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Chad A. Triplett, PharmD, BCPSClinical Pharmacy Specialist

Department of Family MedicineUniversity of Iowa Hospitals and Clinics

Disclosure

� Chad Triplett reports no actual or potential conflicts of interest associated with this presentation

www.google.com/images_ducktails

Objectives

� Identify appropriate candidates eligible to receive DOACs

� Compare and contrast the available DOACs� Review some of the key trials supporting the

utilization of the DOACs� Review peri-procedural management of

anticoagulation in patients on DOACs� Discuss DOAC reversibility and management of

bleeding

Ideal Anticoagulant

� No need for routine monitoring � Oral administration � Use in acute and chronic conditions � Use in both hospital and home settings� Minimal or no adverse effects� Proven efficacy in treating and/or preventing

thrombosis � No drug or diet interactions� Easily reversible

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Appropriate DOAC Patient

� Appropriate indication (atrial fibrillation (AF), venous thromboembolism (VTE), or VTE prophylaxis post joint replacement

� Good kidney function� Excellent medication compliance� Insurance coverage� Not on strong p-glycoprotein (p-gp) or

cytochrome (CYP) P450 inhibitors or inducers

CHEST Recommendations

� Non-cancer related thrombosis, DOACs are recommended over vitamin K antagonist (VKA) therapy (Grade 2B)� No direct comparison between agents so efficacy seems similar between

agents� Bleeding risk with DOACs is less than VKA therapy

� For patients with AF and a CHADS2 score of ≥1, suggest dabigatran 150 mg twice daily rather than adjusted-dose VKA (Grade 2B)

Chest. 2016 Feb;149(2):315-52Chest. 2012 Feb:141(2) Supplement: e531S–e575S

Current DOACs� Dabigatran (Pradaxa®)

� Rivaroxaban (Xarelto®)

� Apixaban (Eliquis®)

� Edoxaban (Savaysa®)

� Betrixaban (Bevyxxa®)

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Mechanism of Action

Figure adapted from: Dipiro et al. Pharmacotherapy: A Pathophysiologic Approach, 3rd Ed. 1997.

Warfarin Dabigatran

ApixabanEdoxabanRivaroxaban

Dabigatran� 1st new anticoagulant in U.S. in >50 years

� FDA approved October 2010� Oral direct thrombin (Factor IIa) inhibitor

� Inhibits both clot-bound and circulating thrombin� Prodrug: dabigatran etexilate → dabigatran

� Conversion by plasma esterase� Indications:

� Reduction in risk of stroke and systemic embolismin non-valvular atrial fibrillation

� Treatment of DVT and PE � Risk reduction of recurrence of DVT and PE following initial

treatment� Prevention of VTE in total hip replacement

� Capsules: 75 mg, 110 mg and 150 mgDabigatran Package Insert: 3/2018

Rivaroxaban

� First approved (July 2011) oral, direct, selective Factor Xa inhibitor

� Indications:� Prevention of DVT and PE in total hip and knee replacement

surgery � Prevention of stroke and systemic embolism in atrial fibrillation � Treatment of DVT and PE � Risk reduction of recurrent DVT and/or PE after at least 6

months of initial treatment

� Tablets: 10 mg, 15 mg and 20 mg

Rivaroxaban Package Insert: 8/2018

Apixaban � Oral, direct, selective Factor Xa inhibitor. Approved

December 2012

� Indications: � Prevention of stroke and systemic embolism in patients

with atrial fibrillation� Treatment of DVT and PE � Risk reduction of recurrent DVT and PE following at least 6

months of initial therapy� Prevention of DVT and PE in total hip and knee

replacement surgery

� Tablets: 2.5 mg and 5 mg

Apixaban Package Insert: 6/2018

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Edoxaban

� Oral, direct, selective Factor Xa inhibitor. Approved January 2015

� Indications: � Prevention of stroke and systemic embolism in

patients with atrial fibrillation � Treatment of DVT and PE

� Tablets: 15 mg, 30 mg and 60 mg

Edoxaban Package Insert: 11/2017

DOAC Comparison

Table created by Deanna McDanel, PharmD, BCPS, BCACP

DOAC Comparison

Table created by Deanna McDanel, PharmD, BCPS, BCACP

DOAC Comparison

Table created by Deanna McDanel, PharmD, BCPS, BCACP

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DOAC Drug Interactions

All: Increased risk of bleeding with other anticoagulants, antiplatelet agents and non-steroidal anti-inflammatories (NSAIDs)

Atrial Fibrillation Dosing

VTE Dosing VTE Treatment Course

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DOACs in Obesity� International Society on Thrombosis and

Haemostasis (ISTH) guidance recommendations� We suggest that DOACs should NOT be used in

patients with a BMI >40 kg/m2 or weight >120 kg due to limited clinical data and kinetic data showing decreased drug levels and shorter half lives

� If a DOAC is used in these patients, we suggest checking a peak and trough drug level:○ Anti-factor Xa for apixaban, edoxaban and rivaroxaban○ Ecarin time or dilute thrombin time for dabigatran

� If level falls within expected range, continue DOAC � If the level is below expected range, change to

warfarin rather than adjusting the DOAC dose

Martin K, et al. J of Thrombosis and Haemostasis 2016;14(12):1308-13.

Major Atrial Fibrillation Studies

1. Connolly SJ, et al. NEJM 2009;361:1139-51. 3. Giugliano RP, et al. NEJM 2013;369(22); 2093-2104.2. Granger et al. NEJM 2011; 365(10): 981-92. 4. Patel et al. NEJM 2011; 365(10): 883-891.

Major VTE Studies

1. Schulman S, et al. NEJM 2009;361:2342-52. 4. Agnelli G, et al. NEJM 2013;368(8):699-708. 7. EINSTEIN-PE. NEJM 2012;10.1056.2. Schulman S, et al. NEJM 2013;368:709-18 5. Hokusai-VTE Investigators. NEJM 2013;369(15):1406-15.3. Agnelli G, et al. NEJM 2013;369(9):799-808. 6. EINSTEIN-DVT. NEJM 2010;363:2499-510.

Prosthetic Heart Valves?? � RE-ALIGN trial (open-label, N=252)

� Dabigatran 150 mg, 220 mg or 300 mg BID (dosed on CrCl) vs warfarin (2-3 or 2.5-3.5 INR) in bileaflet mechanical heart valves

� TERMINATED EARLY○ Significantly more thromboembolic events (valve thrombosis,

stroke, transient ischemic attack, and myocardial infarction)○ Excess of any and major bleeding (predominantly post-

operative pericardial effusions requiring intervention for hemodynamic compromise)

: dabigatran is contraindicated in patients with mechanical prosthetic valves ○ Not studied in bioprosthetic valves or other valvular heart

disease

� Safety and efficacy of apixaban, edoxaban and rivaroxaban have not been studied in patients with prosthetic heart valves à NOT RECOMMENDED

Eikelboom et al. NEJM 2013; 369:13:1206-14.

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Case 1� KS is a 43 year old Caucasian male who is 185.4 cm tall and

weighs 83.2 kg (CrCl = 134.6 mL/min). He has a past medical history significant for hypertension and he currently takes chlorthalidone 25 mg daily. He reports to clinic after several episodes of dizziness and palpitations over the past two weeks. An EKG reveals he is in atrial fibrillation. His lab work is as follows:

141

4.3

98

27

13

0.8

91

Case 1 (cont.)

� You wish to start a DOAC in this patient. Which of the following would not be an appropriate agent to initiate?a. Apixaban 5 mg twice dailyb. Edoxaban 60 mg daily c. Dabigatran 150 mg twice dailyd. Rivaroxaban 20 mg daily

Case 2� JT is a 37 year old female (CrCl >90 mL/min; BMI 34 kg/m²)

with no previous medical history. She was recently in a motor vehicle crash requiring surgical repair of a compound fracture of her right femur. She was hospitalized for five days. A week after discharge she reports to clinic with complaints of left lower leg edema and pain. A Doppler shows complete obstruction of her left popliteal vein. Which of the following would be the most appropriate initial DOAC regimen for JT?a. Edoxaban 60 mg daily

b. Dabigatran 75 mg twice daily after 5-10 days of parenteral anticoagulation

c. Rivaroxaban 20 mg twice daily for 21 days then 20 mg dailyd. Apixaban 10 mg twice daily for 7 days then 5 mg twice daily

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Converting from Warfarin to DOAC

Converting from Dabigatran to Warfarin

Converting Xa Inhibitors to Warfarin Case 3

� TM is a 63 year old Caucasian female with a history of hypertension, type 2 diabetes mellitus, atrial fibrillation, hyperlipidemia, and s/p mitral valve replacement. Now that Andexxa® is available, so would like switch from warfarin to a DOAC so she doesn’t have to have her finger stuck every month. Which of the following conversions would you recommend for her?

a) Stop warfarin and start rivaroxaban when next dose of warfarin is due

b) She is not an appropriate candidate for DOAC therapyc) Stop warfarin and begin apixaban when the INR <3.0d) Stop warfarin and begin edoxaban and enoxaparin when

INR <2.5

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Peri-Procedural Management

Dabigatran Reversal� Idarucizumab (Praxbind®)

� Humanized monoclonal antibody fragment to bind dabigatran� Approved October 2015� Indication is reversal of dabigatran if needed for:

○ Emergency surgery/urgent procedures○ Life-threatening or uncontrolled bleeding

� Accelerated approval based healthy volunteers study

� Continued approval contingent upon the results of an ongoing cohort case series study

� Dosing: ○ 5 g IV (2 vials of 2.5 g/50 mL) idarucizumab – Cost $3482○ Limited data to support administration of an additional 5 g

� Resulted in rapid, complete reversal of anticoagulation in patients experiencing life-threatening bleed or requiring urgent surgery

Praxbind® Package Insert: 2015 October

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Idarucizumab (cont.)� Warnings/Precautions:

� Thromboembolic risk: Reversing dabigatran exposes patients to the thrombotic risk of their underlying disease so resume anticoagulant as soon as medically appropriate

� Re-elevation of coagulation parameters: If this happens and there is reappearance of clinically relevant bleeding or requiring a second emergency surgery/urgent procedure, an additional 5 g dose may be used

� Hypersensitivity reactions: Discontinue administration and evaluate

� Hereditary fructose intolerance: Patients with hereditary fructose intolerance may be at risk of adverse reactions due to sorbitol excipient

� Adverse Effects (>5%):� Headache, hypokalemia, delirium, constipation, pyrexia,

and pneumonia

Praxbind® Package Insert: 2015 October

Coagulation Factor Xa (Andexxa®)� Recombinant modified human factor Xa protein� Approved May 2018� Indication is reversal of apixaban and rivaroxaban if

needed for life-threatening or uncontrolled bleeding � Accelerated approval based healthy volunteers study

� Continued approval contingent upon the results of an ongoing cohort case series study

� Not shown effective and not indicated for other Xa inhibitors� Warnings/Precautions:

� Thromboembolic risk: arterial/venous thromboembolism, ischemic and cardiac events (including sudden death) have occurred ○ Resume anticoagulation as soon as medically appropriate

� Re-elevation of coagulation parameters

� Adverse Effects:� Urinary tract infections and pneumonia (>5%); infusion-related

reactions (>3%)

Andexxa® Package Insert: 2018 May

Andexxa®� Dosing: Based on specific Xa inhibitor, dose of Xa inhibitor

and time since the patient’s last dose of the Xa inhibitor

Andexxa® Package Insert: 2018 MayUniversity of Iowa Hospitals and Clinics Pharmacy and Therapeutics Committee

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DOACs Place in Therapy Summary: Which to Choose?

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