fibrinogen fibrin common pathway thrombin xa prothrombin clot xa blocker apixaban rivaroxaban...

Fibrinogen Fibrin

Common Pathway

Thrombin

Xa

Prothrombin

Clot

Xa Blocker

ApixabanRivaroxaban

Dabigatran

New Oral Agents

Replacing Traditional Anticoagulants

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


6 months

Warfarin TTR= 60%

RE-COVER StudyIndex Events


Dabi1273

Warfarin1266

RE-COVER StudyMajor Bleeding


Dabi Warfarin

RE-COVERA 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”


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


Warfarin TTR = 57.7%

Einstein Acute DVT StudyCauses of VTE

Riva Standard


Einstein Acute DVT StudySafety Outcomes


Riva Standard



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


Riva Standard

Einstein PEAnatomical Extent


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.



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


6-12 mo

All Rxed


Double Blind, Randomized Trial

RE-MEDY

VTE


Warfarin INR 2-3

Patient Rx3 to 12 months

1.8% 0.9%

1.3% 1.8%

VTE Major Bld


6 months

RE-SONATE

DVT


Placebo

Patient Rx6 to 18 months

0.4% 0.3%

5.6% 0%

VTE Major Bld


6-18 months


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 Bld1.7% 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 StudiesTrial RE-LY ARISTOTLE ROCKET-AF

Design Randomized Open LabelN=18,113

Randomized Double blindN=18,209

Randomized double blind & dummyN=14,000

Treatment Dabigatran150 mg, BID110 mg, BID

Apixaban5 mg, BID

Rivaroxaban20 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 Dabigatran1.1%

Warfarin1.7%

RR 0.6695% CI 0.53-0.82

P < 0.001 superiority

ARISTOTLE Apixaban1.3%

Warfarin1.6%

HR 0.7995% CI 0.66-0.95P= < 0.001 Non- I

P= 0.01 Superiority

ROCKET-AF Rivaroxaban1.7%

Warfarin2.2%

HR 0.7995% CI 0.66-0.96

P = <0.001Non-Inferiority

Major BleedingAtrial Fibrillation Trials



Warfarin3.6%

RR 0.9395% CI 0.81-1.07

P = 0.31ARISTOTLE Apixaban

2.1%Warfarin3.1%

HR 0.6995% CI 0.60-0.8

P = < 0.001ROCKET-AF Rivaroxaban

5.6%Warfarin5.4%

HR 1.0495% CI 0.90-1.20

P = 0.58

Intracranial HemorrhageAtrial Fibrillation Trials



Warfarin0.7%

RR 0.4095% CI 0.27-0.60

P= <0.001ARISTOTLE Apixaban

0.3%Warfarin0.8%

HR 0.4295% CI 0.30-0.58

P = <0.001ROCKET-AF Rivaroxaban

0.5%Warfarin0.7%

HR 0.6795% CI 0.47-0.93

P = 0.02

Dosing SchedulesAtrial Fibrillation

Agent Dosing Recommendations

Dabigatran75mg, 150mg

CrCl > 30 cc/min: 150 mg, BIDCrCl 15 to 30 cc/min: 75 mg, BIDAvoid < 15 cc/min

Apixaban2.5mg, 5mg

CrCl > 15 cc/min: 5 mg, BIDAny 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID)Avoid < 15 cc/min

Rivaroxaban10mg, 15mg, 20mg

CrCl > 50 cc/min: 20 mg, QdayCrCl 15-50 cc/min: 15 mg, QdayAvoid CrCl < 15 cc/min

Atrial Fibrillation StudiesWhen should new orals be started?

RE-LY (Dabigatran)Stroke within 14 daysSevere stroke within last 6 months

ARISTOTLE (Apixaban)Stroke within 7 days

ROCKET-AF (Rivaroxaban)Stroke within 14 daysSevere stroke within last 3 months

Modified-Ahrens I, et al Thromb Haemost 2011;105

Medically ill Patient

EXCLAIMExtended VTE Px Medically-ill

Endpoint Enoxaparin Placebo RRR

VTE 28 +/- 4 d 2.5% 4.0% -1.5395% CI -2.54 to -0.52

Major Bleed 0.8% 0.3% 0.5195% 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 BIDControl RRR

VTE during parenteral Rx

1.73% 1.61%Enox

1.0695% CI 0.69-1.63

Non-Inferior P=NSVTE at 30 days 2.71% 3.06%

Placebo0.87

95% CI 0.62-1.23Superior P=NS

Major Bleed 35 days

0.47% 0.19% 2.58P=0.04

CR Bleeding 35 days

2.67% 2.08% 1.28P=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, QdayControl RRR

VTE at 10 days 2.7% 2.7%Enox

0.9795% CI 0.713-1.334

Non-Inferior P=0.0025VTE at 35 days 4.4% 5.7%

placebo0.77

95% CI 0.618-0.962Superior P=0.021

Major Bleed 35 days

1.1% 0.4% 2.9P=0.0004

CR Bleeding 35 days

4.1% 1.7% 2.5P < 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

denc

e (%

)

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

0.3 0.8*

2.12.7

1.7

4.1*(Major Bleeding)

* p < 0.05

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 StudyGroup Riva Warfarin HR P

value

TemporaryInterruption

6.2 (9) 5.05 (8) 1.280.49-3.31

0.62

PermanentDiscontinuation

25.6 (42) 23.28 (36) 1.100.71-1.72

0.66

After end of study 6.42 (22) 1.73 (6) 3.721.51-9.16

0.004

All Discontinuation + End of study

11.2 (73) 7.57 (50) 1.51.05-2.15

0.026


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

Cum

ulat

ive

Prop

ortio

n w

ith IN

R >

2


Rocket AF Study

What happened in ROCKET AF ?

Warfarin patients continued warfarin Rivaroxaban patients discontinued study

drug and then began warfarinNot anticoagulated during warfarin

titrationNo “Bridging”

Strokes during the 30 days post studyWarfarin group – 6Rivaroxaban group - 22

Black Box WarningRivaroxaban

Epidural or Spinal HematomaUse of epidural catheterConcomitant use of NSAID, Anti-plateletTraumatic or repeated spinal punctureHistory 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 EventsAdjudicated

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 CharacteristicsCharacteristics 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% renal33% biliary

25% renal75% biliary

Metabolism Conjugation to active glucuronides

CYP3A4CYP2J2

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


Rivaroxaban 20 mg BID

Prothrombin Time

PCC

Placebo

PCC or Placebo


aPTT

PCC

Dabigatran 150mg BID

PCC or Placebo

Placebo



PCC or Placebo

Placebo PCC

Thrombin Time



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 ConcentrateActivated Factor VIIDialysis

Rivaroxaban & ApixabanProthrombin Complex ConcentrateFour Factor Concentrate (KCentra)FFP

fibrinogen fibrin common pathway thrombin xa prothrombin clot xa blocker apixaban rivaroxaban...

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