Compared to Heparin/Enoxaparin with GP IIb/IIa inhibitors,Bivalirudin monotherapy significantly...

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

II

FibrinFibrinogen

Clot

Xa

Va

PL

Ca2+

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 onset:Inclusion ST mm prec leads or 2 mm limb leads 1

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

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 indicatedUFH not indicated

OASIS-6: Randomized, Double Blind

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

StratificationStratification

UFH indicatedUFH indicatedRandomization Randomization

Fondaparinux2.5 mg Placebo

Fondaparinux2.5 mg UFH

JAMA 2006;295:1519-30

Primary Efficacy OutcomeDeath/MI at 30 Days

Days

Cum

ulati

ve H

azar

d0.

00.

020.

040.

060.

080.

100.

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

0.0

0.02

0.04

0.06

0.08

0.10

0.12

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 day 9

Safety:Major bleeds

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

•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.

00.

020.

040.

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

d

0.0

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

0.0

0.01

0.02

0.03

0.04

0.05

0.06

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.

00.

050.

100.

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 .