4antithrombotiques ir 1213.pdf
TRANSCRIPT
Centre de Référence et d’Education
des Anti Thrombotiques
Gestion des antithrombotiques chez l’insuffisant rénal chronique
C. Bal, S-Y Park, Z Thoux, I Clavijo
A. Davout , L. Drouet*N. Ajzenberg** M -G Huisse **
*Consultation hémostase thromboses antithrombotique s Laboratoire Hématologie & IVS hôpital Lariboisière
**Laboratoire Hématologie, hôpital Bichat***Service Médecine Interne, hôpital Louis Mourier
[email protected] 42 81 12 13 (24/24 7/7)
Fax : 01 49 95 63 97 01 49 95 80 78
d’ Ile de France N. Ajzenberg** M -G Huisse **I Mahé***, E. Peynaud
HTA est PS > à 160 mmHg. A dysfonction rénale = dialyse chronique ou transplantation rénale ou Créatinine ≥ à 200 µmol/L. A dysfonction hépatique = hépatopathie chronique (cirrhose) ou biologique (bilirubine > à 2 N + ASAT/ALAT > à 3N). B saignement = antécédent de saignement ou une prédisposition (anémie).ou une prédisposition (anémie).D Médicaments: antiplaquettaires, AINS.
Anticoagulants « anciens » et fonction renale: la vue simpliste
et reglementaire• HBPM curatif CI CC<30mL/mn• HBPM preventif MEG CC<30mL/mn• Pas de restriction pour les HNF• Pas de restriction pour les HNF
– Car le curatif est adapté sur les controles (anti Xa a utiliser TCA : réponses ininterprétables)
• AVK pas de restriction – Car adapté sur l’INR
In patients with severe renal insufficiency (creatinine clearance [CrCl] < 30 mL/min) who require mL/min) who require therapeutic anticoagulation, we suggest the use of UFH instead of LMWH (Grade 2C).
Renal Impairment and Anticoagulant Dosing
W.H.Geerts, Chest 2008, Jun 133,(6 suppl); 381S-453S
“ 1.4.6. We recommend that renal function be considered when making decisions about the use and/or the dose of LMWH, fondaparinux, and other antithrombotic drugs that are cleared by the kidneys , particularly in elderly patients, patients with diabetes mellitus, and those at high with diabetes mellitus, and those at high risk for bleeding (Grade 1A).we recommend one of the following options in this situation: avoiding the use of an anticoagulant that bioaccumulates in the presence of renal impairment , using a lower dose of the agent, or monitoring the drug level or its anticoagulant effect (Grade 1B)”
UFH is cleared through a combination of a rapid saturable and a much slower first-order mechanismThe saturable phase of heparin clearance is thought to be due to binding to endothelial cell receptors and macrophages. Bound heparin is internalized and depolymerizedThe slower nonsaturable mechanism of clearance is largely renal . At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism. The complex dependent mechanism. The complex kinetics of clearance renders the anti-coagulant response to heparin nonlinear at therapeutic doses, with both theintensity and duration of effect rising disproportionately with increasing dose. Thus, the apparent biological half-life of heparin increases from # 30 min after an IV bolus of 25 U/kg,45 to 60 min with an IV bolus of 100 U/kg,46 to 150 min with a bolus of 400 U/kg.
How about LMWHs?
• Unfractionated heparin (UFH) = Heterogeneous mixture of Glyco-AminoGlycans (GAG) of various molecular size ranging from 3 000 to 30 000 daltons (mean ~ 15 000)1
• LMWHs = Depolymerization of UFH resulting in a lower mean molecular weight of 4 000 to 5 000 Da (<=>15 monosaccharide units), with chains ranging from 2 000 to 9 000 Da1
Example: 3D structure of an
dodecasaccharide (12) chain2
Unfractionated Heparin
Molecular Weight
Low Molecular Weight heparin
2000 5000 10000 15000 20000 25000
1. Hirsh et al. CHEST 2004; 126:188S–203S2. Gandhi NS et al. Chem Biol Drug Des 2008; 72: 455–482
The endothelial glycocalyx
� A negatively charged, organized mesh of membranous glycoproteins,
proteoglycans, GAGs and plasma proteins
� Major components: Hyaluronic acid and heparan sulfate proteoglycans
Electron microscopy image of the endothelial glycocalyx in a coronary capillaryElectron microscopy image of the endothelial glycocalyx in a coronary capillary
Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511
Endothelial glycocalyxPhysiological functions
Under physiological conditionsRoles: Barrier, storing compartment, coagulation/inflammation pathways,
shear stress transducer
Glycocalyx
Endothelium
Subendothelial space
EndotheliumNO-synthesis,
superoxide dysmutation
Permeability
sieving barrier
Coagulation
Inhibition of platelet adhesion
Coagulation regulatory factors
InflammationPrevention of
Leukocyte
adhesion
Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511
vasomotricityBlood flow
regulation
Anticoagulants « anciens » et fonction renale: la vue pratique
• HNF que des inconvénients – difficulté adaptation– risque superieur de TIH– osteoporose– osteoporose
• HBPM – en adaptant la dose
For treatment of VTEE, with UFH it would be reasonable to select an aPTT range that correlates with a heparin level of 0.3 to 0.7 U anti-Xa
With heparin levels of 0.3 to 0.7 anti-Xa U/mL, modern aPTT reagents and coagulometers produce aPTT
0.7 U anti-Xa
3.7
6.2
and coagulometers produce aPTT ratios that range from 1.6 to 2.7 times to 3.7 to 6.2 times control. Although various heparin dose-adjustment nomograms have been developed, none is applicable to all aPTT reagents. For these reasons, the therapeutic aPTT range should be adapted to the responsiveness of the reagent and coagulometer used
0.3 U anti-Xa
1.6
2.7
Anticoagulants « anciens » et fonction rénale: la vue pratique
• HNF que des inconvénients – difficulté adaptation– risque supérieur de TIH– ostéoporose– ostéoporose
• HBPM – en adaptant la dose
Prophylactic doses, LMWH has not beenshown to increase the risk of bleeding complications, irrespective of the degree of impairment of renal function.
Higher anti-Xa levels were found in patients with renal failure who received chronic OD prophylactic doses of enoxaparin, mean Cmax anti-Xa prophylactic doses of enoxaparin, mean Cmax anti-Xa level only 0.6 U/mL, and mean Cmin 0.2 U/mL. No increased bleeding observed.
Prophylactic doses, LMWH has not beenshown to increase the risk of bleeding complications, irrespective of the degree of impairment of renal function.
In a prospective cohort study of critically ill patients with a wide range of renal function, including acute renal failure who required hemodialysis, dalteparin bio-failure who required hemodialysis, dalteparin bio-accumulation was not observed despite repeated dosing. Therefore, therefore their is no evidence to reduce the prophylaxis dose of dalteparin in patients with renal insufficiency
Population
Événements
Ensemble des patients
patients
> 75 ans
Ins Rénaux modérés clear créat 20-50
ml/min
Population patients 100 % 16 % 6 %TVP totales +
Décès +EP
18 % (253/1389) 27,2 % (58/213) 27,8 % (25/90)
Bras Énoxaparine 40 mg des Études Européennes, éval uant le dabigatran dans la prévention des ETEV dans la PTH + la PTG program mées
Décès +EP (CI 21,4 % - 33,7 %) (CI 18,9 % - 38,2 %)
TVP majeures 3,3 %
(69/2096)
6, 0 % (13/218)
(CI 3,2 % - 10,0 %)
9,0 % (8/89)
(CI 4,0 % - 16,9 %)
Saignements majeurs 1,5 % (27/1848) 2,9 % (9/306)
(CI 1,4 % - 5,5 %)
4,7 % (6/128)
(CI 1,7 % - 9,9 %)
19
The current recommendation for prophylactic dose enoxaparin in patients with a CrCl <30 mL/min is 50% of the usual (north-american dose (ie, 30 mg once daily). No specific recommendations have been made for other LMWH preparations.
.
In patients receiving intermittent hemodialysis, we suggest that the LMWH be administered after the dialysis session.
Renal Impairment and Anticoagulant Dosing
W.H.Geerts, Chest 2008, Jun 133,(6 suppl); 381S-453S
“ 1.4.6. We recommend that renal function be considered when making decisions about the use and/or the dose of LMWH, fondaparinux , and other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients, patients particularly in elderly patients, patients with diabetes mellitus, and those at high risk for bleeding (Grade 1A).
we recommend one of the following options in this situation: avoiding the use of an anticoagulant tha t bioaccumulates in the presence of renal impairment, using a lower dose of the agent , or monitoring the drug level or its anticoagulant effect (Grade 1B)”
Population
Événements
Etudes Européennes,
PTH + PTG
enoxaparine 40 mg
patients
> 75 ans
Ins Rénaux modérés clear
créat 20-50 ml/min
PROPICE
Population patients
100 % 16 % 6 % 442
TVP totales +
Décès +EP
18 % (253/1389) 27,2 % (58/213)
(CI 21,4 % - 33,7 %)
27,8 % (25/90)
(CI 18,9 % - 38,2 %)
TVP majeures 3,3 %
(69/2096)
6,0 % (13/218)
(CI 3,2 % -10,0 %)
9,0 % (8/89)
(CI 4,0 % -16,9 %)
0,9 %
Saignements majeurs
1,5 %(27/1848)
2,9 % (9/306)
(CI 1,4 % - 5,5 %)
4,7 % (6/128)
(CI 1,7 % - 9,9 %)
3,8 %
22
If LMWH is used in patients with severe renal insufficiency (CrCl < 30 mL/min) who require therapeuticanticoagulation, we suggest using 50% of the recommended dose (Grade 2C).
If LMWH is chosen, anti-Xa monitoring and/or dose reduction should be done to ensure that there is no accumulation
For treatment of venous thromboembolism, a conservative peak anti-Xa level with twice-daily enoxaparin or nadroparin is 0.6 to 1.0 U/mL. The target range for peak anti-Xa levels is measured 4 h after dosing
If LMWH is used in patients with severe renal insufficiency (CrCl < 30 mL/min) who require therapeuticanticoagulation, we suggest using 50% of the recommended dose (Grade 2C).
If LMWH is chosen, anti-Xa monitoring and/or dose reduction should be done to ensure that there is no accumulation
For treatment of venous thromboembolism, a conservative peak anti-Xa level with twice-daily enoxaparin or nadroparin is 0.6 to 1.0 U/mL. The target range for peak anti-Xa levels is measured 4 h after dosing
Risk of major bleeding in patients with severe rena l insufficiency (CrCl< 30 mL/min) receiving LMWHIn 12 studies involving 4,971 patients given LMWHthe OR for major bleeding was 2.25 in patients with a CrCl<30 mL/min compared with those with a CrCl>30 mL/min. Therapeutic dose enoxaparin was associated with a further increase in major bleeding in patients witha CrCl<30 mL/min (8.3% vs 2.4%; OR 3.88), but a CrCl<30 mL/min (8.3% vs 2.4%; OR 3.88), but this was not observed when enoxaparin was empirically dose reduced (0.9% vs 1.9%; OR 0.58;). Based on these data, nondialysis-dependent patients with CrCl<30 mL/ min who are treated with standard therapeuticdoses of enoxaparin have an increased risk of major bleeding, and empiric dose reduction appears to reduce this risk. No conclusions could be made regarding other LMWHs because of limited data
Saignements Cliniquement PertinentsDans les 90 jours ± 5
Tinzaparine
(n=269)HNF
(n=268)
Tous les patients 11.9% 11.9%
Clairance Creat ≤30mL/min 15.7% 20.6%
Clairance Creat >30 mL/min 10.6% 9.0%
Risque relatif: 0.99 [0.63- 1.57].Pas de différence statistiquement significative en terme de SCP; p=0.972
Dans les 12 jours ± 2Tous les patients 7.1% 7.1%
Tinzaparine
175 UI anti-Xa / kg / j
HNFdosage habituel
5 jours au moins
AVK
Initiation possible après la randomisation
Arrêt d’innohep ou HNF après 5 jours minimum et 2 jours consécutif INR
entre 2 et 3
90 jours
Randomisation
Hammerstingl C et al BRAVE registry Thromb Haemost 2009; 101: 1085–1090
Bridging with 100u/kg once a day in patients with renal impairment
ReillyP A et al. The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients in the RE-LY Trial JACC 2013
ReillyP A et al. The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients in the RE-LY Trial JACC 2013
Nouveaux anticoagulants « NACO »
« ACOD » et fonction rénale: la vue
simple et réglementaire: tous à la
même enseigne• ACOD CI CC<30mL/mn
• ACOD diminution de dose • ACOD diminution de dose
30mL/mn<CC<50mL/mn
• Pour ce qui est de la TVP/EP le seul qui ait
actuellement l’AMM est le Xarelto pour lequel la
dose >21°j est diminué du 20mg par jour à 15mg
sans recommandation d’adaptation de la dose
initiale de 30mg / j (15mg X2/J)
Quels examens doit-on avoir
pour la mise au traitement ?
Une imagerie indiscutable prouvant l’ETEV
D’un point de vue biologique D’un point de vue biologique
NFS, TP-TCA, Créatinine+calcul Cockcroft
Autres
D-Dimères, Bilan hépatique
Les points importants à ne pas
oublier
Contention
Education / formation du patient à ce nouveau
traitement anticoagulant traitement anticoagulant
Organiser et informer le réseau de soin habituel du
patient
Quels examens doit-on avoir
pour la mise au traitement ?
Une imagerie indiscutable prouvant l’ETEV
D’un point de vue biologique D’un point de vue biologique
NFS, TP-TCA, Créatinine+calcul Cockcroft
Les points importants à ne pas
oublier
Contention
Education / formation du patient à ce nouveau
traitement anticoagulant traitement anticoagulant
Organiser et informer le réseau de soin habituel du
patient
Doit-on repeter examens les examens
au cours du traitement ?
D’un point de vue biologique
NFS
Créatinine+calcul Cockcroft Créatinine+calcul Cockcroft
A quelle frequence
Cockcroft / 10 (exemple tous les 6 mois pour un Crockcroftà 60mL/mn) et à chaque fois que le patient a une
pathologie intercurrente ouun traitement intercurrent suscpetible de degrader sa fonction renale
Antiagregants plaquettaires et
fonction rénale
• Les oraux : aspirine, clopidogrel (Plavix®), prasugrel
(Efient®), ticagrelor (Brilique®)(Efient®), ticagrelor (Brilique®)
• Pas de restriction d’utilisation
PLATO Inclusion CriteriaPLATO Inclusion Criteria• Hospitalization for STEMI or NSTEMI ACS, with onset
during the previous 24 hours
• With STEMI, the following two inclusion criteria were required– Persistent STEMI or new LBBB*– Primary PCI planned
• With NSTEMI ACS, at least two of the following three were requiredwere required– STEMI changes on ECG indicating ischemia– Positive biomarker indicating myocardial necrosis– One of the following risk indicators
• ≥60 years of age• Previous MI or CABG• CAD with ≥50% stenosis in ≥2 vessels• Previous ischemic stroke, TIA, carotid stenosis (≥50%)• Diabetes mellitus• Peripheral artery disease• Chronic renal dysfunction (creatinine clearance <60 mL/min)
*LBBB = left bundle branch block; ECG = electrocardiogram; CABG = coronary artery bypass graft; CAD = coronary artery disease
James SK, et al. Amer Heart J. 2009;157:599-605. 42
B
No DM
>7565-74
<65
FemaleMale
STEMIUA/NSTEMI
Age
Reduction in risk (%)18
2112
25146
14
21
CV Death, MI, StrokeCV Death, MI, StrokeMajor SubgroupsMajor Subgroups
OVERALL
No GPIGPI
DESBMS
DMNo DM
0.5 1 2Prasugrel Better Clopidogrel BetterHR
1430
2018
2116
19 Pinter = NS
CrCl > 60CrCl < 60 14
20