Terapia antidotica e gestione delle emergenze nei pazienti in terapia con NAO

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1 Terapia antidotica e gestione delle emergenze nei pazienti in terapia con NAO Fabrizio Corsini Medicina d Urgenza - Pronto Soccorso AO S. Croce e Carle Cuneo Con la preziosa collaborazione della Dr.ssa M FP Viglione, SC Farmacia

2 LAB in NOACs

3 ESC NOACs management guidelines

4 Interpretation of coagulation assays in patients treated with different NOACs (Heidbuchel Europace 2015) PT, prothrombin time; aptt, activated partial thromboplastin time; dtt, diluted thrombin time; ECT, ecarin clotting time; INR, international normalized ratio; ACT: activated clotting time; ULN, upper limit of normal.

5 LAB in NOACs

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8 Test di laboratorio facilmente disponibili in regime di urgenza, utili in paz in terapia con NOACs in situazioni particolari Valutare sempre dosaggio e tempo trascorso dall ultima somministrazione (picco/valle), anamnesi di possibile insufficienza renale ac/cr, interazioni farmacologiche. Dabigatran: APTT: test qualitativo, relazione alquanto lineare con l effetto anticoagulante raggiunto dal farmaco (scarsa linearità ad elevati dosaggi). Interpetrazione/dati utili Normale : verosimile scarso effetto anticoagulante presente A valle (12-16 ore dall ultima dose) > 2 rispetto ai limiti superiori di riferimento maggior rischio di sanguinamento Valori intermedi tra picco e valle meritano ricontrollo a distanza PT/INR: non utile

9 Test di laboratorio facilmente disponibili, utili in paz in terapia con NOACs in situazioni particolari Inibitori diretti del F Xa PT: test qualitativo per rivaroxaban (per apixaban ed endoxaban scarsa attendibilità) Interpetrazione/dati utili Normale : verosimile scarso effetto anticoagulante presente Alterato effetto anticoagulante presente (non nota relazione con rischio di sanguinamento) APTT: non utile NB: PT/INR e aptt non vanno considerati test diagnostici quantitativi della attività anticoagulante dei NOACs

10 Test quantitativi Dabigatran Tempo di Trombina diluito (dtt) (Hemocloth,) Tempo di Ecarina (ECT), activated clotting time (ACT) Apixaban, Rivaroxaban, Endoxaban Dosaggio cromogenico anti- Fattore Xa *Tutti i NOA: drvvt, diluite Russel viper venom time Sensibile ma ancora da studiare

11 NOACs POWER In clinical trials, NOACs have demonstrated favourable safety and efficacy profiles compared with warfarin 19% STROKE/SE 51% HAEMORRHAGIC STROKE 10% ALL-CAUSE MORTALITY 52% 14% INTRACRANIAL MAJOR BLEED BLEED Meta-analysis of data from RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48; Ruff et al. Lancet 2014

12 But, ADR may happens like bleedings

13 La potenza è nulla senza controllo ed in setting d urgenza è auspicabile avere il controllo Courtesy of Dr V Russo AO Monaldi NA

14 What would I What choose is an for ideal an reversal ideal reversal agent? agent? No procoagulant effects Specifically targets the NOAC Easy to use Predictable Acts immediately Effect is sustained

15 REVERSAL THERAPY AL PAZ SANGUINANTE IN TERAPIA CON NAO Definizione gravità del sanguinamento Schulman S et al. Journal of Thrombosis and Haemostasis vol 3; 4: , April 2005

16 RACCOMANDAZIONE DELLE SOCIETA SCIENTIFICHE NEL PAZ SANGUINANTE IN TERAPIA CON VKA

17 REVERSAL THERAPY DEI VKA

18 apcc, activated prothrombin complex concentrate ; CrCl, creatinine clearance; FFP, fresh frozen plasma; IV, intravenous; PCC, ; prothrombin complex concentrate; RBC, red blood cell; rfviia, activated factor VII 1. Heidbuchel H et al. Europace 2015 EHRA 2015 guidance on the management of bleeding in patients using NOACs Bleeding while using a NOAC Inquire about last NOAC intake Blood sample to determine CrCl, haemoglobin, white blood cells Inquire with lab about possibility of rapid coagulation assessment Mild bleeding Moderate/severe bleeding Life-threatening bleeding Delay or discontinue next dose Reconsider concomitant medication + + Supportive measures Mechanical compression Endoscopic haemostasis if GI bleed Surgical haemostasis Fluid replacement (colloids if needed) RBC transfusion if needed FFP (as plasma expander) Platelet transfusion (if platelet count /L) Dabigatran-treated patients Idarucizumab 5 g IV Maintain adequate diuresis Consider haemodialysis Consider For dabigatran-treated patients, idarucizumab 5 g IV PCC 50 U/kg + 25 U/kg if indicated; apcc 50 U/kg; max 200 U/kg/day rfviia 90 µg/kg In patients treated with dabigatran, idarucizumab is the preferred reversal agent 1

19 NON LIFE-THREATENING BLEEDING Inquire wich NOAC, last intake + dosing regimen Estimate normalization of haemostasis: Normal / impaired renal function h (for Dabigatran in CKI up to 48 h) Maintain diuresis Local haemostatic measures Fluid replacement RBC substitution if necessary Platelet substitution (in case of thrombocytopenia <60 x 109/L or thrombopathy). Fresh frozen plasma as plasma expander (not as reversal agent) Tranexamic acid can be considered as adjuvans Desmopressin can be considered in special cases (coagulopathy or thrombopathy) For Dabigatran consider dialysis (preliminary evidence: -65% after 4 h) Heidbuchel H et al. Europace 2015

20 LIFE-THREATENING BLEEDING All of the non life threatening mesures + Dabigatran: Idarucizumab 5 g IV total reversal Fxa Inhibitors (or Idaricuzimab not yet avalaible): Prothrombin complex concentrate (PCC) 50 U/kg (with additional 25 U/kg if clinically needed) Activated PCC 50 U/kg; (max 200 U/kg/day): no strong data about additional benefit over PCC. Off Label Activated factor VII (rfviia; 90 mg/kg) no data about additional benefit + expensive (only animal evidence). Off Label

21 CONCENTRATI di COMPLESSO PROTROMBINICO UMANO disponibili in Italia, composizione e dosaggi ATC B02BD - Fattori della coagulazione del sangue ATC B02BD01 - Fattori IX, II, VII e X di coagulazione in associazione Complesso protrombinico umano CCP N. di fattori presenti Tipo di fattori presenti Contenuto Altri fattori presenti Eccipienti Kedcom Kedrion S.p.A. UmanComplex Kedrion S.p.A. Protromplex Tim3 Baxalta Italy S.r.l. 3 II, IX, X Fattore II 25UI/ml Fattore IX 25UI/ml Fattore X 20UI/ml 3 II, IX, X Fattore II 30UI/ml Fattore IX 30UI/ml Fattore X 30UI/ml Eparina Antitrombina III Eparina Pronativ Octapharma Italy S.p.A. Confidex Behring S.p.A. 4 II, VII, IX, X Fattore II 14-38UI/ml Fattore VII 9-24UI/ml Fattore IX 25UI/ml Fattore X 18-30UI/ml 4 II, VII, IX, X Fattore II 20-48UI/ml Fattore VII 10-25UI/ml Fattore IX 20-31UI/ml Fattore X 22-60UI/ml Proteina C Proteina S Eparina Proteina C Proteina S Eparina Albumina umana Antitrombina III umana Courtesy FP

22 Prodotti emostatici disponibili in Italia per la Reversal Therapy dei sanguinamenti in corso di TAO: dosi e costi per paziente standard (70kg) SPECIALITA MEDICINALE TIPO FORMULAZIONE POSOLOGIA QUANTITA PER PAZIENTE STANDARD COSTO PER PAZIENTE STANDARD INDICAZIONE KEDCOM UMAN COMPLEX CCP a 3 fattori Flacone 500 UI/20ml UI/kg 4-7 flaconi (Prezzo Regione Piemonte) ON-LABEL per VKA PROTROMPLEX TIM3 CCP a 3 fattori Flacone 600 UI/20ml UI/kg 3-6 flaconi (Prezzo Regione Piemonte) ON-LABEL per VKA PRONATIV CCP a 4 fattori Flacone 500 UI/20ml UI/kg 4-7 flaconi (Prezzo Ex-factory RCP Codifa) ON-LABEL per VKA CONFIDEX CCP a 4 fattori Flacone 500UI/20ml UI/kg 4-7 flaconi (Prezzo Regione Piemonte) ON-LABEL per VKA FEIBA CCP attivato (accp) Flacone 1.000UI/20ml 30-50UI/kg 2-4 flaconi (Prezzo Regione Piemonte) OFF-LABEL NOVOSEVEN Fattore VIIa ricombinante (rfviia) Flacone 1mg (50KUI) Flacone 2mg (100UI) Flacone 5mg (250KUI) μg/kg 6.3g 8.4g (Prezzo Regione Piemonte) OFF-LABEL by FP

23 NOAC real reversal agents: present & future NOAC reversal agent Target Mechanism of action Idarucizumab 1 (Praxbind ) Andexanet alfa (PRT064445) 1 Ciraparantag/ Aripazina (PER977) 1 Dabigatran FXa inhibitors Universal Humanized Fab: specifically binds dabigatran with high affinity 2 Recombinant modified FXa: competitive affinity for direct FXa inhibitors 3 Synthetic small molecule: hydrogen bonds (NOACs); charge charge interactions (heparin) 4 FXa, activated Factor X 1. Greinacher et al. Thromb Haemost 2015; 2. Schiele et al. Blood 2013; 3. Lu et al. Nat Med 2013; 4. Ansell et al. N Engl J Med 2014

24 NOAC reversal agents: stages of development Idarucizumab 1 Target: dabigatran Studies in healthy volunteers Phase III Patients requiring urgent surgery/ with major bleeding; started May ,3 Submitted to EMA/FDA Feb/Mar 2015 Approval FDA Oct EMA Nov AIFA APPROVED 23 Feb 2016 Andexanet alfa (PRT064445) 1 Target: FXa inhibitors Studies in healthy volunteers Phase III Patients with major bleeding; started Jan Submitted to FDA Dec Ciraparantag (Aripazina) (PER977) 1 Target: universal Studies in healthy volunteers 8 1. Adapted from Greinacher et al. Thromb Haemost 2015; 2. Clinicaltrials.gov: NCT ; 3. Pollack et al. Thromb Haemost 2015; 4. US FDA press release 16 Oct 2015; 5. European Commission Community Register of Medicinal Products for Human Use 20 November 2015; 6. ClinicalTrials.gov Identifier: NCT ; 7. ClinicalTrials.gov Identifier: NCT

25 Key differences between NOACs reversal agents Idarucizumab Andexanet alfa Aripazine (PER977) Target Dabigatran FXa inhibitors Mechanism of action Immediate, complete, and sustained reversal in volunteers Specific Humanized Fab: specifically binds dabigatran Non-specific Recombinant modified activated FX: competitive affinity for direct FXa inhibitors Universal: FXa inhibitors, dabigatran, and heparins Non-specific Synthetic small molecule: hydrogen bonds (NOACs); charge charge interactions (heparin) + +/- +/- Acts only against more target drug No direct prothrombotic signals + +/-? Administration IV: bolus, or short infusion IV: bolus and/or continuous infusion Ready-to-use solution IV Re-initiate anticoagulation +? (No data available. Interaction with heparin)? (No data available. Interaction with heparin) Inclusion criteria in patient trial Emergency surgery/procedures or uncontrolled bleeding Uncontrolled bleeding only No patient trial yet

26 The first NOAC real specific Antidote

27 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 Dabigatran IV administration, immediate onset of action Short half-life Idarucizumab No intrinsic procoagulant or anticoagulant activity expected Schiele et al. Blood 2013; Praxbind : EU SPC, 2016

28 Relative size and affinity of dabigatran, idarucizumab, and thrombin Dabigatran ~500 daltons Idarucizumab (Fab) ~47800 daltons Thrombin ~37000 daltons Pollack et al. Thromb Haemost 2015

29 Idarucizumab is a humanized monoclonal antibody fragment Monoclonal mouse antibody developed with high dabigatran binding affinity Monoclonal antibody was then humanized and directly expressed as a Fab fragment in mammalian cells (hamster) The use of a humanized Fab instead of an intact antibody results in a shorter half-life and a reduced potential for immunologic reactions. Fab region Mouse Human Fc region Mouse antibody Fab region This is the part of the antibody that binds to dabigatran Chimeric Fab Humanized Fab van Ryn J. Presented at the AHA Congress, Los Angeles, USA. 5 November 2012.

30 Dabigatran distribution following administration of dabigatran etexilate Dabigatran inhibiting thrombin Dabigatran bound to plasma proteins Thrombin Dabigatran molecule Unbound dabigatran Blood compartment Dabigatran unspecifically bound in tissues Unbound dabigatran Other compartments

31 Eikelboom Circulation 2016 Administration of the antidote Thrombin Dabigatran molecule Antidote Blood compartment Other compartments

32 New equilibrium established Thrombin Dabigatran molecule Antidote Blood compartment X Other compartments Glund S et al. Thromb Haemost 2015;19;113(5); Glund S et al.sh 2014; abstr 344; Schiele F et al. Blood 2013;121: ; Eikelboom Circulation 2016

33 Unbound idarucizumab and the idarucizumab dabigatran complex are renally eliminated The idarucizumab dabigatran complex is very stable, i.e. the binding of dabigatran is essentially irreversible (half-life of the molecular complex ~260 hours) Blood compartment Dabigatran molecule Idarucizumab Bound and unbound idarucizumab is eliminated by the kidney (partly catabolized) and is also catabolized to amino acids and reabsorbed; 90% of the dose is eliminated within 5 hours* Kidney Urine Idarucizumab degradation products Idarucizumab is eliminated renally Renal impairment did not impact the reversal effect of idarucizumab *Glund S et al. Thromb Haemost 2015;19;113(5); Glund S et al. ASH 2014; abstr 344; Schiele F et al. Blood 2013;121: ;

34 Reversal of the anticoagulant effect of dabigatran with idarucizumab differs from PCC for NOAC reversal Idarucizumab PCC 3 / 4 Factor, apcc Mode of action Specific reversal Repletion of coagulation factors Immediate effect For use prior to emergency surgery/urgent procedure For use in life-threatening or uncontrolled bleeding Clear dose recommendation Clinical studies in patients receiving a NOAC Reversal reflected in coagulation test results No prothrombotic effect? *Not approved for NOAC-treated patients; Not approved for NOAC-treated patients, but listed in EU NOAC labels and in guidelines/expert statements as treatment option in cases of severe haemorrhage with NOAC. (a)pcc, (activated) prothrombin complex concentrate. 1. Pollack CV et al. N Engl J Med 2015; 2. Goldstein JN et al. Lancet 2015; 3. Sarode R et al. Circulation 2013; 4. NovoSeven: EU SPC, 2014; 5. KCENTRA: US PI, 2014; 6. Hanley JP et al. J Clin Pathol 2004; Praxbind : EU SPC, 2015 *

35 Expected to enter about 500 patients in 400 center RE-VERSE AD is a multicentre, open-label, single-arm Phase III trial Group A: Uncontrolled bleeding + dabigatrantreated 2x2.5 g idarucizumab N=500 Group B: Emergency surgery or procedure* + dabigatran-treated 2x2.5 g idarucizumab 0 15 minutes 90 days follow-up 0 24 hours Hospital arrival Pre-1st dose Pre-2nd dose ~20 min 1 h 2 h 4 h 12 h 24 h 30 d 90 d Blood samples 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 Pollack et al. Thromb Haemost 2015

36 RE-VERSE AD : interim results from the first 90 patients have been presented and published Group A: Uncontrolled bleeding Group B: Emergency surgery or procedure 51 patients 39 patients Pollack et al. Presented at ISTH 2015; Pollack et al. N Engl J Med 2015

37 RE-VERSE AD trial Inclusion and exclusion criteria for Inclusion criteria Exclusion criteria Group A (patients with uncontrolled bleeding): Overt bleeding judged by physician to require a reversal agent Group B (patients requiring emergency surgery or procedure): Condition requiring emergency surgery or invasive procedure where adequate haemostasis is required (emergency = next 8 hours) Group A (patients with uncontrolled bleeding): Minor bleeds (epistaxis, haematuria) that can be managed with standard supportive care No clinical signs of bleeding Group B (patients requiring emergency surgery or procedure): Surgery or procedure that is elective or with low risk of uncontrolled or unmanageable bleeding All patients Currently taking dabigatran etexilate 18 years of age Written informed consent All patients Contraindications to study medication including known hypersensitivity to drug or excipients* RE-VERSE AD is an opportunity to investigate idarucizumab under the rigours of a clinical study setting, but without stringent exclusion criteria that could make the patient population unrepresentative of real-world practice *Subjects with hereditary fructose intolerance may react to sorbitol Pollack et al. Thromb Haemost 2015

38 RE-VERSE AD : multicentre, ongoing, single-arm, open-label Phase III study Group A: Uncontrolled bleeding + dabigatran-treated 5 g idarucizumab N=500 Group B: Emergency surgery or procedure* + dabigatran-treated 0 15 minutes 90 days follow-up Hospital arrival Pre-1st vial Pre-2nd vial h 2 h 4 h 12 h 24 h 7 d 30 d 90 d min Blood samples *Other than bleeding. dtt, diluted thrombin time; ECT, ecarin clotting time Pollack et al. Thromb Haemost 2015

39 RE-VERSE AD : multicentre, ongoing, single-arm, open-label Phase III study Group A: Uncontrolled bleeding + dabigatran-treated Group B: Emergency surgery or procedure* + dabigatran-treated 5 g idarucizumab Reverses up to the 99th percentile of dabigatran levels measured in RE-LY N= minutes 90 days follow-up Hospital arrival Pre-1st vial Pre-2nd vial h 2 h 4 h 12 h 24 h 7 d 30 d 90 d min Blood samples *Other than bleeding. dtt, diluted thrombin time; ECT, ecarin clotting time Pollack et al. Thromb Haemost 2015

40 RE-VERSE AD : multicentre, ongoing, single-arm, open-label Phase III study Group A: Uncontrolled bleeding + dabigatran-treated Group B: Emergency surgery or procedure* + dabigatran-treated 5 g idarucizumab Primary endpoint: dabigatran reversal within 4 hours N=500 (dtt or ECT) 0 15 minutes 90 days follow-up Hospital arrival Pre-1st vial Pre-2nd vial h 2 h 4 h 12 h 24 h 7 d 30 d 90 d min Blood samples *Other than bleeding. dtt, diluted thrombin time; ECT, ecarin clotting time Pollack et al. Thromb Haemost 2015

41 dtt (s) Group A interim results: reversal of dabigatran anticoagulation with idarucizumab based on dtt Idarucizumab g Group A: Uncontrolled bleeding No idarucizumabrelated safety concerns identified to date in the analysis Assay upper limit of normal 0 Baseline Between vials min 1 h 2 h 4 h 12 h 24 h Time post idarucizumab Adapted from: Pollack et al. N Engl J Med 2015

42 dtt (s) Group B interim results: reversal of dabigatran anticoagulation with idarucizumab based on dtt Group B: Emergency surgery or procedure Clinical outcomes Idarucizumab g Of 36 patients undergoing surgery: 33 patients had normal intraoperative haemostasis (as judged by the physician) 2 mildly abnormal 1 moderately abnormal Assay upper limit of normal 20 0 Baseline Between vials min 1 h 2 h 4 h 12 h 24 h Time post idarucizumab Adapted from: Pollack et al. N Engl J Med 2015

43 E possibile considerare l utilizzo di una seconda dose da 5 gr di Praxbind in presenza di recidiva di sanguinamento clinicamente rilevante con tempi di coagulazione prolungati* se la potenziale ricomparsa del sanguinamento dovesse essere pericolosa per la vita e se si dovessero osservare tempi di coagulazione prolungati, se i pazienti dovessero avere necessità di un secondo intervento chirurgico di emergenza/una seconda procedura d urgenza e presentare tempi di coagulazione prolungati. *Relevant coagulation parameters are activated partial thromboplastin time (aptt), diluted thrombin time (dtt), or ecarin clotting time (ECT); Praxbind : EU SPC, 2015

44 La terapia anticoagulante con Dabigatran puo essere ripresa 24 ore dopo la somministrazione di Praxbind Dabigatran puo essere ripreso dopo 24 h dopo la somministrazione di Idarucizumab se il paziente e clinicamente stabile ed e stata raggiunta una adeguata emostasi Ogni trattamento antitrombotico (es. Eparina) puo essere iniziato in ogni momento dopo somministrazione di Idarucizumab L assenza di terapia antitrombotica espone il paziente a un elevato rischio trombotico a causa della sottostante patologia o condizione Praxbind : EU SPC, 2015

45 PRAXBIND : come si usa Indicazione terapeutica : Praxbind è un inattivatore specifico per dabigatran ed è indicato nei pazienti adulti trattati con Pradaxa (dabigatran etexilato) nei casi in cui si rende necessaria l inattivazione rapida dei suoi effetti anticoagulanti: Il flacone contiene una soluzione (2.5 g/50 ml) pronta per infusione o iniezione in bolo Nessuna controindicazione all uso Somministrato con dose fissa(5 g, 2.5 g per flacone) Nessun adattamento della dose per eta, per insuff. Renale etc Praxbind : EU SPC, 2015

46 Potenza e controllo?

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48 Per Dabigatran: Idarucizumab (Praxbind ) 5 g ev (2 fl da 2,5 g in bolo od infusione rapida in max 15 min totali)

49 SANGUINAMENTI IN PAZ IN NAO SEGNALATE DA PRONTO SOCCORSO A.O. S. CROCE E CARLE CUNEO ANNO I QUADRIMESTRE 2016 N. ADR/FARMACO TIPOLOGIA ADR REVERSAL THERAPY 2 emorragia cerebrale 2 rettorragia 2 melena 12 ADR DABIGATRAN 9 ADR APIXABAN 7 ADR RIVAROXABAN 2 macroematuria 1 emorragia addominale 1 emotorace 1 emottisi 1 epistassi 3 emorragia cerebrale 2 epistassi 1 ematoma 1 ematemesi 1 anemia 1 emotorace 2 emorragia cerebrale 2 emorragia gastrointestinali 2 ematuria 1 melena 6/12 ADR 4/9 ADR 4/7 ADR Courtesy FP

50 REAZIONI AVVERSE A NAO PIU FREQUENTI RETE NAZIONALE DI FARMACOVIGILANZA ANNO ADR DABIGATRAN APIXABAN RIVAROXABAN Ematoma 1,40% 2,60% 2,10% Emorragia 1,20% 0,90% 1,70% Melena 4% 4% 4,80% Dispepsia 13,10% 0,60% 1,50% Dolore addominale 2,70% 0,60% 2,10% Emorragia del retto 7,10% 6,60% 6,80% Dolore addominale superiore 18,60% 2,30% 2,40% Emorragia gastrointestinale 2,40% 2% 2,40% Ematuria 4,40% 5,70% 8% Emorragia cerebrale 2,10% 5,10% 3,30% Anemia 5,90% 7,40% 7,60% Prurito 2,10% 4% 4,10% Epistassi 3,80% 10,30% 9,20% Astenia 1,60% 1,10% 3% Courtesy FP

51 SITUAZIONI PARTICOLARI INTERVENTO CHIRURGICO URGENTE STOP NOACs se possibile, attendere h dall ultima dose assunta esami di laboratorio: info qualitativa, ma non basarsi su di essi se non è possibile attendere, soppesare con il Chirurgo il rischio emorragico intraoperatorio con il rischio di procrastinare un intervento necessario Misure di supporto (idratazione, diuresi forzata e dialisi etc) Idarucizumab per dabigatan (efficace in trial REVESe-AD) Reversal therapy come per paz sanguinante

52 REVERSAL THERAPY NAO - TAKE HOME MESSAGE La reversal therapy dei NAO necessità di ulteriori basi scientifiche Attualmente l unico vero antidoto è l Idarucizumab, specifico ed efficace per la reversal therapy del Dabibatran Il miglior antidoto resta il tempo Nella maggior parte dei casi misure generali di supporto al paziente emorragico sono sufficienti Nei casi gravi ed a rischio di vita sono indicati, oltre le misure generali, ed Idarucizumab per Dabigatran, i PCC (eventualmente apcc e FEIBA) Non ci sono dati per il monitoraggio del reverse se non con Idarucizumab (aptt, dtt, ECT)

53 L anticoagulante ideale senza bisogno di reversal Grazie