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IntroductionBasic science clinical aspectsPlatelets

P2Y12Pro thrombotic factors

Thrombin

0

5

10

15

20

25

<95% INHIB 10 min

>95% INHIB 10 min

<70% INHIB @ 8 hrs

>70% INHIB @ 8 hrs

14.4

6.4

25

8.1

MACE

P<0.009P<0.006

N=500 PCI patients2b3a inhibitors2b3a inhibitors

Circulation. 2001;103:2572-2578Circ 103-2572 gold paper steinhubl PCI and Platel inhib.pdf

Composite of death, myocardialinfarction, and urgent target vessel

revascularization

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45 y/o Hispanic women45 y/o Hispanic women--type 2 DMtype 2 DM

molecular changes during MI.pdf

Events leading to Reperfusion Events leading to Reperfusion Induced “ Induced “ inflammatoryinflammatory “ Injury“ Injury

Ambrosio Am Heart J 1999;138:s69

01020304050607080

40 minutes 3 hours 6 hours Closed

28

70 7279

% Necrosis

Reperfused @

Reimer KA. Lab Invest. 1979 Jun;40(6):633-44

Most viable area subepicardial tissue

Time is Muscle

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Basic science

Highlight summary

Poor platelet inhibition is associated with increased CV risk

Time is muscle…70% of heart muscle dead in 120 minutes w/o blood

Highlight summary

Poor platelet inhibition is associated with increased CV risk

Time is muscle…70% of heart muscle dead in 120 minutes w/o blood

Healthy vascular endothelium Prevents

Platelet adhesion and activation

(antithrombotic factors)

CD39 (ectoADPase), prostaglandin, nitric oxide, heparin, matrix

metalloproteinase-9,protein S, and thrombomodulin

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Lipids are involved in the prothrombotic stateLipids are involved in the prothrombotic state

LDL

oxLDL

InflamedMONOCYTE

IP3

ADPTxA2others

Platelets are activated by many conditions-increasing prothrombotic state

Platelet

2b3a receptor

Fibrinogen

IP3

ADP

Anti-thrombins

Arachidonic acid

ADP receptor

Prost G2Prostacyclin

Thromboxane A2

AgonistReceptorAgonist

Receptor

Oral clopidogrel/ prasugrel

Irreversible

Ticagrelor (reversible)

2b3a receptor

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Chest pain for 2 hours …waited in University ER for 8 hours

Microparticles with tissue factor are released

Microparticles with tissue factor are released

Tissue Factor bearing cell

Prothrombin

ThrombinThrombinVa

Factor XFactor X

Xa PlateletPlatelet

VIII/vWFOthers

Activated platelets

FibrinogenFibrinogen

FibrinFibrin

ClotClot

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Platelets and P2Y12

Highlight summary

Healthy vascular endothelium protects from atherothrombotic events

Elevated oxLDL/inflammation increased platelet and prothrombotic risk

Thrombin/tissue factor others activate platelets

Highlight summary

Healthy vascular endothelium protects from atherothrombotic events

Elevated oxLDL/inflammation increased platelet and prothrombotic risk

Thrombin/tissue factor others activate platelets

Molecular Steps in Platelet ActivationMolecular Steps in Platelet Activation

P2Y12 Inhibits adenylyl cyclase (AC) and a decrease in cyclic AMP (cAMP)

P2Y12 Inhibits adenylyl cyclase (AC) and a decrease in cyclic AMP (cAMP)

Nat Rev Drug Disc Bhatt 2- 15 p2y12 +++++++.pdf

3 subtypes of P2 receptors: P2X1, P2Y1, and P2Y12

Activation of P2Y12 receptor -responsible for sustained platelet

aggregation and secretion

Activation of P2Y12 receptor -responsible for sustained platelet

aggregation and secretion

Activated platelets secrete ADP, platelet-derived growth factor, and thromboxane

A2 (TXA2). ADP and TXA2 cause circulating platelets to change shape and

become activated.

Thromboxane A2 (TXA2), adenosine diphosphate (ADP),

thrombin, serotonin, epinephrine, and collagen

Platelet ActivatorsPlatelet Activators

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Platelet aggregationPlatelet aggregation

Irreversible inhibition

Reversible inhibition of P2Y12 receptor

Receptor nonfunctional for the life of the platelet

Normal

Cardiovascular Therapeutics 27 (2009) 259–274

Oral blockade of platelets

NEJM 2009;361:1108

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Inhibition of Platelet

Aggregation* Route Peak EffectOffset of Action

Consistency of Response

Clopidogrel 300 mg ~30% Oral ~ 4 hours ~5 days +Clopidogrel 600 mg ~40% Oral ~ 4 hours ~5 days ++

Prasugrel 60 mg 75–80% Oral 1 hour ~5 days +++AZD6140 90 mg BID 75–80% Oral 1–2 hours 1–2 days +++Cangrelor >90% IV minutes 20 min +++

SCH 530348 2.5 mg daily (>90% to TRAP) Oral

With load: hours Without load: days Weeks +++

Sabatine MS. Cleve Clin J Med. 2009;76 Suppl 1:S8-15.

Emerging Antiplatelet Therapies

*Adenosine 5'-diphosphate (ADP)-induced aggregation to ADPBID, twice daily; TRAP, thrombin receptor antagonist peptide

nejm plato 1045.pdf

SCH 530348 par 1 Lancet 373- 919.pdf

020406080

100120140160

30 ug 100 ug 15 ug 30 ug

114

150

109

140

AdenosineTicagrelor

Circulation 2007;116(Suppl):II-28:A-245

Perc

ent o

f Bas

elin

e

S. Husted and J.J .J . van Giezen CV Therap 27- 259 adenosine.pdf

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S. Husted and J.J .J . van Giezen CV Therap 27- 259 adenosine.pdf

Cardiovascular Therapeutics 27 (2009) 259–274

Abciximab is an ant ibodyAbciximab is an ant ibodySmall peptides

Type Monoclonal antibodyfragment

Small Molecular(KGD

sequence)

Small Molecular(RGD

sequence)Platelet bound

half lifeHours Seconds Seconds

Plasma half live Minutes 2.5 hours 1.8 hours

Drug to receptor ratio

1.5-2.0 250-2500 >260

½ of dose in bolus

75% <2-5% <2-5%

Renal adjust NONE YES YES

2b/3a receptor2b/3a receptor

FibrinogenFibrinogen

Platelet

IV platelet inhibition

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Only Abciximab is an antibody (do not repeat 2 weeks)Only Abciximab is an antibody (do not repeat 2 weeks)

Small peptides

Type Monoclonal antibody fragment

Small Molecular(KGD sequence)

Small Molecular(RGD sequence)

IIb/IIIa xxx xxx xxx

avb3 xxx x

Mac-1 x

Thrombingeneration

xx x x

ACT ++30 seconds +20 seconds 0

Reversible withoutplatelets

24 hrs 4 hrs 4 hrs

Reversible with platelets

YES no no

2b/3a receptor2b/3a receptor

FibrinogenFibrinogen

Platelet

Clinical trials

Highlight summary

Irreversible binding to P2Y12 receptor…clopidogrel & prasugrel

Ticagrelor reversible binding to P2Y12, given bid in preclinical trials, and releases adenosine in animal studies

IV 2b/3a inhibitors: 7E3 is antibody and should not be given for 2 weeks after treatment, but is the only platelet reversible compound

Highlight summary

Irreversible binding to P2Y12 receptor…clopidogrel & prasugrel

Ticagrelor reversible binding to P2Y12, given bid in preclinical trials, and releases adenosine in animal studies

IV 2b/3a inhibitors: 7E3 is antibody and should not be given for 2 weeks after treatment, but is the only platelet reversible compound

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Irreversible P2Y12 receptor antagonistProdrug metabolized by CYP450 enzymesCYP2C19 reducedreduced--functionfunction allele (CYP2C19*2) associated with 32% reduction in exposure to active metabolite of clopidogrel

Mega JL, et al. N Engl J Med. 2009;360(4):354-362.

Acute (<1 month)•N=544•Coronary stenting/ volunteers/ HF/stroke

Long term (>1 month)•N=359•Coronary stenting/stroke

41.9 ±20.8%* 52.9 ±8.1%*

Serebruany VL, et al. Am Heart J. 2007;153(3):371-377.Serebruany VL, et al. J Am Coll Cardiol. 2005;45(2):246-251.

*Mean ±SD

0 10–20 30–40 50–60 70–80 >90

5 M ADP Platelet Aggregation (%)

60

120

180

0

Inhibition of Platelet Aggregation (%)

35–40 41–45 45–50 51–55 56–60 61–65 66–70

40

0

20

60

80

100

No.

of

Pati

ents

No.

of

Pati

ents

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Pharmacogenomics of Antiplatelet Intervention Study (PAPI)7 days clopidogrelN=429 healthy Amish Platelet aggregometryGenome wide association study

JAMA. 2009;302(8):849-858

Carriers of the CYP2C19*2 genotype have higher cardiovascular Carriers of the CYP2C19*2 genotype have higher cardiovascular event rates compared with event rates compared with noncarriersnoncarriers

(20.9% vs 10.0%; hazard ratio [HR], 2.42; 95% CI, 1.18-4.99; P=.02)

CYP2C19 reducedreduced--functionfunction allele (CYP2C19*2) associated with 32% reduction in exposure to active metabolite of clopidogrel JAMA. 2009;302(8):849-858

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White population: 24% have at least 1 alleleMexican population: 18%African American population: 33%Asian population: 51%

Clin Pharmacol Ther. 2006;80(1):33-40Pharmacogenetics. 1996;6(3):265-267

FDA…The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix.

GI absorption is limited by the P-glycoprotein efflux-transporter encoded by the adenosine triphosphate-binding cassette containing gene ABCB1, also known as the multidrug resistant (MDR1) gene

AMI populationPrimary EP (death, nonfatal MI, or stroke at 1 year)

Abnormal genotype (carriers)-15.5%Normal genotype (noncarriers)-10.7% (HR 1.72 (1.20,2.47))

Patients with 2 CYP2C19 loss of function alleles and 1 ABCB1 variant allele----HR 5.31 (2.13-13.20)

JACC 2010;56:321ACCF-AHA Clopidogrel Clinical Alert JACC 56- 321 holmes.pdf

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Prospective, observational, single center, cohort studyN=1069All receive clopidogrel for PCI5 Tests

VerifyNOW P2y12Plateletworks assaysIMPACT-RPFA-100PFA P2YPrimary endpoint: all cause death, MI, thrombosis, stroke

JAMA. 2010;303(8):754-762

Platelet blockedHigh Reactivity0

5

10

15

6 5.7 6.1

11.7 13.3 12.6

% of Patients - Primary EP

All p<0.001

VerifyNow and Plateletworks good in post stent patients preds events JAMA 303- 754 Werkum.pdf

Amish studyPatients with the CYP2C19*2 variant (reduced function) were more likely (20.9% vs 10.0%) to have a CV ischemic event or death during 1 year of follow-up

Other studies support the clinical importance of risk allele CYP2C19*2Loss of function genotype varies in different ethic groupsCombination of both ABCB1 polymorphism with CYP2C19*2 increases risk for CV event 5X

Clopidogrel-CYP2C19*2 reduced function allele (drug not metabolized to active form). 150 mg qd increase cost to level higher than prasugrel

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Prasugrel..TRITON-TIMI 38 trial-FDA approvedTicagrelor..PLATO trial pending FDA approval

Contra-indication /caution by FDA-History of transient ischemic attack or stroke

75 years of age<60 kg

Prasugrel

Double-blind, randomized phase III

Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015.

13,608 patientsACS (STEMI/NSTE ACS) and planned PCI

Treatment duration: 6–15 mo

Aspirin75–162 mg

•1° composite endpoint: CV death/nonfatal MI/nonfatal stroke•2° endpoints at 30 and 90 days: composite of CV death/nonfatal MI/nonfatal

stroke, composite of CV death/nonfatal MI/urgent target vessel revascularization (uTVR)

•2° endpoints: stent thrombosis; composite (CV death, nonfatal MI/stroke stroke, rehospitalizationfor cardiac ischemic event)

•Safety endpoints: TIMI major and life-threatening bleeds

Prasugrel.pdf

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Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015.

Overall Days 0–3

Prasugrel: TRITON–TIMI 38

Days 3–450

1° composite endpoint: CV death/nonfatal MI/nonfatal

stroke

Randomized double blind, multicenter

Targeted number of 1780 primary endpoints

Primary endpoint @ 1 yearComposite: Death from v ascular disease, MI, Stroke

TicagrelorOral reversible, direct inhibitor of ADP receptor p2y12180 mg load90 mg bidStent thrombosis 71/5640 (1.3%)

Clopidogrel600 load75 mg qdStent thrombosis 106/5649 (1.9%) p<0.009

nejm plato 1045.pdf

N Engl J Med 2009;361:1045-57

0

5

10

15

Ticagrelor Clopidogrel

9.8 11.7

4.55.9

Primary EP Death Vascular Dx

1 year

ARR 1.9% (HR 0.84-0.77,0.92)

Major bleeding (not CABG)Ticagrelor 4.5%Clopidogrel 3.8%

P<0.03

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nejm plato 1045.pdf

Primary end point: death from vascular causes, MI, or stroke

N Engl J Med 2009;361:1045-57

STEMI-38%NSTEMI-42%PVDx-6.2%HT-65%Abn Lipids-46%DM-25%Prior MI-20%Statins-89%

NEJM 2009;361:1108

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First time in decades: new class of oral thrombin inhibitor

Non inferiority trialRandomized 18,113Atrialfibrillation

Risk for stroke

F/Y 2 yearsPrimary endpoint: preventionof stroke or systemic embolism

Non inferiority trialRandomized 18,113Atrialfibrillation

Risk for stroke

F/Y 2 yearsPrimary endpoint: preventionof stroke or systemic embolism

RELY trial dabigatran nejm 361- 1056.pdf

Dabig 110 mg (182/6015) 3%Dabig 150 mg (134/6076) 2.2%Warfarin (INR 2-3) (199/6022) 3.3%

ARR 1.1%ARR 1.1%P<0.001

150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage N Engl J Med 2009;361:1139-51

NNT 90 for 2 yearsNNT 90 for 2 years

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Dabig 110 mg (182/6015) 3%Dabig 150 mg (134/6076) 2.2%Warfarin (INR 2-3) (199/6022) 3.3%

Dabig 110 mg (322/6015) 5.3%Dabig 150 mg (375/6076) 6.1%Warfarin (INR 2-3) (397/6022) 6.59%

ARR 1.1% (NNT=90 for 2 years)ARR 1.1% (NNT=90 for 2 years)

Major BleedingMajor Bleeding

Prevent stroke/systemic embolismPrevent stroke/systemic embolism

AR Increase 0.49% (NNH=204 for 2 years)AR Increase 0.49% (NNH=204 for 2 years)

RELY trial dabigatran nejm 361- 1056.pdf N Engl J Med 2009;361:1139-51

204 patient treated for 2 years with dabigatranbefore 1 major bleed

was prevented vs warfarin

prevent 2 strokes if treat 200 patients for 2 years 1 bleed for each 200 patients treated for 2 years

Dabigatran-RE-LY trial reduces strokes in Afib vswarfarin (direct thrombin inhibitor)New agents-pending

Factor Xa inhibitorsRivaroxaban (Xarelto)

Bayer/J&JROCKET-AF

Stroke prevention studyAHA Nov 2010

ApixabanBristol-Myers Squibb/PfizerFDA application on f ileARISTOTLE

2011AVERROES trial

Lower strokes and systemic embolic events vs ASAFXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin

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Condition Points

C Congestive heart failure 1

H

Hypertension: blood pressure consistently above 140/90 mmHg

(or treated hypertension on

medication)

1

A Age >/=75 years 1

D Diabetes Mellitus 1

S2 Prior Stroke or TIA 2

Annual Stroke Risk

CHADS2Score

Stroke Risk %

95% CI

0 1.9 1.2–3.0

1 2.8 2.0–3.8

2 4.0 3.1–5.1

3 5.9 4.6–7.3

4 8.5 6.3–11.1

5 12.5 8.2–17.5

6 18.2 10.5–27.4

Score Risk Anticoagulation Therapy Considerations

0 Low Aspirin Aspirin daily

1 Moderate Aspirin or Warfarin

Aspirin daily or raise INR to 2.0-3.0,

depending on factors such as patient

preference

2 or greater Moderate or High Warfarin

Raise INR to 2.0-3.0, unless contraindicated

(e.g. clinically significant GI bleeding,

inability to obtain regular INR screening)

Risk factors and inflammation increases prothrombotic cardiovascular risk

Oral P2Y12 inhibitors have very different actions, but all work if platelets are inhibitedIV 2b/3a inhibitors: 7E3 is reversible with platelets

Atrial fibrillation patients: dabigatran (first direct oral thrombin inhibitor) was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage to warfarin

Thank you