State of art in anticoagulation in non valvular Atrial Fibrillation: the additional value of Rivaroxaban real life data

State of art in anticoagulation in non valvular Atrial Fibrillation: the additional value of Rivaroxaban real life data Massimo Grimaldi Ospedale F. Miulli Acquaviva delle Fonti - Bari

Disclosure Biosense Webster (J&J): Patent licensing agreement Ospedale F. Miulli Acquaviva delle Fonti - Bari

Randomized clinical trial Vs. Real life data

Rivaroxaban Dataset Highest quality Independent Central Adjudication Committee (CAC) RCT Prospective, noninterventional study Rocket AF 1 Xantus 2 Xapass 3 Prospective Registry Dresden NOAC Registry 4 US PMSS 5 Retrospective databases RELIEF 6 REVISIT US 7 1) Patel MR et al, N Engl J Med 2011;365:883 891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost 2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63 68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

XANTUS: Study Objective and Design Objective: to collect real world data on NVAF patients treated with rivaroxaban Primary outcomes: major bleeding, all-cause mortality, any other adverse events Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention N=6,784 Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit/hospital discharge and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature Final visit: 1 year # *Exact referral dates for follow-up visits not defined (every 3 months recommended); # for rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed Camm AJ et al. Eur Heart J 2016;37:1145-53

Rivaroxaban: Randomized Clinical Trial and the Real World Rivaroxaban 1 XANTUS 1 Baseline ROCKET AF 2 2.0 CHADS 2 3.5 Rivaroxaban 2 41% 0 1 0% 41% 29% 30% 29% 19% 2 3 Heart failure 13% 63% 87% 13% 30% 75% 37% Hypertension Age >75 years 44% 91 % 87% 20% Diabetes 40% 19% Prior stroke # 55% 10% Prior MI 17% *Events per 100 patient-years; # includes prior stroke, SE or TIA Adapted from 1. Camm AJ et al. Eur Heart J 2016;37:1145-53 2. Patel MR et al, N Engl J Med 2011;365:883 891 CHADS 2 score 1 2 3 6

Incidence rate Event per 100 patient-years and ROCKET AF XANTUS 4,0 3,6 CHADS 2 Prior stroke* 3,0 ROCKET AF 3.5 55% XANTUS 2.0 19% 2,0 1,7 2,1 1,9 1,9 1,7 2,0 1,0 0,8 0,7 0,5 0,4 0,9 0,0 Stroke/SE Major bleeding Death All strokes ICH GI bleeding *Includes prior stroke, SE or TIA. {1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466}

Objective: XAPASS To confirm the safety and effectiveness profile of rivaroxaban across NVAF patients in Japanese realworld clinical practice. Primary outcomes: adverse events (AEs) including bleeding events (eg, major bleeding) and efficacy events (stroke, systemic embolism [SE], and myocardial infarction [MI]) Study population: patients with NVAF in Japan who start treatment with rivaroxaban for stroke/non-cns SE prevention Rivaroxaban; treatment duration and dose (15/10 mg) at the attending physician s discretion Data collection at visit, 6-month, 1-year, and 2-year Enrolment: from April 2012 to June 2014 2 years Standard observation period Once a year Maximum 5 years Follow-up investigation Prospective, single-arm, observational study Statistical analyses were descriptive and exploratory in nature Ogawa et al., J Stroke Cerebrovasc Dis, 2014;23:2520-6

XAPASS: Results Hori M. et al: Circ J 2012;76:2104 2111 Abstract presented at ESC congress 2016 Results are not intended for direct comparison XAPASS mean CHADS 2 score= 2,2 J-ROCKET AF mean CHADS 2 score=3.3

Rivaroxaban Provides a Consistent and Unique Dataset Covering the Full Patient-Risk Spectrum Highest quality Independent Central Adjudication Committee (CAC) RCT Prospective, non-interventional study Rocket AF 1 Xantus 2 Xapass 3 Prospective Registry Dresden NOAC Registry 4 US PMSS 5 Retrospective databases RELIEF 6 REVISIT US 7 1) Patel MR et al, N Engl J Med 2011;365:883 891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost 2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63 68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

Dresden NOAC Registry Effectiveness and Safety of Rivaroxaban for AF Using data from the Dresden NOAC Registry, a large multicentric registry, we prospectively evaluated the management and outcome of patients with SPAF treated with rivaroxaban Major bleeding ROCKET AF (n=7111) (mean CHADS 2 =3,5) 1 Stroke/TIA/SE All rivaroxaban SPAF patients Dresden registry 2 (n=1204) (mean CHADS 2 =2,4) 0 1 2 3 4 1. Patel MR et al, N Engl J Med 2011;365:883 891 2. Adapted from Hecker J et al, Thromb Haemost 2016;115:939-49 Results are not intended for direct comparison

% pts/year Outcome of VKA treated patients with AF not switched to NOACs-Dresden NOAC Registry 5.0 4.0 3.0 2.0 1.0 1.3 4.1 1.7 3.0 Stroke TIA/SE MB Stroke TIA/SE MB VKA, median TTR 75.5% 1 Rivaroxaban 2 1. Adapted from Michalski et al, Thromb Haemost 2015;114:1076-84. 2. Adapted from Hecker J et al, Thromb Haemost 2016;115:939-49

Rivaroxaban Provides a Consistent and Unique Dataset Covering the Full Patient-Risk Spectrum Highest quality Independent Central Adjudication Committee (CAC) RCT Prospective, non-interventional study Rocket AF 1 Xantus 2 Xapass 3 Prospective Registry Dresden NOAC Registry 4 US PMSS 5 Retrospective databases RELIEF 6 REVISIT US 7 1) Patel MR et al, N Engl J Med 2011;365:883 891 2) Camm AJ et al. Eur Heart J 2016;37:1145-53 3) Abstract presented at ESC congress 2016 4) Hecker J et al, Thromb Haemost 2016;115:939-49 5) Tamayo S et al, Clin Cardiol 2015;38:63 68 6) Coleman CI et al. Int J Cardiol 2016;203:882-4 7)Coleman CI et al, Curr Med Res Opin 2016;Sep 20:1-7

Major Bleedig (MB) in patients with NVAF: pharmacovigilance of 27.467 patients taking rivaroxaban Patients characteristics MB n=478 No MB n=26.989 Age, y, mean (SD) 78,4 (7,7) 75,7 (9,7) Comorbid condition, % 100,0 87,0 CHADS2 score, mean (SD) 3,0 (1,2) 2,2 (1,3) CHA2DS2-VASc score, mean (SD) 4,8 (1,5) 3,7 (1,7) MB characteristics* MB n=478 MB cases with fatal outcome 14 MB incidence rate %person-years (95% CI) 2,86 (2,61-3,13) Bleeding cases with fatal outcome (95% CI) 0,08 (0,05-0,14) Adapted from Tamayo S. et al, Clin Cardiol 2015;38:63-8 *MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites.

Major bleeding events (%/year) Real World Evidence: Major Bleeding in Patients with Renal Disease Taking Rivaroxaban (US DoD) Analysis of electronic records from the DoD over a 2-year period Of 39,052 rivaroxaban users, 15.5% had renal disease Major bleeding in patients taking rivaroxaban 6 5 4 3 2 1 0 4,52 Mean CHA 2 DS 2 - VASc 5.2 Renal disease 2,59 Mean CHA 2 DS 2 VASc 4.7 No renal disease Major bleeding rates were higher in patients with renal disease than those without, and CHA 2 DS 2 -VASc scores were also higher in patients with renal disease Error bars indicate 95% CI Tamayo et al, Circulation 2015;132: abstract A15905

Real World Evidence for Patients with Renal Impairment Major bleeding Fatal bleeding 4,49 4,70 4,52 0,28 0,74 0,09 Rivaroxaban Warfarin Rivaroxaban Rivaroxaban Warfarin Rivaroxaban %/year %/year %/year %/year %/year %/year ROCKET AF RENAL IMPAIRMENT TAMAYO RENAL IMPAIRMENT ROCKET AF RENAL IMPAIRMENT TAMAYO RENAL IMPAIRMENT 1. Adapted from Fox et al, Eur Heart J 2011;32:2387-94 2. adapted from Tamayo Poster presentation at AHA 2015

Real World Evidence for Patients with Diabetes Mellitus Major bleeding 3,79 3,90 3,68 Intracranial hemorrhage 0,50 0,82 0,19 Rivaroxaban Warfarin Rivaroxaban Rivaroxaban Warfarin Rivaroxaban %/year %/year %/year %/year %/year %/year ROCKET AF DIABETES TAMAYO DIABETES ROCKET AF DIABETES TAMAYO DIABETES Adapted from: 1.Bansilal S et al, Am Heart J 2015;170:675 682.e8; 2.Patel M et al. Major bleeding among rivaroxaban users with non-valvular atrial fbrillation and diabetes. Poster presentation at the American College of Cardiology 65th Annual Scientifc Session. Chicago, Illinois, 2016

%/year The RELIEF Study Demonstrated Favourable Effectiveness of Rivaroxaban in NVAF Patients in Real-World Practice RELIEF: retrospective study of German outpatients newly initiated on rivaroxaban or VKA using data from an electronic medical record database VKA (n=1039) Rivaroxaban (n=1039) 3.7 2.0 1.6 *Not otherwise specified Composite endpoint Coleman C et al, Int J Card Med 2015;203:882 884 0.7 Ischaemic stroke 1.1 0.6 0.3 0.1 0.1 0 0.7 TIA ICH Other nontraumatic MI ICH 0.6

REVISIT-US Study Design to Optimize Internal Validity Combined Endpoint of Ischemic Stroke and ICH Most likely to be coded accurately and with less variability in claims data and of equal importance to allow for benefit/risk assessment Used validated ICD-9 coding algorithms and restricted codes to the primary diagnosis code position May miss cases, but greater robustness in those identified Coleman CI et al. Curr Med Res Opin 2016;20:1-7

REVISIT-US Baseline characteristics Parameters Rivaroxaban (n=11,411) VKA (n=11,411) Apixaban (n=4083) VKA (n=4083) Age, years, mean (DS) 70.7 (11.0) 70.7 (11.4) 71.2 (11.3) 71.0 (11.3) Gender, % (n) male 53.6 (6115) 53.9 (6145) 53.2 (2217) 53.6 (2189) CHADS 2 score, mean (DS) CHA 2 DS 2 -VASc score, mean (DS) HAS-BLED score, mean (DS) 1.92 (1.08) 1.94 (1.08) 1.93 (1.07) 1.92 (1.07) 3.46 (1.37) 3.48 (1.35) 3.47 (1.38) 3.47 (1.35) 1.62 (0.69) 1.62 (0.71) 1.66 (0.72) 1.65 (0.69) NAOC low dose 15 mg od; 17.3% N/A 2.5 mg bid; 15.5% N/A Modifed from: Coleman Cl et al,curr Med Res Opin 2016 Sep 15 Coleman CI et al, presented at ESC 2016

REVISIT US - Significant Reduction in the Combined Endpoint for Rivaroxaban vs warfarin Rivaroxaban was associated vs warfarin with a Significant 47% reduction in ICH Non-significant 29% decrease in ischemic stroke Significant 39% reduction in the combined endpoint of ICH and ischemic stroke Rivaroxaban Warfarin Rate (%/year) Rate (%/year) HR (95% CI) rivaroxaban vs. warfarin HR (95% CI) rivaroxaban vs. warfarin ICH 0.49 0.96 0.53 (0.35 0.79)* Ischemic stroke 0.54 0.83 0.71 (0.47 1.07) Combined 0.95 1.6 0.61 (0.45 0.82)* *p<0.05 0,125 0,25 0,5 1 2 4 Favors rivaroxaban Favors warfarin Coleman CI et al. Curr Med Res Opin 2016;20:1-7

HR vs Warfarin HR vs Warfarin ICHs and Ischaemic Strokes of NOACs Compared with VKA in Large Retrospective Observational Analysis 1 0,8 0,6 0,4 0,2 0 1,4 1,2 1 0,8 0,6 0,4 0,2 0 ICH 0,71 0,71 0,66 0,53 0,53 0,56 0,38 0,37 0,3 Coleman CMRO 2016 Staerk EHJ 2016 Larsen BMJ 2016 Rivaroxaban Dabigatran Apixaban Ischaemic Stroke 1,22 1,13 1,11 0,98 0,87 0,89 0,89 0,71 0,82 Coleman CMRO 2016 Staerk EHJ 2016 Larsen BMJ 2016 Rivaroxaban Dabigatran Apixaban Warfarin Warfarin Adapted from Coleman CI et al. Curr Med Res Opin 2016;20:1-7; Staerk L. et al. Eur Heart J 2016.pii:ehw496.[Epub ahead of print]; Larsen TB et al. BMJ 2016;353:i3189 Results are not intended for direct comparison

Safety Profile of Rivaroxaban Confirmed Through Real-World Evidence Regardless of Data Source 6 Major bleeding event rate/year Randomized Prospective clinical trial registry ROCKET AF 1* Dresden NOAC 2# n=7111 n=1200 3.6% 3.1% 2.9% Retrospective Observational database study US DoD PMSS 3 XANTUS 4* n=27,467 n=6784 2.1% Major GI bleeding 2.0% event rate/year 1.2% 1.5% 0.9% Mean CHADS 2 score 3.5 2.4 2.2** 3,0*** 2.0 ** *** Referred to patient population with no major bleeding cohort ( representative of > 98% of the patient population) Referred to pts with major bleeding ( Beyer-Westendorf et Al. Thromb and Haemost Suppl 2/2016) *Major bleeding definition according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding); major bleeding defined by the Cunningham algorithm 5 ; Warfarin MB 3,4% Warfarin MB-GI 1,24 1. Patel MR et al, N Engl J Med 2011;365:883 891; 2. Hecker J et al, Thromb Haemost 2016 Jan 21;115(5) ]; 3. Tamayo S et al, Clin Cardiol 2015;38:63 68; 4 ; Camm AJ et al, Eur Heart J 2016;37(4):1145-53 5. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560 566 6. Modified from Beyer-Westendorf J et al Thromb Hemost 2016:116:S13-S23 Results are not intended for direct comparison

Adherence and Persistence Start medication or observation Adherence Percentage of doses taken as prescribed Persistence Days taking medication (without exceeding permissible gap) Stop medication or end observation Cramer JA et al. Value Health 2008;11(1):44-47

Non optimal adherence (PDC <80%) and ischemic stroke M.J. Alberts et al. / International Journal of Cardiology 215 (2016) 11 13

Treatment Persistence and Discontinuation with Rivaroxaban, Dabigatran, and warfarin for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation in the United States Retrospective cohort analysis of the US MarketScan Coleman, et al., PLOS ONE DOI:10.1371/journal.pone.0157769

Comparison of Adherence to Rivaroxaban vs. Apixaban Among Patients with AF Objective: to compare adherence with rivaroxaban and apixaban among patients with NVAF in routine clinical practice. Proportion of days covered (PDC) 0.80-matched analysis of apixaban and rivaroxaban users (n=2992 per cohort) Proportion of days covered (PDC) 0.90-matched analysis of apixaban and rivaroxaban users (n=2992 per cohort) Percentage Point Difference: 5,4; p < 0.001 85,3% 79,9% Percentage Point Difference: 3,6; p = 0.001 75,8% 72,2% Percentage Point Difference: 8,1; p < 0.001 Percentage Point Difference: 78,8% 7,0; p < 0.001 70,7% 61,9% 54,9% PDC at 90 days PDC at 180 days PDC at 90 days PDC at 180 days PDC: number of days of supply divided by 90 and 180 days respectively. McHorney CA et al. Clin Ther 2016;doi: 10.1016/j.clinthera.2016.09.014. [Epub ahead of print] Rivaroxaban Apixaban

Pharmacy quality alliance measure: adherence to non-warfarin oral anticoagulant medications rivaroxaban: n = 4194, dabigatran: n = 5489, apixaban: n = 265 McHorney CA, Crivera C, et al. Curr Med Res Opin. 2015 Sep 22:1-16

Adjusted HR (65%CI) for ischemic stroke when PDC* < 80% Association between OD and BID DOAC adherence in NVAF patients and rates of ischemic stroke 1,5 1 0,5 0 +50 % All DOAC users +47 % Oncedaily users +50 % Twicedaily users Suboptimal adherence to DOACs was found to be associated with an increased hazard of ischemic stroke Patients prescribed DOACs requiring twice-daily dosing were less adherent than once-daily users. These results did not support the hypothesis that twice-daily dosing of a DOAC is more forgiving in the presence of suboptimal adherence Adapted from Alberts MJ et al, Int J Cardiol 2016;215:11-3 CI= confidence interval; HR= hazard ratio; N= sample size; DOAC= direct oral anticoagulant; PDC= proportion of days covered; Pys = person years. a PDC < 80% represents suboptimal adherence. b p < 0.001 compared to once-daily DOAC use.

One-Third of Twice-Daily Prescribed Medications Were Being Taken Once Daily Therapy adherence Self-reported patient survey (N=266) Taking OAC once daily Taking OAC twice daily 94% Rivaroxaban 6% 27% 73% Dabigatran 30% Apixaban 70% 86% Warfarin 14% Andrade JG et al, Can J Cardiol 2016;32:747-53

Conclusions Real world data confirm the safety and effectiveness profile of rivaroxaban when compared to randomized clinical trial data The adherence and persistence are poor in warfarin users but are also not optimal in direct oral anticoagulants Adherence and persistence are higher in Rivaroxaban users when compared to warfarin and twice day direct oral anticoagulants users