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.