Gli studi "real-world" che cosa aggiungono alla nostra conoscenza? Vittorio Pengo (Padova)

Dimensions of Real World Evidence Effectiveness and safety Adherence and persistence Management of the active bleeding APPROVAL NUMBER: L.IT.MA.10.2016.1795

Observational vs Randomized studies Data from RCT derive from highly selected patients and show the efficacy of intervention. There is the need of data representative of real life to show the effectiveness and safety: Observational studies (cohort and case-control studies) Registries

Observational vs Randomized studies Results may differ Benson K. NEJM 2000

Registry Disease or patient registries are collections of secondary data related to patients with a specific diagnosis, condition, or procedure, and they play an important role in post marketing surveillance of pharmaceuticals. Sponsored (paid for performance), investigators sponsored or not sponsored Retrospective, prospective From Electronic or not electronic medical records Hospital-based, population-based Naive/not naive patients Centralized/not centralized quality of data Quality of registries (procedures) Adjudication of events

Rivaroxaban Provides a Consistent and Unique Dataset Covering the Full Patient-Risk Spectrum High quality RCT Rocket AF 1 Independent Central Adjudication Committee (CAC) Prospective, non-interventional study Xantus 2 Xapass 3 Prospective Registry Dresden NOAC Registry 4 Retrospective 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: Rationale u Rivaroxaban approved for the reduction of stroke/se in patients with NVAF and 1 additional stroke risk factor(s) 1 ROCKET AF: rivaroxaban was non-inferior to warfarin for the reduction of stroke/se and provided safety benefits in terms of a significantly reduced risk of ICH and fatal bleeding but an increase in GI bleeds 2 u Safety and effectiveness data for unselected NVAF patients from everyday practice is needed u XANTUS included a diverse range of patients representative of those seen in routine clinical practice 3 1. Rivaroxaban SmPC; 2. Patel MR et al, N Engl J Med 2011;365:883 891; 3. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Study Objective and Design u To collect real world data on adverse events in patients with NVAF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice Primary outcomes: major bleeding (ISTH definition), 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 (if applicable) and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature *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 1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466 Final visit: 1 year #

Rivaroxaban tested in different populations in 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% 30% 2 13% 41% 29% 29% 19% 3 Heart failure 63% 87% 13% 30% 75% Hypertension 91% 87% 37% Age >75 years 44% 20% Diabetes 40% 19% Prior stroke # 55% 10% Prior MI 17% Results are not intended for direct comparison *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

External Communication of Real-World Data Reaffirming Findings from ROCKET AF Clinical Trial ROCKET AF 1 Rivaroxaban mean CHADS 2 -Score 3.5 Event rate (%/year) 4 n=7,111 3.6 3 2 1 Retrospective Database US DoD PMSS 2 mean CHADS 2 -Score 2.2 Event rate (%/year) 4 n=27,467 3 2.9 2 1 Prospective Study XANTUS 3 mean CHADS 2 -Score 2.0 Event rate (%/year) 4 n=6,784 3 2 2.1 1 0 Major bleeding* 0 Major bleeding** 0 Major bleeding* Consistent results for major bleeding across clinical trial, prospective Registry, and retrospective database in patients with NVAF treated with rivaroxaban Results are not intended for direct comparison US DoD PMSS = US Department of Defense Post-Marketing Surveillance Study; *Major bleeding definitions according to ISTH; **Major bleeding was defined by the Cunningham algorithm 4 ; 1. Patel MR et al. N Engl J Med 2011; 365(10):883-891; 2. Tamayo S et al. Clin Cardiol. 2015;38(2):63-68; 3. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 4. Cunningham A et al. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566

Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS 2 Prior stroke # ROCKET AF 1 3.5 55% XANTUS 2 2.0 19% # Includes prior stroke, SE or TIA; *Events per 100 patient-years 1. Patel MR et al, N Engl J Med 2011;365:883 891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

Rivaroxaban versus warfarin in patients with atrial fibrillation: treatment effect by age

XAPASS: Study Objective and Design Objective: To confirm the safety and effectiveness profile of rivaroxaban across the broad range of NVAF patients in Japanese real-world 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

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 Stroke/TIA/SE 1 ROCKET AF (n=7111) (mean CHADS 2 =3,5) All rivaroxaban SPAF patients 2 Dresden registry (n=1204) (mean CHADS 2 =2,4) 0 1 2 3 4 The rates of centrally adjudicated stroke/tia/systemic embolism were considerably lower than those in the ROCKET AF trial. Major bleeding events during rivaroxaban therapy occurred less frequently than in the ROCKET AF trial. 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

MB in patients with NVAF: pharmacovigilance of 27.467 patients taking rivaroxaban The objective of this ongoing observational study is to provide longitudinal safety data by actively obtaining information associated with MB among rivaroxaban users with NVAF in the post-approval setting 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) These data show that the MB are generally consistent with those reported in the previous large randomized FDA registration trial of rivaroxaban 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.

Real World Evidence Also Shows Consistent Safety for Patients with Diabetes Mellitus ROCKET AF 1 DIABETES (5.695) TAMAYO DIABETES 2 (12.039) Rivaroxaban %/year (n) Warfarin %/year (n) Rivaroxaban %/year (n) Major bleeding 3.79 (165) 3.90 (169) 3.68 (472) Intracranial hemorrhage 0.50 (22) 0.82 (36) 0.19 (24) Rivaroxaban safety is also consistent in real life for patients with diabetes mellitus Results are not intended for direct comparison 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

Real World Evidence Also Shows Consistent Safety for Patients with Renal Impairment ROCKET AF 1 Renal impairment (2.950) TAMAYO Renal desease 2 (6.921) Rivaroxaban %/year Warfarin %/year Rivaroxaban %/year Major bleeding 4.49 4.70 4.52 Fatal bleeding 0.28 0.74 0.09 Rivaroxaban safety is also consistent in real life for patients with renal impairment. Results are not intended for direct comparison 1. Adapted from Fox et al, Eur Heart J 2011;32:2387-94 2. adapted from Tamayo Poster presentation at AHA 2015

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 %/year 2.0 1.6 1.1 0.7 0.6 0.7 0.6 0.3 0.1 0.1 0 Composite endpoint *Not otherwise specified Coleman C et al, Int J Card Med 2015;203:882 884 Ischaemic stroke TIA ICH Other nontraumatic MI ICH

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 - Significant Reduction in the Combined Endpoint for Rivaroxaban vs warfarin urivaroxaban 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

Safety Profile of Rivaroxaban Confirmed Through Real-World Evidence Regardless of Data Source 6 Randomized clinical trial ROCKET AF 1* n=7111 Prospective registry Dresden NOAC 2# n=1200 Retrospective database US DoD PMSS 3 n=27,467 Observational study XANTUS 4* n=6784 Major bleeding event rate/year 3.6% 3.0% 2.9% 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 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

Aderenza e persistenza alla terapia Aderenza: percentuale di assunzione del farmaco sul totale prescritto in un determinato intervallo di tempo. Persistenza: la durata complessiva della terapia nel tempo

Come può essere misurata l aderenza Coleman CI, Current Medical Research Opinion 2012:28:669.

Misure di Aderenza Percentuale di aperture del contenitore del farmaco in relazione al totale delle aperture previste (il tappo del contenitore contiene un microprocessore) (Taking adherence) Percentuale di giorni in cui il farmaco è stato assunto in modo adeguato (Regimen adherence) Percentuale di giorni in cui l Intervallo di tempo tra l assunzione di una dose del farmaco e la successiva è stato adeguato (Timing adherence). Di solito l assunzione delle dosi di farmaco non dovrebbe eccedere il 25% dell intervallo tra i dosaggi (esempio: per un farmaco assunto due volte al giorno l intervallo adeguato tra le dosi è 12±3 ore). Claxton Aj, Clinical Therapeutics 2001,23:1296.

Taking Adherence N di studi (%) Adherence (95%CI) * * * p<0.01 nel confronto con QD (reference) Coleman CI, Current Medical Research Opinion 2012:28:669.

Regimen adherence N di studi (%) Adherence (95%CI) * *p<0.01 nel confronto con QD (reference) p<0.0001 nel confronto con QD (reference) Coleman CI, Current Medical Research Opinion 2012:28:669.

Timing adherence N di studi (%) Adherence (95%CI) * * * p<0.01 nel confronto con QD (reference) Coleman CI, Current Medical Research Opinion 2012:28:669.

Direct association between dosing frequency and medication adherence in studies using electronic monitoring across a variety of therapeutic classes (modified from Claxton Aj, Clinical Therapeutics 2001) Review Sebastian Ewen Drug adherence in patients taking oral anticoagulation therapy Clinical Research in Cardiology Springer-Verlag Berlin Heidelberg 2013 10.1007/s00392-013-0616-8

NAO: Aderenza al trattamento Spiegare al paziente l importanza di assumere scrupolosamente il nuovo farmaco alle dosi e con le modalità indicate. Spiegare che la mancata assunzione anche temporanea potrebbe avere gravi conseguenze Spiegare che a differenza dell aspirina, la mancata assunzione del nuovo farmaco lascia rapidamente il paziente non protetto Spiegare che non si deve interrompere spontaneamente il farmaco in caso di emorragie trascurabili (emorragia congiuntivale o gengivale). Rivolgersi sempre al medico.