P2Y12 Receptor InhibitorsReceptor Inhibitorssummitmd.com/pdf/pdf/15_CWLee.pdf · 2012. 5. 17. · 180fusion. p

P Y Receptor InhibitorsP2Y12 Receptor InhibitorsClopidogrel Prasugrel and TicagrelorClopidogrel, Prasugrel and Ticagrelor

Which Drug and for Whom?g

Cheol Whan Lee, MD

Professor of Medicine, University of Ulsan College of Medicine, Heart Institute, Asan Medical Center, Seoul, Korea 

A Miracle Drug!

The Great JourneyP2Y12 Receptor Blockers

y

P2Y12 Receptor: A Key Player12 p y y

Curr Pharm Des 2006;12:1255Circulation 2010;121:171

The In entor of TiclopidineA New Chapter!

The Inventor of TiclopidineJean‐Pierre Maffrand, 1972 (retire 2008)

Cumulative Risk of Stoke MI or Vascular Clopidogrel monotherapy

Cumulative Risk of Stoke, MI or Vascular Death in Patients in the CAPRIE Trial

16Aspirin 8.7%*Event rate/year

19,185 patients with atherosclerotic disease

te (%

)

12

16

Clopidogrel

Overall Relative Risk

Reduction

8.7%Aspirin5.83%

Event rate/year

Even

t Rat

85.32%

mul

ative

E

4

5.32%Clopidogrel

P = 0.043

No major safety differences

Any bleed 9.28% 9.27%Aspirin Plavix

Months of Follow-Up

Cum

0 0 3 6 9 12 15 18 21 24 27 30 33 36

P 0.043 Any bleedICHGI bleed*

9.28% 9.27%0.49% 0.35%2.66% 1.99%

*p<0.05Months of Follow-Up

Lancet 1996;348:1329

STARS: P2Y12 Receptor InhibitorDual anti-platelet therapy

STARS: P2Y12 Receptor InhibitorN=1 965N 1,965

ASA alone 3.5% vs. Dual 0.5% (ST 86%↓)

NEJM 1998 339 1665NEJM 1998;339:1665

After coronary stenting, aspirin & ticlopidine should be consideredfor the prevention of the serious complication of stent thrombosis.

Superior Efficacy of ADP ReceptorSuperior Efficacy of ADP Receptor Antagonists in Coronary Stenting

12 Ticlopidine + ASACoumadin + ASA11ASA

Clopidogrel + ASAClopidogrel LD + ASAClopidogrel

MI, r

evas

c.)

88.3

Clopidogrel

(% d

eath

, M

6.2 5.7 5.6Dual therapy (aspirin & clopidogrel)

- PCI: BMS (1 month), DES (12 months)

vent

rate

s ( 4

1.62.7

3.6

1 5

PCI: BMS (1 month), DES (12 months)- ACS: 12 months

A P2Y12 inhibitor should be added to aspirin as soon as possible and

Ev

0ISARN 517

FANTASTICN 485

STARSN 1653

MATTISN 350

1.60.5

CLASSICSN 1020

1.5 1.20.9p p

maintained over 12 months in ACS patients unless contraindication (IA, ESC2011)

An alternative to aspirinN=517 N=485 N=1653 N=350 N=1020

… FurtherDrama

Th Ch llWhich one is better?The ChallengeWhich one is better?

P2Y12 Antagonists Form follows function!

COOCH

Evolution Revolution

F

FN

COOCH 3

N

HO

HN

O S

F

NN

N

NN

S Cl

Clopidogrel

S Cl

Ticlopidine

HO OH

O SNNC op dog e

O

Ticlopidine

AZD6140(CPTP: Cyclo-Pentyl-

NOCH3

O

Triazolo-Pyrimidine;orally active)

SO F

PrasugrelPrasugrel

TRITON – TIMI 38ACS (STEMI or UA/NSTEMI) & Planned PCI (99%)

TRITON TIMI 38ACS (STEMI or UA/NSTEMI) & Planned PCI (99%)

ASA N = 13,000Double-blind

PRASUGREL CLOPIDOGREL

Median duration of therapy – 12 months

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke,

Rehosp Re-isch CV death, MI, UTVRp , ,

TRITON TIMI 38 Prasugrel Lowers Events

Early Benefits, Late Hazards!

TRITON-TIMI 38 Prasugrel Lowers Events but Ups Bleeding versus Clopidogrel in ACS

Cardiovascular death/MI/stroke

13, 608 ACS patients scheduled for PCI (STEMI 26%)

15 Cardiovascular death/MI/strokeHR0.81 (0.73 - 0.90), p<0.001

Nonfatal MIHR 0.76 (0.67 - 0.85) p<0.001t (

%)

Clopidogrel12.1(781)

HR 0.76 (0.67 0.85), p<0.001Stent thrombosis (1.1% vs. 2.4%)

HR 0.48 (0.36 - 0.64), p<0.00110

Endp

oint 9.9

(643)

HR 0.81Prasugrel

Fatal bleeding (0.4% vs 0.1%)HR 4.19 (1.58 - 11.11), p=0.002

TIMI major/minor bleeding5

Prim

ary

HR 0.77P=0.0001

HR 0.80P=0.0008

(0.73-0.90)P=0.0004NNT=46

j gHR 1.31 (1.11 - 1.56), p=0.002

Risk groups: age>75 & lean<60kg or history of stroke/TIA

0 30 60 90 180 270 360 4500

LTFU=14(0.1%)ITT=13,608

0 30 60 90 180 270 360 450Days

NEJM 2007;357:2001

TRITON: St d LimitationsTRITON: Study Limitations

Randomization after coronary angiogram (PCI trials)- clopidogrel naïve: any user within 5 days excluded

•Prasugrel in ACS

- lower loading dose of clopidogrel (300mg)- timing of enrolment (3 days vs 8 hours in PLATO) It is not our recommendation that prasugrel be 

NSTE-ACS, ACCF/AHA Guideline 2011

g ( y )

Outcome difference (<10 days): driven by ↓ non-fatal MI ↑

•

p gadministered routinely before angiography, such as in an emergency department, or be 

d h h dy

(half of these was non-clinical MI [↑biomarker criterion])g

used in patients who have not undergone PCI. Circulation2011;123:2022-60

ACS ESC Guideline 2011 Prasugrel in Clopidogrel out for STEMINo difference in all‐cause mortality: balance between ↓0.3% absolute reduction in CV death, ↑0.3% fatal bleeding

• ACS, ESC Guideline 2011 Prasugrel in, Clopidogrel out for STEMI

TRILOGY ACSTRILOGY – ACSMedically Managed NSTE-ACS

Low-dose ASA N = 10,300 (<75y: ~7800)Low dose ASA N 10,300 (<75y: 7800)

Randomization within 10 days of index eventStratified by age (75y) BWt (60kg) clopidogrel treatmentStratified by age (75y), BWt (60kg), clopidogrel treatment(300mg LD within 72h of index event & daily MD; or MD≥ 5 days)

PRASUGREL5 or 10mg/day

CLOPIDOGREL75mg/day5 or 10mg/day 75mg/day

Duration of therapy : minimum 6m, maximum30m

1o endpoint: CV death, MI, Stroke

PLATO A Study of PLATelet PLATO yInhibition & Patient Outcomes

ACS (STEMI/NSTEMI) (<24 h after chest pain)

ASA N = 18,624Double-blind

ASA N 18,624

Ticagrelor Clopidogrel

IIbIIIa 27%

g p g

Median duration of therapy: 6-12 months

1o endpoint: CV death, MI, Stroke (15%RRR)2o endpoints: Death, CV death, MI, stroke,

recurrent ischemia arterial thrombotic eventsrecurrent ischemia, arterial thrombotic events

Major OutcomesA Hard ACT to Follow

j

HR 0.84(0.77-0.92)P=.0003NNT=54

CV Death / MI / StrokeClopidogrel

9.8

11.7

%)

10

12

In 1000 ACS patients replacing NNT 54

Ticagrelor

cide

nce(

%

8

In 1000 ACS patients, replacingclopidogrel with ticagrelor for 12 months,

HR 0.79(0 69-0 91)

CV deathClopidogrel

5.1

ativ

e In

c

6‐ 14 fewer deaths (absolute risk reduction 1 4%) (0.69-0.91)

P=.001NNT=90Ticagrelor

4.0

Cum

ula

2

4(absolute risk reduction 1.4%)

‐ 11 fewer MI‐ 6~8 fewer cases of stent thrombosis

0

Definite ST33%p=0.009

Total death 22%↓ (NNT )

‐ 6~8 fewer cases of stent thrombosis‐ no increase in bleeding 

i i  t f iDays After Randomization

120 1800 60 p<0.0001 (NNT70)requiring transfusion.

Major Bleedingj g

Ti l i ACSTicagrelor in ACS

ESC2011Ticagrelor in, clopidogrel out

Adenosine Hypothesis ?yp

- vasodilation- preconditioningpreconditioning--immunomodulation

-dyspnea-dyspnea-heart block-renal funtion

IC Adenosine for Myocardial S l i P ti t With STEMISalvage in Patients With STEMI

- Adenosine 4mg- CMRI on day 2-3y 3- Salvage index=

necrotic area/risk arearisk area

Eur Heart J 2011;32:867

AMIP2Y12R SMC CD31

P2Y12R SMC CD31

Stable anginaStable angina

Beyond PlateletsSummary

Beyond Platelets

ADP

P2Y12 ReceptorpPlatelets Endothelial Cells VSMCs

Acute Coronary SyndromeAcute Coronary Syndrome

P2Y12 receptor inhibitors may have a dual antiP2Y12 receptor inhibitors may have a dual anti--ischemic effectischemic effectP2Y12 receptor inhibitors may have a dual antiP2Y12 receptor inhibitors may have a dual anti--ischemic effect ischemic effect by inhibiting both platelet activation and plaque destabilization.by inhibiting both platelet activation and plaque destabilization.

P2Y12 Receptor InhibitorsKing of kings

p

Heart 2010;96:656

d d Unanswered Unanswered QQuestionsuestionsQQuestionsuestions• STEMI: thrombolytic or medical therapy

•AMI: 1 year after AMI (PEGASUS)•AMI: 1 year after AMI (PEGASUS)• Stable angina: after DES Stable angina: after DES • Ischemic stroke• Primary prevention

Right Balance

h kThe DilemmaBleeding is the key!g

d

Trade-off, Dual Therapy

Safety: More Potent, More Bleeding!

8.8%

8%

10% ASA + ClopidogrelASA + Placebo

ng (%

)

P=0.07

6.7%6%

blee

din

P=0.001 P=0.0013.7%

2.7%3.8%

2.6%2%

4%

nific

ant

0%

2%

CURE CREDO CHARISMA

Sign

CURE CREDO CHARISMAN=12,5631 year FU

CURE major bleed

N=2,1161 year FU

TIMI major bleed

N=15,6032.5 year FU

GUSTO majorCURE major bleedNEJM 2001;345:494-502

TIMI major bleedNEJM 2001;345:494-502

GUSTO major + moderate bleed

NEJM 2001;345:494-502

Fragile Brain vs. Tough Heart

Intracranial Bleeding• Patient history of stroke or TIA

• TRITON-TIMI 38: incidence of stroke in patients with pa history of prior TIA or stroke greater with prasugrel + ASA (6.5% total: 4.2% thrombotic, 2.3% ICH) vs

l id l ASA (1 2% t t l ll th b ti )clopidogrel + ASA (1.2% total, all thrombotic)

O C• PLATO: Fatal ICH higher in ticagrelor vs clopidogrel (0.1 vs 0.01; P=.02)

TRACER, Gone without Any Trace, y

Bleeding (p<0.001): GUSTO severe (HR1.66), TMIMI major(HR1.53), ICH (HR3.39)Total death: HR1 05 (P 0 52)Total death: HR1.05 (P=0.52)In pts with ACS, the addition of vorapaxar to standard therapy did not significantly reduce the primary endpoint but significantly increased the risk of major bleeding.

Endnd of theof the CChapter?hapter?

Evolution of Anti-platelet Therapy (%

)tio

n ev

ents

-20%19%

-22%

-8% (p=NS)15%

Red

uct

emic

e -19% -15%

Rn

isch

ein

Placebo DAPT+Aspirin+ Aspirin+Aspirin

+60% +38% +32%

Aspirin+

0% +43%

Placebo DAPT+Vorapaxar

Aspirin+Clopidogrel

Aspirin+Prasugrel

Aspirin AspirinTicagrelol

… largely replacedby Newer Onesy

Old Soldiers Never Die.Small bleed becomes a big bleed!

N P Y t i hibit

Old Soldiers Never Die.

New P2Y12 receptor inhibitorswill be the key players in CV medicine.

감사합니다감사합니다.