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Things we knew, things we did… Things we have learnt, things we should do
Congrès international de médecine pluridisciplinaire
sous l’égide de l’IFDA
GAMMARTH, TN - 27 et 28 mars 2010
Anti-coagulants :
Quoi de neuf en 2010 ?
Pr Soraya BENYOUSSEF / Pr Ag Lilia ZAKHAMAService de Cardiologie
Hôpital des FSI . La Marsa
Jusque là ……..
A
V
K
iatrogénicité induite par AVK bien connue responsables de >17 000 hospi/an et 4 000
DC/an.
Heparines ont fait preuve d’efficacité en préventif / curatif
1. injectables2. effets secondaires : thrombopénie+++
héparine (1 pt/1000 (1 pt/100 HNF)
Jusque là ……..
L’anticoagulant Idéal
OralDoses fixesPas de dosage d’efficacité nécessaire mais possibleSécuritaire
Fenêtre thérapeutique largeActivité d’action rapide et courtePeu d’interactions médicamenteuses et alimentaires Réversible
Indications d’anticoagulationPrévention
ETE Veineux Post opératoire (chirurgie orthopédique = risque très élevé) Pt hospitalisé
ETE Artériel FA IM Valve cardiaque
Traitement et prévention secondaire des ETE veineux et artériels
Rosenberg & Aird. N Engl J Med 1999;340:1555–64Wessler & Yin. Thromb Diath Haemorrh 1974;32:71–
8
Intrinsic pathway Extrinsic pathway
1
Xa X
II
FibrinFibrinogen
Clot
Xa
Va
PLCa2+ IIa
VIIIa
Ca2+
PL
IXa
Choisissons notre cible …..
Nouveaux Anticoagulants
indirect
OASIS 5: A Randomized, Double-Blind, Non inferiority, Double-Dummy Trial20,078 Patients with NSTE ACS, Chest discomfort < 24 hours
2 of 3: Age>60, ST Segment Δ, cardiac markers
Fondaparinux2.5 mg subcut once daily up to 8 days or
hospital discharge
Aspirin, Clopidogrel, GPIIb/IIIa inhibitor, planned Cath/PCI as per local practice
Randomization
Enoxaparin1 mg/kg subcut bid for 2-8 days
1 mg/kg subcut daily if CrCl<30mL/min
Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 OASIS 5 Investigators. N Engl J Med2006;354: 1464-76
Mean treatment : 5.5 daysMean time to PCI: 2.4 days
ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L
Mean treatment : 5.2 daysMean time to PCI: 2.6 days
Fondaparinux Non-Inferior to Enoxaparin at Day 9 (Primary Efficacy)
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux HR: 1.01 95% CI: 0.90-1.13P non-inferiority: 0.007
Death/MI/RI
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Fondaparinux Significantly Reduced Mortality vs. Enoxaparin at Day 30
Fondaparinux: 295 deathsEnoxaparin: 352 deaths
Days
0 3 6 9 12 15 18 21 24 27 30
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
HR: 0.83 95% CI: 0.71-0.97p=0.02
Enoxaparin
Fondaparinux
0.04
3.5 %
2.9 %
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76Bassand JP Expert Rev Cardiovasc Ther 2007;5:1013-26
17 % RRR
The Reduction in Mortality with Fondaparinux was Maintained at 6 Months
Fondaparinux: 574 deathsEnoxaparin: 638 deaths
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Days
Cu
mu
lati
ve H
azar
d
0.0
0.02
0.04
0.06
0 20 40 60 80 100 120 140 160 180
HR: 0.8995% CI: 0.80-1.00 p=0.05
Enoxaparin
Fondaparinux
0.08
6.5 %
5.8 %
Significant Early Major Bleeding reduction with Fondaparinux
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
*Am J Cardiovasc Drugs 2008; 8 (1):in press
48% relative
risk reduction
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR: 0.52 95% CI: 0.44-0.61 p<0.0001
Enoxaparin
Fondaparinux
4.1 %
2.2 %
*At day 5, the reduction was already significant, p 0.048
*
Major Bleeding Was significantly Reduced at Day 30
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0.05
0 3 6 9 12 15 18 21 24 27 30
HR: 0.62 95% CI: 0.54-0.72p<0.001
Enoxaparin
Fondaparinux
5.0%
3.1%
38% relative
risk reduction
Significant Reduction in Major Bleeding Maintained at 6 Months
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Days
Cu
mu
lati
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
At 6 monthsHR: 0.7295% CI: 0.64-0.82p<0.001
Enoxaparin
Fondaparinux
5.8%
4.3%
4.1%
2.2%
Major Bleeding at Day 9 Lower with Fondaparinux Irrespective of Renal Function*
Maj
or
Ble
ed
40 60 80 100 120 140
0.02
0.04
0.06
0.08
0.10
Enoxaparin(dose adjusted for renal function)
Fondaparinux
GFR mL/min/1.73 m2
Fox KAA. Ann Int Med 2007;147:304-310
* Fondaparinux is contra-indicated in patients with creatinin clearance<20mL/min
Significant Net Clinical Benefit at Day 9 with Fondaparinux
Days
0.109.0 %
Cu
mu
lati
ve H
azar
d
0.0
0.02
0.04
0.06
0.08
0 1 2 3 4 5 6 7 8 9
HR: 0.81 95% CI: 0.73-0.89p<0.001
Enoxaparin
Fondaparinux
7.3%
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Death/MI/RI/Major Bleeding at Day 9
Significant Net Clinical Benefit with Fondaparinux maintained at 6 Months
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76Days
Cu
mu
lati
ve H
azar
d
0.0
0.05
0.10
0.15
0 20 40 60 80 100 120 140 160 180
Enoxaparin
Fondaparinux
HR: 0.8695% CI: 0.81-0.93p<0.001
0.2017.1%
15.0%
Death/MI/RI/Major Bleeding at 6 months
Anti Xa directs oraux
Rivaroxaban (Xarelto®)
Antithrombine (anti-IIa) oraux
Dabigatran (Pradaxa®)
RE - LY
EN RESUME…..
CONCLUSIONLes Anti Xa et IIa oraux vont-ils remplacer les
HBPM dans le traitement préventif de la MTVE ?
Les Anti Xa et IIa oraux vont-ils remplacer les AVK dans le traitement curatif de la MTVE ?
Les Anti Xa et IIa oraux vont-ils remplacer les AVK dans la prise en charge de la FA ?
Things we knew, things we did… Things we have learnt, things we should do
Congrès international de médecine pluridisciplinaire
sous l’égide de l’IFDA
GAMMARTH, TN - 27 et 28 mars 2010
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