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Take It Back: Management of direct oral anticoagulants and reversal agents

Mid-Winter Conference 2/7/2019

Contact information: [email protected] 1

TAKE IT BACKManagement of Direct Oral Anticoagulants and Reversal Agents

February 7th, 2019

1:30 PM – 2:30 PM

Connecticut Pharmacists Association

Mid-Winter Conference

Lydia Tran, PharmD, BCPS

Cardiovascular Clinical Pharmacist

Yale New Haven Hospital

DISCLOSURE

Dr. Tran does not have any conflicts of interest

This activity is supported by an educational grant by Bristol-Myers Squibb and Pfizer Alliance

Off-label or investigational uses of medications will be discussed

OBJECTIVES

Compare and contrast the characteristics of direct oral anticoagulants (DOACs)

Explain the risk factors for bleeding complications from the use of direct oral anticoagulants

Discuss current and emerging strategies for reversing the effects of direct oral anticoagulants

ANTICOAGULATION REVERSALDOACs

ANTICOAGULATION (AC)


UTILITY OF ANTICOAGULATION

Venous thromboembolism (VTE) prophylaxis

Venous thromboembolism (VTE) treatment

Atrial fibrillation (AF) - stroke/systemic embolism prophylaxis

Coronary artery disease (CAD) /Peripheral artery disease (PAD)


TRENDS IN ORAL ANTICOAGULANT USE

IMS Health National Disease and Therapeutic Index, 2009-2014.

All Anticoagulants

Warfarin

DOACsRivaroxabanApixabanDabigatran

1 2

3 4

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RISK FACTORS FOR BLEEDING WITH AC THERAPY

Age > 65 yo; Age > 75 yo Recent surgery

Previous bleeding/Hx bleeding disorder Antiplatelet therapy (triple therapy)

Previous stroke Renal failure

Comorbidity and reduced functional capacity

Liver failure

Diabetes Frequent falls

Cancer Alcohol misuse

Anemia NSAID use

Thrombocytopenia


WARFARIN (VITAMIN K ANTAGONIST)

Widely used oral anticoagulant

Reversibility with Vitamin K

Ability to identify degree of AC

Ability to manage drug interactions

Disadvantages Delayed onset of action

Narrow therapeutic window

Inconsistent metabolism

Education and compliance

Monitoring and follow-up required

Drug, diet, and disease interactions

N Engl J Med. 2011;365(21):2002-2012


COAGULATION CASCADE

Adapted from Dager WE. Managing and Reversing Direct Oral Anticoagulants. www.DOACresources.org

XIIa

XIaXI

Fibrinogen

IXaIX

VIIIaVIII

X

VaV

II

XII

Fibrin

VIIa VII

Xa

IIa


COAGULATION CASCADE


XIIa

XIaXI

Fibrinogen

IXaIX

VIIIaVIII

X

VaV

II

XII

Fibrin

VIIa VII

Xa

IIa

Warfarin


COAGULATION CASCADE


XIIa

XIaXI

Fibrinogen

IXaIX

VIIIaVIII

X

VaV

II

XII

Fibrin

VIIa VII

Xa

IIa Dabigatran

RivaroxabanApixabanEdoxaban

DOACs


DIRECT ORAL ANTICOAGULANTS (DOACs)

DOAC vs. NOAC vs. TSOAC vs. DSOAC

Direct Thrombin Inhibitors

DabigaTran (Pradaxa®)

Factor Xa Inhibitors

Apixaban (Eliquis®)

Rivaroxaban (Xarelto®)

Edoxaban (Savaysa®)

“NOACs” = NO AC

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9 10

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DOACs = SAFER BRIDGE FROM HOSPITAL TO HOME

Widely used oral anticoagulantImmediate acting

“One size fits most” dosing regimen

Education and compliance

Minimal monitoring and follow-up

Limited drug interactions

Disadvantages Affordability and prior authorization

Under-dosing/Over-dosing

Compliance and adherence

Bleeding complications and reversibility


EVOLUTION OF ANTICOAGULATION

1954 2010 2011 2012 2015

Warfarin Rivaroxaban (ROCKET AF)

Edoxaban(ENGAGE TIMI 48)

Apixaban(ARISTOTLE)

Dabigatran(RE-LY)


DOAC COMPARISON

ADAPTED FROM DAGER WE. MANAGING AND REVERSING DIRECT ORAL ANTICOAGULANTS. WWW.DOACRESOURCES.ORG

APIXABAN RIVAROXABAN DABIGATRAN EDOXABAN

Target for activity Factor Xa Factor Xa Factor IIa (thrombin) Factor Xa

Bioavailability ~50% 66%(>90% with food)

3–7% (increased by 75% if capsules broken, chewed, or opened)

62%

Time to peak plasma conc.

3–4h 2–4h (delayed by food)

1–3h (delayed by food)

1–2h

Half-life 12h 5–9h (11–13 elderly) 12–17h 10–14h

Renal elim. of unchanged drug 27% 36% 80% 50%

Dialyzable?Protein binding No; 87% No; 92-95% Yes; 35% No; 55%

Key drug interactions P-gp or CYP3A4 P-gp or CYP3A4 P-gp, no CYP P-gp, no CYP


FDA-APPROVED INDICATIONS AND DOSING

Eliquis (apixaban). Package insert. Bristol-Myers Squibb Company and Pfizer Inc; 2015 Sep.Xarelto (rivaroxaban). Package insert. Janssen Pharmaceuticals, Inc; 2016 May.Pradaxa (dabigatran etexilate mesylate). Package insert. Boehringer Ingelheim Pharmaceuticals, Inc; 2015 Nov.Savaysa (edoxaban). Package insert. Daiichi Sankyo, Inc; 2015 Sep.Adapted from Dager WE. Managing and Reversing Direct Oral Anticoagulants. www.DOACresources.org

DABIGATRAN APIXABAN RIVAROXABAN EDOXABAN

VTE Prophylaxis

150 mg twice dailya 2.5 mg twice daily 10 mg daily x 6 months --

VTE Treatment 150 mg twice dailya10 mg twice daily x 7 days, then 5 mg twice daily

15 mg twice daily x 21 days, then 20 mg daily

60 mg dailyd

30 mg dailye

Atrial Fibrillation

150 mg twice daily75 mg twice dailyb

5 mg twice daily 2.5 mg twice dailyf

20 mg daily 15 mg dailyc

CrCl > 95mL/min: do not use60 mg dailyd

30 mg dailye

CAD/PAD -- -- 2.5 mg twice daily --

a CrCl > 30 mL/minb CrCl 15-30 mL/minc CrCl ≤50 mL/mind CrCl 50-95 mL/mine CrCl 15-50 mL/minf In patients with at least 2 of the following: age ≥ 80yo, body weight ≤ 60kg, or SCr ≥1.5 mg/dL


DOAC TRIALS -VTE

Trial DrugMaintenance

DoseBleeding

DOAC vs warfarinHR

(95% CI)Primary Outcome

DOAC vs warfarinHR

(95% CI)

RE-COVER Dabigatran 150 mg BID 1.6 vs 1.9% occurrence

0.82 (0.45-1.48)

2.4 vs 2.1% occurrence 1.1 (0.65-1.84)

EINSTEIN-DVT Rivaroxaban 20 mg daily 0.8 vs 0.2%0.65 (0.33-1.3) 2.1 vs 3%

0.68 (0.45-1.48)

AMPLIFY Apixaban 5 mg BID 0.6 vs 1.8%0.31(0.17-0.55) 2.3 vs 2.7%

0.84 (0.6-1.18)

HOKUSAI-VTE Edoxaban 60 mg daily 1.4 vs 1.6%0.84 (0.59-1.21) 3.2 vs 3.5%

0.89 (0.7-1.13)

Hillis C, et al. Thromb Haemost. 2015; 113(6):1193-202


DOAC TRIALS – ATRIAL FIBRILLATION

Trial Drug Dose Bleeding DOAC vs Warfarin

HR(95% CI)

Incidence of stroke DOAC vs Warfarin

HR(95% CI)

RELY Dabigatran 150 mg BID 3.1 vs 3.4% per year0.93(0.81-1.07) 1.1 vs 1.69% per year

0.66 (0.53-0.82)

ROCKET-AF Rivaroxaban 20 mg daily 3.6 vs 3.4%1.04 (0.90-1.20) 2.1 vs 2.4%

0.79(0.66-0.96)

ARISTOTLE Apixaban 5 mg BID 2.1 vs 3.1%0.57 (0.46-0.70) 1.27 vs 1.6%

0.71 (0.53-0.95)

ENGAGE-TIMI Edoxaban 60 mg daily 2.75 vs 3.43% 0.80 (0.71-0.91)

1.57 vs 1.8% 0.81 (0.65-1.03)

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15 16

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OBESITY

No randomized controlled trials of DOACs administered to large numbers of obese patients exist

PK/PD studies indicate that increasing body weight has a modest overall effect on PK parameters of the DOACs

reduced drug exposure?

lower peak concentration?

shorter half-lives?

Unknown clinical implications in possible underdosing

Martin K, et al. J Thromb Haemost 2016;14: 1308–13.


OBESITY: INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS

Recommend appropriate standard dosing of the DOACs in patients with BMI ≤ 40 and weigh ≤ 120kg

Suggest that DOACs should not be used in patients with a BMI > 40 or a weight of > 120 kg

Concerns for underdosing

If DOACs are used in a patient with a BMI >40 or a weight of > 120 kg, ISTH suggests checking a drug-specific peak and trough level

Anti-FXa apixaban, edoxaban, and rivaroxaban

Echarin time or dilute thrombin time dabigatranMartin K, et al. J Thromb Haemost 2016;14: 1308–13.


IMPAIRED RENAL FUNCTION/CKD

CKD patients are predisposed to thrombotic events

Pharmacokinetics vary among the DOACs

Dabigatran found higher AUCs in patients with decreased CrCl

Edoxaban extrapolated data provided suggested dosing for CrCl 30-50 mL/min but no guidance provided in both extremes of renal function (impaired and higher)

Rivaroxaban drug levels found to be consistent between varying degrees of renal dysfunction

Apixaban dosing based on 3 criteria: weight, SCr, and age

Drug Clearance Cut Off

Apixaban < 25 mL/min

Dabigatran < 30 mL/min

Edoxaban < 30 mL/min

Rivaroxaban < 30 mL/min

Exclusion from trials

Circ J. 2015;79(7):1486-95.Circulation. 2015;131(11):972-9.


THE DOAC BALANCING ACT

Advantages Advantages DisadvantagesDisadvantages

Cost

Lack of monitoring

Bleeding

Targeted mechanism

Rapid and reliable onset of action

Low potential for drug and food interactions


RISK OF BLEEDING COMPLICATIONS

Major bleeding

Fatal bleeding

Intracranial hemorrhage

Bleeding requiring hospitalization

Non-fatal bleeding

GI bleeding

Epistasis


TAKE IT BACK: HOW TO REVERSE

19 20

21 22

23 24





REVERSAL: THE BALANCING ACT

Risk for bleeding

Risk for thrombosis

Presence, site, and severity of bleeding

Anticoagulant reversal strategy depends on the setting (ED, OR, ICU) and urgency

Risk for thrombosis

Bleeding


REVERSAL TREATMENT

Initial therapy

Discontinue anticoagulant

Consider reversal agents/strategies

Consider consults (GI, Surgery, Hematology)

Consider supportive care: HASHTI

Salvage therapy (life-threatening bleeding)

Activate Massive Transfusion Protocol

Consider blood factor (rFactor VIIa)

Supportive Care

H Hold further doses of anticoagulant

A Consider Antidote

S Supportive Treatment: Volume resuscitation, Inotropes as needed

H Local or surgical Hemostatic measures

T Transfusion

I Investigate for bleeding source


REVERSAL STRATEGIES

Reversal Agents

Idarucizumab

Andexanet alfa

Ciraparantag

Clotting factor concentrates (PCC)

Other strategies

Desmopressin IV

Fresh frozen plasma (FFP)

Activated charcoal

Hemodialysis (for dabigatran only)


WARFARIN REVERSAL

Factor Half-life

VII 8 hr

IX 24

X 48

II 72

INR Active bleeding Antidote

Vitamin K

FFP

PCC


YNHH WARFARIN REVERSAL


EVOLUTION OF REVERSAL AGENTS

1954 2010 2011 2012 2015 2018 Future

WarfarinRivaroxaban (ROCKET AF)

Edoxaban(ENGAGE TIMI 48)

Apixaban(ARISTOTLE)

Dabigatran(RELY)

Idarucizumab (REVERSE AD)

Andexanet alfa (ANNEXA)

Ciraparantag

25 26

27 28

29 30





TARGETS OF REVERSAL AGENTS

XIIa

XIaXI

Fibrinogen

IXaIX

VIIIaVIII

X

VaV

II

XII

Fibrin

VIIa VII

Xa

IIa Dabigatran

Andexanet alfaRivaroxabanApixabanEdoxaban

Idarucizumab


Idarucizumab (Praxbind®)

Praxbind (idarucizuman). Package insert. Boehringer Ingelheim Pharmaceuticals, Inc.; 2015 Oct.

MOA: FULLY HUMANIZED

MONOCLONAL ANTIBODY FRAGMENT

THAT BINDS DABIGATRAN WITH HIGH AFFINITY TO PREVENT DABIGATRAN

INHIBITION OF THROMBIN

INDICATIONS: LIFE THREATENING

BLEED NEED FOR

URGENT SURGERY

DOSE: 5GM BOLUS

MONITORING: APTT, DTT, TT

CAUTION: REBOUND

DABIGATRAN ACTION AT 24H AS

THE DRUG REDISTRIBUTES


Andexanet alfa (Andexxa®)

Andexxa (andexanet alfa). Package insert. Portola Pharmaceuticals, Inc; 2018 Dec.

MOA:

FACTOR XA DECOY THAT TARGETS AND

SEQUESTERS DIRECT AND INDIRECT FACTOR

XA INHIBITORS WITH HIGH SPECIFICITY

INDICATIONS:

LIFE THREATENING OR

UNCONTROLLED BLEEDING

DOSE:

BOLUS FOLLOWED BY CONTINUOUS

INFUSION

MONITORING:

ANTI-XA LEVEL

CAUTION:

ARTERIAL AND VENOUS THROMBOEMBOLIC EVENTS, ISCHEMIC

EVENTS, AND CARDIAC EVENTS, INCLUDING

SUDDEN DEATH


Andexanet alfa (Andexxa®): Dosing Strategies

Andexxa (andexanet alfa). Package insert. Portola Pharmaceuticals, Inc; 2018 Dec.


COMPARISON OF REVERSAL AGENTS

Idarucizumab(Praxbind®)

Andexanet alfa(Andexxa®)

MOA fully humanized monoclonal Ab fragment recombinant human factor Xa decoy protein that binds to the anticoagulant

Target Dabigatran (Pradaxa®) Apixaban (Eliquis®) Rivaroxaban(Xarelto®)

Apixaban RivaroxabanEdoxabanEnoxaparin

Trial RE-VERSE AD ANNEXA-A ANNEXA-R ANNEXA-4

Dose Idarucizumab 5gmBolus Bolus + infusion

Bolus Bolus + infusion Bolus + infusion

Results

dTT/ECT normalization:98% Life-threatening bleed 93% Requiring urgent procedure Clinical cessation of bleeding: 11.4 h Thrombotic events: 5 patients

∆anti-Xa activity:92% bolus+infusion vs. 33% placebo (P<0.001)

∆anti-Xa activity:97% bolus+infusion vs. 45% placebo (P<0.001)

Hemostasis 12h after infusion: 79% (95% CI 64-89)

≥80% reversal of anti-Xa activity: 100 vs. 0% (P<0.001)


Ciraparantag (PER977)

MOA: SYNTHETIC SMALL MOLECULE

BINDS DIRECTLY TO AND REVERSES THE ANTICOAGULANT

EFFECTS OF FACTOR XA AND IIAINHIBITORS

“UNIVERSAL” ANTIDOTE

PLACE IN THERAPY:

EMERGENT BLEEDING CAUSED BY AN

UNKNOWN DOAC

CLINICAL TRIALS COMPLETED

ENOXAPARIN

UNFRACTIONATED HEPARIN

EDOXABAN

ONGOING CLINICAL TRIALS

(RECRUITING)

RIVAROXABAN

APIXABAN

Perosphere, Inc.. ClinicalTrials.gov [internet]. http://clinicaltrials.gov/show/NCT02206100Perosphere, Inc.. ClinicalTrials.gov [internet]. http://clinicaltrials.gov/show/NCT02206087Perosphere, Inc.. ClinicalTrials.gov [internet]. http://clinicaltrials.gov/show/NCT01826266Perosphere, Inc.. ClinicalTrials.gov [internet]. http://clinicaltrials.gov/show/NCT03172910Perosphere, Inc.. ClinicalTrials.gov [internet]. http://clinicaltrials.gov/show/NCT03288454

31 32

33 34

35 36





CLOTTING FACTOR CONCENTRATES

Prothrombin Complex Concentrates (PCC)

Three-factor PCC (PCC3) – Bebulin® or Profilnine®

Four-factor PCC (PCC4) – Kcentra®

Activated PCC (aPCC) – FEIBA®

Recombinant Factor VIIa (rFVIIa) – NovoSeven®

3-PCC 4-PCC

Factor II

Factor IX

Factor X

Factor VII X

Protein C/S X

Antithrombin III X

Price ↑30%


ANDEXANET ALFA BENCHMARKING SURVEY

14 Institutions

9 Approved formulary addition: all require criteria for use/ restricted

Reasons for not approving

Denied due to lack of convincing evidence and extremely high cost

To date multiple inquiries but not added to formulary

KCentra is formulary and is recommended for reversal of rivaroxaban and apixaban (will revisit after head to head studies with KCentra)


ANDEXANET ALFA COST

Andexanet is produced as 100 mg lyophilized powder in single-use vials.

Sold in a package of four vials. The current estimated cost for a single package of four100mg vials is $11,000.

Low dose regimen = ~$24,750

High dose regimen = ~$49,500


REVERSAL CONSIDERATIONS

Optimal timing of DOAC reversal before an invasive procedure

Urgency of the situation

Severity of bleeding

Long-term risk for thromboembolism

Etiology of excessive anticoagulation

Supportive management

Risk for thrombosis

Bleeding complications


TAKE-AWAY POINTS

DOACs offer at least as efficacious, if not safer and more convenient anticoagulation than warfarin

More data is still needed to establish the safety and efficacy for DOACs beyond traditional indications and special populations

Anticoagulation increases risk of harm across care settings, though DOACs may help streamline care continuum

Pharmacists play an integral role in ensuring safe and appropriate use of DOACs


TAKE-AWAY POINTS

Risk vs benefit of reversing DOACs with reversal agents and strategies

Warfarin reversal with 4F-PCC and Vitamin K preferred

Dabigatran reversal with Idarucizumab

Apixaban, Rivaroxaban, Edoxaban reversal with 4-PCC or Andaxanet alfa based on bleeding etioloty

37 38

39 40

41 42




QUESTIONS?

CONTACT INFORMATION

Lydia Tran, PharmD, BCPSCardiovascular Clinical Pharmacist

Adjunct Assistant Professor of Pharmacy PracticeUniversity of Connecticut School of Pharmacy

Yale New Haven Hospital 20 York Street, PS LL-01 New Haven, CT 06510

Email: [email protected] Office number: 475-246-4973

Office Location: SP 5-329

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