MILANO, 21 SETTEMBRE 2016 PhD Sergio Agosti Responsabile UTIC SOC Cardiologia Ospedale Novi Ligure Expert Panel AF NORD NAO: Quale dosaggio per quali pazienti?

Qual è la solidità dei dati a favore del dossagio ridotto? Domanda 1

Edoxaban mg QD regimen Warfarin (INR 2.0–3.0) Edoxaban mg QD regimen PATIENTS AF on electrical recording within last 12 months Intended oral anticoagulant CHADS 2 ≥2 N=21,105 Median duration of follow up 2.8 years Study design: ENGAGE AF-TIMI 48 *Dose reduced by 50% if CrCl 30–50 mL/min, body weight ≤60 kg or patient receiving verapamil, quinidine or dronedarone AF=atrial fibrillation; CrCl=creatinine clearance INR=International Normalized Ratio; QD=once daily RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score and need for edoxaban dose reduction* Randomized, double-blind, double-dummy, event-driven study Giugliano et al. N Engl J Med 2013

NOAC AF studies RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 ENGAGE AF 4 DrugDabigatranRivaroxabanApixabanEdoxaban N18,11314,26418,20121,105 Dose (mg)150, , 30 FrequencyBIDQDBIDQD Initial dose reductionNo20→15 mg5→2.5 mg60→30 mg Dose reduction at baseline, % Dose modification after randomizationNo Yes (7%) Target INR (warfarin)2.0–3.0 DesignPROBE2x blind Follow up (years) Connolly et al. N Engl J Med 2009;361:1139–1151; 2. Patel et al. N Engl J Med 2011;365:883– Granger et al. N Engl J Med 2011;365:981–992; 4. Giugliano et al. N Engl J Med 2013; e-pub ahead of print 32% pt

ENGAGE-AF, ROCKET-AF, ARISTOTELE Popolazioni studiate mg OD mg OD 7081 W mg BID mg BID 9081 W Connolly et al. NEJM 2009; 361: ; Patel et al. NEJM 2011; 365:883-91; Granger et al. NEJM 2011; 365:981-92; Fox et al. European Heart Journal 2011; 32: mg OD mg OD 7036 W

Quali sono le indicazioni di prescrivibilità del dosaggio ridotto di Edoxaban? Domanda 2

Dose reduction for patient characteristics in NOAC studies RE-LY 1 ARISTOTLE 3 ENGAGE-AF 4 60→30 mg QD for: –Creatinine clearance 30–50 mL/min –body weight ≤60 kg –Use of quinidine, verapamil or dronedarone 5→2.5 mg BID for ANY TWO of: –Age ≥80 years –body weight ≤60 kg –Serum creatinine ≥1.5 mg/dL None ROCKET-AF 2 20→15 mg QD for: –Creatinine clearance <30–49 mL/min BID=twice daily; QD=once daily 1.Connolly et al. New Engl j Med 2009;361:1139–1151; 2. Patel et al. N Engl J Med 2011;365:883– Granger et al. N Engl J Med 2011;365:981–992; 4. Giugliano et al. N Engl J Med 2013; N= 428 (5%) N= 1462 (21%) N= 1784 (25%) + 7% during study N tot=2251 N= 0

Dose reduction Patients aged 80 years or above Patients who receive concomitant verapamil For the following groups the daily dose of Pradaxa of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding: Patients between years Patients with moderate renal impairment Patients with gastritis, esophagitis or gastroesophageal reflux Other patients at increased risk of bleeding In patients with moderate (creatinine clearance ml/min) or severe (creatinine clearance ml/min) renal impairment the following dosage recommendations apply: For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2). The recommended dose of Eliquis is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 micromole/L). Therapy should be continued long term. For NVAF and VTE the recommended dose is 30 mg Lixiana once daily in patients with one or more of the following clinical factors: Moderate or severe renal impairment (creatinine clearance (CrCL) mL/min) Low body weight ≤ 60 kg Concomitant use of the following P-glycoprotein (P-gp) inhibitors: Cyclosporine Dronedarone Erythromycine Ketoconazole Confronto riduzione di dose nella FA (prescrivibilità) AFDabigatranRivaroxabanApixabanEdoxaban

Quali sono i vantaggi di Edoxaban nel setting di pazienti che devono utilizzare un dosaggio ridotto? Domanda 3

Lancet, 2015 Jun 6;385(9984):

ENGAGE AF: Stroke or SEE (%/Year) 48.5 Edox Conc. (ng/mL) 0.85 Anti-FXa (IU/mL) No dose reductionDose reduction Warfarin HD Edox 60 mg Warfarin HD Edox 30 mg NA NA HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) DR: HR 0.81 (0.58–1.13) P int =0.85 Ruff et al., Lancet, 2015 P int =0.85

ENGAGE AF: Major bleed (%/Year) 48.5 Edox Conc. (ng/mL) 0.85 Anti-FXa (IU/mL) No dose reductionDose reduction Warfarin HD Edox 60 mg Warfarin HD Edox 30 mg NA NA HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) DR: HR 0.63 (0.50–0.81) Ruff et al., Lancet, 2015 P int =0.02

Relative Efficacy and Safety of Edoxaban vs. Warfarin by Dose Reduction Status CI = confidence interval; DR = dose reduction; GI = gastrointestinal; HR = hazard ratio; ICH = intracranial hemorrhage; SEE = systemic embolic event. Ruff et al. Lancet. 2015;385:2288– (0.32–0.68) 0.61(0.35–1.07) 0.88(0.76–1.03) 0.78(0.61–0.99) 0.94(0.76–1.17) Edoxaban 60/30 mg vs. warfarin 0.81(0.58–1.13) HR (95% CI) (0.70–1.24) 0.91 Ischemic stroke No DR DR 0.96(0.63–1.46) 0.85(0.62–1.17) All-cause mortality DR No DR (0.50–0.81) Major bleed DR No DR (0.23–0.92) Fatal bleed DR No DR (0.27–0.78) ICH DR No DR Stroke or SEE DR No DR Endpoint 1.32(1.06–1.65) 1.00(0.67–1.47) GI bleed DR No DR 0.21 P-interaction

ng/mL HD EdoxabanLD Edoxaban No DR 30 mg No DR 60 mg DR 30 mg DR 15 mg Concentrazione media edoxaban a valle (N=6780) HD = Alta dose LD = bassa dose DR = riduzione dose ENGAGE AF: concentrazioni di Edoxaban Ruff et al., Lancet, 2015 IL DOSAGGIO È LO STESSO MA LE CONCENTRAZIONI PLASMATICHE SONO DIVERSE -50% -29%

Probability of clinical outcomes versus edoxaban concentration Ruff et al., Lancet, 2015

Qual è il supposto meccanismo alla base della grande riduzione di stroke emorragico con i NAO? Domanda 4

Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014 Haemorrhagic stroke 56% RRR

Mackmann, Anesth Analg May; 108(5): The role of tissue factor and factor VIIa in hemostasis. Haemorrhagic stroke (TF receptor)

Major bleeding Engage-TIMI 48 Giugliano et al. N Engl J Med 2013;369:2093–2104 Outcome Warfarin (n=7,012) Edoxaban 60/30 mg (n=7,012) Edoxaban 60/30 mg versus warfarin n%/yrn HR (95% CI)P Major bleeding Fatal Critical organ/area ≥2 g/dL blood loss (0.71–0.91) 0.55 (0.36–0.84) 0.51 (0.41–0.65) 0.98 (0.84–1.14) < < Intracranial Fatal (0.34–0.63) 0.58 (0.35–0.95) < Gastrointestinal Upper Lower (1.02–1.50) 1.27 (0.99–1.63) 1.20 (0.89–1.61) Other location (0.50–0.78)<0.001

Pensate che ci sia un razionale adeguato ed un vantaggio nella scelta della monosomministrazione? Domanda 5

Phase II data Atrial Fibrillation

N=1146 Weitz et al. Thromb Haemost 2010;104: Study design: Randomized, double blind edoxaban dose regimens, open-label warfarin, parallel treatment groups Primary Objective: Evaluation of safety of four fixed dose-regimens of Edoxaban vs. Warfarin in patients with atrial fibrillation (CHADS 2 ≥ 2) Primary endpoints: Occurrence of major and/or clinically relevant non-major bleeding, elevated hepatic enzymes and/or bilirubin Edoxaban study 018: Dose Finding Study in Atrial Fibrillation Day 1 Screening Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID* Active control (Warfarin, INR 2.0–3.0) 3-month randomized treatment period Follow-up assessment Edoxaban 30 mg QD ≤30 days +30 days after last dose

WarfarinEdoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID Bleeding incidence (%) n/N 8/2507/23511/23419/24419/ Edoxaban study 018: major and clinically relevant non-major bleeding * ** *p<0.05, **p<0.01, vs warfarin QD, once daily; BID, twice daily Weitz et al. Thromb Haemost 2010;104:633-41

Edoxaban phase II dose finding study in atrial fibrillation: exposure and bleeding AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state; C max, maximum steady-state plasma concentration; C min, minimum steady-state concentration; QD, once daily; BID, twice daily ng/mL 30 QD 60 QD 30 BID 60 BID C max 30 QD 60 QD 30 BID 60 BID Ng*h/mL AUC 30 QD 60 QD 30 BID 60 BID ng/mL C min Bleeding incidence, % 30 QD 60 QD 30 BID 60 BID Edoxaban Weitz et al. Thromb Haemost 2010;104:633-41

Edoxaban study 018: any stroke, TIA and/or SEE Weitz et al. Thromb Haemost 2010;104:633-41

Conclusioni Edoxaban 60/30 Grossa solidità dei dati a favore di dosaggio ridotto È possibile una riduzione di dose sulla base di criteri clinici, con mantenimento efficacia ed un aumento di sicurezza Regime di monosomministrazione supportato da solida evidenza di fase II Enorme risultato nei confronti della prevenzione di emorragie intracraniche

Pensate che ci sia un razionale adeguato di riduzione da 60 mg a 30 mg nella popolazione che presenta le caratteristiche riportate? Domanda 6

Edoxaban: Dosaggio raccomandato

Impact of renal impairment and concomitant P-glycoprotein inhibitors on edoxaban exposure Keto, ketoconazole; Quin, quinidine; Ery, erythromycin; Amio, amiodarone; Verap, verapamil; CL CR, creatinine clearance; C min, ss, trough concentration at steady state. Salazar et al. Thromb Haemost 2012;107:925–934 C min,ss ratio CL CR 80 mL/minCL CR 50 mL/minCL CR 30 mL/min 50% 20% Increase in exposure

Somministrazione concomitante di forti inibitori della glicoproteina P fanno aumentare l’esposizione a edoxaban + 50% + 20% Ciclosporina DronedaroneEritromicinaKetoconazolo

Features of novel oral anticoagulants Dabigatran 1 Rivaroxaban 1, 2 Apixaban 1,3 Edoxaban 4-7 Target IIa (thrombin) Xa Hours to Cmax CYP metabolism NoneYes moderate Minimal <4% Bioavailability6% 80% (with food) 50%62% TransportersP-gpP-gp/BCRP P-gp Protein binding 35%93%87%50% Half-life14-17 h (BD) 7-11 h (QD/BD) 8-15 h (BD)10-14 h (QD) Renal elimination 80%*33% # 25% # 35% # 1. Eriksson et al. Clin Pharmacokinet 2009;48:1-22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011; 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics in Cardiology 2009;18:1-32; 5. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 6. Ogata et al. J Clin Pharmacol 2010;50:743-53; 7. Gonzalez-Quesada, Giugliano Am J Cardiovasc Drugs 2014 Feb 7. [Epub ahead of print]

Il basso peso corporeo è associato a un alto rischio di sanguinamento nei pazienti sottoposti ad anticoagulazione Studio di fase II con braccio warfarin di controllo su 536 pazienti giapponesi con FA Yamashita et al. Circ J 2012,

RE-LY, ROCKET-AF, ARISTOTELE Popolazioni studiate mg BID mg BID 6022 W mg OD mg OD 7081 W mg BID mg BID 9081 W Connolly et al. NEJM 2009; 361: ; Patel et al. NEJM 2011; 365:883-91; Granger et al. NEJM 2011; 365:981-92; Fox et al. European Heart Journal 2011; 32:

mg OD mg OD 7036 W RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF Popolazioni studiate Connolly et al. NEJM 2009; 361: ; Patel et al. NEJM 2011; 365:883-91; Granger et al. NEJM 2011; 365:981-92; Fox et al. European Heart Journal 2011; 32:

In which patients  Elderly patients  Patients with renal insufficiency

Edoxaban in Elderly Patients

( last accessed 21 Nov 2014)

Edoxaban in Patients with Renal Insufficiency

Chronic kindney disease is common among AF patients Kooiman et al. J Thromb Haemost 2011;9:1652–3

Chronic kindney disease increases the risk of stroke, bleeding, and all-cause death in AF patients Olesen et al. N Engl J Med 2012;367:625–35.

NOA are eliminated from the body via multiple routes

Ruff et al., Lancet, 2015 Stroke or Major Bleeding with Chronic kindney disease

Conclusions Edoxaban 60/30 Efficacia e sicurezza in linea con gli altri NAO, anche in popolazioni fragili È possibile una riduzione di dose sulla base di criteri clinici, con mantenimento efficacia ed un aumento di sicurezza Regime di monosomministrazione supportato da solida evidenza di fase II NAO studiato in casistica più ampia e verso un Warfarin meglio controllato