Complications h Complications h é é morragiques morragiques des traitements des traitements anticoagulants/ anticoagulants/ antithrombotiques antithrombotiques chez les patients cardiaques chez les patients cardiaques E. Schroeder E. Schroeder 13 13 e e Colloque d Colloque d ’ ’ Orval Orval – – 23 23 - - 24 mars 2013 24 mars 2013
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Complications hComplications héémorragiques morragiques des traitements des traitements
anticoagulants/anticoagulants/antithrombotiquesantithrombotiqueschez les patients cardiaqueschez les patients cardiaques
E. SchroederE. Schroeder
1313ee Colloque dColloque d’’Orval Orval –– 2323--24 mars 201324 mars 2013
DDééfinitions de la sfinitions de la séévvééritritéé de lde l’’hhéémorragiemorragie
Impact des hImpact des héémorragies sur la survie des patientsmorragies sur la survie des patients
Evaluation du risque des complications hEvaluation du risque des complications héémorragiquesmorragiques
Evaluation du risque thromboemboliqueEvaluation du risque thromboembolique
Recommandations en prRecommandations en préésence dsence d’’une fibrillation une fibrillation
auriculaire, dauriculaire, d’’origine non valvulaireorigine non valvulaire
ProblProblèèmes rmes réésiduelssiduels
EvEvéénements hnements héémorragiquesmorragiques
DEFINITIONSDEFINITIONS
CritCritèères de pertinence clinique variable :res de pertinence clinique variable :
Menace de survie : Menace de survie : -- ddééccèès par hs par héémorragie morragie
HbHb drop > 4 g/dl drop > 4 g/dl withoutwithout overtovert bleedingbleeding
HbHb drop > 3 g/dl drop > 3 g/dl withwith overtovert bleedingbleeding
ReoperationReoperation for for bleedingbleeding
AnyAny transfusion of transfusion of bloodblood productsproducts
GRACE : major GRACE : major bleedingbleeding
DeathDeathIntracranialIntracranial bleedingbleedingLife Life threateningthreatening requiringrequiring transfusion of transfusion of ≥≥ 2 U RBC2 U RBCHcHc drop drop ≥≥ 10 %10 %
ProcProcéédures invasives voies d'accdures invasives voies d'accèèssSurdosages des antiplaquettairesSurdosages des antiplaquettairesSurdosages des anticoagulantsSurdosages des anticoagulantsDurDuréée des traitementse des traitementsChoix / Switch des anticoagulantsChoix / Switch des anticoagulants
SSéécuritcuritéé : : complications hcomplications héémorragiques (selon des critmorragiques (selon des critèères res ±± sséévvèères)res)
BBéénnééfice clinique net : fice clinique net : RRééduction duction de la survenue des de la survenue des éévvéénements ischnements ischéémiques et miques et hhéémorragiques (tous des morragiques (tous des éévvéénements dnements dééfavorables) favorables) -- but de toutes nos dbut de toutes nos déémarches diagnostiques marches diagnostiques -- ththéérapeutiquesrapeutiques
mais la himais la hiéérarchie de gravitrarchie de gravitéé entres les diffentres les difféérents rents éévvéénementsnementsest "gommest "gomméée" par la technique des crite" par la technique des critèères d'res d'éévaluation combinvaluation combinéés,s,
pourtant pourtant ……
BBéénnééfice clinique net fice clinique net (2)(2)
Patients Patients àà haut risque hhaut risque héémorragique = patients morragique = patients àà haut risque ischhaut risque ischéémiquemique
Les substances AP/AC "puissantes" (pour Les substances AP/AC "puissantes" (pour ééviter viter les les éévvéénements ischnements ischéémiques) augmentent le risque miques) augmentent le risque hhéémorragiquemorragique
Les substances "Les substances "ééquipuissantes" (pour quipuissantes" (pour ééviter les viter les éévvéénements ischnements ischéémiques) avec un meilleur profil miques) avec un meilleur profil de sde séécuritcuritéé sont prsont prééfféérables.rables.
DDééfinitions de la sfinitions de la séévvééritritéé de lde l’’hhéémorragiemorragie
Impact des hImpact des héémorragies sur la survie des patientsmorragies sur la survie des patients
Evaluation du risque des complications hEvaluation du risque des complications héémorragiquesmorragiques
Evaluation du risque thromboemboliqueEvaluation du risque thromboembolique
Recommandations en prRecommandations en préésence dsence d’’une fibrillation une fibrillation
auriculaire, dauriculaire, d’’origine non valvulaireorigine non valvulaire
ProblProblèèmes rmes réésiduelssiduels
Connolly S Connolly S –– RERE--LY, NEJM 2009LY, NEJM 2009
Patel M – ROCKET AF. NEJM 2011
Camm A. Eur Heart J 2012Camm A. Eur Heart J 2012
Camm A. Eur Heart J 2012Camm A. Eur Heart J 2012
Camm A. Eur Heart J 2012Camm A. Eur Heart J 2012
Camm A. Eur Heart J 2012Camm A. Eur Heart J 2012
DDééfinitions de la sfinitions de la séévvééritritéé de lde l’’hhéémorragiemorragie
Impact des hImpact des héémorragies sur la survie des patientsmorragies sur la survie des patients
Evaluation du risque des complications hEvaluation du risque des complications héémorragiquesmorragiques
Evaluation du risque thromboemboliqueEvaluation du risque thromboembolique
Recommandations en prRecommandations en préésence dsence d’’une fibrillation une fibrillation
auriculaire, dauriculaire, d’’origine non valvulaireorigine non valvulaire
ProblProblèèmes rmes réésiduelssiduels
ProblProblèèmes rmes réésiduelssiduels
Traitement AC/AT chez les personnes Traitement AC/AT chez les personnes trtrèès âgs âgééesesEvaluation de la fragilitEvaluation de la fragilitéé de la personne âgde la personne âgééeeCoCoûût / efficacitt / efficacitéé dans la pratique rdans la pratique rééelleelleIndication prIndication préécise : quel prix pour quel cise : quel prix pour quel avantage ?avantage ?Pas de donnPas de donnéées par les patients en es par les patients en insuffisance rinsuffisance réénale chroniquenale chronique
30 Day Death According to Bleeding OASIS Registry, OASIS-2, CURE
14
12 Bleeding
10
8 5-fold ↑ risk
6
4 No Bleeding
2
0 0 5 10 15 20 25 30
Days Eikelboom Circulation 2006;114: 774 - 782
ESC Guidelines for the Management of NSTE-ACS (100)
http://www.mdcalc.com/grace-acs-risk
Connolly S Connolly S –– RERE--LY, NEJM 2009LY, NEJM 2009
Connolly S Connolly S –– RERE--LY, NEJM 2009LY, NEJM 2009
Patel M – ROCKET AF. NEJM 2011
Patel M – ROCKET AF. NEJM 2011
TIMI‐classification• Major: Intracranial haemorrhage, ≥ 5g/dl decreasein the haemoglobin concentration, ≥ 15% absolute decrease in the haematocrit
• Minor: – Observed blood loss: ≥ 3 g/dl decrease in the haemoglobin concentration, ≥ 9% decrease in the haematocrit
– No observed blood loss: ≥ 4 g/dl decrease in the haemoglobin concentration or ≥ 12% decrease in the haematocrit
• Minimal: Any clinically overt sign of haemorrhage (including imaging) that is associated with a < 3g/dl decrease in the haemoglobin concentration
Effets thrombotiques suite Effets thrombotiques suite àà l'arrêt des substances l'arrêt des substances antiplaquettaires antiplaquettaires -- anticoagulantesanticoagulantes
HHéémorragies dans la plaque vulnmorragies dans la plaque vulnéérablerable
Population Population àà haut risque (fragile) : facteur aggravant haut risque (fragile) : facteur aggravant
Moscucci M. Eur Heart J. 2003; 24 : 1815
FOX A. et al. Ann. Intern. Med 2007; 147 : 304FOX A. et al. Ann. Intern. Med 2007; 147 : 304
Recommendations for Anticoagulation (1)
• Anticoagulation is recommended for all patients in addition toantiplatelet therapy (I-A).
• Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B). Several anticoagulants are available, namely UFH, LMWH, fondaparinux, bivalirudin. The choice depends on the initial strategy, urgent invasive, early invasive, or conservative (I-B) (see section Management Strategy).
• In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa- B) or bivalirudin (I-B) should be immediately started.
ESC Guidelines for the Management of NSTE-ACS (53)
Recommendations for Anticoagulation (2)
• In an non-urgent situation, as long as decision between early invasive or conservative strategy is pending :
– Fondaparinux is recommended on the basis of the most favorable efficacy/safety profile. (I-A)
– Enoxaparin with a less favourable efficacy/safety profile than fondaparinux should be used only if the bleeding risk is low (IIa- B)
– As efficacy/safety profile of LMWH (other than enoxaparin) or UFH relative to fondaparinux is unknown; these anticoagulants cannot be recommended over fondaparinux (IIa-B) ESC Guidelines for theManagement of NSTE-ACS (54)
Recommendations for Anticoagulation (3)
• At PCI procedures the initial anticoagulant should be maintained also during the procedure regardless whether this treatment is UFH (I-C), enoxaparin (IIa-B) or bivalirudin (I-B), while addititional UFH in standard dose (50-100 IU/kg bolus) is necessary in case of fondaparinux (IIa-C).
• Anticoagulation can be stopped within 24 hours after invasive procedure (IIa-C). In a conservative strategy, fondaparinux, enoxaparin or other LMWH may be maintained up to hospital discharge (I-B).
ESC Guidelines for the Management of NSTE-ACS (55)
Recommendations for Oral Antiplatelet Drugs (1)
• Aspirin is recommended for all patients presenting with NSTE-ACS without contraindication at an initial loading dose of 160 - 325mg (non-enteric) (I-A), and at a maintenance dose of 75 to 100mg long-term (I-A). • For all patients, immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A).
• For all patients with contraindication to aspirin, clopidogrel should be given instead (I-B).
ESC Guidelines for the Management of NSTE-ACS (61)
Recommendations for Oral Antiplatelet Drugs (2)
• In patients considered for an invasive procedure/PCI, a loading dose of 600mg of clopidogrel may be used to achieve more rapid inhibition of platelet function (IIa-B).
• In patients pretreated with clopidogrel who need to undergo CABG, surgery should be postponed for 5 days for clopidogrel withdrawal if clinically feasible (IIa-C).
ESC Guidelines for the Management of NSTE-ACS (62)
Recommendations for GP IIb/IIIa Inhibitors (1)
• In patients at intermediate to high risk, particularly patients with elevated troponins, ST-depression, or diabetes, either eptifibatide or tirofiban for initial early treatment are recommended in addition to oral antiplatelet agents (IIa-A).
• The choice of combination of antiplatelet agents and anticoagulants should be made in relation to risk of ischaemic and bleeding events. (I-B)
• Patients who received initial treatment with eptifibatide or tirofiban prior to angiography, should be maintained on the same drug during and after PCI (IIa-B)
ESC Guidelines for the Management of NSTE-ACS (65)
Recommendations for GP IIb/IIIa Inhibitors (2)
• In high risk patients not pretreated with GP IIb/IIIa inhibitors and proceeding to PCI, abciximab is recommended immediately following angiography. (I-A) The use of eptifibatide or tirofiban in this setting is less well established (IIa-B).
• GP IIb/IIIa inhibitors must be combined with an anticoagulant (I-A). • Bivalirudin may be used as an alternative to GP IIb/IIIa inhibitors plus UFH/LMWH. (IIa-B)
• When anatomy is known and PCI planned to be performed within 24 hours with GP IIb/IIIa inhibitors, most secure evidence is for abciximab (IIa-B)
ESC Guidelines for the Management of NSTE-ACS (66)
Clinical Use of Antithrombotic Therapy. Oral Antiplatelet Therapy
• Aspirin initial dose: 160–325 mg nonenteric formulation, followed by 75–100mg daily Clopidogrel 75 mg/d after a loading dose of 300mg (600mg when rapid onset of action is wanted)
Anticoagulants
• Fondaparinux* 2.5mg subcutaneously daily • Enoxaparin* 1mg/kg subcutaneously every 12 h • Dalteparin* 120 IU/kg every 12 h • Nadroparin* 86 IU/kg every 12 h • UFH intravenous Bolus 60–70 U/kg (maximum 5000 IU) followed by infusion of 12–15 IU/kg/h (maximum 1000 U/h) titrated to aPTT 1.5–2.5 times control • Bivalirudin* intravenous bolus of 0.1 mg/kg and infusion of 0.25 mg/kg/hr. Additional intravenous bolus 0.5 mg/kg and infusion increased to 1.75 mg/kg/hour before PCI
GP IIb/IIIa inhibition*
• Abciximab 0.25 mg/kg intravenous bolus followed by infusion of 0.125 µg/kg/min (maximum 10 µg/min) for 12 to 24 h • Eptifibatide 180 µg/kg intravenous bolus (second bolus after 10 min for PCI) followed by infusion of 2.0 µg/kg/min for 72 to 96 h • Tirofiban 0.4 µg/kg/min intravenously for 30 minutes followed by infusion of 0.10 µg/kg/min for 48 to 96 h.
A high dose regimen (bolus 25µg/kg + 0.15µg/kg/min infusion for 18 hours) is tested in clinical trials. ESCGuidelines for the Management of NSTE-ACS (71)
Recommendations for Thrombocytopenia
•Significant thrombocytopenia (<100,000/µL or >50% drop in platelet count) occurring during treatment with GP IIb/IIIa inhibitors and/or heparin (LMWH or UFH) requires the immediate interruption of these drugs. (I-C)
•Severe thrombocytopenia (<10,000/µL) induced by GP IIb/IIIa inhibitors requires platelet transfusion with or without fibrinogen supplementation with fresh frozen plasma or cryoprecipitate in case of bleeding. (I-C)
•Interruption of heparin (UFH or LMWH) is warranted in case of documented or suspected HIT. In case of thrombotic complications, anticoagulation can be achieved with DTI (I-C).
•Prevention of HIT can be achieved with use of anticoagulants devoid of risk of HIT,
such as fondaparinux or bivalirudin, or by brief prescription of heparin (UFH or LMWH)
in case these compounds are chosen as anticoagulant (I-B). ESC Guidelines
for the Management of NSTE-ACS (106)
Recommendations for the Use of Drugs in Case of CKD Drug Recommendations in case of CKD
Simvastatin* Low renal elimination. In patients with severe renal failure (CrCl <30ml/min), careful with doses >10mg
Ramipril* Dose adaptation required if CrCl <30ml/min (initial dose 1.25mg daily). Dose must not exceed 5mg per day.
Losartan* Recommended for the treatment of hypertension or renal failure in diabetes type 2 with microalbuminuria 50-100mg per day. Regular monitoring of electrolyte balance and serum creatinine is recommended.
Clopidogrel No information in patients with renal failure
Enoxaparin* In case of severe renal failure (CrCl<30mL/min), either contraindicated or dose adjustment required, according to country-specific labelling.
Contraindicated in severe renal failure (CrCl <30ml/min). However, as much lower risk of bleeding Fondaparinux complications were observed in Oasis-5 with fondaparinux as compared with enoxaparin, even in patients with severe renal failure, this drug might be the anticoagulant of choice in this situation.
Bivalirudin If the CrCl < 30 mL/min, reduction of the infusion rate to 1.0 mg/kg/h should be considered. If a patient is on haemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is needed.
Tirofiban Dose adaptation required in patients with renal failure. 50% of the dose only if CrCl <30ml/min.
Eptifibatide As 50% of eptifibatide is cleared through the kidney in patients with renal failure, precautions must be taken in patients with impaired renal function (CrCl <50ml/min). The infusion dose should be reduced to 1µg/kg/min in such patients. The dose of the bolus remains unchanged at 180µg/kg. Eptifibatide is contra-indicated in patients with creatinine clearance <30mL/min.
Abciximab No specific recommendations for the use of abciximab, or for dose adjustment in case of renal failure. Careful evaluation of haemorrhagic risk is needed before using the drug in case of renal failure.
Atenolol Half dose recommended for patients with CrCl between 15 and 35ml/min (50mg/day). Quarter dose (25mg/day) recommended if CrCl <15ml/min.
ESC Guidelines for the Management of NSTE-ACS (120)
Choix Choix des substances antiplaquettaires des substances antiplaquettaires -- anticoagulantesanticoagulantes en fonction en fonction du risque hdu risque héémorragique morragique etet thrombotiquethrombotiquePrescription appropriPrescription appropriééee (dosage, dur(dosage, duréée) e) des substances antiplaquettaires des substances antiplaquettaires -- anticoagulants anticoagulants en respectant les recommandations (poids, âge, fonction ren respectant les recommandations (poids, âge, fonction réénale, nale, antantééccéédents hdents héémorragiques)morragiques)
DDéétection de la thrombocytoptection de la thrombocytopéénienie : : [plaquettes] [plaquettes] -- 8 heures apr8 heures aprèès le ds le déébut des GP 2B/3A but des GP 2B/3A
-- en cas d'hen cas d'héémorragiemorragieProcProcéédures moins invasivesdures moins invasives : : -- approche radialeapproche radiale
-- ééviter procviter procéédures peu utiles dures peu utiles (KT droit, proc(KT droit, procéédures par dures par éétapes)tapes)
Monitoring prospectifMonitoring prospectif des complications hdes complications héémorragiques en utilisant morragiques en utilisant des ddes dééfinitions claires (analyse en dfinitions claires (analyse en déétail des dossiers, contrôle de qualittail des dossiers, contrôle de qualitéé, , rapport annuel)rapport annuel)