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Welcome to Department of Medicine Grand Rounds

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Title: Welcome to Department of Medicine Grand Rounds


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 10.57 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,
2013. 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
  • JJ Research, Scientific Advisory
  • Bristol-Meyer Squibb Research, Scientific
    Advisory
  • Sanofi-Aventis Research
  • Portola Research

7
Common Pathway
New Oral Agents
Xa Blocker
Apixaban Rivaroxaban
Dabigatran
Thrombin
Prothrombin
Clot
Fibrin
Fibrinogen
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
RE-COVER Study
Dabigatran 150 mg, BID for 6 months Double Blind,
Double Dummy, Non-Inferiority
Schulman S, et al NEJM 20093612342-2352
12
RE-COVER Study
VTE Major Bld
2.4 1.6
Dabigatran 150 mg, BID
VTE
2.1 1.9
Warfarin INR 2-3
6 months
Parenteral Anticoagulant Median 9 days
Warfarin TTR 60
Schulman S, et al NEJM 20093612342-2352
13
RE-COVER Study
2.4
Dabigatran 150mg, BID
2.1
INR 60 TTR
HR 1.1 (0.65-1.84)
TTR Therapeutic Time in Range
Schulman S, et al NEJM 20093612342-2352
14
RE-COVER Study
Warfarin Major Bld 1.9
Dabigatran Major Bld 1.6
Schulman S, et al NEJM 20093612342-2352
15
RE-COVER Study Index Events
Dabi 1273
Warfarin 1266
Schulman S, et al NEJM 20093612342-2352
16
RE-COVER Study Major Bleeding
Warfarin
Dabi
Schulman S, et al NEJM 20093612342-2352
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 20093612342-2352
18
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
Einstein Investigators NEJM 20103632499-2510
19
Einstein DVT
Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday
VTE Major Bld
2.1 8.1
DVT
Enoxaparin Warfarin INR 2-3
3.0 8.1
3, 6, 12 months
Proximal DVT
Warfarin TTR 57.7
Einstein Investigators NEJM 20103632499-2510
20
Einstein Acute DVT Study
Acute DVT Study
INR 57.7 TTR
3.0
2.1
TTR Therapeutic Time in Range
Einstein Investigators NEJM 20103632499-2510
21
Einstein Acute DVT Study Causes of VTE
Riva
Standard
Einstein Investigators NEJM 20103632499-2510
22
Einstein Acute DVT Study
8.1
8.1
HR 0.97 (95 CI, 0.76 to 1.22, P0.77)
Einstein Investigators NEJM 20103632499-2510
23
Einstein Acute DVT Study Safety Outcomes
Riva
Standard
Einstein Investigators NEJM 20103632499-2510
24
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
Einstein Investigators NEJM 20123661287-1297
25
Einstein PE
Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday
VTE Major Bld
2.1 1.1
PE
Non-Inferior
Enoxaparin Warfarin INR 2-3
1.8 2.2
3, 6, 12 months
Warfarin TTR 62.7
Einstein-PE Investigators NEJM 20123661287-1297
26
Einstein PE
2.1
1.8
INR 62.7 TTR
Einstein Investigators NEJM 20123661287-1297
27
Einstein PE Causes
Riva
Standard
Einstein Investigators NEJM 20123661287-1297
28
Einstein PE Anatomical Extent
Riva
Standard
Einstein Investigators NEJM 20123661287-1297
29
Einstein PE
Major Bleeding
2.2
1.1
Einstein Investigators NEJM 20123661287-1297
30
ED - OBS
History Physical Laboratory Testing Diagnosis
DVT Select Treatment
Hospital Admission
OBS Discharge Plan
Secure Rx
Communication
Follow Up
Acquire Med
Contact PCP
Phone call 24 hrs
Pt Education
D/C Summary
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
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
Einstein Investigators NEJM 20103632499-2510
33
Einstein DVT-Extend
Rivaroxaban 20 mg, Qday
VTE Major Bld
1.3 0.7
All Rxed
DVT
Placebo
7.1 0
3, 6, 12 mo
6-12 mo
Einstein Investigators NEJM 20103632499-2510
34
Double Blind, Randomized Trial
Schulman S, et al NEJM 2013368709-718
35
RE-MEDY
VTE Major Bld
Dabigatran 150 mg, BID
1.8 0.9
VTE
Warfarin INR 2-3
1.3 1.8
6 months
Patient Rx 3 to 12 months
Schulman S, et al NEJM 2013368709-718
36
RE-SONATE
VTE Major Bld
Dabigatran 150 mg, BID
0.4 0.3
DVT
Placebo
5.6 0
6-18 months
Patient Rx 6 to 18 months
Schulman S, et al NEJM 2013368709-718
37
RE-MEDY Study
Dabigatran
1.8
1.3
Warfarin
Schulman S, et al NEJM 2013368709-718
38
RE-SONATE Study
Placebo
Dabigatran
5.6
0.4
Schulman S, et al NEJM 2013368709-718
39
RE-MEDY Study
Warfarin
26.2
Dabigatran
Any Bleeding
19.4
Major Bleeding Dabigatran 0.9 Warfarin 1.3
Schulman S, et al NEJM 2013368709-718
40
RE-SONATE Study
Dabigatran 10.5
Any Bleeding
Placebo 5.9
Major or Clinically Relevant Bleeding Dabigatran
5.3 Placebo 1.8
Schulman S, et al NEJM 2013368709-718
41
RE-SONATE Study
Schulman S, et al NEJM 2013368709-718
42
Agnelli G, et al NEJM 20121-10
43
AMPLIFY-EXT
VTE Major Bld
Apixaban 2.5 mg, BID
1.7 0.2
1.7 0.1
Apixaban 5.0 mg, BID
VTE
8.8 0.5
Placebo
Rx 6-12 mo
12 months
Agnelli G, et al NEJM 2013368(8)699-708
44
AMPLIFY-EXT
Apixaban 5
Placebo
Apixaban 2.5
Agnelli G, et al NEJM 2013368(8)699-708
45
AMPLIFY-EXT Symptomatic Recurrent VTE or VTE
Related Death
8.8
1.7
1.7
Agnelli G, et al NEJM 2013368(8)699-708
46
AMPLIFY-EXT Major-Clinical Relevant Non-Major
Bleeding
3.2
4.3
2.7
Agnelli G, et al NEJM 2013368(8)699-708
47
Warfarin to NOAC
Agent Recommendation
Rivaroxaban Start when INR lt 3.0 (we recommend lt 2.0)
Apixaban Start when INR lt 2.0
Dabigatran Start when INR lt 2.0
NOAC New Oral Anticoagulants
48
Non-Valvular Atrial Fibrillation
49
Atrial Fibrillation Studies
Trial RE-LY ARISTOTLE ROCKET-AF
Design Randomized Open Label N18,113 Randomized Double blind N18,209 Randomized double blind dummy N14,000
Treatment Dabigatran 150 mg, BID 110 mg, BID Apixaban 5 mg, BID Rivaroxaban 20 mg, Qday
Comparator Warfarin 2-3 (67 TTR) Warfarin 2-3 (66 TTR) Warfarin 2-3 (57.8 TTR)
Mean CHADS2 2.1 2.1 3.5
Time Therapeutic Range TTR
Modified Ahrens I, et al Thromb Haemost 2011105
50
Primary Endpoints Atrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran 1.1 Warfarin 1.7 RR 0.66 95 CI 0.53-0.82 P lt 0.001 superiority
ARISTOTLE Apixaban 1.3 Warfarin 1.6 HR 0.79 95 CI 0.66-0.95 P lt 0.001 Non- I P 0.01 Superiority
ROCKET-AF Rivaroxaban 1.7 Warfarin 2.2 HR 0.79 95 CI 0.66-0.96 P lt0.001 Non-Inferiority
51
Major Bleeding Atrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran 3.3 Warfarin 3.6 RR 0.93 95 CI 0.81-1.07 P 0.31
ARISTOTLE Apixaban 2.1 Warfarin 3.1 HR 0.69 95 CI 0.60-0.8 P lt 0.001
ROCKET-AF Rivaroxaban 5.6 Warfarin 5.4 HR 1.04 95 CI 0.90-1.20 P 0.58
52
Intracranial Hemorrhage Atrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran 0.3 Warfarin 0.7 RR 0.40 95 CI 0.27-0.60 P lt0.001
ARISTOTLE Apixaban 0.3 Warfarin 0.8 HR 0.42 95 CI 0.30-0.58 P lt0.001
ROCKET-AF Rivaroxaban 0.5 Warfarin 0.7 HR 0.67 95 CI 0.47-0.93 P 0.02
53
Dosing Schedules Atrial Fibrillation
Agent Dosing Recommendations
Dabigatran 75mg, 150mg CrCl gt 30 cc/min 150 mg, BID CrCl 15 to 30 cc/min 75 mg, BID Avoid lt 15 cc/min
Apixaban 2.5mg, 5mg CrCl gt 15 cc/min 5 mg, BID Any 2 ( gt 80 yrs, lt 60 kg, SCr gt 1.5mg/dL 2.5 mg, BID) Avoid lt 15 cc/min
Rivaroxaban 10mg, 15mg, 20mg CrCl gt 50 cc/min 20 mg, Qday CrCl 15-50 cc/min 15 mg, Qday Avoid CrCl lt 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 2011105
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
Endpoint Enoxaparin Placebo RRR
VTE 28 /- 4 d 2.5 4.0 -1.53 95 CI -2.54 to -0.52
Major Bleed 0.8 0.3 0.51 95 CI 0.12 to 0.89
Hull R, et al, Ann Intern Med 20101538-18
58
ADOPT
Apixaban 2.5 mg BID Enoxaparin 40mg, Qday
Goldhaber S, et al NEJM 2011365(23)2167-2177
59
ADOPT Study
Endpoint Apixaban 2.5 mg BID Control RRR
VTE during parenteral Rx 1.73 1.61 Enox 1.06 95 CI 0.69-1.63 Non-Inferior PNS
VTE at 30 days 2.71 3.06 Placebo 0.87 95 CI 0.62-1.23 Superior PNS
Major Bleed 35 days 0.47 0.19 2.58 P0.04
CR Bleeding 35 days 2.67 2.08 1.28 P0.12
Goldhaber S, et al, NEJM, 2011 365 2167-2177
60
Cohen A, et al NEJM 2013368513-523
61
MAGELLAN Study
Endpoint Rivaroxaban 10 mg, Qday Control RRR
VTE at 10 days 2.7 2.7 Enox 0.97 95 CI 0.713-1.334 Non-Inferior P0.0025
VTE at 35 days 4.4 5.7 placebo 0.77 95 CI 0.618-0.962 Superior P0.021
Major Bleed 35 days 1.1 0.4 2.9 P0.0004
CR Bleeding 35 days 4.1 1.7 2.5 P lt 0.0001
Cohen A, et al NEJM 2013368513-523
62
Extended VTE Prophylaxis In Medical Patients
Net Clinical Benefit of Factor Xa Inhibitors
EXCLAIM
ADOPT
MAGELLAN
p lt 0.05
6
p lt 0.05

3

0
Incidence ()
3
(Major Bleeding)
6
(n 5,963)
(n 8,101)
(n 6,528)
Hull R, et al, Ann Intern Med 20101538-18
Cohen A, et al NEJM
2013368513-523 Goldhaber S, et al, NEJM, 2011
365 2167-2177
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
ROCKET AF
Patel M et al, NEJM 2011365883-891
67
Patel M, et al JACC 201361651-658
68
Rocket AF Study
Group Riva Warfarin HR P value
Temporary Interruption 6.2 (9) 5.05 (8) 1.28 0.49-3.31 0.62
Permanent Discontinuation 25.6 (42) 23.28 (36) 1.10 0.71-1.72 0.66
After end of study 6.42 (22) 1.73 (6) 3.72 1.51-9.16 0.004
All Discontinuation End of study 11.2 (73) 7.57 (50) 1.5 1.05-2.15 0.026
Patel M, et al JACC 201361651-658
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 16.49 14.05 1.21 (0.81-1.81) 0.35
Temporary Interruptions 6.20 5.05 1.28 (0.49-3.31) 0.62
Permanent Discontinuations 25.60 23.28 1.10 (0.71-1.72) 0.66
End of Study Transition to Open-Label 6.42 1.73 3.72 (1.51-9.16) 0.0044
All discontinuations and interruptions prior and after study 11.20 7.57 1.50 (1.05-2.15) 0.026
  1. 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
Rocket AF Study
Warfarin
81
49
Rivaroxaban
Cumulative Proportion with INR gt 2
Days after Last Dose at End of Study
Patel M, et al JACC 201361651-658
71
(No Transcript)
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
Remove Epidural gt 18 hrs from Last dose Riva
10 AM Leave PACU
Surgery 8AM

Noon Next Day
Epidural Placed
Riva 10 mg 6-8 hrs postop 4 PM 6 PM
Start Riva 6 hrs after Epidural Removed
Half-Life 7 11 hrs
75
7 Clinical Trials Evaluated 2 Stroke Prophylaxis
in Atrial Fibrillation 1 Acute Venous
Thromboembolism 1 Acute Coronary Syndrome 3 VTE
Prophylaxis Joint Replacement Surgery
Uchino K, et al Arch Intern Med 2012172397-402
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 2012172397-402
77
Eriksson B, et al Thromb Res 2012130396-402
78
Dabigatran ACS Events Orthopedic Surgery
ACS Events Adjudicated Dabi 150 mg (2665) Dabi 220 mg (2611) Enoxaparin (2639)
MI 1 1 5
Unstable Angina 1 0 0
Cardiac Death 0 0 3
Total Definite ACS 2 (0.8) 1 (0.04) 7 (0.27)
Conclusion No ACS signal identified
Eriksson B, et al Thromb Res 2012130396-402
79
Major Bleeding
80
Pharmacologic Characteristics
Characteristics Dabigatran Rivaroxaban Apixaban
Target IIa Xa Xa
Bioavailability 7 60-80 80
Half-Life 12-17 hrs 7-11 hrs 12 hrs
Clearance 80 renal 60 renal 33 biliary 25 renal 75 biliary
Metabolism Conjugation to active glucuronides CYP3A4 CYP2J2 CYP3A4
P-GP interaction Yes Yes Yes minimal
Galanis T et al Thromb Thrombolysis
201131310-320
81
Laboratory Testing New Oral Agents
Lab Tests Useful Lab Test Dabigatran Rivaroxaban Apixaban
Lab Tests Strong ECT Chromogenic Anti-Xa Chromogenic Anti -Xa
Lab Tests TT aPTT, PT
Lab Tests aPTT
Lab Tests Weak PT / INR
Palladino M et al A J Hem 201287 SupplS127-S132
82
Novel Anticoagulant Comparison
Dabigatran Rivaroxaban Apixaban
Dialyzable Yes Probably Not Probably Not
Molecular Weight 628 Daltons 436 Daltons 460 Daltons
Protein Binding 35 gt90 87

Catalytic Binding Site Reversible Reversible Reversible
Reversing Agent No Possibly Possibly
Erikkson BI, et al. Clin Pharmacokinet
2009481-22.
83
  • COFACT (Prothrombin Complex Concentrate)
  • Non-activated PCC
  • Factor II, VII, IX, X
  • Protein C, S, ATIII
  • 50 IU PCC/kg dosing

Eerenberg E, et al Circulation 20111241573-1579
84
Prothrombin Time
Placebo
PCC
Rivaroxaban 20 mg BID
PCC or Placebo
Eerenberg E, et al Circulation 20111241573-1579
85
aPTT
PCC
Placebo
PCC or Placebo
Dabigatran 150mg BID
Eerenberg E, et al Circulation 20111241573-1579
86
Thrombin Time
Placebo
PCC
Dabigatran 150mg BID
PCC or Placebo
Eerenberg E, et al Circulation 20111241573-1579
87
ECT
PCC
Placebo
PCC or Placebo
Dabigatran 150mg BID
Eerenberg E, et al Circulation 20111241573-1579
88
Four Factor vs Three Factor PCC Rivaroxaban
Reversal
Agent Reduction PT (sec)
Beriplex (50 IU/kg) 2.5 sec 3.5 sec
Profilnine (50 IU/kg) 0.6 1.0 sec
Rivaroxaban 20mg, BID x 4 days 30 minute
following infusion effect noted
Levi M, et al Abstract ISTH July 2013
89
GI Bleed Rivaroxaban
PTT PT/INR Abnormal
Impaired Hemodynamic Status
Normal Hemodynamic Status
Transfuse
Transfuse
PCC 50 IU/kg over 5-10 minutes
PCC
PRBC
PCC
Recheck CBC, PT/INR PTT
Recheck CBC, PT/INR PTT
Re-Evaluate
Re-Evaluate
90
CNS Bleed Dabigatran
Dialysis removes 60
PTT Creatinine
Abnormal
Presence of any of following Neuro Deterioration
Renal Dysfunction (CrCl lt 50 ml/min) Recent
Dabigatran Dose (lt 6 hrs prior)
Neuro Intact
Monitor Neuro Status
Dialysis
Recheck PTT Q6hrs x 24 hrs
Neuro Deterioration
Neuro Intact
Dialysis as indicated by PTT/TT
Reassess Need for Anticoagulation
Neuro Stable
91
Package Insert Recommendations
  • Dabigatran
  • FFP, Prothrombin Complex Concentrate
  • Activated Factor VII
  • Dialysis
  • Rivaroxaban Apixaban
  • Prothrombin Complex Concentrate
  • Four Factor Concentrate (KCentra)
  • FFP

92
Geno.Merli_at_Jefferson.edu
93
Symptomatic VTE/ VTE-Related Death ADOPT
RR0.44 (0.19, 1.00)
Enoxaparin 40mg Qday
Apixaban 2.5 mg BID
Goldhaber S, et al NEJM 2011365(23)2167-2177
94
Drug Interactions
95
Apixaban
Action Agents Recommendations
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 Rifampin Avoid use
96
Rivaroxaban
Action Agents Recommendations
Strong P-gp Inducers and CYP3A4 Inducers Rifampin Carbamazipine Phenytoin St. Johns 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
Action Agents Recommendations
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 Rifampin Avoid use
98
ADOPT Study
Placebo
Apixaban
Goldhaber S, et al NEJM 2011365(23)2167-2177
99
ISTH Major or CRNM Bleeding
RR1.28 (0.93, 1.76)
Apixaban 2.5 mg BID
Enoxaparin 40mg Qday
Goldhaber S, et al NEJM 2011365(23)2167-2177
100
MAGELLAN Study Day 10
Cohen A, et al NEJM 2013368513-523
101
MAGELLAN Study Day 35
Cohen A, et al NEJM 2013368513-523
102
MAGELLAN Study Day 10 35
Cohen A, et al NEJM 2013368513-523
103
Primary efficacy outcome Day 10 MAGELLAN
Rivaroxaban (n2,939) Rivaroxaban (n2,939) Enoxaparin (n2,993) Enoxaparin (n2,993)
n n
Primary efficacy outcome 78 2.7 82 2.7
Asymptomatic proximal DVT 71 2.4 71 2.4
Symptomatic lower extremity DVT 7 0.2 6 0.2
Symptomatic non-fatal PE 6 0.2 2 lt0.1
VTE-related death 3 0.1 6 0.2
1.334
0.968
0.713
0
p0.0025 for non-inferiority (one-sided)
1.00
1.50
Relative risk ratio
Inferior
Superior
Non-inferior

104
Primary efficacy outcome Day 35 MAGELLAN
Rivaroxaban (n2,967) Rivaroxaban (n2,967) Enoxaparin/placebo (n3,057) Enoxaparin/placebo (n3,057)
n n
Primary efficacy outcome 131 4.4 175 5.7
Asymptomatic proximal DVT 103 3.5 133 4.4
Symptomatic lower extremity DVT 13 0.4 15 0.5
Symptomatic non-fatal PE 10 0.3 14 0.5
VTE-related death 19 0.6 30 1.0
0.962
0.618
0.771
ARR 1.3, RRR 22.9
p0.0211 for superiority (two-sided)
1.00
0
Relative risk ratio

Inferior
Superior
Non-inferior
105
Principal Safety Outcome
Rivaroxaban (n3,997) Rivaroxaban (n3,997) Enoxaparin/ placebo (n4,001) RR p value
Day 10 Day 10 Day 10
Clinically relevant bleeding (major non-major clinically relevant bleeding) Clinically relevant bleeding (major non-major clinically relevant bleeding) 111 (2.8) 49 (1.2) 2.3 lt0.0001
Major bleeding Major bleeding 24 (0.6) 11 (0.3) 2.2 0.0318
Fatal Fatal 5 (0.1) 1 (lt0.1) 5.0 0.1415
Day 35 Day 35
Clinically relevant bleeding (major non-major clinically relevant bleeding) Clinically relevant bleeding (major non-major clinically relevant bleeding) 164 (4.1) 67 (1.7) 2.5 lt0.0001
Major bleeding Major bleeding 43 (1.1) 15 (0.4) 2.9 0.0004
Fatal Fatal 7 (0.2) 1 (lt0.1) 7.0 0.0687
106
Black Box Warning Rivaroxaban
107
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