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

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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

Geno.Merli@Jefferson.edu

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For questions about the content, please contact Dr. Merli at Geno.Merli@jefferson.edu