Le conferme dalla real life superano gli studi registrativi

Le conferme dalla real life superano gli studi registrativi E. Gronda, MD, FESC Cardiologyand and Research Unit IRCCS MultiMedicaSesto S. Giovanni CardiovascularDepartment MultiMedicaGroup.

Rate (% / yr) Years Atrial Fibrillation Investigators, Arch Intern Med 1994;154:1449.

Di Pasquale G, et al, Current presentation and management of 7148 patients with atrial fibrillation in cardiology and internal medicine hospital centers: The ATA AF study, Int J Cardiol (2012),

In the real world : WHY? Why don t old patients, running the highest risk for stroke, receive OA treatment? Fears for: Bleeding Negative interaction with age Lack of laboratory control Lack of compliance in therapy persistence

Major and Fatal Bleeding are High with VKA in NVAF Patients in Real World Study drug Patients (n) Rate of major bleeding (%/year) Fatal bleeding (%) Warfarin starters 1 125,195 3.8 1.6 # Warfarin starters 2 820 6.5 2.3 # VKA starters 3 682 6.0 1.0 Warfarin users 4 261 5.3* 0.4 # Coumarin derivative users 5 10,757 7.2 0.3 # # Values are calculated (not reported); *In the first year. 1. Gomes T et al. CMAJ. 2013;185(2):E121-127; 2. Beyth RJ et al. Am J Med. 1998;105(2):91-99; 3. Steffensen FH et al. J Intern Med.1997;242(6):497-503; 4. Gitter MJ et al. Mayo Clin Proc. 1995;70(8):725-733; 5.Linkins LA etal. Ann Intern Med. 2003;139(11):893-900;

Granger C B, and Armaganijan L V Circulation 2012;125:159-164 Copyright American Heart Association

Information on AF pt characteristics, management, and outcome has limitation - largely drawn from RCTs, which are highly selected -information gathered from hospital sources or on the occasion of an event, therefore not reflective of th status of stable outpatient with AF -not contemporary as epidemiology and practice are evolving There is a need for data which are: - contemporary, international, end representative Registriesand administrative databases provide complementary information from real world

About registry event adjudication statistics The new era of clinical research: Using data for multiple purposes The CLARICOR study 1. The most common errors were false-positive attributions from the registry in cases that were ruled non-eventsby the adjudication committee. 2. This is not surprising because clinical diagnoses tend to err on the more serious side of classification, whereas an Adjudication Committee applies rigorous criteria that would exclude borderline cases. 3. A similar issue with estimation of death from cardiovascular causes was observed, although this is less concerning, given the known difficulty of determining cause of death with even the best data available. CALIFF RM American Heart Journal August 2014

Rivaroxaban Safety Profile in Real World was Consistent with Results from ROCKET AF ROCKET AF 1 US DoDPMSS 2 mean CHADS mean CHADS 2 -Score 3.5 2 -Score 3.0 # Event rate (%/year) 4 3 2 1 0 Rivaroxaban 3.6 Major bleeding* n=7,111 4 Event rate (%/year) 3 2 1 0 2.9 Major bleeding** n=27,467 Clinical endpoint % (n) Clinical endpoint % (n) ICH 0.8 (55) Fatal Bleeding 0.4 (27) Major GI Bleeding 3.2 (224) Median duration of treatment exposure was 590 days ICH 0.1 (36) Fatal Bleeding <0.1 (14) Major GI Bleeding 1.5 (423) Results are not intended for direct comparison Rivaroxaban users were followed for 455 days *Major bleeding definitions according to ISTH; **Major bleeding was defined by the Cunningham algorithm 3 ; # refers to mean CHADS 2 among patients who experienced MB 1. Patel MR et al. N Engl J Med2011;365(10):883-891; 2. Tamayo S et al. Clin Cardiol2015; 38(2):63-68; 3. Cunningham A et al. PharmacoepidemiolDrugSaf 2011; 20(6): 560-566

Major Bleeding Rates with Rivaroxaban in Real World Studies were Consistent with Findings from ROCKET AF Event rate (%/year) Clinical Trial ROCKET AF 1 mean CHADS 2 -Score 3.5 Rivaroxaban 4 3.6 3 2 n=7,111 Event rate (%/year) Prospective Registry Dresden NOAC Registry 2 mean CHADS 2 -Score 2.4 4 3 3.1 2 n=1,204 Retrospective Database US DoDPMSS 3 mean CHADS 2 -Score 2.2 Event rate (%/year) n=27,467 2.9 2.9 1 1 0 Major bleeding* 0 Major bleeding# Results are not intended for direct comparison US DoD PMSS = US Department of Defense Post-Marketing Surveillance Study *Major bleeding definitions according to ISTH; # modified ISTH definition (additionally included surgical revision from bleeding) **Major bleeding was defined by the Cunningham algorithm 4 1. Patel MR et al. N Engl J Med2011;365(10):883-891; 2. Beyer-Westendorf et al. Blood 2014;124(6); 955-962; 3. Tamayo S et al. Clin Cardiol. 2015;38(2):63-68; 4. Cunningham A et al. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566

Rivaroxaban, Dabigatran and Warfarin: Findings on Risk of Major Bleeding in Real World Two retrospective analyses ofu.s. Department of Defense records 1,2 RivaroxabanPMSS 1 DabigatranPMSS 2 n=27,467 n=25,586 Event rate (%/year) 4 3 2 1 0 2.9 Rivaroxaban Rivaroxaban (%) ICH 0.1 Fatal bleeding <0.1 Major GI bleeding 1.5 Event rate (%/year) Major bleeding was defined by the Cunningham algorithm in both studies 3 1. Tamayo S et al. Clin Cardiol. 2015;38(2):63-68; 2. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/11-17-14-us-department-defense-study-supports-favorablebenefit-risk-profile-pradaxa-dabigatran-etexilate-mesylate-reducing-stroke-risk-non-valvular-atrial-fibrillation.html; 3. Cunningham A et al. Pharmacoepidemiol Drug Saf. 2011;20(6):560-566. 3.1 Dabigatran (%/year) 3.7 Warfarin (%/year) ICH 0.27 0.56 Fatal bleeding Not reported Not reported Major GI bleeding 2.54 2.37

Dresden NOAC Registry: Outcomes of Major Bleedings may be Better with Rivaroxaban than those reported for VKAs Approach (%) 70 60 50 40 30 Conservative = no treatment/ compression/ tamponade/ transfusion Case fatality rate (%) 10 9 8 7 6 5 4 3 2 1 0 VKA Rivaroxaban 20 2 1 10 0 Conserva ve Surg/Interv RBC Most MB cases could be treated conservatively, rarely requiring procoagulants 1 Vit K FFP only PCC only FFP + PCC rfvii With Rivaroxaban Case-fatality rate was 6.3% atday90 after bleedingrelated hospitalization compared to 9.1% with VKA 1,2 Different studies report Case fatality rates of VKA-related major bleeding of 13% -18% 3-5 1. Beyer-Westendorf J et al. Blood. 2014;124(6):955-962; 2. Michalski F et al. Thromb Haemostat 2015; 114(4) epub 3. Gomes et al., CMAJ. 2013;185(2):E121- E127: 4. Linkins et al. Ann Intern Med. 2003;139(11):893-900; 5. Halbritter et al. J Thromb Haemost. 2013;11(4):651-659

German prospective, non-interventional NOA registry Rates, management and outcome of rivaroxabanrelated bleeding events analysed (n=1776)

Characterizing Major Bleeding in Patients With Nonvalvular Atrial Fibrillation: A Pharmacovigilance Study of 27 467 Patients Taking Rivaroxaban Tamayo S et al Clinical Cardiology DOI:10.1002/clc.22373 Patient Characteristics MB No MB Age 78.4 (±7.7) vs 75.7 (±9.7) years More prevalent comorbidities HBP 95.6% vs 75.8% CAD 64.2% vs 36.7% HF 48.5% vs 23.7% CKD 38.7% vs 16.7 % Concomitant medication of interest 29.1% (139/478) vs 36.6% (9878/26 989) CHADS2 MB, n=478 No MB, n=26 989 3.0 ±1.2 2.2 ±1.3

Greater Net Clinical Benefit of Rivaroxaban vs. Warfarin in a Real World AF Population Background/rationale Evaluate the net clinical benefit (NCB)* of rivaroxaban compared with warfarin for stroke prevention in patients with AF using real-world stroke/ich event rates Results Event rates (±warfarin treatment) collected from the Danish AF registry Results adjusted for rivaroxaban using relative risk of events from ROCKET AF HAS-BLED 2 CHA 2 DS 2 -VASc=0 Warfarin Rivaroxaban CHA 2 DS 2 -VASc=1 Warfarin Rivaroxaban CHA 2 DS 2 -VASc=2 9 Warfarin Rivaroxaban 1.0 0 1.0 2.0 3.0 Net clinical benefit favours drug Conclusion Rivaroxaban demonstrated a NCB for stroke prevention in patients with AF, which may be greater than the NCB achieved with warfarin treatment across low- and highrisk stroke/bleeding risk groups HAS-BLED 3 CHA 2 DS 2 -VASc=1 Warfarin Rivaroxaban CHA 2 DS 2 -VASc=2 9 *To quantify the balance between risk of IS and risk of ICH Banerjee A et al. Thromb Haemost 2012;107(3):584-589 Warfarin Rivaroxaban 1.0 0 1.0 2.0 3.0 Net clinical benefit favours drug

Stroke/ Embolia Sistemica Wallentin L et al.circulation. 2013;127:2166-76. doi: 10.1161/CIRCULATIONAHA.112.142158

TAXUS data integrity and quality Tamayo S et al Clinical Cardiology DOI:10.1002/clc.22373 Data quality assurance 1Outcome variables and covariates recorded on a standardized CRF 2Reporting bias minimized by verifying source data from at least 10% of the sites. 350% of the sites underwent random visits to monitor study conduct. 4Selection bias minimized by requiring investigators to document consecutive patients prescribed rivaroxaban, with no omissions. Data management and administrative organization 1.XANTUS study major bleeding, stroke, systemic embolism, TIA, and myocardial infarction 2.Adjudicated centrally (blinded adjudication committee) 3.Data verification at study sites for identification of any relevant outcomes not submitted for adjudication. 4.The XANTUS study had one centralized database to receive results.

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: 10.1093/eurheartj/ehv466

XANTUS: Baseline Demographics Distribution of StrokeRiskFactors Mean score±sd = 2.0±1.3 Mean score±sd = 3.4±1.7 Prop portion of patients (%) 35,0 35,0 30,4 30,0 30,0 25,0 25,0 20,0 16,4 20,0 15,0 15,0 10,4 9,1 10,0 10,0 5,0 3,3 5,0 30,0 Prop portion of patients (%) 0,5 0,0 0,0 0 1 2 3 4 5 6 CHADS 2 score 23,3 19,4 20,7 12,3 11,6 10,1 2,6 0 1 2 3 4 5 6 9 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: 10.1093/eurheartj/ehv466

XANTUS: Event-Free Rate (Kaplan Meier) for Treatment-Emergent Primary Outcomes In total, 6522 (96.1%) patients did not experience any of the outcomes of treatment-emergent all-cause death, major bleeding or stroke/se 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Cumulative Rates (Kaplan Meier) for Treatment-Emergent Primary Outcomes 1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

ARISTOTLE (average CHADS 2 2,1) OUTCOMES The rate of death from any cause was 3.09% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P = 0.047 as compared to 3.52% in the warfarin group. The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001) The rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P = 0.42).

XANTUS: Outcomes According to Dosing (20/15 mg od) Major bleeding, all-cause death and thromboembolic events (stroke/se/tia/mi) occurred at higher incidence rates for the 15 mg od versus the 20 mg od dose Inciden nce rate, %/year* 4,0 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 15 mg dose 3,7 20 mg dose 3,1 2,3 1,8 1,6 1,4 Thromboembolic events Major bleeding All-cause death *Events per 100 patient-years Camm AJ et al,eurheart J 2015; doi: 10.1093/eurheartj/ehv466;

In Real World AF Patients Stayed Longer on Rivaroxaban Than on Warfarin Two retrospective U.S. database analyses Matched sample included 3,654 Rivaroxaban and 14,616 Warfarin patients 1 Patient persistence (%) 100 90 80 70 HR 0.66 (95% CI 0.60 0.72); p<0.0001 Rivaroxaban Warfarin 7,259 Rivaroxaban patients were matched 1:1 with Warfarin patients 2 Patient persistence (%) 100 90 80 70 60 50 HR 0.63 (95% CI 0.59 0.68); p<0.001 Rivaroxaban Warfarin 60 0 30 60 90 120 150 180 Time to non-persistence (days) 40 0 60 120 180 240 300 360 Time to non-persistence (days) Patients were significantly more persistent with Rivaroxaban than with Warfarin 1. Laliberté F et al. Curr Med Res Opin. 2014;30(7):1317-1325; 2. Nelson WW et al. Curr Med Res Opin. 2014;30(12):2461-2469

BMJ 2015;350:h1857 doi: 10.1136/bmj.h1857

Dresden NOAC Registry: Higher Treatment Persistence with Rivaroxaban than with Dabigatran Two analyses of the prospective Dresden NOAC registry 1,204 AF patients treated with Rivaroxaban 1 341 AF patients treated with Dabigatran 2 Event-free survival for treatment discontinuation (%) 100 80 60 40 U.S. database 15/20 mg OD Rivaroxaban 0 120 240 360 480 600 720 Event-free survival for treatment discontinuation (%) 100 80 60 40 150 mg BID Dabigatran 110 mg BID Dabigatran All patients 0 120 240 360 480 600 720 840 960 Time (days) Time (days) Median follow-up: 544 days Median follow-up: 671 days The rate for Rivaroxaban discontinuation was 13.6%/year Rate of Dabigatran discontinuation was 25.8%/yr and therefore higher than rates reported in RE-LY 3 1. Beyer-Westendorf J et al. Europace 2015;17(4):530-538; 2. Beyer-Westendorf J et al. Thromb Haemost. 2015;113(6):1247-1257; 3. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151

Conclusion Only ~6% of all bleeding events were major; >60% of these were managed conservatively Outcomes with rivaroxaban are at least no worse than with VKA German prospective, non-interventional NOA registry Rates, management and outcome of rivaroxaban-related bleeding events analysed (n=1776)

Similar Risk of Gastrointestinal Bleeding with Rivaroxaban Compared to Warfarin in Real World Population based retrospective cohort study 1 Patients: 4,907 Dabigatran, 1,649 Rivaroxaban, 39,607 Warfarin Analysis (reference: warfarin) Dabigatran Rivaroxaban All patients n = 44,514 n = 41,256 Adjusted HR (95% CI) 1.21 (0.96-1.53) 0.98 (0.36-2.69) Patients < 65 years n = 34,038 n = 32,099 Adjusted HR (95% CI) 1.34 (0.98-1.83) 1.03 (0.33-3.18) Patients > 65 years n = 10,476 n = 9,157 Adjusted HR (95% CI) 1.07 (0.75-1.53) 0.62 (0.18-2.08) Results are similar to a recent observational study from the US that reported no statistically significant differences in real world rates of bleeding between rivaroxaban and warfarin (HR for Major bleeding 1.08, 95% CI 0.71-1.64) 2 The rate of GI bleeding was highest among Dabigatran users and lowest among Rivaroxaban users (9,0%/year Dabigatran, 3.4%/year, Rivaroxaban, 7.0%/year Warfarin) 1 1. Chang et al. BMJ 2015;350:h1585 doi:10.1136/bmj.h1585; 2. Laliberté F et al. Curr Med Res Opin. 2014;30(7):1317-1325