I nuovi anticoagulanti orali Fulvio POMERO Medicina Interna S. Croce e Carle Cuneo

INTERAZIONI FARMACOLOGICHE INTERAZIONI ALIMENTARI

TEMPO in RANGE TERAPEUTICO 48% degli eventi tromboembolici 44% degli eventi emorragici TTR ~ 60% Oake N et al. CMAJ 2007;176:1589-94

Schirmer SH et al. JACC 2010; 56: 2067-76

DABIGATRAN RIVAROXABAN APIXABAN Meccanismo d’azione Inibitore diretto TROMBINA FXa Biodisponibilità 6.5% 80% 50% Via di somministrazione Orale Pro-farmaco SI NO Interazioni alimentari Clearance renale 85% 66% (36% immodif.) 27% Emivita (T1/2) 14-17 h 7-11 12 h T max 0.5-2 h 2-4 h 3 h Interazioni farmacologiche P-gp inhibitors P-gp inducers (Es: amiodarone) CYP3A4 inhibitors CYP3A4 inducers CYP3A4 inducers P-gp inhibitors Ansell J. Haematology 2010; 2010: 221-228

Profilassi in chirurgia ortopedica maggiore Eriksson BI et al. Annu Rev Med 2011; 62: 41-57 6

Primary efficacy outcome DABIGATRAN vs ENOXAPARINA * Not inferiority ** Inferiority Studio Chirurgia Protocollo RE-NOVATE Protesi d’anca E 40 mg 28-35 gg D 150 mg 28-35 gg D 220 mg 28-35 gg RE-MODEL Protesi ginocchio E 40 mg 6-10 gg D 150 mg 6-10 gg D 220 mg 6-10 gg RE-MOBILIZE E 30 mg x 2 12-15 gg D 150 mg 12-15 gg D 220 mg 12-15 gg Primary efficacy outcome Enox. Dabig. 150 mg 220 mg 6.7% * 8.6% (< 0.0001) 6.0% 37.7% 40.5% (0.017) 36.4% (0.0003) 25.3% ** 33.7% (0.0009) 31.7% (0.02) Mannucci PM et al. Annals of Medicine 2011; Early online: 1-8

Primary safety outcome DABIGATRAN vs ENOXAPARINA Studio Chirurgia Protocollo RE-NOVATE Protesi d’anca E 40 mg 28-35 gg D 150 mg 28-35 gg D 220 mg 28-35 gg RE-MODEL Protesi ginocchio E 40 mg 6-10 gg D 150 mg 6-10 gg D 220 mg 6-10 gg RE-MOBILIZE E 30 mg x 2 12-15 gg D 150 mg 12-15 gg D 220 mg 12-15 gg Primary safety outcome Enox. Dabig. 150 mg 220 mg 1.6% 1.3% (0.60) 2.0% (0.44) (-) 1.5% (0.82) 1.4% 0.6% (NA) Mannucci PM et al. Annals of Medicine 2011; Early online: 1-8

Primary efficacy outcome RIVAROXABAN vs ENOXAPARINA Studio Chirurgia Protocollo RECORD 1 Protesi d’anca R 10 mg 5 sett E 40 mg 5 sett RECORD 2 E 40 mg 10-14 gg RECORD 3 Protesi ginocchio R 10 mg 10-14 gg RECORD 4 E 30 mg x 2 10-14 gg Primary efficacy outcome Rivaroxaban Enoxaparina p 1.1% 3.7% < 0.001 2.0% 9.3% 9.6% 18.9% 6.9% 10.1% 0.012 Mannucci PM et al. Annals of Medicine 2011; Early online: 1-8

Primary safety outcome RIVAROXABAN vs ENOXAPARINA Studio Chirurgia Protocollo RECORD 1 Protesi d’anca R 10 mg 5 sett E 40 mg 5 sett RECORD 2 E 40 mg 10-14 gg RECORD 3 Protesi ginocchio R 10 mg 10-14 gg RECORD 4 E 30 mg x 2 10-14 gg Primary safety outcome Rivaroxaban Enoxaparina p 0.3% 0.1% 0.18 - 0.6% 0.5% 0.77 0.7% 0.32% 0.11 Mannucci PM et al. Annals of Medicine 2011; Early online: 1-8

EFFICACY Eriksson BIet al. Annu Rev Med 2011; 62: 41-57

BLEEDING RISK Eriksson BIet al. Annu Rev Med 2011; 62: 41-57

RIVAROXABAN (XARELTO) DABIGATRAN (PRADAXA) Prevenzione di episodi di Tromboembolismo Venoso (TEV) in pazienti sottoposti a chirurgia sostitutiva elettiva del ginocchio o a chirurgia sostitutiva elettiva dell’anca : la dose raccomandata di Pradaxa è di 220 mg una volta al giorno, assunta sotto forma di 2 capsule da 110 mg. Il trattamento deve iniziare per via orale entro 1 – 4 ore dalla conclusione dell’intervento con una capsula e continuare dal giorno successivo con 2 capsule una volta al giorno. Tempo: chirurgia sostitutiva elettiva del ginocchio: 10 giorni. chirurgia sostitutiva elettiva dell’anca: 28 - 35 giorni. RIVAROXABAN (XARELTO) La dose raccomandata è di 10 mg di rivaroxaban una volta al giorno per via orale. La dose iniziale deve essere assunta 6 - 10 ore dopo l'intervento, a condizione che sia stata ottenuta l'emostasi. Nei pazienti sottoposti a interventi di chirurgia maggiore all'anca: trattamento di 5 sett.. Nei pazienti sottoposti a interventi di chirurgia maggiore al ginocchio:trattamento di 2 sett.

Terapia del TEV Eriksson BI et al. Annu Rev Med 2011; 62: 41-57

rischio di recidiva (%) RRR = 80% TEV acuto (1° mese) TEV acuto (2-3 mese) TEV ricorrente rischio di recidiva (%) 8% 2% 3% RRR = 80% Kearon C et al N Engl J Med 1997;336:1507-1511

TEV confermato obiettivamente Single dummy Double dummy DABIGATRAN ETEXILATO (150 mg bid) Placebo Placebo N° 2550 N° 1275 TEV confermato obiettivamente Osservazione di 30 giorni R N° 1275 Placebo WARFARIN WARFARIN (INR 2-3) Terapia Parenterale (5-10 gg) 6 MESI Schulman S et al. NEJM 2009; 361: 2342-2352

Recurrent venous thromboembolism Efficacy outcome Recurrent venous thromboembolism Event rate DABIGATRAN 2.4 % WARFARIN 2.1 % p< 0.001 for non inferiority Schulman S et al. NEJM 2009; 361: 2342-2352

Safety outcome Major bleeding / any bleeding RR 71% P < 0.001 Event rate (any bleeding) WARFARIN 21.9 % DABIGATRAN 16.1 % Event rate ( major bleeding) WARFARIN 1.9 % DABIGATRAN 1.6 % P=0.38 Safety outcome Major bleeding / any bleeding Schulman S et al. NEJM 2009; 361: 2342-2352

Safety outcome Schulman S et al. NEJM 2009; 361: 2342-2352

* p < 0.001 TOLLERABILITA‘ Dispepsia * 3.1 0.7 Dispnea 3.2 4.2 Dabigatran % Warfarin % Dispepsia * 3.1 0.7 Dispnea 3.2 4.2 Edema periferico 3.4 3.8 Nausea 4.6 Artralgia 2.6 Dolore alla schiena 3.6 3.9 Nasofaringiti 4.3 Diarrea Cefalea 6.2 7.0 Dolore alle estremità 5.0 5.6 Schulman S et al. NEJM 2009; 361: 2342-2352 20

30 giorni R 30 giorni R RIVAROXABAN RIVAROXABAN TVP confermata senza EP sintomatica 15 mg bid 20 mg od N° 2900 gg 21 Osservazione di 30 giorni R Periodo di trattamento predefinito (3-6-12 mesi) Enoxaparina 1 mg/Kg bid per almeno 5 gg + VKA (INR 2-3) RIVAROXABAN 20 mg od EP o TVP confermata che abbia completato i 6-12 mesi di rivaroxaban o VKA N° 1197 Osservazione di 30 giorni R Periodo di trattamento predefinito (6-12 mesi) Placebo EINSTEIN investigators NEJM 2010; 363: 2499-2510

Efficacy outcome Safety outcome Recurrent venous thromboembolism Event rate RIVAROXABAN 2.1 % Enox- WARFARIN 3.0 % p< 0.001 for non inferiority Safety outcome Major bleeding or clinically relevant nonmajor bleeding P= 0.77 Event rate RIVAROXABAN 8.1 % Enox- WARFARIN EINSTEIN investigators NEJM 2010; 363: 2499-2510

Con o senza TVP sintomatica TVP confermata senza EP sintomatica N° 2900 RIVAROXABAN RIVAROXABAN 15 mg bid 20 mg od gg 21 Osservazione di 30 giorni R EP confermata Con o senza TVP sintomatica Periodo di trattamento predefinito (3-6-12 mesi) N° 3300 Enoxaparina 1 mg/Kg bid per almeno 5 gg + VKA (INR 2-3) RIVAROXABAN 20 mg od TVP confermata che abbia completato i 6-12 mesi di rivaroxaban o VKA N° 1197 Osservazione di 30 giorni R Periodo di trattamento predefinito (6-12 mesi) Placebo EINSTEIN investigators NEJM 2010; 363: 2499-2510

Efficacy outcome Recurrent venous thromboembolism p< 0.001 for superiority Event rate (Efficacy outcome) RIVAROXABAN 1.3 % Enox- WARFARIN 7.1 % Event rate (Safety outcome) Major or clinically relevant non major Major bleeding RIVAROXABAN 6.0 % 0.7 Enox- WARFARIN 1.2 % p < 0.001 p = 0.11 EINSTEIN investigators NEJM 2010; 363: 2499-2510

Profilassi dello stroke nella Fibrillazione Atriale Eriksson BI et al. Annu Rev Med 2011; 62: 41-57 25

ANTITROMBOTICI nella FIBRILLAZIONE ATRIALE TAO vs Controlli ASA vs Controlli TAO vs ASA Riduzione rischio relativo (%) Hart RG et al. Ann Int Med 2007;146:857-67

% 1. Sudlow et al. Lancet 1998; 352: 1167–1171. The study by Sudlow et al. showed that in a population-based survey, 43% had standard contraindications to warfarin with irreversible contraindications were present in 26%.1 The study by Brass et al. (488 patients) showed that contraindications to warfarin were present in 38%.2 In the study by Kalra et al. (patients over 75), contraindications to warfarin were present in 37%.3 The study by Go et al. (13,428 patients) reported contraindications to warfarin in 17.5% patients.4 One of the difficulties of OACs in clinical practice is the extensive list of contraindications. The following list is taken from the exclusion criteria in the Stroke Prevention in AF (SPAF) study:5 Patient/physician refused OAC Gastrointestinal or genito-urinary bleed in last 6 months Positive stool test for occult blood Anaemia Hb < 100 g/L BP > 180/100 despite treatment Previous intracranial hemorrhage Alcoholism History of severe bleeding with a therapeutic INR while on OAC Predisposition to head trauma Requirement for non-steroidal anti-inflammatory drug (NSAID) Occupational hazards requiring OAC. 1 2 3 4 Conventional contraindication to warfarin (ASA and NSAID not included) Standard contraindications to warfarin use in AF patients >65 years Standard contraindication to OAC (including ASA and NSAID) Contraindications to OAC in randomly selected AF patients aged >75 years 1. Sudlow et al. Lancet 1998; 352: 1167–1171. 2. Brass LM et al. Stroke 1997; 28: 2382–2389. 3. Kalra et al. Stroke 1999; 30: 1218–22/ Heart 1999; 82: 570–574. 4. Go et al. Ann Intern Med 1999; 131: 927–934. References: 1. Sudlow et al. Lancet 1998; 352: 1167–1171. 2. Brass LM et al. Stroke 1997; 28: 2382–2389. 3. Kalra et al. Stroke 1999; 30: 1218–22/ Heart 1999; 82: 570–574. 4. Go et al. Ann Intern Med 1999; 131: 927–934. 5. Stroke Prevention in AF Study, SPAF I, Circulation 1991; 84: 527–539.

R Fibrillazione Atriale non valvolare con almeno 1 fattore di rischio aggiuntivo R Warfarin (INR 2.0-3.0) N=6000 Dabigatran etexilato 110 mg bid 150 mg bid PROBE = Prospective Randomized Open Trial with Blinded Adjudication of Events Endpoint primario di EFFICACIA = stroke o embolismo sistemico Endpoint primario di SICUREZZA = sanguinamenti maggiori Connolly S et al. NEJM 2009; 361: 1139-1151

CARATTERISTICHE DEI PAZIENTI Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4 Connolly S et al. NEJM 2009; 361: 1139-1151

Ictus o embolismo sistemico RR 0.91 (95% CI: 0.74–1.11) P <0.001 (NI) RR 0.66 (95% CI: 0.53–0.82) P <0.001 (sup) % per anno RRR 34 % Connolly S et al. NEJM 2009; 361: 1139-1151

Ictus o embolismo sistemico RRR 34% Connolly S et al. NEJM 2009; 361: 1139-1151

SANGUINAMENTI MAGGIORI RR 0.80 (95% CI: 0.69–0.93) p=0.003 (sup) RR 0.93 (95% CI: 0.81–1.07) RRR 20 % p=0.31 (sup) % per anno Connolly S et al. NEJM 2009; 361: 1139-1151

SANGUINAMENTI INTRACRANICI RRR 69 % RRR 60 % RR 0.31 (95% CI: 0.20–0.47) P< 0.001 (sup) RR 0.40 (95% CI: 0.27-0.60) P< 0.001 (sup) % per anno RRR 69 % RRR 60 % Connolly S et al. NEJM 2009; 361: 1139-1151

SANGUINAMENTI MAGGIORI Caratteristiche D 110 mg 150 mg Warfarin p-value 110 vs. W 150 vs. W Numero di pazienti (n) 6015 6076 6022 Sanguinamenti maggiori 2.71 3.11 3.36 0.003 0.31 Pericolosi per la vita Non pericolosi per la vita Gastrointestinali 1.22 1.66 1.12 1.45 1.88 1.51 1.80 1.76 1.02 <0.001 0.56 0.43 0.037 0.47 Connolly S et al. NEJM 2009; 361: 1139-1151

* p <0.001 TOLLERABILITA‘ Dispepsia * 11.8 11.3 5.8 Dispnea 9.3 9.5 Dabigatran 110 mg % Dabigatran 150 mg Warfarin Dispepsia * 11.8 11.3 5.8 Dispnea 9.3 9.5 9.7 Vertigini 8.1 8.3 9.4 Edema periferico 7.9 7.8 Fatica 6.6 6.2 Tosse 5.7 6.0 Dolore toracico 5.2 5.9 Artralgia 4.5 5.5 Dolore alla schiena 5.3 5.6 Nasofaringiti 5.4 Diarrea 6.3 6.5 Infezioni al tratto urinario 4.8 Infezioni delle alte vie aeree 4.7 * p <0.001 Connolly S et al. NEJM 2009; 361: 1139-1151

HAS-BLED bleeding risk score ESC Guidelines. European Heart Journal 2010; 31, 2369–2429

ESC Guidelines. European Heart Journal 2010; 31, 2369–2429

HAS-BLED score 0-2 Dabigatran 150 mg b.i.d. HAS-BLED score ≥ 3 ESC Guidelines. European Heart Journal 2010; 31, 2369–2429

HAS-BLED score 0-2 Dabigatran 110 mg b.i.d HAS-BLED score ≥ 3 ESC Guidelines. European Heart Journal 2010; 31, 2369–2429

IPOTESI: il livello di qualità del controllo dell’INR (TTR) durante il “RELY trial” può influenzare i relativi effetti di dabigatran 110 mg e dabigatran 150 mg vs warfarin ? Wallentin L et al. Lancet 2011; 376: 975-83

For the primary efficacy and safety endpoints, the main RELY study results are consistent showing reductions in stroke and major bleeding with Dabigatran compared Warfarin irrespective of centre based INR control Wallentin L et al. Lancet 2011; 376: 975-83

Study Design Atrial Fibrillation Rivaroxaban Warfarin G02-536 w_script.ppt 3/27/2017 7:01:09 AM Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus Study Design At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 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% 44

Baseline Characteristics Rivaroxaban (N=7081) Warfarin (N=7090) CHADS2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.48 13 43 29 2 3.46 44 28 12 Prior VKA Use (%) 62 63 Congestive Heart Failure (%) Hypertension (%) 90 91 Diabetes Mellitus (%) 40 39 Prior Stroke/TIA/Embolism (%) 55 Prior Myocardial Infarction (%) 17 18 Rocket AF Investigators, AHA 2010

Primary Efficacy Outcome Stroke and non-CNS Embolism 6 Rivaroxaban Warfarin Event Rate 1.71 2.15 Warfarin 5 RRR 21% 4 Cumulative event rate (%) 3 Rivaroxaban 2 HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 1 120 240 360 480 600 720 840 960 Days from Randomization Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Rocket AF Investigators, AHA 2010

Primary Efficacy Outcome Stroke and non-CNS Embolism   Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 0.5 1.0 2.0 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat Rocket AF Investigators, AHA 2010

Primary Safety Outcomes Rivaroxaban Warfarin Event Rate HR (95% CI) p-value Major and non-major Clinically Relevant 14.91 14.52 1.03 (0.96, 1.11) 0.442 Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 Non-major Clinically Relevant 11.80 11.37 (0.96, 1.13) 0.345 Event Rates are per 100 patient-years Based on Safety on Treatment Population Rocket AF Investigators, AHA 2010

Primary Safety Outcomes Rivaroxaban Warfarin Event Rate or N (Rate) HR (95% CI) P-value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) 0.576 0.019 0.044 0.007 0.003 Intracranial hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population Rocket AF Investigators, AHA 2010

Similar rates of bleeding and adverse events. Summary Efficacy: Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism. Rivaroxaban was superior to warfarin while patients were taking study drug. By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority. Safety: Similar rates of bleeding and adverse events. Less ICH and fatal bleeding with rivaroxaban. Conclusion: Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF. Rocket AF Investigators, AHA 2010

Study outline Eikelboom JW et al. Am Heart J 2010; 159: 348-353

- Patients with serious bleeding in the last 6 m Exclusion criteria - ……. - Patients with serious bleeding in the last 6 m - High risk of bleeding (eg, active peptic ulcer disease, platelet count <100 000/mm3 or hemoglobin <10g/dL, stroke within 10 d, documented hemorrhagic tendencies or blood dyscrasias) - Current alcohol or drug abuse, or psychosocial reasons that make study participation impractical Eikelboom JW et al. Am Heart J 2010; 159: 348-353

Not currently receiving VKA therapy for 1 of the following reasons: Inclusion criteria Not currently receiving VKA therapy for 1 of the following reasons: (a) previous VKA therapy has been demonstrated to be unsuitable, and its use has been discontinued (eg, poor anticoagulant control, adverse events, need for other treatments that may interact with VKA, patient unable or unwilling to adhere to dose or INR monitoring instructions); (b) VKA therapy has not been previously used but would be expected to be unsuitable (eg, unlikely to comply with dosing or monitoring requirement; need for other treatments that may interact with VKA; unlikely to adhere to restrictions on alcohol, diet, or nonprescription medications; risk of VKA therapy considered to outweigh the risk of stroke or systemic embolism; patient is unwilling to take VKA). Eikelboom JW et al. Am Heart J 2010; 159: 348-353

APIXABAN (5 mg bid) 1.6 % / yr ASPIRIN (81-324 mg) 3.7 % / yr Event rate APIXABAN (5 mg bid) 1.6 % / yr ASPIRIN (81-324 mg) 3.7 % / yr Stroke or Systemic Embolism p < 0.001 HR = 0.45 Connolly S et al. NEJM 2011; 364: 806-817

APIXABAN (5 mg bid) 1.4 % / yr ASPIRIN (81-324 mg) 1.2 % / yr Event rate APIXABAN (5 mg bid) 1.4 % / yr ASPIRIN (81-324 mg) 1.2 % / yr Major Bleeding HR = 1.13 p = 0.57 Connolly S et al. NEJM 2011; 364: 806-817

Trattare 1000 pazienti per 1 anno con APIXABAN (5 mg bid) vs ASPIRINA Analisi intention-to-treat Trattare 1000 pazienti per 1 anno con APIXABAN (5 mg bid) vs ASPIRINA Significa prevenire: - 33 Ospedalizzazioni per cause cardiovascolari - 21 Ictus o embolie sistemiche - 9 Morti Al costo di: 2 eventi emorragici maggiori Connolly S et al. NEJM 2011; 364: 806-817

Mancanza di antidoti specifici Semplificazione eccessiva della terapia (uso inappropriato ? ) Mancanza di test coagulativi efficaci in circostanze d’urgenza Monitoraggio della “compliance” dei pazienti Comportamento nell’insufficienza renale Gestione perioperatoria Costi Quale paziente trattare ?