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)
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.
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
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 Sanofiaventis; 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).
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
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
Common Pathway
New Oral Agents
Apixaban
Rivaroxaban
Xa
Blocker
Xa
Dabigatran
Prothrombin
Thrombin
Clot
Fibrinogen
Fibrin
Replacing Traditional Anticoagulants
Replacing Current Agents
 Treatment of DVT/PE
 Non-Valvular Atrial Fibrillation
 Hospitalized Medically-ill
 Key Points: Black Box Warnings,
Stroke, MI Risk, Major Bleeding
Treatment VTE
UFH, LMWH Bridge to Warfarin
RE-COVER Study
Dabigatran 150 mg, BID for 6 months
Double Blind, Double Dummy, Non-Inferiority
Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study
VTE
Major Bld
Dabigatran 150 mg, BID
2.4%
1.6%
Warfarin INR 2-3
2.1%
1.9%
VTE
Parenteral
Anticoagulant
Median 9 days
6 months
Warfarin TTR= 60%
Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study
Index Events
Dabi
1273
Warfarin
1266
Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study
Major Bleeding
Dabi
Warfarin
Schulman S, et al NEJM 2009;361:2342-2352
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;361:2342-2352
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 2010;363:2499-2510
Einstein DVT
Rivaroxaban
15 mg, BID x 3 wks
20 mg, Qday
DVT
VTE
Major Bld
2.1%
8.1%
3.0%
8.1%
Enoxaparin
Warfarin INR 2-3
3, 6, 12 months
Proximal DVT
Warfarin TTR = 57.7%
Einstein Investigators NEJM 2010;363:2499-2510
Einstein Acute DVT Study
Causes of VTE
Riva
Standard
Einstein Investigators NEJM 2010;363:2499-2510
Einstein Acute DVT Study
Safety Outcomes
Riva
Standard
Einstein Investigators NEJM 2010;363:2499-2510
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 2012;366:1287-1297
Einstein PE
Rivaroxaban
15 mg, BID x 3 wks
20 mg, Qday
PE
Enoxaparin
Warfarin INR 2-3
VTE
Major Bld
2.1%
1.1%
Non-Inferior
1.8%
2.2%
3, 6, 12 months
Warfarin TTR = 62.7%
Einstein-PE Investigators NEJM 2012;366:1287-1297
Einstein PE
Causes
Riva
Standard
Einstein Investigators NEJM 2012;366:1287-1297
Einstein PE
Anatomical Extent
Riva
Standard
Einstein Investigators NEJM 2012;366:1287-1297
ED - OBS
History & Physical
Laboratory Testing
Diagnosis DVT
Select Treatment
Hospital Admission
Secure Rx
OBS Discharge Plan
Communication
Follow Up
Acquire Med
Contact PCP
Phone call 24 hrs
Pt Education
D/C Summary
Appointment 3-5 days
Discharge OBS
Your patient who has been on
long term warfarin would like to
convert to one of the new oral
anticoagulant.
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 2010;363:2499-2510
Einstein DVT-Extend
Rivaroxaban
20 mg, Qday
DVT
VTE
Major Bld
1.3%
0.7%
7.1%
0%
All Rxed
Placebo
3, 6, 12 mo
6-12 mo
Einstein Investigators NEJM 2010;363:2499-2510
Double Blind, Randomized Trial
Schulman S, et al NEJM 2013;368:709-718
RE-MEDY
Dabigatran 150 mg, BID
VTE
Major Bld
1.8%
0.9%
1.3%
1.8%
VTE
Warfarin INR 2-3
Patient Rx
3 to 12 months
6 months
Schulman S, et al NEJM 2013;368:709-718
RE-SONATE
Dabigatran 150 mg, BID
VTE
Major Bld
0.4%
0.3%
5.6%
0%
DVT
Placebo
Patient Rx
6 to 18 months
6-18 months
Schulman S, et al NEJM 2013;368:709-718
RE-SONATE Study
Schulman S, et al NEJM 2013;368:709-718
Agnelli G, et al NEJM 2012;1-10
AMPLIFY-EXT
VTE
VTE
Rx 6-12 mo
Major Bld
Apixaban 2.5 mg, BID
1.7%
0.2%
Apixaban 5.0 mg, BID
1.7%
0.1%
Placebo
8.8%
0.5%
12 months
Agnelli G, et al NEJM 2013;368(8):699-708
AMPLIFY-EXT
Apixaban 2.5
Apixaban 5
Placebo
Agnelli G, et al NEJM 2013;368(8):699-708
Warfarin to NOAC
Agent
Recommendation
Rivaroxaban
Start when INR < 3.0
(we recommend < 2.0)
Apixaban
Start when INR < 2.0
Dabigatran
Start when INR < 2.0
NOAC= New Oral Anticoagulants
Non-Valvular Atrial Fibrillation
Atrial Fibrillation Studies
Trial
RE-LY
ARISTOTLE
ROCKET-AF
Design
Randomized
Open Label
N=18,113
Randomized
Double blind
N=18,209
Randomized
double blind &
dummy
N=14,000
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 2011;105
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 < 0.001
superiority
ARISTOTLE
Apixaban
1.3%
Warfarin
1.6%
HR 0.79
95% CI 0.66-0.95
P= < 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 = <0.001
Non-Inferiority
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 = < 0.001
ROCKET-AF
Rivaroxaban
5.6%
Warfarin
5.4%
HR 1.04
95% CI 0.90-1.20
P = 0.58
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= <0.001
ARISTOTLE
Apixaban
0.3%
Warfarin
0.8%
HR 0.42
95% CI 0.30-0.58
P = <0.001
ROCKET-AF
Rivaroxaban
0.5%
Warfarin
0.7%
HR 0.67
95% CI 0.47-0.93
P = 0.02
Dosing Schedules
Atrial Fibrillation
Agent
Dosing 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, < 60 kg, SCr > 1.5mg/dL:
2.5 mg, BID)
Avoid < 15 cc/min
Rivaroxaban
CrCl > 50 cc/min: 20 mg, Qday
10mg, 15mg, 20mg CrCl 15-50 cc/min: 15 mg, Qday
Avoid CrCl < 15 cc/min
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
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
Medically ill Patient
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 2010;153:8-18
ADOPT
Apixaban 2.5 mg BID
Enoxaparin 40mg, Qday
Goldhaber S, et al NEJM 2011;365(23):2167-2177
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 P=NS
VTE at 30 days
2.71%
3.06%
Placebo
0.87
95% CI 0.62-1.23
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: 2167-2177
Cohen A, et al NEJM 2013;368:513-523
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 P=0.0025
VTE at 35 days
4.4%
5.7%
placebo
0.77
95% CI 0.618-0.962
Superior P=0.021
Major Bleed
35 days
1.1%
0.4%
2.9
P=0.0004
CR Bleeding
35 days
4.1%
1.7%
2.5
P < 0.0001
Cohen A, et al NEJM 2013;368:513-523
Extended VTE Prophylaxis In Medical Patients
Net Clinical Benefit of Factor Xa Inhibitors
EXCLAIM
Incidence (%)
6
3
ADOPT
MAGELLAN
* p < 0.05
* p < 0.05
5,7
4,4*
4,0
2.5 *
3,1
2,7
0
0.3
0.8*
2.1
3
2.7
1.7
(Major Bleeding)
6
Plac
(n = 5,963)
Apixaban
(n = 6,528)
4.1*
Enox.
(n = 8,101)
Hull R, et al, Ann Intern Med 2010;153:8-18
Cohen A, et al NEJM 2013;368:513-523
Goldhaber S, et al, NEJM, 2011; 365: 2167-2177
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
!!!!!!!!!!!!!!!!
Key Points
Black Box Warnings, Stroke, MI Risk,
Drug Interactions, Major Bleeding
Black Box Warning
Rivaroxaban & Apixaban
ROCKET AF
Patel M et al, NEJM 2011;365:883-891
Patel M, et al JACC 2013;61:651-658
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
11.2 (73)
Discontinuation +
End of study
7.57 (50)
1.5
1.05-2.15
0.026
Patel M, et al JACC 2013;61:651-658
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)
Cumulative Proportion with INR > 2
Rocket AF Study
Warfarin
81%
49%
Rivaroxaban
Days after Last Dose at End of Study
Patel M, et al JACC 2013;61:651-658
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
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
Dosing Rivaroxaban
Epidural Catheters
Surgery
8AM
Remove
Epidural
> 18 hrs from
Last dose
Riva
10 AM
Leave PACU
Epidural
Placed
Half-Life 7 – 11 hrs
Riva 10 mg
6-8 hrs postop
4 PM – 6 PM
Noon
Next
Day
Start Riva
6 hrs after
Epidural
Removed
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 2012;172:397-402
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;172:397-402
Eriksson B, et al Thromb Res 2012;130:396-402
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 2012;130:396-402
Major Bleeding
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 2011;31:310-320
Laboratory Testing New Oral Agents
Lab
Tests
Useful Dabigatran Rivaroxaban
Lab Test
Strong
ECT
Chromogenic
Anti-Xa
TT
aPTT, PT
Apixaban
Chromogenic
Anti -Xa
aPTT
Weak
PT / INR
Palladino M et al A J Hem 2012;87 Suppl:S127-S132
Novel Anticoagulant Comparison
Dabigatran Rivaroxaban Apixaban
Dialyzable
Yes
Probably Not
Probably Not
Molecular
Weight
628 Daltons
436 Daltons
460 Daltons
Protein Binding 35%
>90%
87%
Catalytic
Binding Site
Reversible
Reversible
Reversible
Reversing
Agent
No
Possibly
Possibly
Erikkson BI, et al. Clin Pharmacokinet 2009;48:1-22.
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
Eerenberg E, et al Circulation 2011;124:1573-1579
Prothrombin Time
Placebo
PCC
Rivaroxaban
20 mg BID
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
aPTT
PCC
Placebo
Dabigatran
150mg BID
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
Thrombin Time
Placebo
Dabigatran
150mg BID
PCC
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
ECT
PCC
Placebo
Dabigatran
150mg BID
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
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
GI Bleed
Rivaroxaban
PTT
PT/INR
Abnormal
Normal Hemodynamic Status
Transfuse
PCC
50 IU/kg
over 5-10 minutes
PCC
Recheck: CBC, PT/INR & PTT
Re-Evaluate
Impaired Hemodynamic Status
Transfuse
PCC
PRBC
Recheck: CBC, PT/INR & PTT
Re-Evaluate
CNS Bleed
Dabigatran
Dialysis removes 60%
PTT
Creatinine
Abnormal
Presence of any of following:
Neuro Deterioration
Renal Dysfunction (CrCl < 50 ml/min)
Recent Dabigatran Dose (< 6 hrs prior)
Neuro Intact
Monitor
Neuro Status
Neuro
Intact
Neuro
Deterioration
Reassess Need
for Anticoagulation
Dialysis
Recheck PTT
Q6hrs x 24 hrs
Dialysis as indicated
by PTT/TT
Neuro Stable
Package Insert Recommendations
 Dabigatran
 FFP, Prothrombin Complex Concentrate
 Activated Factor VII
 Dialysis
 Rivaroxaban & Apixaban
 Prothrombin Complex Concentrate
 Four Factor Concentrate (KCentra)
 FFP
Geno.Merli@Jefferson.edu
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