Oral Anticoagulants & Reversal Strategies...Antidote Vitamin K, 4PCC None None None None Cost $0.36 tab $3.16 day $4 per tab $6.80 day ? Adapted from Desai – Novel Oral Anticoagulants

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ISHP Spring Conference

Boise 2015

Oral Anticoagulants & Reversal Strategies

Rob Wills, Pharm.D., BCPSSr Clinical Manager of PharmacySt. Luke’s Treasure Valley

April 12th, 2015

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1. Discuss current updates related to the new oral anticoagulants

2. Describe the indications and differences between agents

3. Evaluate the differences between reversal agents

4. Identify the complications associated with the use of the new oral anticoagulants

Objectives

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J Am Coll Cardiol. 2012;59(16):1413-1425. doi:10.1016/j.jacc.2012.02.008

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Wisconsin Sweet Clover & Rodenticide

ISCONSIN

LUMNI

ESEARCH

OUNDATION

Wardrop & Keeling. British Journal of Haematology, 2008:141;757-763

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5

What’s Wrong With WARFARIN?

Chest. 2008;133(6_suppl):160S-198S

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Well Established Guidelines

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7


8

� Slow on/off

Reversibility with Phytonadione

� Food Interactions

http://theanswerpage.com/uploaded/images/warfarin/warfarin_2-1.pnghttp://www.clinicalcorrelations.org/wp-content/uploads/2011/07/health-benefits-of-vitamin-k.jpg

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9

Year in the life of a Warfarin patient

10

0

1

2

3

4

5

6

INR

Read

ing

INR Trend 2013

Antibiotic

Year in the life of a Warfarin patient

Trip to Europe

Stomach bug

New dietThanksgiving

January March September December

INR

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11

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 and Eur Heart J2006:27:1979–2030.

Time in Therapeutic Range (TTR)

4447 48 49 49

53 53 54 55 55 56 56 56 57 58 58 60 60 62 62 64 64 64 64 64 65 65 66 66 66 67 68 68 70 70 70 71 71 72 72 72 74 7477

0

10

20

30

40

50

60

70

80

90

Ta

iwan

Mexic

o

Peru

Ro

man

ia

Ind

ia

Co

lum

bia

Ru

ssia

Bra

zil

Ch

ina

Ko

rea

Gre

ece

Th

ailan

d

Mala

ysia

Po

lan

d

Jap

an

So

uth

Afr

ica

Fra

nce

Slo

cakia

Po

rtu

gal

Isra

el

Czech

Re

pu

blic

Ph

ilip

pin

es

Bu

lgari

a

Hu

ng

ary

Ho

ng

Ko

ng

Tu

rkey

Belg

ium

Au

str

ia

US

A

Sp

ain

Ge

rman

y

Sw

itzerl

an

d

Sin

gap

ore

Arg

en

tin

a

Neth

erl

an

ds

No

rway

Can

ad

a

Ita

ly

Ukra

ine

UK

Den

mark

Au

str

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Fin

lan

d

Sw

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en

Wallentin L, et al. Lancet. 2010 Sep 18;376(9745):975-83. PMID: 20801496.

USA

Preventing Afib Related Strokes. Boston University Anticoagulation Forum. Accessed 12-28-2014

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a) Rapid onset-offset

b) Predictable pharmacokinetics/pharmacodynamics

c) Low risk of bleeding

d) Low risk of drug-drug or drug-food interactions

e) All of the above

Question: What are the ideal characteristics of an oral anticoagulant?

National warfarin and dabigatran treatment visits, 2007 to 2011.

Kirley K et al. Circ Cardiovasc Qual Outcomes. 2012;5:615-621

Copyright © American Heart Association, Inc. All rights reserved.

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Quarterly prescription expenditures for warfarin and dabigatran (retail value), 2007 to 2011.

Kirley K et al. Circ Cardiovasc Qual Outcomes. 2012;5:615-621

Copyright © American Heart Association, Inc. All rights reserved.

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� Approved 2010

� Use �� 4-fold

� FDA - reports of serious and fatal bleeds

Dabigatran (Pradaxa®)

Pradaxablood.com

McConeghy KW, et al. Pharmacotherapy. 2014;34(6):561-569Southworth et al. N Engl J Med 2013; 368:1272-1274

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Dabigatran (Pradaxa®)

McConeghy KW, et al. Pharmacotherapy. 2014;34(6):561-569Southworth et al. N Engl J Med 2013; 368:1272-1274

Warfarin Dabigatran (Pradaxa®)

Adverse Reports

2038 9029

Bleeding Events

637 (32%) 2347 (26%)

Fatal outcomes

46 (7.1%) 348 (15%)

Lower bound est 150 bleeding fatalities per 100,000 dabigatran patient years

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NOAC – FDA Approval Status

Indication DabigatranPradaxa®

RivaroxabanXarelto®

ApixabanEliquis®

EdoxabanSavaysa®

Atrial fibrillation

FDA approved FDA approved FDA approved FDA approved

VTE Treatment FDA approved FDA approved FDA approved FDA approved

VTE Prevention, Ortho surgery

No FDA activity

FDA approved FDA approved No FDA activity

Adapted from Desai – Novel Oral Anticoagulants. ISHP Fall Conference 2014

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Atrial Fibrillation - Stroke

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Stroke Epidemiology - CDC

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� Age 84

� 3+ yr hx of afib

� HTN

� CHADS2 ≥ 2

� Currently on wafarin

– INR TTR ~ 50%

� Minor complaints of bruising and nose bleeds

� SCr 1.6, Wt 81 kg

Mary

http://www.atrialfibrillation.com.au/images/Practice/ivy.jpg

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http://theanswerpage.com/uploaded/images/afib3/afib3_5-1.png

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Risk Category Recommendation

CHA2DS2-VASc = 0 No Therapy

CHA2DS2-VASc = 1 OAC or ASA or no therapy

CHA2DS2-VASc ≥ 2 OAC

Unstable INR Dabigatran, Rivaroxaban or Apixaban

2014 AHA/ACC/HRS Atrial Fibrillation Guidelines

January CT et al. J Am Coll Cardiol. 2014 Mar 28

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http://afibprofessional.cardiosource.org/~/media/Images/Science%20and%20Quality/Hot%20Topics/hottopic_09272011_hasbled.ashx

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http://neurosurgerysurvivalguide.com/roundy/HAS-BLED%20Bleeding%20risk.png

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HAS-BLED vs. CHADS-VASc

http://img.medscape.com/article/759/348/759348-tab2.jpg

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Drug Feature

Warfarin DabigatranPradaxa®


ApixabanEliquis®

EdoxabanSavaysa®

Target Vitamin K Thrombin Factor Xa Factor Xa Factor Xa

Dose Freq Daily Twice Daily Daily Twice daily Once Daily

Onset Slow Rapid Rapid Rapid Rapid

Peak effect 4 to 5 days 1 to 2 hours 2 to 3 hours 1 to 2 hours 1 to 2 hours

Offset Long Short Short Short Short

Half-life 40 hours 12 to 17 hrs 7 to 11 hours 12 hours 10 to 14 hrs

Renal clearance

None 80% 33% active(70% total)

25% 50%

Interactions Many P-gp CYP3A4;P-gp CYP3A4;P-gp P-gp

Monitoring Yes No No No No

Dialyzable No Yes No No No

Antidote Vitamin K, 4PCC

None None None None

Cost $0.36 tab $3.16 day $4 per tab $6.80 day ?


Drug Feature



ApixabanEliquis®

EdoxabanSavaysa®

Target Vitamin K Thrombin Xa Xa Xa

Dose Freq

Daily or Twice Daily?

Daily





Renal clearance


25% 50%




Antidote Vitamin K, 4PCC

None None None None



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Drug Feature



ApixabanEliquis®

EdoxabanSavaysa®

Target Vitamin K Thrombin Xa Xa Xa

Dose Freq

Daily or Twice Daily?

Daily





Renal clearance


25% 50%




Antidote Vitamin K, 4PCC None None None None



32

RE-LY(18,113)

ROCKET-AF(14,264)

ARISTOTLE(18,201)

ENGAGE(21,108)

Agent Dabigatran Rivaroxaban Apixaban Edoxaban*

Design Open-labelNon-inferiority

Double-blindNon-inferiority



Inclusion Non-valvular AFCHADS2 ≥ 1

Non-valvular AFCHADS2 ≥ 2



Renal impairment (excluded)

CrCl < 30 mL/min CrCl < 30 mL/min Serum creatinine > 2.5 mg/dL or CrCl < 25 mL/min

CrCl ≤ 30 mL/min

Dosing 150 mg Twice Daily

20 mg Daily 5 mg Twice Daily High – 60 mg/dayLow – 30 mg/day

Renal Dose Adjustment

NONE75 mg dose not studied in patients

CrCl = 30 – 49 mL/min15 mg daily

2.5 mg Twice Daily if 2 or more of the following: Age > 80 yo, weight < 60 kg,SCr > 1.5 mg/dL

½ dose if CrCl 30-50 mL/min or weight < 60 kg

Atrial Fibrillation Trials

*Currently not approved in US

Connolly SJ et al. NEJM. 2009;361:1139-51; Patel MR et al. NEJM. 2011;365:883-91.Granger CB et al. NEJM. 2011;365:981-92; Guigliano RP et al. NEJM.2013;369:2093-104.

Adapted from Dager WE, Kalus JS. Preventing stroke in atrial fibrillation: pharmacist roles in optimizing therapy and ensuring patient safety. ASHP Advantage presentation. 2014 ISHP Conference

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RE-LY(18,113)

ROCKET-AF(14,264)

ARISTOTLE(18,201)

ENGAGE(21,108)












CrCl ≤ 30 mL/min












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RE-LY(18,113)

ROCKET-AF(14,264)

ARISTOTLE(18,201)

ENGAGE(21,108)












CrCl ≤ 30 mL/min












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Trial Characteristics

Dabigatran(RE-LY)

Rivaroxaban(ROCKET AF)

Apixaban(ARISTOTLE)

Edoxaban (ENGAGE)

Participants 18,113 14,264 18,201 21,105

Median age 71 (mean) 73 70 72

Mean CHADS2 2.1 3.5 2.1 2.8

Mean TTR 64% 55% 62% 68.4%

Median CrCl 68 67 N/A --

NOAC in A.Fib – trial results


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Stroke or Systemic Embolism

ARISTOTLE apixabanEfficacy results driven by reduction in hemorrhagic stroke

RR (95% CI)

0.66 (0.53 – 0.82)

0.88 (0.74 -1.03)

Favors NOAC 1.0 Favors Warfarin


non-inferior & superior

non-inferior only

RE-LY dabigatran

ROCKET-AF rivaroxaban

150 MG BID arm

Intention-to-treat analysis presented

0.79 (0.66 – 0.95)

Connolly SJ et al. NEJM. 2009;361:1139-51; Patel MR et al. NEJM. 2011;365:883-91.Granger CB et al. NEJM. 2011;365:981-92;

non-inferior & superior

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Stroke or Systemic Embolism

ENGAGE AF-TIMI 48

High Dose Edoxaban (60 mg)

Low Dose Edoxaban (30 mg)

GFR 30-50 mL/min, Wt < 60 kg, potent PG inhibitor

RR (95% CI)

0.87 (0.73 – 1.04)

1.13 (0.96-1.34)

1.38


Guigliano RP et al. NEJM.2013;369:2093-104.

non-inferior

non-inferior


38

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..

Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients

All cause stroke/SEE

Ischemic and unspecified stroke

Hemorrhagic stroke

Preventing Afib Related Strokes. Boston University Anticoagulation Forum. Accessed 12-28-2014


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GI Bleeding

Meta-analysis of Efficacy and Safety of New Oral AnticoagulantsDabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients

Major bleeding

Intracranial bleeding

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.Preventing Afib Related Strokes. Boston University Anticoagulation Forum. Accessed 12-28-2014


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3.11 3.6

2.12.75

3.36 3.453.09

3.43

0

1

2

3

4

5

6

7

8

9

10

Dabigatran Rivaroxaban Apixaban Edoxaban

Lower Major Bleeding Rates

Majo

r B

leed

ing

Rate

P = 0.31P = 0.576

P < 0.001 P < 0.001


Connolly SJ et al. NEJM. 2009;361:1139-51; Patel MR et al. NEJM. 2011;365:883-91.Granger CB et al. NEJM. 2011;365:981-92;

Wa

rfari

n

Wa

rfari

n

Wa

rfari

n

Wa

rfari

n

Edoxa

ban

Apix

aban

Riv

aro

xab

an

Da

big

atr

an

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Trial NOAC Conclusion

RE-LY Dabigatran 150 mg more effective in preventing stroke or systemic embolism without significantly increasing major bleeding

ROCKET-AF Rivaroxaban Non-inferior for preventing stroke or major embolismwithout significantly increasing major bleeding

ARISTOTLE Apixaban Superior to warfarin in preventing stroke or systemic embolism, reducing bleeding and mortality

ENGAGE Edoxaban 30 mg and 60 mg non-inferior for the prevention of stroke or systemic embolism, reduced the risk of major bleeding and cardiovascualar death

AVERROES Apixaban Apixaban 5 mg BID superior to aspirin 81 – 325 mg/day in warfarin unsuitable patients

Trial Conclusions


Chan NC et al. Thromb Haemost. 2014;111:798-807

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� CrCl ~ 40 ml/min

� SCr 1.6, Wt 81 kg

� Age 84

What’s Best For Mary?

http://www.atrialfibrillation.com.au/images/Practice/ivy.jpg

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� Cost of therapy

� Safety (bleeding risks, need for reversal)

� Management support

� Adherence

� Compliance with follow up

� Drug-Drug or Drug-food interactions

� Organ dysfunction (renal/liver)

� Previous experience with anticoagulants

Considerations for Anticoagulation Therapy


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� Effects of acute illness, organ system changes, or new medications (or stopping other meds)?

� Timing/Stopping before invasive procedure

� Switching between agents

� Follow-up plans or monitoring?

� What should be monitored/measured?

� Reversibility

– Is there a way to reverse the effects?

Managing Patients on NOACs


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� 84 yo female, 3+ yr hx of afib

� Changing to Apixaban

� Which option is the best?

a) Start Apixaban and DC warfarin after 5 days

b) DC warfarin and start Apixaban now

c) DC warfarin and start Apixaban when INR < 2

d) DC warfarin and start Apixaban when INR < 1.5

Patient Case 1 Atrial FibrillationHow To Switch?

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ORAL ANTICOAGULANT CONVERSIONS

from warfarinto …

APIXABAN

INR is < 2.

DABIGATRAN

INR is < 2.

RIVAROXABAN

INR is < 3

EDOXABAN

INR is ≤ 2.5

Adapted from NEW ORAL ANTI-COAGULANTS 2013 (Amr A. Soliman, PharmD, BCPS, CGP)

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ORAL ANTICOAGULANT CONVERSIONS

from non-warfarinanti-coagulant to …

Apixaban:

d/c non-warfarin anti-coagulant & beginthe apixaban at thenext scheduleddose of the non-warfarin anti-coagulant.

Dabigatran:

start 0 to 2 hours beforethe time of the next doseof the non-warfarin anti-coagulant or at time ofdiscontinuation ofcontinuously administeredparenteral anti-coagulant(ie, heparin infusion).

Rivaroxaban:

d/c the non-warfarin anti-coagulant & begin therivaroxaban at the nextscheduled dose of the non-warfarin anti-coagulant.

From heparin continuousinfusion to rivaroxaban:stop heparin infusion & startrivaroxaban at same time.

Edoxaban:

d/c the non-warfarin anti-coagulant & begin theedoxaban at the nextscheduled dose

From heparin continuousinfusion to edoxaban: stopheparin infusion & startedoxaban at same time


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DOSING: RENAL DISEASEAPIXABAN (ELIQUIS®)

DABIGATRAN (PRADAXA®)

RIVAROXABAN (XARELTO®)

EDOXABAN(SAVAYSA®)

afib

2.5mg BID if has at least 2 of the following:age = 80+, weight < 60kg, SCr > 1.5

CrCl 15-30: 75mg BID.CrCl <15: AVOID USE .(Per ACCP, contraindicated in CrCl < 30; excluded from RE-LY trial).

(use actual body weight to calculate CrCl)CrCl 15-50: 15mg daily w/evening mealCrCl <15: AVOID USE.

CrCl 15-50: 30mg DailyCrCl <15 or > 95: AVOID USE .

Post-Ortho

(off-label): 2.5mg BID.

(off-label): CrCl <30: AVOID USE; age >75: 150mg daily.

(use actual body weight to calculate CrCl)CrCl<30: AVOID USE .

(na)

VTE Treatment

(off label): VTE prevention after initial treatment: 2.5mg BID.

(off-label): CrCl 30-50: 75mg x1 then 150mg daily (CrCl <30: AVOID USE).

(use actual body weight to calculate CrCl)CrCl<30: AVOID USE .

CrCl 15-50: 30mg DailyORBody wt < 60 kg OR on P-gp inhib


50

Drug Interactions

Dabigatran Interacting Agents

� Serum conc Amiodarone, quinidine, ketoconazole, verapamil, clopidogrel

� Serum conc Antacids, atorvastatin, proton pump inhibitors, rifampin (avoid)

Rivaroxaban Interacting Agents

� Serum conc Ketoconazole, ritonavir, clarithromycin, erythromycinOthers: conivaptan, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine, itraconazole

� Serum conc Carbamazepine, phenytoin, rifampin, St. John’s wort

Apixaban Interacting Agents

� Serum conc Ketoconazole, diltiazem, naproxen, not recommended with azoles (ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (ritonavir)

� Serum conc Carbamazepine, phenytoin, rifampin, St. John’s wort


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DOSING: NG Tube Administration

APIXABAN (ELIQUIS®)

DABIGATRAN (PRADAXA®)

RIVAROXABAN (XARELTO®)

administration via tube

may be crushed & given via any GI tubes.

cannot be given via tube; breaking, chewing or opening capsule = 75% �in absorption = adverse reactions likely.

needs acidic pH; may be crushed & given via GI tubes that end in stomach, but not in intestines.


52

John

http://www.torhoermanlaw.com/uploadedfiles/image/articleHeaders/Concerned_Man.jpg

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– Up to 900,000 people are affected by DVT/PE annually16,51

– ≈550,000 hospitalizations annually in the United States for DVT and/or PE14

– Healthcare costs associated with DVT/PE in 2011 were estimated tobe up to $10 billion16

�

VTE Is a Major Cause of Morbidity and Mortality With a Significant Economic Burden in the United States

CDC Reported Causes of Annual Deaths in the United States15,16

BreastCancer

HIV Traffic Accidents

DVT/PEA

nn

ual

Death

s (

x10

3)

0

20

40

60

80

100

120

41,078

9406

32,216

100,000

VTE kills more people each year than breast cancer, HIV, and traffic accidents…combined15,16

54

PESI Scoring(Pulmonary Embolism Severity Index)

Variable PESI Score

Age > 80 Age in years

Male sex +10

History of Cancer +30

History of heart failure +10

History of chronic lung disease +10

Pulse ≥ 110 beats/min +20

SBP < 100 mmHg +30

Respiratory rate ≥ 30 breaths/min +20

Altered mental status +60

Arterial oxyhemoglobin saturationlevel < 90%

+20

Aujesky et al. Lancet 2011;378:41-48

Score Risk Level

< 66 Class I

66 – 85 Class II

86 – 105 Class III

106 – 125 Class IV

>125 Class V

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sPESI Scoring(Pulmonary Embolism Severity Index)

Variable Simplified PESI Point Scale

Age > 80 1

History of Cancer 1

History of Heart Failure, Chronic Lung Disease

1

Pulse ≥ 110 bpm 1

SBP < 110 mmHg 1

Arterial oxyhemoglobinsaturation level ≤ 90%

1

Total Points =

56

sPESI Scoring(Pulmonary Embolism Severity Index)

sPESIScore

Risk Level Treatment

< 1 & no SxNo Risk(or incidental)

Home

< 1 + SxLow Home?

≥ 1High Admit

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Parenteral Anticoagulation

Initial Therapy: 0 to ≈7 days

Bridging therapy

Oral anticoagulants such as warfarin are used for longer-term protection

Routine INR monitoring is required to ensure adequate anticoagulation26

Mean TTR is low in patients receiving warfarin, particularly during the first 3 months of treatment36

Rapid-onset parenteral anticoagulants are used concurrently

with VKA until therapeutic INR is

reached

Long-term therapy: ≈7 days to 3 months

Extended therapy: ≈3 months to indefinite

INR monitoring required

VKA (INR 2.0-3.0)

Traditional Treatment Approaches for VTERequire Multiple Agents and Close Monitoring60

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Enoxaparin followed by VKA

• EINSTEIN DVT8

− Objectively confirmed proximal DVT without symptomatic PE

• EINSTEIN PE11

− Objectively confirmed PE with or without DVT

R

A

N

D

O

M

I

Z

E

Primary efficacy outcome: Symptomatic recurrent VTE†

Principal safety outcome: Clinically relevant bleeding‡

Rivaroxaban 15 mg

twice daily

Treatment period of 3, 6, or 12 months*

Day 1 Day 21

Rivaroxaban 20 mg

once daily

*Decision to treat for 3, 6, or 12 months made by investigator at time of randomization. †Defined as the composite of recurrentDVT, nonfatal PE, or fatal PE. ‡Defined as the composite of major and clinically relevant nonmajor bleeding.

The EINSTEIN DVT and PE Trials Evaluateda Single-Agent Regimen for VTE Treatment

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RECOVER(5144)

EINSTEIN(7449)

AMPLIFY(5400)

HOKUSAI(7500)

Agent Dabigatran Rivaroxaban Apixaban Edoxaban

Design Double blind Open label Double blind Double-blind

Indication VTE DVT or PE VTE VTE

Heparin Bridge?

Yes. LMWH or heparin for 5 days. Dabigatran was started after DC of parenteral anticoagulation.

No No Yes.LMWH or heparin for 5 days. Edoxaban was started after DC of parenteral anticoagulation.

Dosing Dose: 150 mg Twice Daily

15 mg BID x 3 weeks, then 20 mg daily

10 mg bid x 7 days, then 5 mg TwiceDaily

Dose 60 mg daily(30 mg daily in patients with CrCl 30 – 50 ml/min

Duration (mo)

6 3,6,12 3,6,12 3,6,12

DVT/PE Trials


Schulman et al. N ENGL J MED. 2009:361;24. EINSTEIN Investigatros. N ENGL J MED. 2010;363:2499 . Agnelli et al. N ENGL J MED. 2013;369:799. Hokusai investigators. N ENGL J MED. 2013;369:1406

62

RECOVER(5144)

EINSTEIN(7449)

AMPLIFY(5400)

HOKUSAI(7500)

Agent Dabigatran Rivaroxaban Apixaban Edoxaban

Design Double blind Open label Double blind Double-blind

Indication VTE DVT or PE VTE VTE

Heparin Bridge?

Yes. LMWH or heparin for 5 days. Dabigatran was started after DC of parenteral anticoagulation.

No No Yes.LMWH or heparin for 5 days. Edoxaban was started after DC of parenteral anticoagulation.

Dosing Dose: 150 mg Twice Daily

15 mg BID x 3 weeks, then 20 mg daily

10 mg bid x 7 days, then 5 mg TwiceDaily

Dose 60 mg daily(30 mg daily in patients with CrCl 30 – 50 ml/min

Duration (mo)

6 3,6,12 3,6,12 3,6,12

DVT/PE Trials



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63

AprilR

IVA

RO

XA

BA

NA

PIX

AB

AN

Days 1 - 21Days 21 - ….

Days 1 - 7

Days 7 - ….

64

April

ED

OX

AB

AN

Days 1 – 5 or 10Days 5 or 10 - ….

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65

Recurrent VTE and VTE-related Death

Dabigatran

RR (95% CI)

0.68 (0.44 – 1.04) P < 0.001

0.86 (0.60 -1.18) P < 0.001

Rivaroxaban

Apixaban

1.10 (0.65 – 1.84)


Edoxaban 0.89 (0.70 -1.13)



66

Major Bleeds

Dabigatran

RR (95% CI)

0.97 (0.76 – 1.22)

0.31 (0.17 -0.55) P < 0.001

Rivaroxaban

Apixaban

0.82 (0.45 – 1.48)


Edoxaban 0.81 (0.71 -0.94)



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Trial NOAC Conclusion

RECOVER Dabigatran 150 mg twice daily regimen of dabigatran, following an initial txof parenteral anticoagulation, is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.

EINSTEIN Rivaroxaban Rivaroxaban alone is as effective as standard therapy, with similar safety, for the treatment of acute VTE and that when treatment is continued, rivaroxaban is very effective in preventing recurrences, as compared with placebo, and has an acceptable risk of bleeding.

AMPLIFY Apixaban Apixaban alone was as effective as conventional treatment consisting of enoxaparin followed by warfarin and was associated with a clinically relevant reduction of 69% in major bleeding.

HOKUSAI-VTE

Edoxaban Treatment with heparin followed by oral edoxaban once daily, as compared with standard therapy, was noninferior with respect to efficacy and superior with respect to bleeding.

Trial Conclusions – DVT/PE


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NOAC Conclusion

Dabigatran Non-Inferior to warfarin

Rivaroxaban Non-Inferior to warfarin

Apixaban Non-Inferior to warfarin- Reduced incidence of bleeding

Edoxaban Non-Inferior to warfarin- Reduced incidence of bleeding

Trial Conclusions – DVT/PE


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Transition of Care- The Anticoagulation Clinic

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Drug Renal Function Time of Last Dose Before Minor Procedure

Time of Last Dose Before Major Surgery

Dabigatran

CLcr > 50 mL/min 1 day (24 hrs) 2 days

CLcr 30-50 mL/min 2 days 4 days

CLcr ≤ 30 mL/min 4 days 6 days

Rivaroxaban or Apixaban

CLcr > 50 mL/min 1 day (24 hrs) 2 days

CLcr 30-50 mL/min 1 to 2 days 3 to 4 days

CLcr ≤ 30 mL/min 2 days 4 days

Timing of discontinuation of TSOAC for Non-urgent Procedures

Nutescu E, et al. Management of bleeding and reversal strategies for oral anticoagulants: Clinical practice considerations. Am J Health-Syst Pharm. 2013. 70;e82-97

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http://www.kcentra.com/App_Themes/Professional/images/header-billboard1.png

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a) Watch and wait

b) FFP

c) Novo 7

d) Prothrombin Complex Concentrate

e) Activated PCC

f) Dialysis

g) All of the above

What is the best treatment option for acute reversal of new oral anticoagulant?

http://www.kcentra.com/App_Themes/Professional/images/header-billboard1.png

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Factor Composition of 4PCC (Kcentra™)Composition per Vial of Prothrombin Complex Concentrate 500 Units1

Ingredient Quantity

Total protein 120 to 280 mg

Factor II 380 to 800 units

Factor VII 200 to 500 units

Factor IX 400 to 620 units

Factor X 500 to 1,020 units

Protein C 420 to 820 units

Protein S 240 to 680 units

Heparin 8 to 40 units

Antithrombin III 4 to 30 units

Human albumin 40 to 80 mg

Sodium chloride 60 to 120 mg

Sodium citrate 40 to 80 mg

Hydrochloric acid small amounts

Sodium hydroxide small amounts

Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; April 2013.

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Clinical Efficacy

Median INR After Start of Infusion of Prothrombin Complex

Concentrate or Plasma in Patients Treated with Warfarin1

Prothrombin Complex

Concentrate (n = 98)

Plasma (n = 104)

Baseline 3.9 3.6

30 minutes 1.2a 2.4

1 hour 1.3a 2.1

2 to 3 hours 1.3a 1.7

6 to 8 hours 1.3a 1.5

12 hours 1.2a 1.4

24 hours 1.2 1.3

Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; April 2013.

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Adverse Reaction ComparisonAdverse Reactions Reported in (3 or more Subjects) Following Administration of Kcentra

or Plasma in the Randomized Controlled Trial for the Treatment of Acute Major Bleeding1

Prothrombin Complex

Concentrate (n = 103)

Plasma

(n = 109)

Headache 7.8% 1.8%

Hypotension 4.9% 2.8%

Nausea/vomiting 3.9% 0.9%

Arthralgia 3.9% 0%

Tachycardia 2.9% 0.9%

Blood pressure increase 2.9% 0%

INR increased 2.9% 0%

Intracranial hemorrhage 2.9% 0%

Mental status changes 2.9% 0%

Hypokalemia 1.9% 4.6%

Fluid overload 1% 5.5%

Breath sounds abnormal/rates 1% 2.8%

Chest pain 1% 2.8%

Pulmonary edema 0% 3.7%

Transfusion reaction 0% 3.7%Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; April 2013.

www.clotconnect.org Feb 2014

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Lab Measure Dabigatran Rivaroxaban Apixaban

aPTT � to � � �

PT/INR � to � � to � � to �

Modified PTa� to � ��

Thrombin time ��

Ecarin Clotting Timea��

Antifactor Xaa� to � ��

Heptesta � ��

New Oral Anticoagulant Effects on Coagulation Assays

Adapted from McMillian W, Aloi J. Thrombotic and bleeding diatheses in critically ill patients. Critical & Urgent Care PSAP. 2014

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� Typically given within 2hrs of last dose

� Apixaban is the exception

– Can give up to 6hrs post dose

Activated Charcoal

Wang X, et al. Effect of Activated Charcoal on Apixaban Pharmacokinetics in Healthy Subjects. Am J CardiovascDrugs. 2014. 14:147-154.

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file://home.slhs.org/willsr$/My%20Documents/Downloads/95-330-1-PB.pdf

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PCC vs. aPCC (FEIBA)

Marlu et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108:217-224.

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Eerenberg 2011(RCT;crossover)

No. of patients 12

Disease Healthy

Anticoagulant drug Dabigatran 150 mg BIDOr Rivaroxaban 20 mg BID

Coagulation assays measured after each intervention

Yes

Length of drug therapy prior to intervention

2.5 days for each medication

Intervention 50 units of 4PCC/kg

Outcome PCC immediately and completely reversed PT for rivaroxaban (P<0.001)

PCC had No effect on aPTT, ECT, and TT for dabigatran

Reversal of Dabigatran and Rivaroxaban: A Crossover Randomized Controlled Trial

Adapted from: Thigpen J and Limdi N. Reversal of Oral Anticoagulation. Pharmacotherapy 2013;33(11):1199-1213.

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Level of Urgency

Warfarin Dabigatran Rivaroxaban or Apixaban

No rush (>24 hrs)

Hold and consider vit K

Hold dose and monitor

Hold dose and monitor

Expedited (1 to 24 hrs)

Hold & consider vit K

Hold and consider act charcoal if within 2 hrs (dabigatran/rivaroxaban or 6 hr for apixaban)

Emergent (<1hr)

Hold & give vitK

Hold & give act charcoal based on last admin time

Consider factor (listed in order of preference)

4PCC aPCC 4PCC

3PCC + rFVIIa 4PCC aPCC

aPCC 3PCC + rFVIIa 3PCC + rFVIIa

3PCC 3PCC 3PCC

rFVIIa rFVIIa

Nutescu E, et al. Management of bleeding and reversal strategies for oral anticoagulants: Clinical practice considerations. Am J Health-Syst Pharm. 2013. 70;e82-97

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Pharmacotherapy: The Journal of Human Pharmacology and Drug TherapyVolume 35, Issue 2, pages 198-207, 3 FEB 2015 DOI: 10.1002/phar.1532

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http://i.ytimg.com/vi/LXA7aIAA7yQ/maxresdefault.jpg

http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11395

http://www.clinicalcorrelations.org/?p=7373

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http://www.businesswire.com/news/home/20150303005100/en/Boehringer-Ingelheim-submits-applications-approval-idarucizumab*-specific#.VQBbj1W8DW0