Compared to Heparin/Enoxaparin with GP IIb/IIa inhibitors,Bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection, and improves net clinical

outcome.

Bivalirudin Advantage

ATIIa

Hep

UFH

IIaS

C

Direct antithrombin

LMWH

AT Xa AT Xa

Pentasaccharide

IIa II

Fibrinogen Fibrin clot

Extrinsic pathway

Intrinsicpathway

AT XaAT AT

Fondaparinux

Xa

Antithrombin

Fondaparinux: A Synthetic Factor Xa Inhibitor

Adapted with permission from Turpie AGG et al. N Engl J Med. 2001;344:619.

THROMBIN

Key Steps in Coagulation Pathway

Inhibition of one molecule of factor Xa can inhibit the

generation of 50 molecules of thrombin2

Intrinsic pathway Extrinsic pathway

1 .Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2 .Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.

Intrinsic pathway

1

50

Xa X

IIFibrinFibrinogen

Clot

Xa

Va

PLCa2+

IIa

VIIIa

Ca2+

PL

IXa

Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1 .van Boeckel CAA et al. Angew Chem, Int Ed Engl. 1993;32:1671 .

·Once daily administration ·Rapid onset (Cmax/2=25 min)·Half life: 15-18 h.·Effects reversible with administration

of activated Factor VII (Novoseven®)·No liver metabolism·Renal clearance·No protein binding (other than AT)·No reported cases of HIT·No dose adjustment necessary in

elderly

Fondaparinux: A Synthetic Inhibitor of Factor Xa

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

UFH not indicated

OASIS-6: Randomized, Double Blind

Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)

Stratification

UFH indicatedRandomization Randomization

Fondaparinux2.5 mg Placebo Fondaparinux

2.5 mg UFH JAMA 2006;295:1519-30

Primary Efficacy OutcomeDeath/MI at 30 Days

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 3 6 9 12 15 18 21 24 27 30

UFH/Placebo

Fondaparinux

HR 0.86 95% CI 0.77-0.96

P=0.008

The OASIS-6 Trial Group. JAMA 2006;295:1519-30

Death or MI 3 or 6 months

Days

Cum

ulati

ve H

azar

d

0.00.0

20.0

40.0

60.0

80.1

00.1

2

0 18 36 54 72 90 108 126 144 162 180

UFH/Placebo

Fondaparinux

HR 0.88 95% CI 0.79-0.99

P=0.029

The OASIS-6 Trial Group. JAMA 2006;295:1519-30

•Primary: Efficacy: Death, MI, refractory ischemia 9 day

Safety: Major bleeds

Risk benefit: Death, MI, refractory ischemia, major bleeds•Secondary: Above & each component (especially deaths) at 30 & 180 d•Hypothesis: First test non-inferiority, then test superiority

Death at 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0 20 40 60 80 100 120 140 160 180

HR 0.8995% CI 0.79-0.99

p=0.037

Enoxaparin

Fondaparinux

Death or MI: 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 20 40 60 80 100 120 140 160 180

HR 0.9195% CI 0.84-0.99

p=0.036

Enoxaparin

Fondaparinux

Major Bleeding: 6 Months

Days

Cum

ulati

ve H

azar

d

0.00.0

10.0

20.0

30.0

40.0

50.0

6

0 20 40 60 80 100 120 140 160 180

HR 0.7295% CI 0.63-0.82

p<<0.00001

Enoxaparin

Fondaparinux

Death, MI, RI or Major Bleeding at 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.05

0.10

0.15

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

HR 0.8795% CI 0.81-0.93

p<<0.00001

Fondaparinux

•Difficult to monitor (no aPTT or ACT)

•Long half-life•Catheter thrombosis

during PCI

DisadvantagesAdvantages•SC administration

―Potential exists for outpatient

management•Once-daily

administration•Predictable

anticoagulant response•Fixed dose•No antigenicity•Potentially no need for

serologic parameters•Does not cross the

placenta•HIT antibodies do not

cross-react•Decreased bleeding

complications vs UFH or LMWH

Simoons ML, et al. J Am Coll Cardiol. 2004;43:2183-2190.Yusuf S, et al. N Engl J Med. 2066;354:1464-1476 .