GESTIONE PRATICA DEI NAO DAVIDE IMBERTI

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1 GESTIONE PRATICA DEI NAO DAVIDE IMBERTI CENTRO EMOSTASI E TROMBOSI MEDICINA INTERNA DIPARTIMENTO DI MEDICINA GENERALE OSPEDALE GUGLIELMO DA SALICETO PIACENZA

2 Il sottoscritto Imberti Davide dichiara di aver avuto negli ultimi due anni rapporti di consulenza con i seguenti soggetti portatori di interessi commerciali in campo sanitario: - BAYER - BMS-PFIZER - BOHERINGER INGELHEIM - DAIICHI-SANKYO - KEDRION - IL - ITALFARMACO - SANOFI AVENTIS

3 Nuovi anticoagulanti: pratica clinica Monitoraggio laboratoristico Reverse dell effetto anticoagulante Gestione complicanze emorragiche Gestione perioperatoria Switch da VKA (e viceversa) Quali pazienti

5 EHRA 2013 guidelines: management of bleeding with new oral anticoagulants EHRA Practical Guide, Europace, 2013

6 Dickneite, Thromb Haemost, 2014 Reversing the NOACs with PCCs: what is the evidence?

7 Reversing the NOACs with PCCs: what is the evidence? Dickneite, Thromb Haemost, 2014

8 Reversing the NOACs with PCCs: what is the evidence? - Systematic review about NOACs (dabigatran, rivaroxaban, apixaban). - PCCs (including activated PCCs) show promise for reversing the anticoagulant effects of the NOACs and may be considered a reasonable approach in dire clinical situations. - Conventional laboratory assays do not correlate well with bleeding or reversal of anticoagulation in this setting; thrombin generation assays appear to have the best predictive value. Dickneite, Thromb Haemost, 2014

9 Management of major bleeding events in patients tretaed with rivaroxaban vs warfarin: results from the ROCKET AF Pharmacologic management post-major bleed (0-24 hours) Rivaroxaban (n=431) Warfarin (n=409) Vitamin K Protamine Desmopressin Epsilon-aminocaproic acid Tranexamic acid Prothrombin complex concentrates Recombinant factor VIIa Factor VIII concentrate Factor IX concentrate 32 (7.4%) 0 (0.0%) 0 (0.0%) 2 (0.5%) 2 (0.5%) 4 (0.9%) 0 (0.0%) 1 (0.2%) 0 (0.0%) 54 (13.2%) 0 (0.0%) 0 (0.0%) 3 (0.7%) 11 (2.7%) 9 (2.2%) 1 (0.2%) 1 (0.2%) 3 (0.7%) Piccini, Eur Heart J, 2014

10 Outcomes following ISTH major bleeding Stroke or systemic embolism Events Riva Warfarin (N=431) (N=409) 20 (4.7%) 22 (5.4%) HR (95% CI) Interaction P Value (0.420, 1.876) Composite of all stroke, non-cns embolism, MI/UA, and all-cause death 104 (24.8%) 120 (29.9%) (0.530, 1.082) All-cause death 86 (20.4%) 105 (26.1%) (0.455, 1.042) MI/UA 11 (2.6%) 7 (1.7%) (0.572, 5.971) Favors rivaroxaban 1 10 Favors warfarin Piccini, Eur Heart J, 2014

11 Strategies used for management of major bleeding: RE-LY trial results Dabigatran* Warfarin P value Patients with major bleeds, n (%) 741 (100) 421 (100) Blood transfusion, n (%) 439 (59.2) 210 (49.9) Fresh frozen plasma, n (%) 147 (19.8) 127 (30.2) <0.001 Vitamin K, n (%) 70 (9.4) 115 (27.3) <0.001 Prothrombin complex concentrate, n (%) 5 (0.7) 5 (1.2) 0.36 Recombinant Factor VIIa, n (%) 8 (1.1) 3 (0.7) 0.53 Major bleeds in the dabigatran groups were more frequently treated with blood transfusions than those on warfarin but less frequently with plasma Data derived based on the randomized set of RE-LY *Data combined from dabigatran 150 mg and 110 mg BID treatment groups Mayeed, Blood, 2012

12 Mortality rate (%) 0.2 Mortality after a major bleed: five Phase III trials results Warfarin Dabigatran Time (days) The Kaplan Meier analysis indicated a reduced risk for death with dabigatran* vs warfarin during 30 days from the bleeding (P=0.052) *Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major bleed included. Analysis not adjusted for covariates

13 Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical Outcomes Characteristics of major extracranial hemorrhage Characteristics of ISTH Major Extracranial Hemorrhage Overall Apixaban Warfarin Hazard Ratio (95% CI) P Value Event Rate (%/yr) Event Rate (%/yr) Event Rate (%/yr) Apixaban vs. Warfarin Led to hospitalization 1.23 (374) 1.05 (162) 1.41 (212) 0.75 ( ) Fall in hemoglobin 2 g/dl 1.25 (381) 1.06 (164) 1.44 (217) 0.74 ( ) Led to transfusion 1.06 (325) 0.89 (137) 1.25 (188) 0.71 ( ) Required a medical or surgical consultation Required a medical or surgical intervention to stop Associated with hemodynamic compromise Caused changed in antithrombotic therapy 1.74 (527) 1.54 (236) 1.94 (291) 0.79 ( ) (236) 0.65 (100) 0.90 (136) 0.72 ( ) (97) 0.26 (40) 0.38 (57) 0.69 ( ) (398) 1.14 (176) 1.47 (222) 0.78 ( ) Hylek, JACC, 2014

14 Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical Outcomes Major bleeding followed by death within 30 days 53 Hylek, JACC, 2014

15 Major bleedings on rivaroxaban: registry study on 1776 patients (Dresden registry) PCC to 6 cases, dose from 18 to 47 UI/kg: 1 improved PT and aptt, 3 patients had minimal changes, 2 unknown 4 survived, 2 died (1 for pneumonia); FFP administered with PCC to 3 patients Beyer-Westendorf, Blood, 2014

16 Favourable benefit-risk profile of dabigatran 150 mg BID confirmed in independent FDA study of > Medicare patients Medicare 1 > patients RE-LY 2 4 > patients In the USA, the licensed doses for dabigatran etexilate are 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Numbers on bars denote These hazard ratios results 110 mg BID, indicated for certain patients, vs warfarin were achieved in the absence of a specific antidote was shown to be as effective as warfarin in preventing stroke or systemic embolism in RE-LY, which was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial Connolly SJ et al. N Engl J Med 2009;361: ; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 6; 4. Pradaxa : EU SPC 2014

17 Weitz, Hematology Am Soc Educ Program, 2012 (mod) Monitoring and Antidotes Monitoring Antidote Warfarin INR TTR Vitamin K Dabigatran TT - Hemoclot Monoclonal Ab (IDARUCIZUMAB) ECT (aptt) FXa Inhibitors Factor Xa activity (PT) Universal antidote (FX analogue) (ANDEXANET ALFA) All Hb concentrations HAS-BLED # ARIPAZINE Fresh frozen plasma Prothrombin complex concentrate FEIBA rfviia

18 Idarucizumab preclinical and clinical studies to date Idarucizumab binds dabigatran with high affinity No detectable procoagulant effect in vitro or ex vivo Immediate and complete reversal of dabigatran anticoagulant effect in animal models Idarucizumab infusion: immediate, complete, and sustained reversal of dabigatran anticoagulation in healthy volunteer study RE-VERSE AD: phase III study in patients is currently ongoing

19 Study to evaluate reversal of the anticoagulant effects of dabigatran with idarucizumab in: Bleeding patients Overt bleeding judged by the physician to require a reversal agent Surgical patients Require an emergency surgery or procedure for a condition other than bleeding Started in April 2014, currently recruiting in >35 countries worldwide Idarucizumab is currently in development and still under investigation and is not approved for use in any country. The information presented here is intended for medical education purposes only NCT : Available at ttp:// Accessed July 2014

20 r- Antidote (PRT064445) (Andexanet) has a high affinity for Xa inhibitors

21 r- Antidote (PRT064445) Andexanet Alfa (Portola) Tre studi di fase 3, randomizzati, in doppio cieco, in volontari sani (ANNEXA-A*, ANNEXA-R, ANNEXA-E) 400 mg EV in bolo di andexanet oppure placebo (3:1) End-points: - reverse dell effetto anticoagulante (attività anti-fxa) - misurazione del farmaco libero nel plasma - test di generazione della trombina * I risultati sono stati presentati in occasione dell American Heart Association 2014 Scientific Sessions (Monday, November 17, 2014, at 8:28 a.m.)

22 Phase III studies on Andexanet Alfa (ANNEXA ): press release 6 Oct 2014 In the first ANNEXA-A study, 33 older healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus or to placebo. Efficacy is being evaluated using biomarker endpoints, including anti-factor Xa levels as the primary endpoint. Results showed that andexanet alfa immediately and significantly reversed the anticoagulation activity of apixaban. Andexanet alfa was well tolerated with no serious adverse events reported. In the second ANNEXA-A study, 32 healthy volunteers will be given apixaban 5 mg twice daily for 4 days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes or to placebo. These data are expected in early We anticipate filing a Biologics License Application with the FDA for Accelerated Approval at the end of

23 PER977 (aripazine)

25 NAO: tempistica di interruzione perioperatoria In base a: Funzionalità renale del paziente Tipologia d intervento Tipo di farmaco EHRA Practical Guide, Europace, 2013

26 Intervento e rischio emorragico correlato Interventi per i quali non è sempre necessario sospendere i NAO Estrazioni dentali Incisioni di ascessi Cataratta/glaucoma Endoscopie senza chirurgia Chirurgia superficiale (dermatologica) Interventi a basso rischio emorragico Endoscopia con biopsia Studio elettrofisiologico/ablazi one Angiografia Impianto di pacemaker Interventi ad elevato rischio emorragico Interventi con anestesia spinale o epidurale Chirurgia toracica Chirurgia addominale Chirurgia ortopedica maggiore Biopsia del fegato/reni Resezione della prostata NCH EHRA Practical Guide, Europace, 2013

28 From VKAs to NOACs The NOAC can immediately be initiated once the INR is lower than 2.0. If the INR is , NOACs can be started immediately or (better) the next day. For INR >2.5, the actual INR value and the half-life of the VKA need to be taken into account to estimate the time when the INR value will likely drop to below this threshold (acenocoumarol 8 14 h, warfarin h, phenprocoumon h). At that time, a new INR measurement can be scheduled. EHRA Practical Guide, Europace, 2013

29 From NOACs to VKAs NOACs and VKAs should be administered concomitantly until the INR is in a range that is considered appropriate, similarly as when LMWHs are continued during VKA initiation. A loading dose is not recommended for acenocoumarol and warfarin NOACs may have an additional impact on the INR (especially the FXa inhibitors), influencing the measurement while on combined treatment during the overlap phase EHRA Practical Guide, Europace, 2013

30 Quali pazienti Nuovi anticoagulanti: pratica clinica Monitoraggio laboratoristico Reverse dell effetto anticoagulante Gestione complicanze emorragiche Gestione perioperatoria Switch da VKA (e viceversa)

31 Le raccomandazioni dell AIAC Nei pazienti warfarin-naïve i nuovi anticoagulanti orali sono da preferire al warfarin in presenza di: difficoltà logistiche nell effettuare il monitoraggio della TAO, pregresso ictus ischemico, pregressa emorragia intracranica, giovane età, paziente candidato a cardioversione elettrica G Ital Cardiol 2013;14(3):

32 Le raccomandazioni dell AIAC Nei pazienti warfarin-experienced è proponibile lo switch ai nuovi anticoagulanti orali in caso di: difficoltà logistiche nell effettuare il monitoraggio della TAO/ labilità dell INR impiego giornaliero di basse dosi di warfarin (8-10 mg/settimana) pregressa emorragia maggiore (escluse le emorragie gastrointestinali) qualità subottimale della TAO (tempo trascorso all interno del range terapeutico <60%) G Ital Cardiol 2013;14(3):

33 Le raccomandazioni dell AIAC Nei pazienti warfarin-experienced è proponibile lo switch ai nuovi anticoagulanti orali in caso di: impiego a lungo termine di farmaci interferenti con il warfarin e non interferenti con i nuovi anticoagulanti orali pregressa emorragia cerebrale in corso di terapia con warfarin con INR in range terapeutico pregresso ictus/tia in corso di terapia con warfarin con INR in range terapeutico G Ital Cardiol 2013;14(3):

34 Cosa fare prima e durante l uso dei NAO EHRA Practical Guide, Europace, 2013