PrasugrelPrasugrel
Presenter Presenter Dr.Md.Sirajum MunirDr.Md.Sirajum MunirMD 3MD 3rdrd Part Student Part Student
Moderator Moderator
Dr. A.MuttalibDr. A.MuttalibAssistant Professor Assistant Professor
NICVDNICVD
Prasugrel (marketing name Effient in the US and Efient in EU) is a novel platelet inhibitor developed by Daiichi Sankyo Co. in cooperation with Eli Lilly
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate
Thienopyridine derivatives Pro-drug. Hydrolyzed in the intestine to inactive
thiolactone which is further metabolized to active form R-138727 (M3) by cytochrome P-450 .
Appears in plasma within 15 min of dosing and achieving maximum plasma concentration by 30 min-1hr.
Excretion : Renal-70%. Remaining with feaces
The plasma half-life approximately 8 days .
Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors
Reduce the aggregation of platelets by irreversibly binding to P2Y12 receptors.
Storey RF. Current Pharmaceutical Design 2006
Thrombin
ThromboxaneA2
5HT
P2Y12
ADP ADPADP
5HT
PLATELETACTIVATION
P2Y15HT2A
PAR1
PAR4
Densegranule
Thrombingeneration
Shapechange
IIb3
IIb3
FibrinogenIIb3
Aggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsInflammatory mediators
TP
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
xCLOPIDOGRELPRASUGREL
ACTIVE METABOLITE
x AZD6140 CANGRELOR
GPIIB/IIIA ANTAGONISTS
x
Acute Coronary Syndrome -STEMI & NSTEMI Who are undergoing PCI
H/O TIA & Stroke Bleeding disorder
Loading Dose-60mg Maintainance Dose-10mg Route of administration-Oral
Bleeding -easy bruising to major bleeding Dyspnoea(rarely)
Goals of stent analysisGoals of stent analysis
To compare the efficacy and safety of PRASUGREL and CLOPIDOGREL in 12,844 patients with at least one stent as part of the index procedure with respect to:
–Stent thrombosis (ARC definitions)– Ischemic events, bleeding–Overall and stratified by stent type received
Double-blind
ACS (STEMI or UA/NSTEMI) and planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o end point: CV death, MI, stroke2o end point: Stent thrombosis Safety end points: Major bleeds
Duration of therapy: 6-15 months
N = 13,608
Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006 Oct;152(4):627-635..
0
5
10
15
0 30 60 90 180 270 360 450
P = 0.0004
Prasugrel
Clopidogrel
Days
En
d P
oin
t (%
)
12.1
9.9
P = 0.03
Prasugrel
Clopidogrel1.82.4
Main trial: Primary resultsMain trial: Primary results
CV death/MI/stroke
Major bleeding
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-2015. Epub 2007 Nov 4.
Randomized 13,608
Stent placed 12,844 (94%)
BMS only 6461 (47%)
DES only 5743 (42%)
Both BMS/DES 640 (5%)
PES only 2766 (20%)
SES only 2454 (18%)
Other/mixed523 (4%)
Wiviott SD, Braunwald E, McCabe CH, Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008 Mar 28. Epub ahead of print.
Definite: Total occlusion within or < 5 mm of the stent or thrombus within or < 5 mm of the stent
Probable: Unexplained death < 30 days or MI in stented territory without angiographic confirmation of ST and without alternative cause
Possible: Unexplained death > 30 days following stenting
Early: 0 - 30 days Late: > 30 days
Based on Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stentsN Engl J Med. 2007 Mar 8;356(10):1020-1029. Epub 2007 Feb 12.
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
% o
f S
ubje
cts
P < 0.0001
1 year: 1.06 vs 2.15% P < 0.0001
2.35%
1.13%
52%
DAYS
CLOPIDOGREL
PRASUGREL
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 450
% o
f S
ubje
cts
P < 0.0001 P = 0.03
DAYS
EARLY ST LATE ST
1.56%
0.64%
59% 0.82%
0.49%
40%
CLOPIDOGREL
PRASUGREL
PROB P < 0.0001
DEFINITE P < 0.0001
POSS P < 0.0001
CLOPIDOGREL
PRASUGREL
% o
f S
ubje
cts
% o
f S
ubje
cts
P < 0.0001
1 year: 0.74% vs 2.05% P < 0.0001
2.31%
0.84%
64%
DAYS
CLOPIDOGREL
PRASUGREL
% o
f S
ubje
cts
P = 0.0001P = 0.04
DAYS
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 450
EARLY ST LATE ST
1.44%
0.42%
71% 0.91%
0.42%
54%
CLOPIDOGREL
PRASUGREL
N = 2454 N = 2766
Sirolimus only P = 0.004
Paclitaxel only P = 0.002
CLOPIDOGRELPRASUGREL
67% 67%
% o
f S
ubje
cts
2.41%
1.27%
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
% o
f S
ubje
cts
P = 0.0009
1 year: 1.22 vs 2.27%
48%
DAYS
CLOPIDOGREL
PRASUGREL
% o
f S
ubje
cts
P = 0.0009 P = 0.24
DAYS
0
0.5
1
1.5
2
2.5
30 90 150 210 270 330 390 4500
0.5
1
1.5
2
2.5
0 5 10 15 20 25 30
EARLY ST LATE ST
1.66%
0.75%
55% 0.78%
0.53%
32%
CLOPIDOGREL
PRASUGREL
Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL:
• Substantial reduction in ST:
– Regardless of stent type or ST definition
– Early and late
• More major bleeding