46 CONGRESSO NAZIONALE SOCIETÀ ITALIANA DI BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA (S.I.Bio.C.)

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1 46 CONGRESSO NAZIONALE SOCIETÀ ITALIANA DI BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA (S.I.Bio.C.) Roma, Hotel Marriott Ottobre 2014

2 Sessione congiunta S.I.Bio.C. S.I.C. Fibrillazione Atriale Moderatori: Marcello Ciaccio (Palermo) Maria Penco (L Aquila) Sala Tiziano

3 Università degli studi di Palermo Scuola di Medicina Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS) Sezione di Malattie Cardio-Respiratorie e Endocrino-Metaboliche Master di Malattie Vascolari - Master di Ecocardiografia Centro per la Diagnosi Precoce di Aterosclerosi Preclinica e Pluridistrettuale e per la Prevenzione Secondaria delle Malattie Cardiovascolari Università di Palermo U.O.C. di Cardiologia - Centro di Riferimento Regionale per la Diagnosi e Cura dello Scompenso Cardiaco A.O.U. Policlinico P. Giaccone di Palermo Direttore : Prof. Salvatore Novo I Nuovi Farmaci Anticoagulanti Orali Salvatore NOVO

4 ATRIAL FIBRILLATION Atrial fibrillation (AF) is an abnormal heart rhythm characterized by rapid and disorganized activation (fibrillation) of the atria with an irregular ventricular response

5 PREVALENZA IN BASE ALL ETÀ

6 PREVALENCE OF AFIB IN THE U.S. IS EXPECTED TO INCREASE UPWARDS OF 5.3 MILLION BY 2050 From ATRIA Study Go AS et al. JAMA 2001; 285:

7 AFIB: A COMMON BUT SERIOUS ARRYTHMIA AFib increases the risk of stroke 5-fold 1 particularly in the elderly, similarly for paroxysmal, persistent and permanent AFib 2 Strokes associated with AFib are usually more severe than those from other causes, conferring an increased risk of morbidity, mortality and poor functional outcome 1 1. Savelieva et al. Ann Med 2007; 39: Hart R et al. JACC 2000; 35: 183-7

8 ANTICOAGULATION IN AFIB AND STROKE S RISK REDUCTION Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50% 0-50% -100% Hart R, et al. Ann Intern Med 1999; 131: 492-8

9 VALUTAZIONE RISCHIO TROMBOTICO ED EMORRAGICO RISCHIO TROMBOTICO CHA2DS2-VASC RISCHIO EMORRAGICO HAS-BLED

10 ALCUNI LIMITI DEGLI ANTAGONISTI DELLA VITAMINA K Lento inizio d azione Lenta regressione dell effetto (lunga durata d azione, lunga emivita) Stretto range terapeutico Multiple interazioni con alimenti e farmaci Necessità di monitoraggio per il mantenimento del range terapeutico Difficoltà di gestione peri-procedurale in caso di chirurgia Compromissione qualità di vita dei pazienti Carico di lavoro ed impegno economico del follow-up medico Sottoutilizzo della terapia per timore di effetti avversi o per la complessità di gestione Phillips KW et al, Thromb Haemost 2010; 103: 34-9 Fuster V et al, Eur Heart J 2006; 27:

11 WARFARIN FOR AFIB Limitations Lead to Inadequate Treatment Adequacy of Anticoagulation in Patients with AFib in Primary Care Practice INR above target No warfarin INR in target range Subtherapeutic INR Samsa GP, et al. Arch Intern Med 2000;160:

12 NEW PHARMACOLOGICAL Other antiplatelet drugs ( ACTIVE ) - Clopidogrel + ASA Synthetic pentasaccharide ( AMADEUS ) - Idraparinux Oral direct thrombin inhibitor - ( SPORTIF ) - Ximelagatran ( RELY ) - Dabigatran Oral factor Xa antagonist Rivaroxaban (ROCKET AF) Apixaban (ARISTOTLE ( AVERROES and Edoxaban (ENGAGE) PERSPECTIVES Harenberg J. New Anticoagulants in AF. Semin Thromb Hemost 2009; 35:

13 Cumulative Hazard Rates Cumulative Hazard Rates Lancet 2006; 367: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death Major Bleeding RR = 1.45 P = Clopidogrel+ASA Clopidogrel+ASA 5.64 %/year RR = 1.06 P = %/year 2.2 %/year 3.93 %/year OAC OAC Clopidogrel+ASA Clopidogrel+ASA Years Years Early Termination of ACTIVE W due to evidence of superiority of oral anticoagulation

14 ATRIAL FIBRILLATION PHASE 3 STUDIES TIMELINES Dabigatran RELY Published 2009 Rivaroxaban ROCKET AF Published August 2011 Edoxaban ENGAGE AF TIMI 48 Published AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

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19 Drug-drug interactions and pharmacokinetics of NOACs Absorption and metabolism of NOACs 15

20 ABSORPTION AND METABOLISM OF NOAC Dabigatran Apixaban Edoxaban Rivaroxaban Bioavailability 3-7% 50% 62% 66% (w/o food) ~100% with food Prodrug yes no no no Clearance: non-renal/renal of adsorbed dose if normal renal function 20%/80% 73%/27% 50%/50% 65%/35% Liver metabolism: CYP3A4 no yes (elimination; minor CYP3A4) minimal (<4% of elimination) yes (elimination) Absorption with food no effect no effect 6-22% more +39% Intake with food? no no Absorption with H2B/PPI plasma level -12 to -30% no official recommendation yet mandatory no effect no effect no effect Asian ethnicity plasma level +25% no effect no effect no effect GI tolerability dyspepsia 5-10% no problem no problem no problem Elimination half-life 12-17h 12h 9-11h 5-9h (young)/11-13h (elderly) 16

21 NOACS IN RENAL DYSFUNCTION PRACTICAL RECOMMENDATIONS FOR DOSING IN CHRONIC KIDNEY DISEASE

22 INTERAZIONI FARMACOLOGICHE Heidelbuchel H et al, Europace 2013; 15:

25 INTERAZIONI CON ALTRE VARIABILI Heidelbuchel H et al, Europace 2013; 15:

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27 WHEN TO STOP NOACS BEFORE A PLANNED SURGICAL INTERVENTION Dabigatran Apixaban Edoxaban Rivaroxaban No important bleeding risk and/or local haemostasis possible: perform at trough level (i.e. 12h or 24h after last intake) Low Low Low High High risk Low risk High risk High risk risk risk risk risk CrCl 80 ml/min 24h 48h 24h 48h no data no data yet yet 24h 48h CrCl no data no data 36h 72h 24h 48h ml/min yet yet 24h 48h CrCl no data no data 48h 96h 24h 48h ml/min yet yet 24h 48h CrCl ml/min CrCl <15 ml/min Last intake of drug before elective surgical intervention A not indicate d not indicated 36h 48h no data yet no official indication for use no data yet 36h 48h 40

28 WHEN TO RESTART NOACS AFTER A PLANNED SURGICAL INTERVENTION Procedures with immediate and complete haemostasis: Resume 6 8 h after surgery Atraumatic spinal/epidural anethesia Clean lumbar puncture Procedures associated with immobilization: Procedures with post-operative risk of bleeding: Initiate reduced venous or intermediate dose of LMWH 6 8 h after surgery if haemostasis achieved. Restart NOACs 48 72h after surgery upon complete haemostasis Thromboprophylaxis (e.g. with LMWH) can be initiated 6-8 h after surgery 41

29 WHAT TO DO IF THERE IS A (SUSPECTED) OVERDOSE WITHOUT BLEEDING, OR A CLOTTING TEST IS INDICATING A RISK OF BLEEDING Acute recent ingestion of overdose: activated charcoal to reduce absorption (standard dosing scheme for adults of 30 to 50 g). Consider coagulation tests to assess possible bleeding risk. In absence of bleeding, wait-and see approach. 33

30 POSSIBLE MEASURES TO TAKE IN CASE OF BLEEDING Van Ryn et al Am J Med 2012;125:

31 SWITCHING BETWEEN ANTICOAGULANT REGIMENS VKA to NOAC Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) Low molecular weight heparin (LMWH) NOAC to VKA NOAC to parenteral anticoagulant NOAC to NOAC Aspirin or clodiprogel to NOAC INR <2.0: immediate INR : immediate or next day INR >2.5: use INR and VKA half-life to estimate time to INR <2.5 Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment Start when next dose would have been given Administer concomitantly until INR in appropriate range Measure INR just before next intake of NOAC Re-test 24h after last dose of NOAC Monitor INR in first month until stable values ( ) achieved Initiate when next dose of NOAC is due Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Switch immediately, unless combination therapy needed 22

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33 EHRA NOACs Card

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35 CHECKLIST IN FOLLW-UP OF AF PTS ON NOACS Compliance Interval Each visit Comments Inspect remaining medication Stress importance of compliance Inform about compliance aids Thrombo-embolism Each visit Cerebral, systemic and pulmonary circulation Bleeding Side effects Co-medications Blood sampling Each visit Each visit Each visit Yearly 6-monthly 3-monthly on indication Nuisance bleeding prevention possible? Bleeding with risk or impact on QoL prevention possible? Need to revise dose? Continuation? Temporary cessation with bridging? Change of anticoagulant drug? Prescription or over-the counter drugs? Even temporary use can be risky Haemoglobin, renal, liver function Renal function if CrCl ml/min or if on dabigatran and aged >75 years or fragile If CrCl ml/min If intercurring condition may impact renal or hepatic function. 8

36 ..SEBBENE NON VI SIA UNO STUDIO TESTA-TESTA TRA I NOAC VI SONO ALCUNE CARATTERISTICHE DIFFERENZIALI CHE POSSONO ESSERE UTILI AD ORIENTARE LA SCELTA NEL SINGOLO PAZIENTE

37 CONCLUSIONI DAI TRIAL.. TUTTI i nuovi anticoagulanti orali nella FA hanno dimostrato non inferiorità di efficacia -in due casi superiorità -rispetto al warfarin TUTTI i nuovi anticoagulanti orali nella FA hanno dimostrato non inferiorità di sicurezza sui sanguinamenti maggiori ma superiorità - rispetto al warfarin

38 CONCLUSIONI DAI TRIAL.. TUTTI i NAO si associano ad un incidenza di emorragie maggiori pericolose per la vita inferiore al warfarin e ad un rischio inferiore di emorragie intracraniche rispetto al warfarin Vi è una maggiore incidenza di emorragie GI con dabigatran TUTTI i NAO si associano ad una riduzione simile e sovrapponibile della mortalità

39 CONCLUSIONI..DALLA REAL LIFE I risultati in termini di efficacia (non inferiore) e l incidenza di sanguinamenti maggiori sono concordanti nei registri con i risultati dei trial Nei registri con dabigatran non viene confermato l aumento dell incidenza di infarto del miocardio segnalato nel RE-LY L aumento di emorragie gastrointestinali con dabigatran viene ridimensionato rispetto ai trial a confronto con il warfarin Probabile bias da ipersegnalazione di eventi emorragici trattandosi di nuovi farmaci immessi sul mercato (effetto Weber)

40 THANK YOU FOR YOUR ATTENTION Describe the past, understand the present, predict the future: this is the task of medicine Ippocrate b. C.

41 How to deal with dosing errors Missed dose: BID: take missed dose up to 6 h after scheduled intake. If not possible skip dose and take next scheduled dose. QD: take missed dose up to 12 h after scheduled intake. If not possible skip dose and take next scheduled dose. Double dose: BID: skip next planned dose and restart BID after 24 h. QD: continue normal regimen. Uncertainty about intake: BID: continue normal regimen. QD: take another dose then continue normal regimen. Overdose: Hospitalization advised. 25

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46 RELY-ABLE : conclusioni Nel corso di 2,3 anni di trattamento con Dabigatran successivo allo studio RE-LY (follow-up totale medio di 4,3 anni), il rischio di ictus e sanguinamenti maggiori si è confermato essere basso Non ci sono stati nuovi eventi relativi alla sicurezza rilevati durante il periodo di follow up esteso di 2,3 anni a seguito dello studio RE-LY I risultati dello studio RELY-ABLE confermano quelli ottenuti nello studio RE-LY Circulation 2013; 16; 128:

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48 Larsen et al., JACC 2013; 61, 22:2264-7

49 Larsen et al., JACC 2013; 61, 22:2264-

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51 Larsen et al., JACC 2013; 61, 22:2264-

52 Larsen et al., JACC 2013; 61, 22:2264-

53 N Engl J Med 2009; 361:

54 RELY STUDY DESIGN Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6000 Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 Primary objective: To establish the non-inferiority of dabigatran etexilate versus warfarin. Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up

55 Cumulative hazard rates TIME TO FIRST STROKE RR 0.91 (95% CI: ) p<0.001 (NI) p=0.34 (Sup) RRR 9% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RRR 34% RR 0.66 (95% CI: p<0.001 (NI) p<0.001 (Sup) Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior

56 Number of events HEMORRHAGIC STROKE RR 0.31 (95% CI: ) p<0.001 (sup) RRR 69% RR 0.26 (95% CI: ) p<0.001 (sup) RRR 74% % % 0.10 % D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022

57 % per year MAJOR BLEEDING RATES RR 0.80 (95% CI: ) p=0.003 (sup) RRR 20% RR 0.93 (95% CI: ) p=0.31 (sup) 322 / 6, / 6, / 6,022

58 ATRIAL FIBRILLATION PHASE 3 STUDY TIMELINES Dabigatran RE-LY Published 2009 Rivaroxaban ROCKET AF Published August 2011 Edoxaban ENGAGE AF TIMI 48 Published AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

59 N Engl J Med August 10, 2011

60 ROCKET-AF STUDY DESIGN Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target ( inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

61 Cumulative event rate (%) PRIMARY EFFICACY OUTCOME STROKE AND NON-CNS EMBOLISM Event Rate Rivaroxaban Warfarin Warfarin RRR 21% Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

62 RIVAROXABAN VERSUS WARFARIN (ROCKET-AF) Efficacy Outcomes Stroke/Systemic Embolism Hemorrhagic Stroke Myocardial Infarction Safety Outcomes ICH Major Bleeding Rivaroxiban better Warfarin better

64 Randomization APIXABAN PHASE 3 CLINICAL TRIAL VS ASPIRIN TO PREVENT STROKE OR EMBOLISM IN AF PTS Patient characteristics Aged 50 years Atrial fibrillation 1 additional risk factor for stroke AVERROES N= years Apixaban 2.5 mg bid or 5 mg bid Not suitable for vitamin K antagonist Aspirin mg qd Primary outcome measures: Time to composite outcome of stroke or systemic embolism Time to major bleeding N Engl J Med 2011; 364:

65 AVERROES - PRIMARY EFFICACY OUTCOME The trial was stopped early after a predefined interim analysis revelaleted a clinically important reduction in stroke and systemic embolism with apixaban N Engl J Med 2011; 364:

67 N Engl J Med August 28, 2011

68 ATRIAL FIBRILLATION WITH AT LEAST ONE ADDITIONAL RISK FACTOR FOR STROKE Inclusion risk factors Age 75 years Prior stroke, TIA or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,206) Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device ARISTOTLE Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

69 ARISTOTLE Main Trial Results Stroke or systemic embolism HR 0.79 (95% CI, ); P (superiority)=0.011 ISTH major bleeding HR 0.69 (95% CI, ); P<0.001 RRR 21% 21% RRR RRR 31% 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P=0.011 Median TTR 66% N Engl J Med August 28, 2011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001

70 ATRIAL FIBRILLATION PHASE 3 STUDY TIMELINES Dabigatran RE-LY Published 2009 Rivaroxaban ROCKET AF Published August 2011 Edoxaban ENGAGE AF TIMI 48 Publishes AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

71 N Engl J Med. 2013; 28; 369:

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73 Need for structured follow-up All NOACs are anticoagulants and hence can cause serious bleeding. All NOACs have some drug-drug interactions (DDIs). AF population is a fragile patient population. Patients should return for ongoing review according to a predetermined schedule. Follow-up can be undertaken by specialist or GP with experience in the field and/or appropriate secondary care physicians. Nurse co-ordinated AF clinics may be used Berti et al, Eur Heart J,

74 Factors Favouring Warfarin over NOACs Prosthetic heart valve/rheumatic valve Severe renal failure Well controlled warfarin (good stable INR/high TTR/no bleeding) When INR monitoring preferred/need to titrate dose Extremes of weight/age Poor compliance anticipated Unable to pay for NOAC Drug interactions Anticipated need for antidote Anticipated increased plasma levels (older age, low body weight, renal dysfunction)

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76 PRACTICAL START-UP AND FOLLOW- UP SCHEME FOR PATIENTS ON NOACS Risk/benefit analysis: is a NOAC indicated? When choosing a NOAC, consider co-medications taken by patient. Consider co-medications such as PPI to reduce risk for gastro-intestinal bleeding. Carry information card: generic card could serve for all NOACs. Need to educate patient on importance of strict adherence to regimen discontinuation is dangerous. 4

77 Fibrillazione atriale: rischio embolico Recommendation Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those at low risk (lone AF, aged <65 years, or with contraindications). I A Eur Heart J 2010;31:

78 FUNZIONE RENALE E NAO Tutti i NAO presentano un certo grado di escrezione renale, a differenza di warfarin che è completamente metabolizzato a livello epatico. È indispensabile eseguire la determinazione della funzione renale, utilizzando la CrCl secondo la formula di Cockcroft- Gault, prima di iniziare la terapia, ed anche durante la terapia se si sospettano possibili riduzioni del filtrato glomerulare. I NAO sono controindicati nei pazienti con insufficienza renale severa, ed è sconsigliata la loro somministrazione dalle linee guida europee nei pazienti con CrCl <30 ml/min. G Ital Cardiol 2013; 14:

79 Action to be taken in case of DDIs Three levels of alert: Red contraindicated/not recommended for use Orange adapt NOAC dose dabigatran: 150 mg to 110 mg BID rivaroxaban: 20 mg to 15 mg QD apixaban: 5 mg to 2.5 mg BID Yellow consider dose reduction if two concomitant yellow interactions Where no data available, NOACs not recommended yet 18

80 NOACS: PATIENT INSTRUCTIONS Indication (stroke prevention) Potential side effects Bleeding (minor/major/fatal/ich) dyspepsia with dabigatran Adherence (and risks of nonadherence/discontinuation) Importance of taking every day on time (patients missing 1-2 consecutive doses will be subtherapeutic)

81 ..SEBBENE NON VI SIA UNO STUDIO TESTA- TESTA TRA I NOAC VI SONO ALCUNE CARATTERISTICHE DIFFERENZIALI CHE POSSONO ESSERE UTILI AD ORIENTARE LA SCELTA NEL SINGOLO PAZIENTE Dabigatran etexilato: la maggiore riduzione osservata per l ictus ischemico al dosaggio più alto Rivaroxaban: monosomministrazione giornaliera, unico farmaco tra i NOAC con tutte le indicazioni, dalla prevenzione al trattamento del tromboembolismo venoso in tutte le sue fasi, nella FA, ora anche nelle sindromi coronariche acute (EMA) Apixaban: migliore benificio clinico netto, con riduzione dell ictus per tutte le cause, del sanguinamento, e della mortalità Endoxaban: monosomministrazione, riduzione della mortalità vascolare, flessibilità di aggiustamento del dosaggio.

82 Suggested structured follow-up 7