4antithrombotiques ir 1213.pdf

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Centre de Référence et d’Education des AntiThrombotiques 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 antithrombotiques Laboratoire Hématologie & IVS hôpital Lariboisière **Laboratoire Hématologie, hôpital Bichat ***Service Médecine Interne, hôpital Louis Mourier [email protected] 01 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

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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

Score GRACE = 159

Risque de mortalitéRisque de mortalitéélevé

CRUSADE Registry Bleeding score

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

DeCarolis D D et al Arch Intern Med. 2012;172(22):1713-1718.

Barras M A et al ther Drug Monitor 2010; 32 482-8

Barras M A et al ther Drug Monitor 2010; 32 482-8

Hammerstingl C et al BRAVE registry Thromb Haemost 2009; 101: 1085–1090

Bridging with 100u/kg once a day in patients with renal impairment

31

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

Antiagregants plaquettaires et

fonction rénale

• Les injectables :

– abciximab (ReoPro®) Pas de restriction d’utilisation– abciximab (ReoPro®) Pas de restriction d’utilisation

– Petites molecules (Interilin® et Agrastat®) adaptation

de la dose à fonction renale