NAO complicanze emorragiche

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2 Gestione condivisa della terapia anticoagulante e antiaggregante NAO complicanze emorragiche Dr. Roberto Frediani Medicina Interna ASL TO5 Dipartimento Formazione FADOI

3 Relazioni con soggetti portatori di interessi commerciali in campo sanitario Il sottoscritto Dr. Roberto Frediani ai sensi dell art. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dell Accordo Stato-Regione del 5 novembre 2009, dichiara che negli ultimi due anni NON ha avuto rapporti diretti di finanziamento con soggetti portatori di interessi commerciali in campo sanitario.

4 AGENDA emorragie e VKA major bleeding definizione mortalità ed emorragie studi clinici e mondo reale che fare? il documento buon profilo per emorragie cerebrali, ma. sanguinamenti gastroenterici

5 Cause comuni di aumentato rischio emorragico con la terapia anticoagulante Cause endogene insufficienza renale insufficienza epatica altri fattori di rischio: età - recenti sanguinamenti (GI, intracranici, ) - ipertensione grave non controllata - retinopatia vascolare - ulcere GI attive - malformazioni vascolari intraspinali/intracerebrali - recente neurochirurgia od oftalmica Cause esogene Sovradosaggio accidentale o volontario del farmaco Associazione con antiaggreganti: ASA, clopidogrel, FANS, Associazione con altri farmaci che interferiscono con assorbimento o metabolismo

6 Major and Fatal Bleeding are High with VKA in NVAF Patients in Real Life Study drug Patients (n) Rate of major bleeding (%/year) Fatal bleeding (%) Warfarin starters 1 125, VKA starters VKA starters Warfarin users * 0.4 Coumarin derivative users 5 10, Major bleeding: ~6 8%/year Fatal bleeding: ~1.5% # # Values are calculated (not reported); *In the first year. 1. Gomes T et al. CMAJ. 2013;185(2):E ; 2. Beyth RJ et al. Am J Med. 1998;105(2):91 99; 3. Steffensen FH et al. J Intern Med. 1997;242(6): ; 4. Gitter MJ et al. Mayo Clin Proc. 1995;70(8): ; 5. Linkins LA et al. Ann Intern Med. 2003;139(11): ;

7 Definition of Major Bleedings in the large Phase III NOACs Trials RE-LY ROCKET AF ARISTOTLE ENGAGE AF Major Bleeding: 1 of: Major Bleeding : 1 of: Major Bleeding : 1 of: Major Bleeding : 1 of: 1. With Hb 2.0 g/dl 1. With Hb 2.0 g/dl 1. With Hb 2.0 g/dl 1. With Hb 2.0 g/dl 2. With transfusion 2 U blood or packed cells 3. Symptomatic ocular, cranial, spinal, intramuscular with compartment syndome, retroperitoneal, pericardial 2. With transfusion 2 U blood or packed cells 3. Symptomatic ocular, cranial, spinal, intramuscular with compartment syndome, retroperitoneal, pericardial 2. With transfusion 2 U blood or packed cells 3. Symptomatic ocular, cranial, spinal, intramuscular with compartment syndome, retroperitoneal, pericardial 2. With transfusion 2 U blood or packed cells 3. Symptomatic ocular, cranial, spinal, intramuscular with compartment syndome, retroperitoneal, pericardial

8 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ, (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome), and/or 3. Bleeding causing a fall in hemoglobin level of 2.0 g/dl, or leading to transfusion of two or more units of whole blood or red cells. Schulman S et al. J Thromb Haemost 2005

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11 Principali sedi di sanguinamento maggiore HR rispetto a Warfarin Sede Dabigatran 110 mg 150 mg Gastrointestinali In organo o area critica Rivaroxaban Apixaban Edoxaban 60 mg 30 mg ? 0.69? Hb 2 dr/dl? 1.22? Pericolosi per la vita Clinicamente rilevanti (non maggiori) * Maggiori e non maggiori cllinicamente rilevanti <<? ? << 0.68* Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361: ; Granger C et al, N Eng J Med; 2011; Giugliano RP et al NEJM 2013

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17 Conclusion: The MB incidence rate among rivaroxaban users with NVAF is low in a post-market setting, and generally similar to the registration trial.

18 Characterizing MB in patients with NVAF: a pharmacovigilance study of patients taking rivaroxaban Objective To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Major Bleed Characteristics* Design Observational cohort study US Department of Defense electronic health care records Rates of major bleeding, any bleeding, ICH, fatal bleeding, GI bleeding Endpoint definition approved by FDA *MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites. Tamayo et al., Clin Cardiol 2015

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20 REVISIT US - Significant Reduction in the Combined Endpoint for Rivaroxaban vs warfarin Rivaroxaban was associated vs warfarin with a Significant 47% reduction in ICH Non-significant 29% decrease in ischemic stroke Significant 39% reduction in the combined endpoint of ICH and ischemic stroke Rivaroxaban Warfarin HR (95% CI) rivaroxaban vs. warfarin Rate (%/year) Rate (%/year) ICH ( )* HR (95% CI) rivaroxaban vs. warfarin Ischemic stroke ( ) Combined ( )* *p<0.05 Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) [Presentation at ECAS 2016] Available at: Favors rivaroxaban Favors warfarin

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23 Intracranial and Gastrointestinal Bleedings High dose regimens for dabigatran and edoxaban Dabigatran 150 mg, Edoxaban 60 mg, Rivaroxaban, Apixaban Intracranial Bleeding Gastrointestinal Bleeding Risk Ratio (95% CI) 0.48 ( ) p< ( ) p=0.043 Heterogeneity Intracranial Haemorrhage, p = 0.22 Gastrointestinal Bleeding, p = Favors NOAC Favors Warfarin Ruff CT, et al. Lancet Dec 3. Epub ahead of print]

24 Intracranial and Gastrointestinal Bleedings Low dose regimens for dabigatran and edoxaban Dabigatran 110 mg, Edoxaban 30 mg, Rivaroxaban, Apixaban Intracranial Bleeding Gastrointestinal Bleeding Risk Ratio (95% CI) 0.31 ( ) p< ( ) p=0.58 Heterogeneity Intracranial Haemorrhage, p = 0.90 Gastrointestinal Bleeding, p = Favors NOAC Favors Warfarin Ruff CT, et al. Lancet Dec 3. Epub ahead of print]

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28 NOACs: indicazioni da RCP Preparato Dabigatran Rivaroxaban Apixaban Indicazioni Interruzione del farmaco Favorire la diuresi; dialisi FEIBA, fviia o PCC 3 fattori Consultare esperto in coagulazione Interruzione del farmaco PCC o FEIBA, fviia Consultare esperto in coagulazione Interrompere il farmaco FFP fviia Consultare esperto in coagulazione

29 NOACs: antidotes adabi-fab PRT humanized antibody fragment that binds dabigatran and reverses its anticoagulant effects in vitro and in vivo catalytically inactive recombinant protein that lacks the membranebinding γ-carboxyglutamic acid domain of native fxa, while retaining ability to bind fxa inhibitors (rivaroxaban, apixaban) BAY ??? (rivaroxaban ) Schiele F et al. Blood 2013; Liew A et al. Can J Cardiol 2013

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56 Grazie per l attenzione