-1EMS

Dispatch

EMS on-scene• Encourage 12-lead ECGs.• Consider prehospital fibrinolytic if

capable and EMS-to-needle within 30 min.

GOALS

PCIcapable

Not PCIcapable

Hospital fibrinolysis: Door-to-Needle within 30 min.

EMS Triage Plan

Inter-HospitalTransfer

Golden Hour = first 60 min. Total ischemic time: within 120 min.

Patient EMS Prehospital fibrinolysisEMS-to-needlewithin 30 min.

EMS transportEMS-to-balloon within 90 min.

Patient self-transportHospital door-to-balloon

within 90 min.Dispatch

1 min.

5 min.

8 min.

Antman EM, et al. J Am Coll Cardiol 2008. Published ahead of print on December 10, 2007. Available athttp://content.onlinejacc.org/cgi/content/full/j.jacc.2007.10.001. Figure 1.

Aspirin 325 mg

Aspirin post-PCI

After the PCI procedure, in patients without allergy or increased risk of bleeding, ASA 162-325 mgdaily should be given for at least 1 month after bare-metal stent implantation, 3 months after drug-eluting stent implantation, after which daily chronic ASA use should be continued indefinitely at a dose of 75 to 162 mg.

Those with an increased risk of bleeding:ASA 81 mg a day indefinitely

6

Recommendations for the use of Thienopyridines

A loading dose of thienopyridine is recommended for STEMI patients for whom PCI is planned. Regimens should be one of the following:

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIIIClopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI.

Prasugrel 60 mg should be given as soon as possible for primary PCI.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII or

Platelet ADP PPlatelet ADP P22YY1212 Receptor InhibitorsReceptor Inhibitors

Clopidogrel,Prasugrel, and Ticagrelor: Biotransformationand Mode of Action

Clopidogrel,Prasugrel, and Ticagrelor: Biotransformationand Mode of Action

SchomigSchomig A.A.NEJM 2009;361:1108.NEJM 2009;361:1108.

PrasugrelPrasugrelTRITON TRITON –– TIMI 38 Trial: TIMI 38 Trial: PrasugrelPrasugrel vsvs ClopidogrelClopidogrel

13,608 Patients 13,608 Patients -- ACS and PCIACS and PCI

WiviottWiviott S et al. NEJM 2007;357:2001.S et al. NEJM 2007;357:2001.

CV death, MI, or stroke

TIMI Major Bleed

Clopidogrel

Prasugrel

Clopidogrel

Prasugrel

"Placebo"

0.0

0.1

0.2

0.3

0.4

0.0

0.1

0.2

0.3

0.4

IPA(% )-20 0 20 40 60 80 100

0.0

0.1

0.2

0.3

0.4

C lopidogrel

Prasugrel

"Placebo"

0.0

0.1

0.2

0.3

0.4

0.0

0.1

0.2

0.3

0.4

IPA (% )-20 0 20 40 60 80 100

0.0

0.1

0.2

0.3

0.4

C lopidogrel

Prasugrel

9

0

2

4

6

8

0 1 2 3

1

0 306090 180 270 360 450

HR 0.82P=0.01

HR 0.80P=0.003

5.6

4.7

6.9

5.6

Days

Prim

ary

Endp

oint

(%)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit(Landmark Analysis (Landmark Analysis -- 3 days)3 days)

Adapted with permission from Antman EM JACC 2008.

TRITON TIMI-38

10

0

5

10

15

0 30 60 90 180 270 360 450

Perc

ent (

%)

Days From Randomization

9.5%

6.5%

HR 0.68(0.54-0.87)

P=0.002

12.4%

10.0%HR 0.79

(0.65-0.97)P=0.02

Clopidogrel

PrasugrelNNT = 42

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

Clopidogrel

Prasugrel 2.42.1

STEMI CohortSTEMI CohortN=3534N=3534

Montalescot et al Lancet 2008.Adapted with permission from Antman EM.

TRITON TIMI-38

Prasugrel not indicated in patients with:prior strokeage > 75 (relative)low body weight (<60kg) -- 5 mg dosing

PLATO TrialPLATO TrialTicagrelor vs Clopidogrel in ACSTicagrelor vs Clopidogrel in ACS

Wallentin L et al. NEJM 2009;361:1045Wallentin L et al. NEJM 2009;361:1045

Ischemic EndpointIschemic EndpointIschemic Endpoint

11.7%

9.8%HR = 0.84(0.77–0.92)

p<0.001

11.6%

11.2%HR = 1.04(0.95–1.13)

p = 0.43

Bleeding EndpointBleeding EndpointBleeding Endpoint

12

Thienopyridines

The duration of thienopyridine therapy should be as follows:

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII a. In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily or prasugrel 10 mg daily should be givenfor at least 12 months;

b. If the risk of morbidity from bleeding outweighs the anticipated benefit affordedby thienopyridine therapy, earlier discontinuation should be considered.

Urgent Non-cardiac SurgeryIf possible, operate on ASA 81 mg a dayBMS: 4 weeks of DAPT, then operate week 5-6DES: 3-6 months of DAPT

hold thienopyridine 5-7 days (daily PRA testing)

resume thienopyridine as soon as possible post-op

Elective surgery: wait 1 year

Bleeding: tailored treatment to individualECASA 81mg a day vs thienopyridine

alone

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

ClopidogrelClopidogrel Response VariabilityResponse Variability

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

Variability in individual responsiveness to Variability in individual responsiveness to antiplateletantiplatelet agents is an agents is an emerging clinical problem: poor responsiveness has been associatemerging clinical problem: poor responsiveness has been associated with ed with an increased risk of ischemic events, including an increased risk of ischemic events, including stentstent thrombosis.thrombosis.

Clopidogrel - Pharmacogenetic Information

Clopidogrel product information. Revised March 2010

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

Hazard Ratio 1.53(95% CI 1.07-2.19)

P=0.014

8.0

12.1

1064 1009 999 980 870 755 542

Number at Risk:Days After Randomization

Non-Carrier

395 364 360 348 306 270 181Carrier

CV

Dea

th, M

I, or

Str

oke

(%)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Non-carriers

Carriers

* Carriers ~30% of the population

CYP2C19 Reduced-Function Allele Carriers

N=1,459

Mega JL et al. N Eng J Med. 2009; 360:354-62.

P=0.014

P=0.015

Mega JL et al. N Eng J Med. 2009; 360:354-62.

CYP2C19 and Outcomes: Prasugrel and Clopidogrel, N=2,933

Hazard Ratio 0.89(95% CI 0.60-1.31)

P=0.27

9.8

8.5

1048 991 982 951 849 750 541407 383 376 364 320 276 188

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Number at Risk:Days After Randomization

Non-CarrierCarrier

CV

Dea

th, M

I, or

Str

oke

(%) Non-carriers

Carriers

Mega et al Circulation. 2009;119

Clopidogrel Prasugrel

17

Days from randomization

10

8

6

4

2

00 60 120 180 240 300 360

K-M

est

imat

e (%

)12

Clopidogrel carrier

Ticagrelor Non carrier

11.2

8.68.8

10.0Clopidogrel non carrier

No. at riskClopidogrel LOFClopidogrel No LOF

Ticagrelor LOFTicagrelor No LOF

1,384 1,305 1,274 1,250 1,053 834 6833,554 3,352 3,301 3,222 2,718 2,127 1,761

1,388 1,275 1,259 1,226 1,027 801 6583,516 3,321 3,256 3,186 2,691 2,123 1,757

Ticagrelor carrier

CYP2C19 and Outcomes: Clopidogrel and Ticagrelor, N=10,285

CV Death, MI, Stroke

Wallentin et al. Lancet. 2010; Oonline, 2010 DOI:10.1016/S0140-6736(10)61274-3

Genetic Testing

• Predictor of adverse events including stentthrombosis, but

• Expensive test– Upward of $500– Not readily available

• Variable phenotypic response when checking platelet function testing:– Patients with LOF alelles may have variable plt reactivity

when functional testing performed

LTA 20 μmol/L ADP VerifyNow® P2Y12 Plateletworks®

INNOVANCE® PFA P2Y* PFA-100 COL/ADP IMPACT-R ADP

NPR 6.0%HPR 11.7%

HPR = high-on treatment platelet reactivity

NPR = non-HPR

NPR 6.2%HPR 12.0%

NPR 5.7%HPR 13.4%

NPR 6.1%HPR 12.6%

NPR 7.5%HPR 9.8%

NPR 7.1%HPR 10.8%

NPR 6.3%HPR 12.2%

NPR 6.9%HPR 9.7%

P=0.002p<0.0001p<0.0001 p<0.0001

Composite of death, non-fatal myocardial infarction, definite stent thrombosis and stroke

p=0.17 p=0.06 p=0.02p=0.18

LTA 5 μmol/L ADP

IMPACT-RTests are available, but should they be routinely done?Who should we test?

after clinical events such as stent thrombosishigh risk patients?diabetics, females?

What do we do with “abnormal” results?– more clopidogrel (reload, double dose?)-- switch to prasugrel?

Platelet Function TestsPlatelet Function Tests

•• Platelet Aggregation Platelet Aggregation Light transmittance Light transmittance aggregometryaggregometry (LTA)(LTA)Impedance platelet aggregationImpedance platelet aggregation

•• Flow Flow CytometryCytometryGPIIb/IIIaGPIIb/IIIa receptor activationreceptor activationPP--selectinselectin expressionexpressionMonocyteMonocyte--platelet aggregatesplatelet aggregatesVasodilatorVasodilator--associated stimulated associated stimulated phosphoproteinphosphoprotein (VASP)(VASP)

•• PointPoint--ofof--carecareUltegraUltegra rapid platelet function analyzer (rapid platelet function analyzer (VerifyNowVerifyNow))ThromboelastagraphThromboelastagraph (TEG)(TEG)PlateletworksPlateletworksCone and Cone and plate(letplate(let) analyzer (IMPACT)) analyzer (IMPACT)

•• Genetic testingGenetic testingadapted from Angiolillo DJ et al. J Am Coll Cardiol. 2007.

gold standardgold standard

“Standard Therapy”placebo loading dose

clopidogrel 75mg +placebo/day

“Standard Therapy”placebo loading dose, then

clopidogrel 75mg +placebo/day

“Tailored Therapy”clopidogrel 600-mg*, thenclopidogrel 150-mg/day

Successful PCI with DES (with 600mg clopidogrel load) without major complication or GPIIb/IIIa use

VerifyNow P2Y12 Assay 12-24 hours post-PCI

PRU ≥ 230?

Non-Responder

Clinical Follow-up And Platelet Function Assessment at 30 days, 6M

Primary Endpoint: 6 month CV Death, Non-Fatal MI, ARC definite/prob ST

Yes No

N = 1100 N = 583

Responder

A B C

Random Selection

N = 1100

Safety Endpoint: GUSTO Moderate or Severe Bleeding

ACSRR

G R A V T A S

*total first day dose Price MJ et al, Am Heart J 2009

Efficacy Outcomes: PCI Patients22

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

ClopidogrelStandard

ClopidogrelDouble

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR

Days

Cum

ulat

ive

Haz

ard

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

ClopidogrelStandard

ClopidogrelDouble

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

CV Death, MI, Stroke Definite Stent Thrombosis

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard

Clopidogrel Double

HR 0.7095% CI 0.54-0.92

P=0.011

30%RRR

STEMI-PCI: Myocardial Infarction or All Stent Thrombosis

2009 Updated Labeling for Clopidogrel–PPI Interaction

• FDA-required label changes:2

– Warning: “Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart”

– Drug-Drug Interactions: “Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine”

– Based on PK/PD studies showing concomitant omeprazole reduced clopidogrel active metabolite and effect on platelets1

• Did not include COGENT study data2

• EMEA warning extends to discourage concomitant use of all PPIs3

– Concomitant use of drugs that inhibit CYP2C19 discouraged; concomitant use of any PPI “should be avoided unless absolutely necessary”4

EMEA=European Medicines Agency; FDA=Food and Drug Administration; PD=pharmacodynamic; PK=pharmacokinetic.1Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafety InformationforHeathcareProfessionals/ucm190787.htm. Published November 17, 2009. Accessed January 22, 2010. 2Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2009. 3Wathion N. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/Plavix/32895609en.pdf. Published May 29, 2009. Accessed January 22, 2010. 4Plavix [summary of product characteristics]. Paris, France: Sanofi Pharma Bristol-Myers Squibb SNC; 2009.

Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activity

ClopidogrelClopidogrel is a is a prodrugprodrug; requires conversion by the liver ; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metaboliteprimarily via CYP3A4 and CYP2C19 to an active metabolite

PPIsPPIs are strong inhibitors of CYP2C19 activityare strong inhibitors of CYP2C19 activity

ClopidogrelClopidogrel and and PPIsPPIs –– The OCLA studyThe OCLA study

-32.6

-43.3-50-45-40-35-30-25-20-15-10-50

PRI V

aria

tion

(%)

Omeprazole (n=64)Placebo (n=60)

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

Gilard et al. J Am Coll Cardiol 2008;51:256-60.

p<0.0001

Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Ho PM, Maddox TM, Wang L, et al. JAMA. 2009;301(9):937-944.

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since Discharge

Prop

ortio

n of

D

eath

s or

Rec

urre

nt A

CS

Neither clopidogrel nor PPIPPI without clopidogrelClopidogrel + PPIClopidogrel without PPI

CV

deat

h, M

I or s

trok

e

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

O’Donoghue ML, Braunwald E, Antman EM, et al. Lancet. 2009.

Days

Sur

viva

l Pro

babi

lity

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.90

0.92

0.94

0.96

0.98

1.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite Cardiovascular Events

Adjustment through Cox Proportional Hazards ModelAdjustment through Cox Proportional Hazards ModelAdjusted to Positive NSAID Use and Positive H. Pylori StatusAdjusted to Positive NSAID Use and Positive H. Pylori Status

HR = 1.0295% CI = 0.70; 1.51

Placebo: 67 events, 1821 at riskTreated: 69 events, 1806 at risk

Days

Sur

viva

l Pro

babi

lity

0 30 60 90 120 150 180 210 240 270 300 330 360 390

0.90

0.92

0.94

0.96

0.98

1.00

Placebo

Treated

Survival Curves for PPI Treated vs PlaceboComposite GI Events

HR = 0.5595% CI = 0.36; 0.85

p=0.007

(preliminary)

Placebo: 67 events, 1895 at riskTreated: 38 events, 1878 at risk

Thienopyridines after 1 year?

Very Late Stent Thrombosis

To be answered in “near future” by several large scale DAPT Trials

Event free patients at 12 months randomized to thienopyridine vs placebo along with daily aspirin

31

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

Endp

oint

(%) CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.62.5

Wiviott SD et al Circulation 2008.Adapted with permission from Antman EM.

TRITON TIMI-38

32

StentStent ThrombosisThrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

Endp

oint

(%)

Any Any StentStent at Index PCIat Index PCIN= 12,844N= 12,844

Adapted with permission from Wiviott SD et al Lancet 2008

Significant reductions both with BMS, DESSignificant reductions both with BMS, DESSignificant reductions in early and late Significant reductions in early and late stentstent thrombosesthromboses

TRITON TIMI-38

Prasugrel not indicated in patients with:prior strokeage > 75 (relative)low body weight (<60kg)—5 mg dosing