Oral Anticoagulants Update

Elizabeth Renner, PharmD, BCPS, BCACP, CACP

Outpatient Cardiology and Anticoagulation

Objectives

• List the direct oral anticoagulant (DOAC) drugs currently

available

• Describe advantages and disadvantages to DOAC use

• Compare efficacy and safety of DOACs with warfarin

• Describe adverse effect profile of DOACs

• Determine which patients are good candidates for DOAC therapy

vs warfarin

Warfarin

Kinetics

• Absorption: complete

• Distribution: 99% protein binding

– Only FREE warfarin is available for use at VKORC1

• Metabolism: broken down by cytochrome P450 enzymes in the liver

– R-warfarin – primary via 3A4

– S-warfarin (SERIOUS WARFARIN) – primary via 2C9

• 2C9 inhibitors will RAISE INR significantly.

• 3A4 inhibitors will RAISE INR to a lesser extent.

• Elimination: 92% renal

LOTS of reasons why genetics can have effects on warfarin

Factors that affect warfarin dosing

• Body size

• Age

• Renal function

• Liver function

• Drug-drug interactions

• Dietary vitamin K intake

• Acute & chronic illness

• Smoking

• Alcohol

• Physical activity

• Genetics

• Warfarin manufacturer

Warfarin

PROS

• Effective

• Inexpensive

• INR monitoring

• Reversible

CONS

• Variable Dosing

• INR Monitoring

• Drug-drug interactions

• Lifestyle interactions

• Requirement for

anticoagulation care

provider

Other Oral Options?

TSOACs / DOACs / NOACs

• Current favorite acronym: DOAC (Direct Oral AntiCoagulant)

• Mechanisms of action

– DIRECT binding to active sites of factor II (thrombin) or Xa

– DabigaTran (Pradaxa) – T for THROMBIN

– rivaroXaban (Xarelto), apiXaban (Eliquis), edoXaban (Savaysa) – factor Xa

• Cost per 30 days = $300-400

• Reversible?

The Clotting Cascade

What can we use DOACs for?

The Big Three:

• (non-valvular) Atrial Fibrillation

• Treatment of Venous Thromboembolism (VTE)

– Prevention of Recurrent VTE

• Post-joint-replacement VTE Prophylaxis

Still Being Investigated:

• VTE Associated with Cancer

• VTE Associated with Hypercoagulable State

• Patients with Bioprosthetic Heart Valves

• With Dual Antiplatelet Therapy (DAPT)

Not For Use In:

• Mechanical Heart Valves

• Left Ventricular Assist Devices

Dabigatran (Pradaxa)

• Absorption: 3-7% bioavailable

– Dosage form relies on low gastric pH

– No opening/crushing capsules

Dabigatran (Pradaxa)

• Absorption: 3-7% bioavailable

– Dosage form relies on low gastric pH

– No opening/crushing capsules

• Distribution: 35% protein bound

• Metabolism: metabolized readily after absorption from

dabigatran etexilate to the active moiety, dabigatran

– Gut: p-glycoprotein

• Elimination: 80% renal

– t1/2 = 12-17 hours in healthy people

Dabigatran (Pradaxa®)

• Dosage Forms

– Capsules: 150 mg, 110 mg, 75 mg

– Do not break, chew, or open capsules before administration. Keep

in original bottle.

• Monitoring

– Serum creatinine

• Adverse Effects

– Risk of bleeding

– Dyspepsia (11.3%)

Dabigatran in Atrial Fibrilation: RE-LY

P < 0.001 superiority

P = 0.31

Note: Dabigatran

150 mg increased the

rate of GI bleeding

(p<0.001),

decreased ICH

(p<0.001) when

compared to

warfarin.

Dabigatran in Atrial Fibrilation: RE-LY

Dabigatran in VTE: RE-COVER

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

warfarin (INR 2-3) dabigatran 150mg BID

2.1

2.4

Rate of Recurrent VTE

P < 0.001 for noninferiority

Dabigatran in VTE: RE-COVER

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

warfarin (INR 2-3) dabigatran 150mg BID

1.9

1.6

Rate of Major Bleeding

Other Clinical Trials for Pradaxa

• RE-ALIGN: Mechanical Heart Valves

• RE-SONATE: prevention of recurrent VTE vs placebo

• RE-MEDY: prevention of recurrent VTE vs warfarin

• RE-NOVATE: prevention of VTE after hip replacement surgery (vs

enoxaparin)

Dabigatran Dosing

VTE prevention after

hip-replacement

surgery

Crcl 30ml/min or above 220mg daily

Crcl less than 30ml/min Avoid

Crcl 50ml/min or above

with P-gp inhibitor

220mg daily

Crcl less than 50ml/min

with P-gp inhibitor

Avoid

Xa Inhibitors

Rivaroxaban (Xarelto)

• Absorption: 66-100% bioavailable

– Better absorption with smaller doses & with food

• Distribution: 92-95% protein binding

• Metabolism:

– Gut: p-glycoprotein

– Liver: CYP450 3A4

• Elimination: 66% renal

– T1/2 : 5-12 hours

Rivaroxaban (Xarelto®)

• Dosage Forms

– Tablets: 20 mg, 15 mg, 10 mg

– Breakable/Crushable

• Monitoring

– Renal function

• Adverse Effects

– Bleeding risk

Rivaroxaban in Atrial Fib: ROCKET-AF

0

0.5

1

1.5

2

2.5

Warfarin Rivaroxaban

2.2

1.7

Rate of stroke or systemic embolism (%)

P<0.001 for non-inferiority

Rivaroxaban in Atrial Fib: ROCKET-AF

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Warfarin Rivaroxaban

3.4 3.6

Rate of major bleeding (%)

Rivaroxaban in VTE: EINSTEIN

2.1 2.1

3

1.8

0

0.5

1

1.5

2

2.5

3

3.5

Einstein DVT Einstein PE

Rate of Recurrent VTE

Rivaroxaban

Warfarin

P<0.001 for

non-

inferiorityP=0.003 for non-

inferiority

Rivaroxaban in VTE: EINSTEIN

0.8

1.1

1.2

2.2

0

0.5

1

1.5

2

2.5

Einstein DVT Einstein PE

Rate of Major Bleeding (%)

Rivaroxaban

Warfarin

P=0.21

P=0.03

Other Rivaroxaban Clinical Trials

• Einstein Choice: Rivaroxaban 10mg daily for extended

prophylaxis of VTE

• RECORD 1-4: post-joint-replacement VTE prophylaxis

• PIONEER: low-dose riva + P2Y12 vs. ultra-low-dose riva + DAPT

vs. VKA + DAPT for post-PCI afib patients

Rivaroxaban Dosing

Apixaban (Eliquis)

• Absorption: 50% bioavailable

– No effect of food

• Distribution: 92-95% protein binding

• Metabolism:

– Gut: p-glycoprotein

– Liver: CYP450 3A4

• Elimination: 27% renal

– T1/2 : 7-15 hours

Apixaban (Eliquis®)

• Dosage Forms

– Tablets: 5 mg, 2.5 mg

– Breakable, crushable

– May be administered without regard to food

• Monitoring

– Serum creatinine

• Adverse Effects

– Risk of bleeding

Apixaban in Atrial Fibrillation: ARISTOTLE

0

0.5

1

1.5

2

2.5

3

Warfarin Apixaban

1.6

1.27

Rate of Stroke or Systemic Embolism (%)

P=0.01 for superiority

Apixaban in Atrial Fibrillation: ARISTOTLE

0

0.5

1

1.5

2

2.5

3

Warfarin Apixaban

1.69

0.96

Rate of Major Bleed (%)

P<0.001

Apixaban in VTE: AMPLIFY & AMPLIFY-EXT

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Warfarin Apixaban

2.72.3

Rate of Recurrent VTE (%) in AMPLIFY

P<0.001 for

non-inferiority

0

1

2

3

4

5

6

7

8

9

Apixaban 2.5mg

BID

Apixaban 5mg BID Placebo

1.7 1.7

8.8

Rate of Recurrent VTE (%) in AMPLIFY-EXT

P<0.001 for

superiority of

both doses

vs placebo

Apixaban in VTE: AMPLIFY & AMPLIFY-EXT

0

0.5

1

1.5

2

2.5

3

Warfarin Apixaban

1.8

0.6

Rate of Major Bleeding (%) in AMPLIFY

P<0.001

0

0.5

1

1.5

2

2.5

3

Apixaban 2.5mg BID Apixaban 5mg BID Placebo

0.2 0.1

0.5

Rate of Major Bleeding (%) in AMPLIFY-EXT

Apixaban: Other Clinical Trials

• AVERROES: atrial fib trial vs. ASA

• ADVANCE 1-3: post-joint-replacement VTE prophylaxis

Apixaban Dosing

Extended VTE treatment Without concomitant P-

gp/CYP3A4 inhibitor

2.5mg BID

With concomitant P-

gp/CYP3A4 inhibitor

Avoid

Edoxaban (Savaysa)

• Absorption: 62% bioavailable

– No effect of food

• Distribution: 55% protein binding

• Metabolism:

– Gut: p-glycoprotein

• Elimination: 50% renal

– T1/2 : 10-14 hours

Edoxaban (Savaysa®)

• Dosage Forms

– Tablets: 15mg, 30mg, 60mg

– May be administered without regard to food

• Monitoring

– Renal function

• Adverse Effects

– Risk of bleeding

Edoxaban Clinical Trials

• ENGAGE AF TIMI 48 (atrial fibrillation)

– Efficacy: non-inferior to warfarin

– Safety: less bleeding than warfarin

• HOKUSAI (VTE treatment)

– Efficacy: non-inferior to warfarin

– Safety: less bleeding than warfarin

Edoxaban Dosing

Indication Dose Crcl 15-

50ml/min

Crcl >95

ml/min

Body weight

< 60kg

P-gp

inhibitor

Atrial

fibrillation

60mg daily 30mg daily Do not use No

adjustment

No

adjustment

DVT/PE 60mg daily

(after 5-10

days of

parenteral)

30mg daily No

adjustment

30mg daily 30mg daily

Post-joint

replacement

30mg daily

DOAC Trial Data Summary

Atrial Fibrillation DVT/PE treatment

stroke prevention

(compared to

warfarin)

rates of bleeding

(compared to

warfarin)

rate of recurrent VTE

(compared to LMWH

bridged warfarin)

rates of bleeding

(compared to

warfarin)

Pradaxa

(dabigatran) superior same same same

Xarelto

(rivaroxaban) same same same same

Eliquis

(apixaban) superior superior same superior

Savaysa

(edoxaban) same superior same superior

DOAC Drug-Drug Interactions

• Dabigatran (substrate of p-glycoprotein)

– Inducers (rifampin): avoid co-administration

– Inhibitors (dronedarone, ketoconazole): dose reduce or avoid (see

prescribing info)

– Verapamil: separate by 2 hours

• Xa Inhibitors (substrates of CYP 3A4 & p-gp)

– Dual inducers (carbamazepine, phenytoin, phenobarb, rifampin, St.

John’s wort): avoid coadministration

– Dual inhibitors (ketoconazole, itraconazole, ritonavir,

clarithromycin): reduce dose or avoid (see prescribing info)

Reversal Agents

• Supportive therapies (all anticoagulants)

– Fresh frozen plasma, fluids, blood products

• Prothrombin complex concentrates (all anticoagulants)

– 3-Factor: factors II, IX, X

– 4-Factor: factors II, VII, IX, X

• Warfarin: Vitamin K

• Dabigatran: idarucizumab (Praxbind)

• Xa Inhibitors: andexanet alfa (not available yet)

Peri-Procedural Management

PLEASE DON’T “BRIDGE” DOACs!!

The Ideal DOAC Patient

• Diagnosed with one of the ‘Big Three’

• Good kidney function

• Compliant with medications

• Average body size

• Not on strong p-gp or 3A4 inhibitors or inducers

• History of unstable INRs not related to medication non-

compliance

• Commercially insured

Patient-Centered Care

• Indication & clinical data

• Patient preferences

• Don’t make assumptions

• Utilize manufacturer assistance when appropriate

• Beware the donut hole

Clinical References at Your Fingertips

• Anticoagulationtoolkit.org

• European Heart Rhythm Associate Practical Guide on the Use of

Non-Vitamin K Antagonist Anticoagulants in Patients with Non-

Valvular Atrial Fibrillation

References

• Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.

• Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM. 2009; 361:1139-1151

• Schulman S et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 2009; 361:2342-2352.

• Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November 2011.

• Patel MR. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. NEJM 2011; 365:883-891.

• The Einstein Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. NEJM 2010; 363:2499-2510.

• Eliquis [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company. July, 2016.

• Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2011; 365:981-992.

• Agnelli G et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. NEJM 2013; 369:799-808.

• Agnelli G et al. Apixaban for Extended Treatment of Venous Thromboembolism. NEJM 2013: 368;699-708.

• Savaysa [package insert]. Parsippany, NJ. Daiichi Sankyo, Inc. 2015.

• Giugliano RP et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. NEJM 2013; 369:2093-2104.

• The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. NEJM 2013; 369:1406-1415.

• 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. JACC 2017 ePub ahead of print.

• Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvularatrial fibrillation. Europace 2013; 15(5):625-51.