Gestion des antithrombotiques chez linsuffisant rnal chronique

Centre de Rfrence et C. Bal, S-Y Park, Z Thoux, I Clavijo dEducation A. Davout , L. Drouet* des AntiThrombotiques N. Ajzenberg** M-G Huisse** dIle de France I Mah***, E. Peynaud

*Consultation hmostase thromboses antithrombotiques Laboratoire Hmatologie & IVS hpital Lariboisire **Laboratoire Hmatologie, hpital Bichat ***Service Mdecine Interne, hpital Louis Mourier creatif.lrb@lrb.aphp.fr 01 42 81 12 13 (24/24 7/7) Fax : 01 49 95 63 97 01 49 95 80 78

Score GRACE = 159

Risque de mortalit lev

CRUSADE Registry Bleeding score

HTA est PS > 160 mmHg. A dysfonction rnale = dialyse chronique ou transplantation rnale ou Cratinine 200 mol/L. A dysfonction hpatique = hpatopathie chronique (cirrhose) ou biologique (bilirubine > 2 N + ASAT/ALAT > 3N). B saignement = antcdent de saignement ou une prdisposition (anmie). D Mdicaments: 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
Car le curatif est adapt sur les controles (anti Xa a utiliser TCA : rponses ininterprtables)

AVK pas de restriction

Car adapt sur lINR

In patients with severe renal insufficiency (creatinine clearance [CrCl] < 30 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 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 mechanism The saturable phase of heparin clearance is thought to be due to binding to endothelial cell receptors and macrophages. Bound heparin is internalized and depolymerized The slower nonsaturable mechanism of clearance is largely renal. At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable, dosedependent mechanism. The complex kinetics of clearance renders the anticoagulant response to heparin nonlinear at therapeutic doses, with both the intensity 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

Low Molecular Weight heparin

Unfractionated Heparin

2000
1. Hirsh et al. CHEST 2004; 126:188S203S 2. Gandhi NS et al. Chem Biol Drug Des 2008; 72: 455482

5000

10000

15000

20000

25000

Molecular Weight

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 capillary

Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511

Endothelial glycocalyx
Physiological functions
Under physiological conditions Roles: Barrier, storing compartment, coagulation/inflammation pathways, shear stress transducer

Glycocalyx
Endothelium Subendothelial space

Endothelium
NO-synthesis, superoxide dysmutation

Permeability
sieving barrier

Coagulation
Inhibition of platelet adhesion Coagulation regulatory factors

Inflammation
Prevention of Leukocyte adhesion

vasomotricity
Blood flow regulation

Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511

Anticoagulants anciens et fonction renale: la vue pratique

HNF que des inconvnients
difficult adaptation risque superieur de TIH 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
6.2

With heparin levels of 0.3 to 0.7 anti- 0.7 U anti-Xa Xa U/mL, modern aPTT reagents 3.7 and coagulometers produce aPTT ratios that range from 1.6 to 2.7 0.3 U anti-Xa 2.7 times to 3.7 to 6.2 times control. Although various heparin 1.6 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

Anticoagulants anciens et fonction rnale: la vue pratique

HNF que des inconvnients
difficult adaptation risque suprieur de TIH ostoporose

HBPM
en adaptant la dose

Prophylactic doses, LMWH has not been shown 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 level only 0.6 U/mL, and mean Cmin 0.2 U/mL. No increased bleeding observed.

Prophylactic doses, LMWH has not been shown 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 bioaccumulation was not observed despite repeated dosing. Therefore, therefore their is no evidence to reduce the prophylaxis dose of dalteparin in patients with renal insufficiency

Bras noxaparine 40 mg des tudes Europennes, valuant le dabigatran dans la prvention des ETEV dans la PTH + la PTG programmes

Population

Ensemble des patients

patients > 75 ans

Ins Rnaux modrs clear crat 20-50 ml/min

vnements Population patients TVP totales + Dcs +EP TVP majeures 100 %

16 % 27,2 % (58/213)
(CI 21,4 % - 33,7 %)

6% 27,8 % (25/90)
(CI 18,9 % - 38,2 %)

18 % (253/1389) 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

. current recommendation for The 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 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)

Population

Etudes Europennes, PTH + PTG enoxaparine 40 mg

100 %

patients > 75 ans

vnements
Population patients TVP totales + Dcs +EP

Ins Rnaux modrs clear crat 20-50 ml/min 6% 27,8 % (25/90)

(CI 18,9 % - 38,2 %)

PROPICE

16 % 27,2 % (58/213)
(CI 21,4 % - 33,7 %)

442

18 % (253/1389)

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 % 3,8 %

Saignements majeurs

1,5 %
(27/1848)

2,9 % (9/306)
(CI 1,4 % - 5,5 %)

4,7 % (6/128)
(CI 1,7 % - 9,9 %)

22

If LMWH is chosen, anti-Xa monitoring and/or dose reduction should be done to ensure that there is no accumulation If LMWH is used in patients with severe renal insufficiency (CrCl < 30 mL/min) who require therapeutic anticoagulation, we suggest using 50% of the recommended dose (Grade 2C). 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 antiXa levels is measured 4 h after dosing

If LMWH is chosen, anti-Xa monitoring and/or dose reduction should be done to ensure that there is no accumulation If LMWH is used in patients with severe renal insufficiency (CrCl < 30 mL/min) who require therapeutic anticoagulation, we suggest using 50% of the recommended dose (Grade 2C). 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 antiXa levels is measured 4 h after dosing

Risk of major bleeding in patients with severe renal insufficiency (CrCl< 30 mL/min) receiving LMWH In 12 studies involving 4,971 patients given LMWH the 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 with 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 therapeutic doses 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 Pertinents

Dans les 90 jours 5
Tinzaparine

(n=269) Tous les patients Clairance Creat 30mL/min Clairance Creat >30 mL/min 11.9% 15.7% 10.6%

HNF (n=268) 11.9% 20.6% 9.0%

Risque relatif: 0.99 [0.63- 1.57]. Pas de diffrence statistiquement significative en terme de SCP; p=0.972

Dans les 12 jours 2

Tous les patients
Randomisation

7.1%

7.1%

Tinzaparine
175 UI anti-Xa / kg / j

AVK

90 jours

HNF
dosage habituel
5 jours au moins

Initiation possible aprs la randomisation Arrt dinnohep ou HNF aprs 5 jours minimum et 2 jours conscutif INR entre 2 et 3

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

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

Hammerstingl C et al BRAVE registry Thromb Haemost 2009; 101: 10851090

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 rnale: la vue simple et rglementaire: tous la mme enseigne
ACOD CI CC<30mL/mn ACOD diminution de dose 30mL/mn<CC<50mL/mn Pour ce qui est de la TVP/EP le seul qui ait actuellement lAMM est le Xarelto pour lequel la dose >21j est diminu du 20mg par jour 15mg sans recommandation dadaptation de la dose initiale de 30mg / j (15mg X2/J)

Quels examens doit-on avoir pour la mise au traitement ?

Une imagerie indiscutable prouvant lETEV Dun point de vue biologique NFS, TP-TCA, Cratinine+calcul Cockcroft Autres D-Dimres, Bilan hpatique

Les points importants ne pas oublier

Contention Education / formation du patient ce nouveau traitement anticoagulant Organiser et informer le rseau de soin habituel du patient

Quels examens doit-on avoir pour la mise au traitement ?

Une imagerie indiscutable prouvant lETEV Dun point de vue biologique NFS, TP-TCA, Cratinine+calcul Cockcroft

Les points importants ne pas oublier

Contention Education / formation du patient ce nouveau traitement anticoagulant Organiser et informer le rseau de soin habituel du patient

Doit-on repeter examens les examens au cours du traitement ?

Dun point de vue biologique NFS Cratinine+calcul Cockcroft A quelle frequence Cockcroft / 10 (exemple tous les 6 mois pour un Crockcroft 60mL/mn) et chaque fois que le patient a une pathologie intercurrente ouun traitement intercurrent suscpetible de degrader sa fonction renale

Antiagregants plaquettaires et fonction rnale

Les oraux : aspirine, clopidogrel (Plavix), prasugrel (Efient), ticagrelor (Brilique) Pas de restriction dutilisation

PLATO 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 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

CV Death, MI, Stroke Major Subgroups

UA/NSTEMI STEMI Male Female <65 Age 65-74 >75 No DM DM BMS DES GPI No GPI CrCl < 60 CrCl > 60
B

Reduction in risk (%) 18 21 21 12 25 14 6 14 30 20 18 21 16 14 20

OVERALL
0.5

19
Prasugrel Better
1

Pinter = NS
2

HR

Clopidogrel Better

Antiagregants plaquettaires et fonction rnale

Les injectables :
abciximab (ReoPro) Pas de restriction dutilisation Petites molecules (Interilin et Agrastat) adaptation de la dose fonction renale