EFFICACIA E SICUREZZA METANALISI

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2 EFFICACIA E SICUREZZA METANALISI Endpoint Risultato (NAO vs AVK) Riduzione del Rischio (NAO/AVK) Mortalita totale 5,61% vs 6,02% RR 0,89;IC 95% 0,83-0,96 Mortalita CV 3,45% vs 3,65% RR 0,89; IC 95% 0,82-0,98 Ictus/Embolia sistemica 2,40% vs 3,13% RR 0,77; IC 95% 0,70-0,86 Ictus Ischemico 1,87% vs 2,02 RR 0,92; IC 95% 0,81-1,04* Sanguinamenti maggiori 4,90% vs 5,54% RR 0,86; IC 95% 0,72-1,02* Emorragia Intracranica 0,59% vs 1,30% RR 0,46; IC 95% 0,39-0,56 Infarto Miocardico 1,29% vs 1,29% RR 0,99; IC 95% 0,58-1,15** * Differenze non significative ma con trend favorevole ai NAO **Nessuna differenza significativa tra NAO e AVK

3 I PAZIENTI DEI TRIALS SONO IDENTICI A QUELLI DEL MONDO REALE? PROFILO DI RISCHIO TRATTAMENTI CONCOMITANTI ANALISI EVENTI ADERENZA AL TRATTAMENTO FOLLOW UP

4 Independent FDA study of Medicare patients analysed outcomes in > new users of dabigatran or warfarin Observational cohort study US Medicare database Comparison of ischaemic stroke, ICH, major GI bleeding, acute MI, and mortality rates using insurance-claim and administrative data Study period > new users (OAC treatment-naïve) of dabigatran or warfarin All recently diagnosed with AF All aged 65 years person-years of follow-up Adjustments were made for confounding variables In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Graham DJ et al. Circulation 2015;131:

5 Independent FDA Medicare analysis findings support favourable benefit risk profile of dabigatran shown in RE-LY * Medicare 1 HR: 0.80 P=0.02 HR: 0.34 P<0.001 HR: 0.97 P=0.50 HR: 1.28 P<0.001 HR: 0.92 P=0.29 HR: 0.86 P=0.006 RE-LY 2 5 RR: 0.76 P=0.04 RR: 0.41 P<0.001 RR: 0.94 P=0.41 RR: 1.48 P=0.001 RR: 1.27 P=0.12 RR: 0.88 P=0.05 In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF. Pradaxa 110 mg BID is indicated for certain patients in Europe, and was shown to be as effective as warfarin in preventing stroke or systemic embolism. RE-LY was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) study *Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Numbers above bars denote HRs vs warfarin. 1. Graham DJ et al. Circulation 2015;131:157-64; 2. Connolly SJ et al. N Engl J Med 2009;361: ; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 6; 4. Pradaxa : EU SPC, 2014; 5. Connolly SJ et al. N Engl J Med 2014; 371:

6 Favourable benefit risk profile of dabigatran supported by real-world evidence: US Department of Defense database HR (95% CI) Observational study (Oct 2010 to Jul 2012) US DoD database > new users of dabigatran or warfarin available for matching All NVAF patients Aged years at index date Stroke Ischaemic stroke Haemorrhagic stroke Major bleeding Major ICH Major GI bleeding MI Death 0.73 ( ) 0.84 ( ) 0.32 ( ) 0.87 ( ) 0.49 ( ) 1.13 ( ) 0.65 ( ) 0.64 ( ) Favours dabigatran Favours warfarin In the USA, the licensed doses for Pradaxa are: Pradaxa 150 mg BID and Pradaxa 75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF Comparison groups (each n=12793) established using propensity score matching Villines TC et al. AHA

7 Favourable benefit risk profile of dabigatran supported by realworld evidence: independent Danish registry VKA-naïve stratum HR* (95% CI) Observational cohort study (Aug 2011 to May 2013) Nationwide Danish registries D110 vs W Any Major Fatal 0.72 ( ) 0.93 ( ) 0.52 ( ) GI 0.50 ( ) ICH 0.30 ( ) first-time dabigatran users (7063 VKA-naïve) vs matched warfarin users VKA-naïve = 2 years since last warfarin purchase All AF patients D150 vs W Any Major Fatal GI ICH 0.68 ( ) 0.67 ( ) 0.70 ( ) 1.45 ( ) 0.33 ( ) Favours dabigatran Favours warfarin *Adjusted HR: age, components of CHA 2 DS 2 -VASc, HAS-BLED, months since August 2011, time since initiation of VKA therapy; W, warfarin Larsen TB et al. Am J Med 2014;127:650 6.e5 29

8 Dabigatran adherence in atrial fibrillation patients during the first year after diagnosis: a nationwide cohort study Nationwide Danish patient and prescription purchase registries Final study population 2960 patients Gorst-Rasmussen A, J Thromb Haemost 2015

9 Proportion of patients with a 1-year PDC > 80% was 76.8% 100% was 37.2% More adherent patients: women pts. at high risk of stroke (CHA 2 DS 2 -VASc score 2) pts. with relatively higher morbidity (e.g. recent hospitalizations, use of several cardiovascular medications) pts. with prior bleeding Gorst-Rasmussen A, J Thromb Haemost 2015

10 Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of patients taking rivaroxaban Objective Patient Characteristics To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Design 5-year observational, post-marketing safety surveillance study using fully integrated electronic medical records (EMRs) DATA BASE DIPARTIMENTO DIFESA U.S. Tamayo et al., Clin Cardiol 2015

11 Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of patients taking rivaroxaban Objective Major Bleed Characteristics* To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Design 5-year observational, post-marketing safety surveillance study using fully integrated electronic medical records (EMRs) *MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites. Tamayo et al., Clin Cardiol 2015

12 Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of patients taking rivaroxaban Objective Conclusions To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Design 5-year observational, post-marketing safety surveillance study using fully integrated electronic medical records (EMRs) Observational post-marketing study of patients with NVAF followed for 455 days in real life Rate of MB 2.86% person/y Rate of MB in ROCKET AF trial: 3.6% person/y for rivaroxaban and 3.5 for warfarin* Patients who experienced MB were older and more likely to have comorbidity The most common bleeding site is GI Of the 478 patients who suffered a MB, 14 died (fatal bleeding rate 0.08% person/y) The MB rate was generally consistent with the registration trial results and fatal bleeds were rare. *MB classified using the International Society on Thrombosis and Haemostasis defintion Tamayo et al., Clin Cardiol 2015

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15 SOSPENSIONE DEL TRATTAMENTO 13%TOTALE PZ/ANNO 14,1% NUOVI TRATTATI PZ/ANNO 12,7% VKA>RIVAROX. PZ/ANNO

16 Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with nonvalvular atrial fibrillation Objective Design To compare the rates of medication persistence and discontinuation among rivaroxaban and warfarin patients using real-world data from a large, nationally representative claims database in the US A large nationally representative US claims database of patients with NVAF treated from July 2010 through March 2013 Definitions Medication persistence: absence of refill gap > 60 days Discontinuation: no additional refill for at least 90 days and until the end of follow up of Patient Characteristics Nelson et al., CMRO 2014

17 Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with nonvalvular atrial fibrillation Medication persistence Discontinuation Conclusion Patients receiving rivaroxaban for NVAF had 37% lower hazard of non-persistence, and were 46% less likely to discontinue therapy compared to those receiving warfarin Nelson et al., CMRO 2014

18 Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with nonvalvular atrial fibrillation Medication persistence Nelson et al., CMRO 2014

19 Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with nonvalvular atrial fibrillation Discontinuation Nelson et al., CMRO 2014

20 STUDIO PROSPETTICO OSSERVAZIONALE XANTUS: Patient Flow Major events, specifically major bleeding, stroke, SE, TIA and MI, adjudicated centrally by an independent CAC blinded to individual patient data Primary analysis population: defined as all patients who had taken at least one dose of rivaroxaban Screened (N=10,934) Enrolled (N=6785) Safety population (N=6784) 4149 patients excluded* Patient decision (n=1222) Administrative reason (n=456) Availability of drug (n=18) Medical guidelines (n=399) Price of drug (n=473) Medical reasons (n=442) Internal hospital guidelines (n=30) Type of health insurance (n=183) Other (n=1454) 1 patient Did not take any rivaroxaban (n=1) Rivaroxaban 20 mg od (n=5336) Rivaroxaban 15 mg od (n=1410) Another dose (n=35) # *Reasons for not continuing in the study included, but were not limited to, patient decision, administrative or medical reasons. Some patients could have more than one reason for exclusion; # other dose includes any initial daily rivaroxaban dose besides 15/20 mg od (excluding missing information, n=3) 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466

21 XANTUS: Baseline Demographics Distribution of Stroke Risk Factors Mean score±sd = 2.0±1.3 Mean score±sd = 3.4±1.7 CHADS 2 score CHA 2 DS 2 -VASc score* *3 patients had missing CHA 2 DS 2 -VASc scores 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466

22 XANTUS: Treatment Persistence and Patient Satisfaction Persistence with rivaroxaban in XANTUS was 80% at 1 year Over 75% of patients were very satisfied/satisfied with their treatment 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466

23 RAFFORZA IL PROFILO DI EFFICACIA E SICUREZZA

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27 CONCLUSIONI CON LA RISERVA DI RIVALUTARE I DATI ASSICURATIVI CONTRARIAMENTE A QUANTO DI SOLITO ACCADE I RISULTATI DEI REGISTRI CONFERMANO E AMPLIFICANO I RISULTATI DEI TRIALS IN TERMINI DI VANTAGGIO PER LA SICUREZZA E EFFICACIA DEI NAO VS AVK

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29 SICUREZZA E EFFICACIA DEL DABIGATRAN NEL MONDO REALE FDA > US MEDICARE > PTS US DEPARTMENT DEFENSE PTS US HEALTH INSURANCE PTS DANISH OBSEVATIONAL STUDY

30 5.376 patients with NVAF at least 30 days of follow-up and filling dabigatran prescription of at least 30 days duration at VA pharmacy between October 2010 and September % (n ) patients were adherent to dabigatran (PDC 80%) Shore S, Am Heart J 2014

31 XANTUS: Management of Major Bleeding Major bleeding occurred in 1.9% of patients (n=128) 1 Major bleeding was mostly treated using conservative methods 1 0.8% of patients (n=53) received transfusions of 2 units of packed RBCs or whole blood Throughout the study use of non-specific reversal agents such as prothrombin complex concentrate (PCC) - was low 1 Use of PCC documented in two patients Use of tranexamic acid documented in three patients Use of etamsylate documented in one patient These findings are in line with outcomes from ROCKET AF 2 and the Dresden NOAC Registry 3 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466; 2. Piccini JP et al, Eur Heart J 2014; 35(28): ; 3. Beyer-Westendorf J et al, Blood 2014; 124(6):955-62

32 XANTUS: Module Summary XANTUS is the first large, international prospective study to describe rivaroxaban use in a broad patient population with NVAF Patients were at lower overall risk than in the phase III ROCKET AF trial Over 96% patients receiving rivaroxaban did not experience any of the outcomes of stroke/se, treatment-emergent major bleeding or all-cause death In XANTUS, rivaroxaban demonstrated low rates of stroke/se and major bleeding, including intracranial and GI bleeding Incidences of these outcomes generally increased with higher stroke risk scores Major bleeding was mostly treated conservatively; reversal agents were rarely used Treatment persistence and patient satisfaction were high 80% of patients remained on rivaroxaban 75% reported they were satisfied with their treatment at 1 year RAFFORZA IL PROFILO DI EFFICACIA E SICUREZZA 1. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466

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34 Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration Adverse Event Reporting System Raschi E. et al., British Journal of Clinical Pharmacology, Accepted manuscript online: 16 FEB 2015 In merito alle segnalazioni di danno epatico indotto da farmaco (DILI: Drug- Induced Liver Injury): per dabigatran: nessuna associazione farmaco-evento avverso statisticamente significativa (le segnalazioni di DILI sono state il 1.7% di tutte le segnalazioni) per rivaroxaban si osserva una sproporzione nelle segnalazioni statisticamente significativa (le segnalazioni di DILI sono state il 3,7% di tutte le segnalazioni) per apixaban le segnalazioni post-marketing sono ancora insufficienti per trarre conclusioni definitive

35 Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS 2 Prior stroke # ROCKET AF % XANTUS % ALL STROKES MB GI # Includes prior stroke, SE or TIA; *Events per 100 patient-years 1. Patel MR et al, N Engl J Med 2011;365: ; 2. Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466

36 Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of patients taking rivaroxaban Objective Patient Characteristics To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Design 5-year observational, post-marketing safety surveillance study using fully integrated electronic medical records (EMRs) DATA BASE DIPARTIMENTO DIFESA U.S. Tamayo et al., Clin Cardiol 2015

37 XANTUS: Baseline Demographics Clinical Characteristics Rivaroxaban (N=6784) Rivaroxaban (N=6784) Age (years) Mean ± SD 71.5±10.0 Age <65, n (%) 1478 (21.8) Age 65 75, n (%) 2782 (41.0) Age >75, n (%) 2524 (37.2) Gender (male): n (%) 4016 (59.2) Weight (kg): mean ± SD 83.0±17.3 BMI (kg/m 2 ): mean ± SD 28.3±5.0 BMI >30 kg/m 2, n (%) 1701 (25.1) AF, n (%) First diagnosed 1253 (18.5) Creatinine clearance, n (%) <15 ml/min 20 (0.3) 15 <30 ml/min 75 (1.1) 30 <50 ml/min 545 (8.0) ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4) Existing co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-cns SE/TIA 1291 (19.0) Paroxysmal 2757 (40.6) Persistent 923 (13.6). Camm Permanent AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv (27.0) Congestive HF 1265 (18.6) Prior MI 688 (10.1) Baseline hospitalization, n (%) 1226 (18.1)

38 Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of patients taking rivaroxaban Objective Fatal Outcomes To provide longitudinal safety data by obtaining information associated with MB among rivaroxaban users with NVAF Design 5-year observational, post-marketing safety surveillance study using fully integrated electronic medical records (EMRs) Tamayo et al., Clin Cardiol 2015

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