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Welcome to Department of Medicine Grand Rounds’ series: New Oral Anticoagulants: Are they better than what we have? This program includes a video, test.

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Presentation on theme: "Welcome to Department of Medicine Grand Rounds’ series: New Oral Anticoagulants: Are they better than what we have? This program includes a video, test."— Presentation transcript:

1 Welcome to Department of Medicine Grand Rounds’ series: New Oral Anticoagulants: Are they better than what we have? This program includes a video, test and evaluation modules. After viewing the video, you will be asked to complete a five question test and a brief evaluation in order to be eligible for your CME credits. The estimated time to complete this entire activity is 1 hour and 15 minutes. This program requires: Windows Microsoft Windows 2008 (required Desktop experience), Windows 7, Windows Vista, Windows XP, Windows 2003 Microsoft Internet Explorer 7.0 or later, Firefox 3.6 or later or Google Chrome Windows Media Player 9.0 or later Media Silverlight 5.0 or later Broadband internet connection MAC MAC OS X or later Safari 4.0 or later or Firefox 3.6 or later Microsoft Silverlight 5.0 or later (viewers are prompted to install this when attempting to view a presentation) Broadband internet connection (256 Kbps or more)

2 Welcome to Department of Medicine Grand Rounds’ series: New Oral Anticoagulants: Are they better than what we have? Geno J Merli, MD, MACP, FHM, FSVM Professor of Medicine and Surgery Co-Director Jefferson Vascular Center Jefferson Medical College Thomas Jefferson University Hospital Recorded Wednesday, September 4, This program will be available for CMEs until September 4, 2015.

3 Objectives Following the completion of this program, participants should be able to: 1. Compare and Contrast Treatment of DVT/PE with New Oral Anticoagulants 2. Review Clinical Trials in Atrial Fibrillation 3. Assess the Benefit of the New Oral Anticoagulants in the Hospitalized Medically ill patient 4. Review Data on the Management of Bleeding with the New Oral Anticoagulants

4 Disclosure : Dr. Merli has revealed he provides grant/research support for BMS, Johnson & Johnson, Sanofi-aventis; he is also a scientific consultant for BMS, Johnson & Johnson and Sanofi- aventis; none of the other planners have revealed any significant commercial interests. Accreditation Statement The Lancaster General Hospital is accredited by the Pennsylvania Medical Society to provide continuing medical education for physicians. Designation Statement The Lancaster General Hospital designates this live activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with extent of their participation in the activity. Conflict of Interest Statement Faculty and all others who have the ability to control content of continuing medical education activities sponsored by Lancaster General Hospital are expected to disclose to the audience whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s).

5 New Oral Anticoagulants Are they better than what we have? Geno J Merli, MD, MACP, FHM, FSVM Professor of Medicine and Surgery Co-Director Jefferson Vascular Center Jefferson Medical College Thomas Jefferson University Hospital

6 Disclosure Financial Relationships Geno J. Merli, MD, MACP, FHM, FSVM  J&J: Research, Scientific Advisory  Bristol-Meyer Squibb: Research, Scientific Advisory  Sanofi-Aventis: Research  Portola: Research

7 Fibrinogen Fibrin Common Pathway Thrombin Xa Prothrombin Clot Xa Blocker Apixaban Rivaroxaban Dabigatran New Oral Agents

8 Replacing Traditional Anticoagulants

9 Replacing Current Agents  Treatment of DVT/PE  Non-Valvular Atrial Fibrillation  Hospitalized Medically-ill  Key Points: Black Box Warnings, Stroke, MI Risk, Major Bleeding

10 Treatment VTE UFH, LMWH Bridge to Warfarin

11 Schulman S, et al NEJM 2009;361: RE-COVER Study Dabigatran 150 mg, BID for 6 months Double Blind, Double Dummy, Non-Inferiority

12 RE-COVER Study VTE Dabigatran 150 mg, BID Warfarin INR 2-3 Parenteral Anticoagulant Median 9 days 2.4%1.6% 2.1%1.9% VTEMajor Bld Schulman S, et al NEJM 2009;361: months Warfarin TTR= 60%

13 Schulman S, et al NEJM 2009;361: RE-COVER Study Dabigatran = 150mg, BID 2.4% 2.1% HR = 1.1 ( ) INR = 60% TTR TTR = Therapeutic Time in Range

14 Schulman S, et al NEJM 2009;361: RE-COVER Study Dabigatran Major Bld 1.6% Warfarin Major Bld 1.9%

15 RE-COVER Study Index Events Schulman S, et al NEJM 2009;361: Dabi 1273 Warfarin 1266

16 RE-COVER Study Major Bleeding Schulman S, et al NEJM 2009;361: Dabi Warfarin

17 RE-COVER  A limitation of the study is that the first dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days  “There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism” Schulman S, et al NEJM 2009;361:

18 Einstein Investigators NEJM 2010;363: Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial

19 Einstein DVT DVT Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday Enoxaparin Warfarin INR 2-3 Proximal DVT 2.1%8.1% 3.0%8.1% VTEMajor Bld 3, 6, 12 months Einstein Investigators NEJM 2010;363: Warfarin TTR = 57.7%

20 Einstein Acute DVT Study Einstein Investigators NEJM 2010;363: % 3.0% Acute DVT Study INR = 57.7% TTR TTR = Therapeutic Time in Range

21 Einstein Acute DVT Study Causes of VTE Riva Standard Einstein Investigators NEJM 2010;363:

22 Einstein Acute DVT Study 8.1% HR = 0.97 (95% CI, 0.76 to 1.22, P=0.77)

23 Einstein Acute DVT Study Safety Outcomes Einstein Investigators NEJM 2010;363: RivaStandard

24 Einstein Investigators NEJM 2012;366: Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority

25 Einstein PE PE Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday Enoxaparin Warfarin INR %1.1% 1.8%2.2% VTEMajor Bld 3, 6, 12 months Einstein-PE Investigators NEJM 2012;366: Warfarin TTR = 62.7% Non-Inferior

26 Einstein Investigators NEJM 2012;366: Einstein PE 2.1% 1.8% INR = 62.7% TTR

27 Einstein PE Causes Einstein Investigators NEJM 2012;366: RivaStandard

28 Einstein PE Anatomical Extent Einstein Investigators NEJM 2012;366: Riva Standard

29 Einstein Investigators NEJM 2012;366: Einstein PE 2.2% 1.1% Major Bleeding

30 ED - OBS History & Physical Laboratory Testing Diagnosis DVT Select Treatment Hospital Admission OBS Discharge Plan Secure RxCommunicationFollow Up Acquire Med Pt Education Contact PCP D/C Summary Phone call 24 hrs Appointment 3-5 days Discharge OBS

31 Your patient who has been on long term warfarin would like to convert to one of the new oral anticoagulant.

32 Einstein Investigators NEJM 2010;363: Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial

33 Einstein DVT-Extend DVT Rivaroxaban 20 mg, Qday Placebo 1.3%0.7% 7.1%0% VTEMajor Bld 3, 6, 12 mo Einstein Investigators NEJM 2010;363: mo All Rxed

34 Schulman S, et al NEJM 2013;368: Double Blind, Randomized Trial

35 RE-MEDY VTE Dabigatran 150 mg, BID Warfarin INR 2-3 Patient Rx 3 to 12 months 1.8%0.9% 1.3%1.8% VTEMajor Bld Schulman S, et al NEJM 2013;368: months

36 RE-SONATE DVT Dabigatran 150 mg, BID Placebo Patient Rx 6 to 18 months 0.4%0.3% 5.6%0% VTEMajor Bld Schulman S, et al NEJM 2013;368: months

37 Schulman S, et al NEJM 2013;368: RE-MEDY Study Dabigatran Warfarin 1.8% 1.3%

38 Schulman S, et al NEJM 2013;368: RE-SONATE Study Dabigatran Placebo 5.6% 0.4%

39 Schulman S, et al NEJM 2013;368: RE-MEDY Study Warfarin Dabigatran 26.2% 19.4% Major Bleeding Dabigatran 0.9% Warfarin 1.3% Any Bleeding

40 Schulman S, et al NEJM 2013;368: RE-SONATE Study Placebo 5.9% Dabigatran 10.5% Major or Clinically Relevant Bleeding Dabigatran 5.3% Placebo 1.8% Any Bleeding

41 Schulman S, et al NEJM 2013;368: RE-SONATE Study

42 Agnelli G, et al NEJM 2012;1-10

43 AMPLIFY-EXT VTE Rx 6-12 mo Apixaban 2.5 mg, BID Apixaban 5.0 mg, BID Placebo 12 months VTEMajor Bld 1.7%0.2% 1.7%0.1% 8.8%0.5% Agnelli G, et al NEJM 2013;368(8):

44 AMPLIFY-EXT Apixaban 2.5 Apixaban 5Placebo Agnelli G, et al NEJM 2013;368(8):

45 AMPLIFY-EXT Symptomatic Recurrent VTE or VTE Related Death 8.8% 1.7% Agnelli G, et al NEJM 2013;368(8):

46 AMPLIFY-EXT Major-Clinical Relevant Non-Major Bleeding 4.3% 3.2% 2.7% Agnelli G, et al NEJM 2013;368(8):

47 Warfarin to NOAC AgentRecommendation RivaroxabanStart when INR < 3.0 (we recommend < 2.0) ApixabanStart when INR < 2.0 DabigatranStart when INR < 2.0 NOAC= New Oral Anticoagulants

48 Non-Valvular Atrial Fibrillation

49 Atrial Fibrillation Studies TrialRE-LYARISTOTLEROCKET-AF DesignRandomized Open Label N=18,113 Randomized Double blind N=18,209 Randomized double blind & dummy N=14,000 TreatmentDabigatran 150 mg, BID 110 mg, BID Apixaban 5 mg, BID Rivaroxaban 20 mg, Qday ComparatorWarfarin 2-3 (67% TTR) Warfarin 2-3 (66% TTR) Warfarin 2-3 (57.8% TTR) Mean CHADS Modified Ahrens I, et al Thromb Haemost 2011;105 Time Therapeutic Range = TTR

50 Primary Endpoints Atrial Fibrillation Trials StudyNOACVKAOutcome RE-LYDabigatran 1.1% Warfarin 1.7% RR % CI P < superiority ARISTOTLEApixaban 1.3% Warfarin 1.6% HR % CI P= < Non- I P= 0.01 Superiority ROCKET-AFRivaroxaban 1.7% Warfarin 2.2% HR % CI P = <0.001 Non-Inferiority

51 Major Bleeding Atrial Fibrillation Trials StudyNOACVKAOutcome RE-LYDabigatran 3.3% Warfarin 3.6% RR % CI P = 0.31 ARISTOTLEApixaban 2.1% Warfarin 3.1% HR % CI P = < ROCKET-AFRivaroxaban 5.6% Warfarin 5.4% HR % CI P = 0.58

52 Intracranial Hemorrhage Atrial Fibrillation Trials StudyNOACVKAOutcome RE-LYDabigatran 0.3% Warfarin 0.7% RR % CI P= <0.001 ARISTOTLEApixaban 0.3% Warfarin 0.8% HR % CI P = <0.001 ROCKET-AFRivaroxaban 0.5% Warfarin 0.7% HR % CI P = 0.02

53 Dosing Schedules Atrial Fibrillation AgentDosing Recommendations Dabigatran 75mg, 150mg CrCl > 30 cc/min: 150 mg, BID CrCl 15 to 30 cc/min: 75 mg, BID Avoid < 15 cc/min Apixaban 2.5mg, 5mg CrCl > 15 cc/min: 5 mg, BID Any 2 ( > 80 yrs, 1.5mg/dL: 2.5 mg, BID) Avoid < 15 cc/min Rivaroxaban 10mg, 15mg, 20mg CrCl > 50 cc/min: 20 mg, Qday CrCl cc/min: 15 mg, Qday Avoid CrCl < 15 cc/min

54 Atrial Fibrillation Studies When should new orals be started?  RE-LY (Dabigatran)  Stroke within 14 days  Severe stroke within last 6 months  ARISTOTLE (Apixaban)  Stroke within 7 days  ROCKET-AF (Rivaroxaban)  Stroke within 14 days  Severe stroke within last 3 months Modified-Ahrens I, et al Thromb Haemost 2011;105

55 Atrial Fibrillation My View  All FDA approved  Effective agents compared to warfarin  Patient selection for use is critical  Well managed warfarin will remain an option

56 Medically ill Patient

57 EXCLAIM Extended VTE Px Medically-ill EndpointEnoxaparinPlaceboRRR VTE 28 +/- 4 d2.5%4.0% % CI to Major Bleed0.8%0.3% % CI 0.12 to 0.89 Hull R, et al, Ann Intern Med 2010;153:8-18

58 ADOPT Goldhaber S, et al NEJM 2011;365(23): Apixaban 2.5 mg BID Enoxaparin 40mg, Qday

59 ADOPT Study EndpointApixaban 2.5 mg BID ControlRRR VTE during parenteral Rx 1.73%1.61% Enox % CI Non-Inferior P=NS VTE at 30 days2.71%3.06% Placebo % CI Superior P=NS Major Bleed 35 days 0.47%0.19%2.58 P=0.04 CR Bleeding 35 days 2.67%2.08%1.28 P=0.12 Goldhaber S, et al, NEJM, 2011; 365:

60 Cohen A, et al NEJM 2013;368:

61 MAGELLAN Study EndpointRivaroxaban 10 mg, Qday ControlRRR VTE at 10 days2.7% Enox % CI Non-Inferior P= VTE at 35 days4.4%5.7% placebo % CI Superior P=0.021 Major Bleed 35 days 1.1%0.4%2.9 P= CR Bleeding 35 days 4.1%1.7%2.5 P < Cohen A, et al NEJM 2013;368:

62 Extended VTE Prophylaxis In Medical Patients Net Clinical Benefit of Factor Xa Inhibitors EXCLAIMADOPTMAGELLAN Incidence (%) Hull R, et al, Ann Intern Med 2010;153:8-18 Cohen A, et al NEJM 2013;368: Goldhaber S, et al, NEJM, 2011; 365: (n = 5,963)(n = 8,101)(n = 6,528) * * * p < * * (Major Bleeding) * p < 0.05

63 Medically-ill My View  UFH and LMWH VTE prophylaxis agents in moderate to high risk medically-ill  Apixaban and Rivaroxaban non-inferior in short term Px (not FDA approved)  Apixaban and Rivaroxaban major bleeding in extended use (not FDA approved)  We need to define the extended use group !!!!!!!!!!!!!!!!

64 Key Points Black Box Warnings, Stroke, MI Risk, Drug Interactions, Major Bleeding

65 Black Box Warning Rivaroxaban & Apixaban

66 Patel M et al, NEJM 2011;365: ROCKET AF

67 Patel M, et al JACC 2013;61:

68 Rocket AF Study GroupRivaWarfarinHRP value Temporary Interruption 6.2 (9)5.05 (8) Permanent Discontinuation 25.6 (42)23.28 (36) After end of study6.42 (22)1.73 (6) All Discontinuation + End of study 11.2 (73)7.57 (50) Patel M, et al JACC 2013;61:

69 Interruption or Discontinuation Rivaroxaban Rivaroxaban Events per 100-pt years Warfarin Events per 100-pt years Hazard Ratio (CI)P Value All discontinuations and interruptions prior to the end of the study ( )0.35 Temporary Interruptions ( )0.62 Permanent Discontinuations ( )0.66 End of Study Transition to Open-Label ( ) All discontinuations and interruptions prior and after study ( ) Temporary Interruption (Events starting 3 days after interruption until 3 days after resumption) 2.Early Permanent Study Drug Discontinuation (Events evaluated from 3-30 days after d/c) 3.End of Study Transition to Open-Label (Events evaluated from 3-30 days after d/c)

70 Warfarin Rivaroxaban 81% 49% Days after Last Dose at End of Study Cumulative Proportion with INR > 2 Patel M, et al JACC 2013;61: Rocket AF Study

71

72 What happened in ROCKET AF ?  Warfarin patients continued warfarin  Rivaroxaban patients discontinued study drug and then began warfarin  Not anticoagulated during warfarin titration  No “Bridging”  Strokes during the 30 days post study  Warfarin group – 6  Rivaroxaban group - 22

73 Black Box Warning Rivaroxaban  Epidural or Spinal Hematoma  Use of epidural catheter  Concomitant use of NSAID, Anti-platelet  Traumatic or repeated spinal puncture  History of spinal deformity

74 Dosing Rivaroxaban Epidural Catheters Riva 10 mg 6-8 hrs postop 4 PM – 6 PM Epidural Placed 10 AM Leave PACU Surgery 8AM Remove Epidural > 18 hrs from Last dose Riva Start Riva 6 hrs after Epidural Removed Half-Life 7 – 11 hrs Noon Next Day

75 Uchino K, et al Arch Intern Med 2012;172: Clinical Trials Evaluated 2 Stroke Prophylaxis in Atrial Fibrillation 1 Acute Venous Thromboembolism 1 Acute Coronary Syndrome 3 VTE Prophylaxis Joint Replacement Surgery

76 Dabigatran compared to control (warfarin, enoxaparin, placebo) 1. Increased absolute risk of MI or ACS 0.27% 2. Increased relative risk of MI or ACS 33% Uchino K, et al Arch Intern Med 2012;172:

77 Eriksson B, et al Thromb Res 2012;130:

78 Dabigatran & ACS Events Orthopedic Surgery ACS Events Adjudicated Dabi 150 mg (2665) Dabi 220 mg (2611) Enoxaparin (2639) MI115 Unstable Angina 100 Cardiac Death003 Total Definite ACS 2 (0.8)1 (0.04)7 (0.27) Eriksson B, et al Thromb Res 2012;130: Conclusion: No ACS signal identified

79 Major Bleeding

80 Pharmacologic Characteristics CharacteristicsDabigatranRivaroxabanApixaban TargetIIaXa Bioavailability7%60%-80%80% Half-Life12-17 hrs7-11 hrs12 hrs Clearance80% renal60% renal 33% biliary 25% renal 75% biliary MetabolismConjugation to active glucuronides CYP3A4 CYP2J2 CYP3A4 P-GP interactionYes Yes minimal Galanis T et al Thromb Thrombolysis 2011;31:

81 Lab Tests Useful Lab Test DabigatranRivaroxabanApixaban StrongECTChromogenic Anti-Xa Chromogenic Anti -Xa TTaPTT, PT aPTT WeakPT / INR Laboratory Testing New Oral Agents Palladino M et al A J Hem 2012;87 Suppl:S127-S132

82 Novel Anticoagulant Comparison DabigatranRivaroxabanApixaban DialyzableYesProbably Not Molecular Weight 628 Daltons436 Daltons460 Daltons Protein Binding35%>90%87% Catalytic Binding Site Reversible Reversing Agent NoPossibly Erikkson BI, et al. Clin Pharmacokinet 2009;48:1-22.

83 Eerenberg E, et al Circulation 2011;124: COFACT (Prothrombin Complex Concentrate) 1.Non-activated PCC 2.Factor II, VII, IX, X 3.Protein C, S, ATIII 4.50 IU PCC/kg dosing

84 Eerenberg E, et al Circulation 2011;124: Rivaroxaban 20 mg BID Prothrombin Time PCC Placebo PCC or Placebo

85 Eerenberg E, et al Circulation 2011;124: aPTT PCC Dabigatran 150mg BID PCC or Placebo Placebo

86 Eerenberg E, et al Circulation 2011;124: Dabigatran 150mg BID PCC or Placebo PlaceboPCC Thrombin Time

87 Eerenberg E, et al Circulation 2011;124: Dabigatran 150mg BID PCC or Placebo PCC Placebo ECT

88 Four Factor vs Three Factor PCC Rivaroxaban Reversal AgentReduction PT (sec) Beriplex (50 IU/kg)2.5 sec – 3.5 sec Profilnine (50 IU/kg)0.6 – 1.0 sec Levi M, et al Abstract ISTH July 2013 Rivaroxaban 20mg, BID x 4 days 30 minute following infusion effect noted

89 PTT PT/INR Abnormal Impaired Hemodynamic Status PCC Recheck: CBC, PT/INR & PTT GI Bleed Rivaroxaban PRBC Normal Hemodynamic Status PCC Recheck: CBC, PT/INR & PTT Transfuse Re-Evaluate PCC 50 IU/kg over 5-10 minutes

90 PTT Creatinine Abnormal Neuro Intact Presence of any of following: Neuro Deterioration Renal Dysfunction (CrCl < 50 ml/min) Recent Dabigatran Dose (< 6 hrs prior) Monitor Neuro Status Dialysis Neuro Deterioration Recheck PTT Q6hrs x 24 hrs Dialysis as indicated by PTT/TT Neuro Intact Reassess Need for Anticoagulation Neuro Stable CNS Bleed Dabigatran Dialysis removes 60%

91 Package Insert Recommendations  Dabigatran  FFP, Prothrombin Complex Concentrate  Activated Factor VII  Dialysis  Rivaroxaban & Apixaban  Prothrombin Complex Concentrate  Four Factor Concentrate (KCentra)  FFP

92

93 Symptomatic VTE/ VTE-Related Death ADOPT Apixaban 2.5 mg BID Enoxaparin 40mg Qday RR=0.44 (0.19, 1.00) Goldhaber S, et al NEJM 2011;365(23):

94 Drug Interactions

95 Apixaban ActionAgentsRecommendations Strong Inhibitors CYP3A4 & P-gp Ketoconazole Itraconazole Ritonavir Clarithromycin Reduce Dose to 2.5 mg, BID On 2.5 mg, BID, D/C Other Inhibitors CYP3A4 & P-gp Diltiazem Naproxen No dose adjustment Strong Inducers CYP3A4 & P-gp RifampinAvoid use

96 Rivaroxaban ActionAgentsRecommendations Strong P-gp Inducers and CYP3A4 Inducers Rifampin Carbamazipine Phenytoin St. John’s Wort Avoid concomitant use Strong CYP3A4 Inhibitor and P-gp inhibitors Ketoconazole Itraconazole Ritonavir Lopinavir Indinavir Conivaptan Avoid use Other Inhibitors CYP3A4 & P-gp Clarithromycin Erythromycin Fluconazole May increase riva effect

97 Dabigatran ActionAgentsRecommendations Strong Inhibitors P-gp Ketoconazole Dronedarone CrCl 30 – 50 cc/min reduce dose 75mg, BID Other Inhibitors P-gp Verapamil Amiodarone Quinidine clarithromycin No dose adjustment unless CrCl is 15 to 30 cc/min to 75 mg, BID Strong Inducers CYP3A4 & P-gp RifampinAvoid use

98 ADOPT Study Apixaban Placebo Goldhaber S, et al NEJM 2011;365(23):

99 ISTH Major or CRNM Bleeding RR=1.28 (0.93, 1.76) Apixaban 2.5 mg BID Enoxaparin 40mg Qday Goldhaber S, et al NEJM 2011;365(23):

100 MAGELLAN Study Day 10 Cohen A, et al NEJM 2013;368:

101 MAGELLAN Study Day 35 Cohen A, et al NEJM 2013;368:

102 MAGELLAN Study Day 10 & 35 Cohen A, et al NEJM 2013;368:

103 Primary efficacy outcome: Day 10* MAGELLAN Rivaroxaban (n=2,939) Enoxaparin (n=2,993) n % n % Primary efficacy outcome Asymptomatic proximal DVT Symptomatic lower extremity DVT Symptomatic non-fatal PE60.22<0.1 VTE-related death ‡ Relative risk ratio SuperiorNon- inferior Inferior p= for non-inferiority (one-sided)

104 Primary efficacy outcome: Day 35* MAGELLAN Rivaroxaban (n=2,967) Enoxaparin/placebo (n=3,057) n % n % Primary efficacy outcome Asymptomatic proximal DVT Symptomatic lower extremity DVT Symptomatic non-fatal PE VTE-related death † Relative risk ratio p= for superiority (two-sided) ARR 1.3%, RRR 22.9% SuperiorNon- inferior Inferior

105 Principal Safety Outcome Rivaroxaban (n=3,997) Enoxaparin/ placebo (n=4,001) RRp value Day 10 Clinically relevant bleeding (major + non-major clinically relevant bleeding) 111 (2.8%)49 (1.2%)2.3< Major bleeding24 (0.6%)11 (0.3%) Fatal5 (0.1%)1 (<0.1%) Day 35 Clinically relevant bleeding (major + non-major clinically relevant bleeding) 164 (4.1%)67 (1.7%)2.5< Major bleeding43 (1.1%)15 (0.4%) Fatal7 (0.2%)1 (<0.1%)

106 Black Box Warning Rivaroxaban

107 Thank you for viewing the video. In order to receive your CME credit, please click the “links” icon at the bottom right hand side of your computer screen to take a post test quiz and evaluation receive your CME credits. For technical questions about this program, please contact For questions about the content, please contact Dr. Merli at


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