Bivalirudin Advantage
description
Transcript of Bivalirudin Advantage
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 .