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: 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)

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Page 1: New Oral Anticoagulants Are they better than what we have?

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)

Page 2: New Oral Anticoagulants Are they better than what we have?

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.

 

Page 3: New Oral Anticoagulants Are they better than what we have?

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

  

Page 4: New Oral Anticoagulants Are they better than what we have?

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).

Page 5: New Oral Anticoagulants Are they better than what we have?

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

Page 6: New Oral Anticoagulants Are they better than what we have?

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

Page 7: New Oral Anticoagulants Are they better than what we have?

Fibrinogen Fibrin

Common Pathway

Thrombin

Xa

Prothrombin

Clot

Xa Blocker

ApixabanRivaroxaban

Dabigatran

New Oral Agents

Page 8: New Oral Anticoagulants Are they better than what we have?

Replacing Traditional Anticoagulants

Page 9: New Oral Anticoagulants Are they better than what we have?

Replacing Current Agents

Treatment of DVT/PE

Non-Valvular Atrial Fibrillation

Hospitalized Medically-ill

Key Points: Black Box Warnings, Stroke, MI Risk, Major Bleeding

Page 10: New Oral Anticoagulants Are they better than what we have?

Treatment VTEUFH, LMWH Bridge to Warfarin

Page 11: New Oral Anticoagulants Are they better than what we have?

Schulman S, et al NEJM 2009;361:2342-2352

RE-COVER Study

Dabigatran 150 mg, BID for 6 monthsDouble Blind, Double Dummy, Non-Inferiority

Page 12: New Oral Anticoagulants Are they better than what we have?

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%

Page 13: New Oral Anticoagulants Are they better than what we have?

RE-COVER StudyIndex Events

Schulman S, et al NEJM 2009;361:2342-2352

Dabi1273

Warfarin1266

Page 14: New Oral Anticoagulants Are they better than what we have?

RE-COVER StudyMajor Bleeding

Schulman S, et al NEJM 2009;361:2342-2352

Dabi Warfarin

Page 15: New Oral Anticoagulants Are they better than what we have?

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

Page 16: New Oral Anticoagulants Are they better than what we have?

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

Page 17: New Oral Anticoagulants Are they better than what we have?

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%

Page 18: New Oral Anticoagulants Are they better than what we have?

Einstein Acute DVT StudyCauses of VTE

Riva Standard

Einstein Investigators NEJM 2010;363:2499-2510

Page 19: New Oral Anticoagulants Are they better than what we have?

Einstein Acute DVT StudySafety Outcomes

Einstein Investigators NEJM 2010;363:2499-2510

Riva Standard

Page 20: New Oral Anticoagulants Are they better than what we have?

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

Page 21: New Oral Anticoagulants Are they better than what we have?

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

Page 22: New Oral Anticoagulants Are they better than what we have?

Einstein PECauses

Einstein Investigators NEJM 2012;366:1287-1297

Riva Standard

Page 23: New Oral Anticoagulants Are they better than what we have?

Einstein PEAnatomical Extent

Einstein Investigators NEJM 2012;366:1287-1297

Riva Standard

Page 24: New Oral Anticoagulants Are they better than what we have?

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

Page 25: New Oral Anticoagulants Are they better than what we have?

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

anticoagulant.

Page 26: New Oral Anticoagulants Are they better than what we have?

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

Page 27: New Oral Anticoagulants Are they better than what we have?

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

Page 28: New Oral Anticoagulants Are they better than what we have?

Schulman S, et al NEJM 2013;368:709-718

Double Blind, Randomized Trial

Page 29: New Oral Anticoagulants Are they better than what we have?

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

Page 30: New Oral Anticoagulants Are they better than what we have?

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

Page 31: New Oral Anticoagulants Are they better than what we have?

Schulman S, et al NEJM 2013;368:709-718

RE-SONATE Study

Page 32: New Oral Anticoagulants Are they better than what we have?

Agnelli G, et al NEJM 2012;1-10

Page 33: New Oral Anticoagulants Are they better than what we have?

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

Page 34: New Oral Anticoagulants Are they better than what we have?

AMPLIFY-EXT

Apixaban 2.5 Apixaban 5 Placebo

Agnelli G, et al NEJM 2013;368(8):699-708

Page 35: New Oral Anticoagulants Are they better than what we have?

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

Page 36: New Oral Anticoagulants Are they better than what we have?

Non-Valvular Atrial Fibrillation

Page 37: New Oral Anticoagulants Are they better than what we have?

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

Page 38: New Oral Anticoagulants Are they better than what we have?

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

Page 39: New Oral Anticoagulants Are they better than what we have?

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

Page 40: New Oral Anticoagulants Are they better than what we have?

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

Page 41: New Oral Anticoagulants Are they better than what we have?

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

Page 42: New Oral Anticoagulants Are they better than what we have?

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

Page 43: New Oral Anticoagulants Are they better than what we have?

Atrial FibrillationMy View

All FDA approved

Effective agents compared to warfarin

Patient selection for use is critical

Well managed warfarin will remain an option

Page 44: New Oral Anticoagulants Are they better than what we have?

Medically ill Patient

Page 45: New Oral Anticoagulants Are they better than what we have?

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

Page 46: New Oral Anticoagulants Are they better than what we have?

ADOPT

Goldhaber S, et al NEJM 2011;365(23):2167-2177

Apixaban 2.5 mg BIDEnoxaparin 40mg, Qday

Page 47: New Oral Anticoagulants Are they better than what we have?

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

Page 48: New Oral Anticoagulants Are they better than what we have?

Cohen A, et al NEJM 2013;368:513-523

Page 49: New Oral Anticoagulants Are they better than what we have?

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

Page 50: New Oral Anticoagulants Are they better than what we have?

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

Page 51: New Oral Anticoagulants Are they better than what we have?

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 !!!!!!!!!!!!!!!!

Page 52: New Oral Anticoagulants Are they better than what we have?

Key PointsBlack Box Warnings, Stroke, MI Risk,

Drug Interactions, Major Bleeding

Page 53: New Oral Anticoagulants Are they better than what we have?

Black Box WarningRivaroxaban & Apixaban

Page 54: New Oral Anticoagulants Are they better than what we have?

Patel M et al, NEJM 2011;365:883-891

ROCKET AF

Page 55: New Oral Anticoagulants Are they better than what we have?

Patel M, et al JACC 2013;61:651-658

Page 56: New Oral Anticoagulants Are they better than what we have?

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

Page 57: New Oral Anticoagulants Are they better than what we have?

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)

Page 58: New Oral Anticoagulants Are they better than what we have?

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

Page 59: New Oral Anticoagulants Are they better than what we have?
Page 60: New Oral Anticoagulants Are they better than what we have?

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

Page 61: New Oral Anticoagulants Are they better than what we have?

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

Page 62: New Oral Anticoagulants Are they better than what we have?

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

Page 63: New Oral Anticoagulants Are they better than what we have?

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

Page 64: New Oral Anticoagulants Are they better than what we have?

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

Page 65: New Oral Anticoagulants Are they better than what we have?

Eriksson B, et al Thromb Res 2012;130:396-402

Page 66: New Oral Anticoagulants Are they better than what we have?

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

Page 67: New Oral Anticoagulants Are they better than what we have?

Major Bleeding

Page 68: New Oral Anticoagulants Are they better than what we have?

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

Page 69: New Oral Anticoagulants Are they better than what we have?

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

Page 70: New Oral Anticoagulants Are they better than what we have?

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.

Page 71: New Oral Anticoagulants Are they better than what we have?

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

Page 72: New Oral Anticoagulants Are they better than what we have?

Eerenberg E, et al Circulation 2011;124:1573-1579

Rivaroxaban 20 mg BID

Prothrombin Time

PCC

Placebo

PCC or Placebo

Page 73: New Oral Anticoagulants Are they better than what we have?

Eerenberg E, et al Circulation 2011;124:1573-1579

aPTT

PCC

Dabigatran 150mg BID

PCC or Placebo

Placebo

Page 74: New Oral Anticoagulants Are they better than what we have?

Eerenberg E, et al Circulation 2011;124:1573-1579

Dabigatran 150mg BID

PCC or Placebo

Placebo PCC

Thrombin Time

Page 75: New Oral Anticoagulants Are they better than what we have?

Eerenberg E, et al Circulation 2011;124:1573-1579

Dabigatran 150mg BID

PCC or Placebo

PCC

Placebo

ECT

Page 76: New Oral Anticoagulants Are they better than what we have?

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

Page 77: New Oral Anticoagulants Are they better than what we have?

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

Page 78: New Oral Anticoagulants Are they better than what we have?

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%

Page 79: New Oral Anticoagulants Are they better than what we have?

Package Insert Recommendations

DabigatranFFP, Prothrombin Complex Concentrate

Activated Factor VII

Dialysis

Rivaroxaban & ApixabanProthrombin Complex Concentrate

Four Factor Concentrate (KCentra)

FFP

Page 81: New Oral Anticoagulants Are they better than what we have?

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