new oral anticoagulants are they better than what we have?
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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 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: WindowsMicrosoft Windows 2008 (required Desktop experience), Windows 7, Windows Vista, Windows XP, Windows 2003Microsoft Internet Explorer 7.0 or later, Firefox 3.6 or later or Google ChromeWindows Media Player 9.0 or later Media Silverlight 5.0 or laterBroadband internet connection
MACMAC OS X 10.57 or laterSafari 4.0 or later or Firefox 3.6 or laterMicrosoft 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, FSVMProfessor of Medicine and SurgeryCo-Director Jefferson Vascular CenterJefferson Medical CollegeThomas 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 Anticoagulants2. Review Clinical Trials in Atrial Fibrillation3. 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 Sanofi-aventis; none of the other planners have revealed any significant commercial interests.
Accreditation StatementThe Lancaster General Hospital is accredited by the Pennsylvania Medical Society to provide continuing medical education for physicians.Designation StatementThe 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 StatementFaculty 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 AnticoagulantsAre they better than what we have?
Geno J Merli, MD, MACP, FHM, FSVMProfessor of Medicine and Surgery
Co-Director Jefferson Vascular CenterJefferson 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
Fibrinogen Fibrin
Common Pathway
Thrombin
Xa
Prothrombin
Clot
Xa Blocker
ApixabanRivaroxaban
Dabigatran
New Oral Agents
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 VTEUFH, LMWH Bridge to Warfarin
Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study
Dabigatran 150 mg, BID for 6 monthsDouble Blind, Double Dummy, Non-Inferiority
RE-COVER Study
VTE
Dabigatran 150 mg, BID
Warfarin INR 2-3
Parenteral AnticoagulantMedian 9 days
2.4% 1.6%
2.1% 1.9%
VTE Major Bld
Schulman S, et al NEJM 2009;361:2342-2352
6 months
Warfarin TTR= 60%
RE-COVER StudyIndex Events
Schulman S, et al NEJM 2009;361:2342-2352
Dabi1273
Warfarin1266
RE-COVER StudyMajor Bleeding
Schulman S, et al NEJM 2009;361:2342-2352
Dabi Warfarin
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
Einstein Investigators NEJM 2010;363:2499-2510
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority trial
Einstein DVT
DVT
Rivaroxaban15 mg, BID x 3 wks
20 mg, Qday
EnoxaparinWarfarin INR 2-3
Proximal DVT
2.1% 8.1%
3.0% 8.1%
VTE Major Bld
3, 6, 12 months
Einstein Investigators NEJM 2010;363:2499-2510
Warfarin TTR = 57.7%
Einstein Acute DVT StudyCauses of VTE
Riva Standard
Einstein Investigators NEJM 2010;363:2499-2510
Einstein Acute DVT StudySafety Outcomes
Einstein Investigators NEJM 2010;363:2499-2510
Riva Standard
Einstein Investigators NEJM 2012;366:1287-1297
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority
Einstein PE
PE
Rivaroxaban15 mg, BID x 3 wks
20 mg, Qday
EnoxaparinWarfarin INR 2-3
2.1% 1.1%
1.8% 2.2%
VTE Major Bld
3, 6, 12 months
Einstein-PE Investigators NEJM 2012;366:1287-1297
Warfarin TTR = 62.7%
Non-Inferior
Einstein PECauses
Einstein Investigators NEJM 2012;366:1287-1297
Riva Standard
Einstein PEAnatomical Extent
Einstein Investigators NEJM 2012;366:1287-1297
Riva Standard
ED - OBS
History & PhysicalLaboratory Testing
Diagnosis DVTSelect Treatment
Hospital Admission OBS Discharge Plan
Secure Rx Communication Follow Up
Acquire Med
Pt Education
Contact PCP
D/C Summary
Phone call 24 hrs
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.
Einstein Investigators NEJM 2010;363:2499-2510
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority trial
Einstein DVT-Extend
DVT
Rivaroxaban20 mg, Qday
Placebo
1.3% 0.7%
7.1% 0%
VTE Major Bld
3, 6, 12 mo
Einstein Investigators NEJM 2010;363:2499-2510
6-12 mo
All Rxed
Schulman S, et al NEJM 2013;368:709-718
Double Blind, Randomized Trial
RE-MEDY
VTE
Dabigatran 150 mg, BID
Warfarin INR 2-3
Patient Rx3 to 12 months
1.8% 0.9%
1.3% 1.8%
VTE Major Bld
Schulman S, et al NEJM 2013;368:709-718
6 months
RE-SONATE
DVT
Dabigatran 150 mg, BID
Placebo
Patient Rx6 to 18 months
0.4% 0.3%
5.6% 0%
VTE Major Bld
Schulman S, et al NEJM 2013;368:709-718
6-18 months
Schulman S, et al NEJM 2013;368:709-718
RE-SONATE Study
Agnelli G, et al NEJM 2012;1-10
AMPLIFY-EXT
VTE
Rx 6-12 mo
Apixaban 2.5 mg, BID
Apixaban 5.0 mg, BID
Placebo
12 months
VTE Major Bld
1.7% 0.2%
1.7% 0.1%
8.8% 0.5%
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
Modified Ahrens I, et al Thromb Haemost 2011;105
Time Therapeutic Range = TTR
Primary EndpointsAtrial 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 BleedingAtrial 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 HemorrhageAtrial 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 SchedulesAtrial 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
10mg, 15mg, 20mg
CrCl > 50 cc/min: 20 mg, Qday
CrCl 15-50 cc/min: 15 mg, Qday
Avoid CrCl < 15 cc/min
Atrial Fibrillation StudiesWhen 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 FibrillationMy 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
EXCLAIMExtended 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
Goldhaber S, et al NEJM 2011;365(23):2167-2177
Apixaban 2.5 mg BIDEnoxaparin 40mg, Qday
ADOPT StudyEndpoint 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 StudyEndpoint 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 PatientsNet Clinical Benefit of Factor Xa Inhibitors
0
3
6
3
6
EXCLAIM ADOPT MAGELLAN
Inci
den
ce (
%)
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
(n = 5,963) (n = 8,101)(n = 6,528)
*
*
* p < 0.05
0.30.8*
2.12.7
1.7
4.1*(Major Bleeding)
* p < 0.05
Medically-illMy 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 PointsBlack Box Warnings, Stroke, MI Risk,
Drug Interactions, Major Bleeding
Black Box WarningRivaroxaban & Apixaban
Patel M et al, NEJM 2011;365:883-891
ROCKET AF
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 Discontinuation + End of study
11.2 (73) 7.57 (50) 1.5
1.05-2.15
0.026
Patel M, et al JACC 2013;61:651-658
Interruption or DiscontinuationRivaroxaban
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)
Warfarin
Rivaroxaban
81%
49%
Days after Last Dose at End of Study
Cu
mu
lati
ve P
rop
ort
ion
wit
h IN
R >
2
Patel M, et al JACC 2013;61:651-658
Rocket AF Study
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 WarningRivaroxaban
Epidural or Spinal HematomaUse of epidural catheter
Concomitant use of NSAID, Anti-platelet
Traumatic or repeated spinal puncture
History of spinal deformity
Dosing RivaroxabanEpidural Catheters
Riva 10 mg6-8 hrs postop
4 PM – 6 PM
Epidural Placed
10 AMLeave PACU
Surgery8AM
RemoveEpidural
> 18 hrs from Last dose
Riva
Start Riva6 hrs afterEpidural Removed
Half-Life 7 – 11 hrs
NoonNextDay
Uchino K, et al Arch Intern Med 2012;172:397-402
7 Clinical Trials Evaluated2 Stroke Prophylaxis in Atrial Fibrillation1 Acute Venous Thromboembolism1 Acute Coronary Syndrome3 VTE Prophylaxis Joint Replacement Surgery
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 EventsOrthopedic 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)
Eriksson B, et al Thromb Res 2012;130:396-402
Conclusion: No ACS signal identified
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
Lab Tests
Useful Lab Test
Dabigatran Rivaroxaban Apixaban
Strong ECT Chromogenic Anti-Xa
Chromogenic Anti -Xa
TT aPTT, PT
aPTT
Weak PT / INR
Laboratory Testing New Oral Agents
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.
Eerenberg E, et al Circulation 2011;124:1573-1579
COFACT (Prothrombin Complex Concentrate)1. Non-activated PCC2. Factor II, VII, IX, X3. Protein C, S, ATIII4. 50 IU PCC/kg dosing
Eerenberg E, et al Circulation 2011;124:1573-1579
Rivaroxaban 20 mg BID
Prothrombin Time
PCC
Placebo
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
aPTT
PCC
Dabigatran 150mg BID
PCC or Placebo
Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
Dabigatran 150mg BID
PCC or Placebo
Placebo PCC
Thrombin Time
Eerenberg E, et al Circulation 2011;124:1573-1579
Dabigatran 150mg BID
PCC or Placebo
PCC
Placebo
ECT
Four Factor vs Three Factor PCCRivaroxaban Reversal
Agent Reduction 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 days30 minute following infusion effect noted
PTTPT/INR
Abnormal
Impaired Hemodynamic Status
PCC
Recheck: CBC, PT/INR & PTT
GI BleedRivaroxaban
PRBC
Normal Hemodynamic Status
PCC
Recheck: CBC, PT/INR & PTT
Transfuse Transfuse
Re-Evaluate Re-Evaluate
PCC 50 IU/kg over 5-10 minutes
PTTCreatinine
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
NeuroDeterioration
Recheck PTTQ6hrs x 24 hrs
Dialysis as indicatedby PTT/TT
NeuroIntact
Reassess Needfor Anticoagulation Neuro Stable
CNS BleedDabigatran
Dialysis removes 60%
Package Insert Recommendations
DabigatranFFP, Prothrombin Complex Concentrate
Activated Factor VII
Dialysis
Rivaroxaban & ApixabanProthrombin Complex Concentrate
Four Factor Concentrate (KCentra)
FFP
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