SICUREZZA DEL REVERSAL AGENT PhD, MD Sergio Agosti Dirigente medico SOC Cardiologia Ospedale Novi Ligure

“Storytelling is the most powerful way to put ideas into the world today” Docente di sceneggiatura, padre dei principali scenografi di Holliwood, autore della Bibbia degli scenografi “Story” Robert McKee Screenwriting Lecturer

Caso clinico 1 Luciano, 83 anni Iperteso, IRC, iniziale decadimento cognitivo FANV permanente, portatore di PM Dabigatran 110 mg BID Ricoverato in Medicina per diagnosi di “scompenso cardiaco” Caduta a terra accidentale con trauma cranico ed ematoma subdurale

Caso clinico 1 Somministrato Idarucizumab 5 gr ev per antagonizzare effetto Dabigatran (aPTT 44 sec) Intervento neurochirurgico per evacuazione ematoma subdurale Crisi comiziali post chirurgiche, iniziato Levitiracetam 500 mgx2 Dimesso dopo 15 giorni in discrete condizioni, in terapia con LMWH

Caso clinico 2 Maria, 71 anni Ipertesa FANV parossistica Dabigatran 150 mg BID Si presenta in DEA per emiparesi destra ed afasia insorta da 2 ore Ictus emisferico sinistro (NIHSS 9) TIA, NIHSS <8 lieve, NIHSS 8-14 moderato, NIHSS >14 grave

Caso clinico 2 Somministrato Idarucizumab 5 gr ev per antagonizzare effetto Dabigatran (aPTT 29 sec) Somministrata terapia trombolitica (Alteplase 0.9 mg/kg) Paziente non aveva assunto dose di DOAC del mattino Completo ripristino della capacità motoria e parziale miglioramento afasia

Oggi lasciate che vi racconti una storia, anzi due

19 ischemie cerebrali in dabi, trattate con antidoto e successivamente trombolisi Int J Stroke. 2017 Jun;12(4):383-391

All anticoagulants can cause bleeding Concetto che può sembrare ovvio ma non è banale

Bleeding in VKA anticoagulated patients Is common Major bleeding 1-5% per year in AF Intracranial bleeding 1-1.2% per year in AF Associated with adverse outcomes 3 to 5-fold increase in thrombotic events and death Rapid and timely control of bleeding is likely to improve clinical outcomes but the efficacy of anticoagulant reversal is unproven

Challenges in bleeding Management of bleeding - Prevention - Treatment (….antidotes) sfide

NOACs associated with a non significant RRR of 14% MAJOR BLEEDING No head to head comparisons NOACs associated with a non significant RRR of 14% compared to Warfarin Ruff CT, Lancet, December 4, 2013

EFFICACY AD SAFETY SECONDARY ENDPOINTS NNT PER ICH è 140, linea di indipendenza ICH NNT 141 Ruff CT, Lancet, December 4, 2013

60% RRR Haemorrhagic stroke Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014

"The unthinkable has become conceivable” David Baltimore David Baltimore premio nobel nel 1975 insieme a Renato Dulbecco, per ricerca su relazione tra i virus e i tumori.

Haemorrhagic stroke (TF receptor) Tissue factor (TF) is a transmembrane receptor for Factor VII/VIIa (FVII/VIIa). It is constitutively expressed by cells surrounding blood vessels. The endothelium physically separates this potent "activator" from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. TF is also expressed in certain tissues, such as the heart and brain, and provides additional hemostatic protection to these tissues. Il Fattore tissutale, noto più propriamente come Tissue Factor (TF) ed altrimenti indicato come fattore III o CD142, è una glicoproteina presente nel tessuto subendoteliale, nelle piastrine, e nei leucociti necessaria per la formazione della trombina dal suo zimogeno: la protrombina. La formazione della trombina porta alla coagulazione del sangue. Il tissue factor non va confuso con la tromboplastina, che è infatti un estratto tissutale composto quasi esclusivamente da TF e fosfolipidi anionici. Le diverse tromboplastine in commercio, che differiscono in termini di attività pro-coagulante, sono comunemente utilizzate in laboratorio per effettuare test di screening dell'emostasi. Mackmann, Anesth Analg. 2009 May; 108(5):1447-52 The role of tissue factor and factor VIIa in hemostasis.

Modifiable and non-modifiable risk factors for bleeding in anticoagulated patients based on bleeding risk scores ESC Guidelines 2016

EHRA Guidelines (2015) NOACs and their dosing in CKD Riduzione della dose preserva efficacia e aumenta sicurezza, fino al 30% dei pz non riceve una dose appropriata… sptt sottodosata ma anche sovradosata….

Challenges in bleeding Management of bleeding - Prevention - Treatment (….antidotes) sfide

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

Idarucizumab was designed as a specific reversal agent for the anticoagulant activity of dabigatran Humanized Fab fragment Binding affinity for dabigatran ~350× higher than dabigatran to thrombin IV administration, immediate onset of action Short half-life Idarucizumab is a humanized antibody fragment that binds to dabigatran with a more than 350-fold higher affinity than dabigatran does to thrombin, thus preventing dabigatran from binding to thrombin and so reversing its anticoagulant effects. Humanization of the antibody fragment and the removal of the Fc region reduce the immunogenic potential of the molecule. The antibody fragment does not bind to known thrombin substrates and has no activity in coagulation tests or platelet aggregation, and thus has no procoagulant or anticoagulant effects on its own. Due to its intravenous application route, idarucizumab has a fast onset of action. Idarucizumab has a half-life of approximately 6 hours. It binds rapidly to dabigatran and the antidote–dabigatran complex is eliminated quickly. This potentially allows a patient to resume dabigatran treatment soon after the bleeding event has been resolved. Idarucizumab has no known endogenous targets. It is highly specific to dabigatran, which has no naturally occurring homologues in the human body. References Schiele F et al. Blood 2013;121:3554-62 Stangier J et al. OR 320; presented at ISTH 2015 No intrinsic procoagulant or anticoagulant activity Adapted from Schiele F et al. Blood 2013; Stangier J et al. ISTH 2015, OR320

N Engl J Med, 11 July 2017; 377:431-41

RE-VERSE AD™ is a multicentre, open-label, single-arm Phase III trial Group A: Uncontrolled bleeding + dabigatran-treated 301 pt Group B: Emergency surgery or procedure* + dabigatran-treated 202 pt N=503 0–15 minutes 90 days’ follow-up 0–24 hours 2x2.5 g idarucizumab Hospital arrival Pre-2nd dose 2 h 4 h 12 h 24 h 30 d 90 d Pre-1st dose 1 h Blood samples ~20 min Pollack C et al. Thromb Haemost 2015;114:198–205 Idarucizumab e andexanet hanno ricevuto da FDA la designazione a Breakthrough Therapy Designation, cioè terapia rivoluzionaria, ciò consente un percorso di approvazione accelerato (6 mesi) Efficacy Endpoint Maximum reversal of dabigatran’s activity, based on central laboratory measurements of dTT or ECT from end of first infusion up to 4 hours after completion of last infusion N Engl J Med, 11 July 2017; 377:431-41

RE-VERSE AD results (Primary Outcome) Group A: Uncontrolled bleeding Group B: Emergency surgery or procedure Immediate and complete reversal: evident even after the first vial of idarucizumab Idarucizumab 2×2.5 g dTT (s) dTT (s) Adapted from Pollack CV et al.1 These figures show the primary endpoint of RE-VERSE AD™ – reversal of dabigatran anticoagulation – for the Group A patients, who have uncontrolled bleeding, and the Group B patients, who required urgent reversal of anticoagulation for emergency surgery or procedures. The results show immediate reversal of anticoagulation after administration of the first idarucizumab vial, demonstrated by dTT assay, and sustained through 24 hours in most patients. In Group A, the median maximum percentage reversal within 4 hours was 100%. Looking at normalization of individual coagulation tests, dTT was normalized in 98% of evaluable patients. ECT assays also showed immediate reversal, sustained through 24 hours in most patients. ECT was normalized in 89% of evaluable patients. In Group B, the median maximum percentage reversal was 100%. Looking at normalization of individual coagulation tests, dTT was normalized in 93% of evaluable patients. ECT assays also showed immediate reversal, sustained through 24 hours in most patients. ECT was normalized in 88% of evaluable patients. Data are presented as box and whisker plots where the top and bottom of the rectangles reflect the 75th and 25th percentiles, respectively; the horizontal lines within the rectangles reflect the 50th percentile; and the horizontal lines above and below the rectangles reflect the 90th and 10th percentiles, respectively. Reference Pollack CV et al. N Engl J Med 2015;373:511–20 Time post-idarucizumab Time post-idarucizumab Similar results were also demonstrated with ECT, aPTT N Engl J Med, 11 July 2017; 377:431-41

Indications for Dabigatran Reversal With a median time to bleeding cessation of: 2.5 hrs N Engl J Med, 11 July 2017; 377:431-41

Indications for Dabigatran Reversal N Engl J Med, 11 July 2017; 377:431-41

Group B: most patients had normal haemostasis during surgery Periprocedural haemostasis was classed as: 1.5% 93.4% 5% Normal Mildly abnormal Moderately abnormal 1.6 hrs Overall median time from first vial to procedure: N Engl J Med, 11 July 2017; 377:431-41

Re-initiation of antithrombotic treatment within 90 days RE-VERSE AD™: no safety concerns and no evidence of a prothrombotic effect At 90 days, thrombotic events occurred in 6.3% of patients in group A and 7.4% of patients in group B Re-initiation of antithrombotic treatment within 90 days Antithrombotic (n, %)* Group A (n = 301) Group B (n = 202) None 84 (28%) 20 (10%) Any antithrombotic 216 (72%) 181 (90%) Median time to re-start (days) 13.2 3.5 RE-VERSE AD™: mortality reflects severity of the underlying diseases Follow-up Group A (N = 298) Group B (N = 196) 30 days Mortality, % 13.5 12.6 90 days 18.8 18.9

REVERSE-AD conclusions Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran There were no safety concerns The major limitation is the lack of a control group Concerns: preoccupazioni

Specific Antidotes for NOACs Ciraparantag… antidoto per tutti i nao Yoonsun Mo, Felix K. Yam. Pharmacotherapy 2015;35(2):198–207

Connolly SJ et al. NEJM; August 30, 2016 per il momento (ott 2016) non ci sono novità da parte di AIFA, stiamo ancora aspettando i pareri positivi da parte di FDA e quindi di EMA, immagino ci vorrà un po' di tempo ancora, comunque ho chiesto ad una collega che si occupa di rapporti con AIFA e entro oggi mi farà sapere qualcosa di più. Non ci sono al momento analisi ad interim dell'ANNEXA disponibili. All'ESC di Barcellona è stato presentato un abstract sull'utilizzo di andexanet in maiali sottoposti a politrauma trattati con apixaban che ha evidenziato un reversal efficace senza indurre uno stato ipercoagulativo. Connolly SJ et al. NEJM; August 30, 2016

ANNEXA-4 study design 67 pt Connolly SJ et al. NEJM; August 30, 2016 Life-threatening bleeding Haemodynamic compromise Hg drop<2 g/dL Hb<8 g/Dl Critical organ N=270 2 hours 12 hours 45 days Receive andexanet Safety follow-up Assess anti-FXa Assess haemostasis Anlisi ad interim su 67 pz, bolo più infusione, 400 mg bolo e 480 mg infusione in 2 ore Co-primary endpoints: Change in anti-FXa levels within 2h; Haemostatic efficacy by 12 hours 67 pt Connolly SJ et al. NEJM; August 30, 2016

Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Apixaban Connolly SJ et al. NEJM; August 30, 2016

Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Rivaroxaban Connolly SJ et al. NEJM; August 30, 2016

http://www.pharmastar.it/index.html?cat=search&id=22160

Nella CRL per andexanet alfa, lʼFda ha chiesto che Portola fornisca ulteriori informazioni relative alla produzione del farmaco. Essendo andexanet alfa una proteina complessa, la sua produzione richiede un elevato livello di sofisticazione tecnica. Inoltre dati presentati a fda sono su 60 per riva e 60 per apix… nessuno su edoxab e 3-4 su enoxap… http://www.pharmastar.it/index.html?cat=search&id=22160

Conclusioni Antidoto: importante novità scientifica e clinica Migliora ulteriormente profilo di sicurezza dei DOAC (Dabigatran) Pazienti in triplice o duplice terapia Pazienti con HASBLED>4 non modificabile Pregressa emorragia maggiore

GRAZIE PER L’ATTENZIONE www.arcaliguria.it