prasugrel

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