ROCKET AF Results - cardiomil.com.uy

Relevant Financial Relationships Kenneth W. Mahaffey, MD• Research Grants: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J,Merck, Novartis, Portola, Regado, Sanofi-Aventis, The MedicinesCompany• Consulting Fees: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J,Merck, Novartis, Sanofi-Aventis• No stock ownership• http://www.dcri.duke.edu/research/coi.jsp Keith AA Fox, MB ChB• Research Grants: Bayer, Eli Lilly, J&J, Sanofi-Aventis• Consulting Fees: Bayer, Eli Lilly, J&J, Sanofi-Aventis• No stock ownership

BackgroundRivaroxaban Direct, specific, competitivefactor Xa inhibitorXTF/VIIaIX Half-life 5-13 hours Clearance :• 1/3 direct renal excretionVIIIaVaIXaRivaroxaban• 2/3 metabolism via CYP 450enzymesXa Oral, once daily dosingwithout need for coagulationmonitoring Studied in >25,000 patientsin post-op, DVT, PE andACS patientsFibrinogenIIIIaFibrinAdapted from Weitz et al, 2005; 2008

Statistical Methodologies Sample Size• Warfarin event rate ~2.3• Type 1 error 0.05 (2-sided)• 405 events; >95% powerSuperiorityNon-inferiorityInferiorityRivaroxabanBetter1.0 1.46WarfarinBetter• ~14,000 patients Primary Efficacy Evaluation: Stroke or non-CNS Embolism• Non-Inferiority: Protocol Compliant on treatment• Superiority: On Treatment and then by Intention-to-Treat Primary Safety Evaluation: Major or non-Major ClinicallyRelevant Bleeding

Study ConductRivaroxabanWarfarinRandomized, nLost to Follow-up, nPremature Discontinuation, n (%)Withdrew Consent, nMedian (25 th , 75 th ) Exposure (days)Median (25 th , 75 th ) Follow-up (days)7131181693 (23.9%)626589 (396, 805)706 (522, 884)7133181589 (22.4%)620593 (404, 810)708 (518, 886)

Baseline DemographicsRivaroxaban(N=7081)Warfarin(N=7090)Age (years) 73 (65, 78) 73 (65, 78)Female (%) 40 40Race (%)WhiteBlackAsianRegion (%)North AmericaLatin AmericaAsia-PacificCentral EuropeWestern EuropeCreatinine Clearance (ml/min) (%)30 - 80Values are median (IQR)Based on Intention-to-Treat Population831131913153815214732831131913153815214831

Baseline DemographicsCHADS 2 Score (mean)2 (%)3 (%)4 (%)5 (%)6 (%)Rivaroxaban(N=7081)3.48134329132Warfarin(N=7090)3.46134428122Prior VKA Use (%) 62 63Congestive Heart Failure (%) 63 62Hypertension (%) 90 91Diabetes Mellitus (%) 40 39Prior Stroke/TIA/Embolism (%) 55 55Prior Myocardial Infarction (%) 17 18Based on Intention-to-Treat Population

Trial ResultsKenneth W. Mahaffey, MDon Behalf of the ROCKET AF Investigators

Key Secondary Efficacy OutcomesRivaroxabanWarfarinVascular Death,Stroke, EmbolismStroke TypeHemorrhagicIschemicUnknown TypeEvent Rate Event Rate HR (95% CI) P-value3.11 3.63 0.86 (0.74, 0.99) 0.0340.261.340.060.441.420.100.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67)0.0240.5810.366Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121All Cause MortalityVascularNon-vascularUnknown Cause1.871.530.190.152.211.710.300.200.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41)0.0730.2890.0940.370Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Key Secondary Efficacy OutcomesRivaroxabanWarfarinVascular Death,Stroke, EmbolismStroke TypeHemorrhagicIschemicUnknown TypeEvent Rate Event Rate HR (95% CI) P-value4.51 4.81 0.94 (0.84, 1.05) 0.2650.261.620.150.441.640.140.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)0.0120.9160.871Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464All Cause MortalityVascularNon-vascularUnknown Cause4.522.911.150.464.913.111.220.570.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)0.1520.3500.6110.195Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population

Time in Therapeutic Range (TTR)INR DataWarfarinINR range Median (25 th , 75 th )5.0 0.0 (0.0 – 0.5)Based on Rosendaal method with all INR values includedBased on Safety Population

Primary Efficacy Outcome by Quartiles of cTTRStroke and non-CNS EmbolismCenter TTRRivaroxabanEvents%EventRateEvents%WarfarinEventRate0.0 - 50.6% 2.6 1.8 3.7 2.550.7 - 58.5% 3.0 1.9 3.5 2.258.6 - 65.7% 3.1 1.9 3.5 2.165.7 - 100.0% 2.2 1.3 3.0 1.8HR(95% CI)0.71(0.48, 1.03)0.83(0.62, 1.29)0.92(0.62, 1.28)0.77(0.49, 1.12)Based on Rosendaal method with all INR values includedBased on Safety PopulationEvent Rates are per 100 patient-years

Primary Safety OutcomesMajor and non-majorClinically RelevantRivaroxabanEvent RateWarfarinEvent RateHR(95% CI)P-value14.91 14.52 1.03 (0.96, 1.11) 0.442Major 3.60 3.45 1.04 (0.90, 1.20) 0.576Non-major ClinicallyRelevant11.80 11.37 1.04 (0.96, 1.13) 0.345Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Major>2 g/dL Hgb dropTransfusion (> 2 units)Critical organ bleedingBleeding causing deathPrimary Safety OutcomesRivaroxabanEvent Rateor N (Rate)3.602.771.650.820.24WarfarinEvent Rateor N (Rate)3.452.261.321.180.48HR(95% CI)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)P-value0.5760.0190.0440.0070.003Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060Intraventricular 2 (0.02) 4 (0.04)Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051Subarachnoid 4 (0.04) 1 (0.01)Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Adverse Events and Liver Enzyme DataAny Adverse EventAny Serious Adverse EventAE leading to study drug discontinuationEpistaxisPeripheral edemaDizzinessNasopharyngitisCardiac failureBronchitisDyspneaDiarrheaALT Elevation>3 x ULN>5 x ULN>3 x ULN and T Bili > 2 x ULNValues are N (%)Based on Safety PopulationRivaroxaban(N=7111)82.437.315.710.16.16.15.95.65.65.35.32.91.00.4Warfarin(N=7125)82.238.215.28.66.26.36.45.95.95.55.62.91.00.5

Efficacy:Summary• Rivaroxaban was non-inferior to warfarin for prevention ofstroke and non-CNS embolism.• Rivaroxaban was superior to warfarin while patients weretaking study drug.• By intention-to-treat, rivaroxaban was non-inferior to warfarinbut 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 orhigh risk patients with AF.

Study OrganizationSponsorsJ & J and BayerChristopher Nessel, Kimberly Schwabe,Scott Berkowitz, John PaoliniSteering CommitteeDiego Ardissino, Alvaro Avezum, PhilAylward, Barbara Biedermann,Christoph Bode, Antonio Carolei,Ramon Corbalan, Laszlo Csiba,Anthony Dalby, Rafael Diaz, HansDiener, Geoffrey Donnan, ShaunGoodman, Bas Hamer, HeinHeidbuchel, Dai-Yi Hu, Kurt Huber,Gorm Jensen, Matyas Keltai, BasilLewis, Jose Lopez-Sandon, Jean LouisMas, Ayrton Massaro, GordonMacInnes, Bo Norrving, MartinPenicka, Dorairaj Prabhakaran, RistoRoine, Tan Ru San, Per Anton Sirnes,Veronika Skvortsova, Gabriel Steg,Harvey White, Lawrence WongExecutive SteeringCommitteeDuke Clinical ResearchInstituteJonathan Piccini, KarenHannan, Jyotsna Garg, LisaEskenazi, Angela Kaiser,Patricia StoneCanadian HeartResearch CenterShaun GoodmanMaggie Godin-EdgecombIDMCJoe Alpert, ChairAllen Skene, Co-chairGudrun BoysenJohn EikelboomPeter RothwellCECManesh PatelJoni O'BriantLauren Price