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Update on antiplatelet and anticoagulant drugs: sticky stuff

KFJ Ng

May 2011

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Direct thrombin inhibition

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Indirect thrombin inhibitionHeparin/antithrombin/thrombin complex

Heparin

Antithrombin

Thrombin

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Direct thrombin inhibition

Directthrombininhibitor

Thrombin

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Direct thrombin inhibitors

• hirudin, bivalirudin

• argatroban

• dabigatran

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Dabigatran (Pradaxa)

Annu Rev Med 2011;62:41

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fXa inhibition (anti-Xa)

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Anti-Xa and thrombus formation?

Xa

Extrinsic Pathway

IntrinsicPathway

VIII

V

IIa THROMBUS

AT

5aXa activity of AT-penta complex blocks initial thrombin generation & thrombin recruitment through feedback loops

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Factor Xa inhibitors

• Indirect– Fondaparinux (Arixtra)

• Direct– Rivaroxaban (Xarelto)

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Fondaparinux (N=1098) LMWH (N=1107)Matisse DVTFatal PE 5 (0.5 %) 5 (0.5 %)

Non-fatal PE or DVT 38 (3.5 %) 40 (3.6 %)

Total symptomatic recurrent VTE 43 (3.9 %) 45 (4.1 %)

-0.15 %

= 3.5%0 1.5% -1.8%

Fondaparinux - LMWH (95 % CI )

Primary Efficacy Outcome (non-fatal or fatal recurrent VTE to 3 months)

Fondaparinux (N=1103) UFH (N=1110)

Fondaparinux - UFH (95 % CI )

Matisse PE

-1.2%

= 3.5%0 0.5% -3.0%

Fatal PE 16 (1.5 %) 15 (1.4 %)

Non-fatal PE or DVT 26 (2.4 %) 41 (3.6 %)

Total symptomatic recurrent VTE 42 (3.8 %) 56 (5.0 %)

ATI S S

EM ... .

. ..

NEJM 2003;349:1695

Ann Intern Med 2004;140:867

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Matisse DVTFondaparinux

sc LMWH 1.2%

1.1%

3.0%

2.6%

0% 2% 4% 6% 8%

Major bleed Clinically relevant non-major bleed

1.1%

1.3%

5.2%

3.2%

0% 2% 4% 6% 8%

3.7 %

4.2 %

Principal Safety OutcomeMajor bleeding during initial

treatment

Fondaparinux

iv UFH

Matisse PE

ATI S S

EM ... .

. ..

4.5 %

6.3 %NEJM 2003;349:1695

Ann Intern Med 2004;140:867

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Rivaroxaban (Xarelto)

J Clin Pharm Ther 2011;36:111

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Rivaroxaban (Xarelto)

J Clin Pharm Ther 2011;36:111

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Copyright ©2010 American Heart Association

Mackman, N. et al. Arterioscler Thromb Vasc Biol 2010;30:369-371

Targets of new anticoagulant drugs

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Discontinuation

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Anti-platelet agents

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Gp IIb/IIIa (integrin αIIbβ3) antagonists

• Abciximab (Reopro)

• Eptifibatide (Integrilin)

• Tirofiban (Aggrastat)

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Gp IIb/IIIa antagonists FDA approval

• PCI– Abciximab– Eptifibatide

• ACS– Eptifibatide– Tirofiban

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Circulation 2010;121:171. JCI 2004;113:340.

P2Y12

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P2Y12 inhibitors

• Irreversible– Clopidogrel (Plavix)– Prasugrel (Effient)

• Reversible– Ticagrelor (Brilinta)– Cangrelor

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Prasugrel vs Clopidogrel

NEJM 2007;357:2001 (TRITON-TIMI 38)

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Ticagrelor vs Clopidogrel

NEJM 2009;361:1045 (PLATO)

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Cangrelor

NEJM 2009;361:2330 (CHAMPION-PLATFORM)

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Figure 1 The CHAMPION trials reaffirm that pretreatment with a P2Y12 antagonist is superior to delaying treatment until after the PCI procedure

David P. Faxon (2010) Cangrelor for ACS—lessons from the CHAMPION trialsNat. Rev. Cardiol. doi:10.1038/nrcardio.2009.247

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BRIDGE trial

• http://www.clinicaltrials.gov/ct2/show/NCT00767507

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Nat Rev Drug Discovery 2010;9:154

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Discontinuation (Gp IIbIIIa)

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Discontinuation (P2Y12)

29A&A 2011;112:292

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Monitoring

• Coagulation– TEG– PT/aPTT

• Platelet– PFA-100– Thrombelastography (TEG) Platelet Mapping– VerifyNow

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EPICT = 188 secSensitivity = 88%Specificity = 52%

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http://www.asra.com/publications-anticoagulation-3rd-edition-

2010.php

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Thank You