9/27/2017

Direct Oral Holly Jahn, PharmD, CACP

Objectives

• Identify the FDA approved indications for use, appropriate dosing, and monitoring parameters for each direct oral . • Distinguish the key differences among the direct oral anticoagulants. • Discuss perioperative management with direct oral anticoagulants. • Acknowledge the impact of drug interactions when considering anticoagulation therapy. • Review the currently available and still in clinical trials for the reversal of direct oral anticoagulants. • List the newest recommendations related to direct oral anticoagulants from the 10th edition CHEST guidelines.

Direct Acting Oral Anticoagulants

• • • • • Betrixaban – approved June 23, 2017

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Drug Class

• Factor Xa inhibitor ▫ Rivaroxaban ▫ Apixaban ▫ Edoxaban ▫ Betrixaban

• Direct inhibitor ▫ Dabigatran

Warfarin

Warfarin Apixaban Rivaroxaban Edoxaban Betrixaban

Dabigatran

Indications for VTE Treatment & PPX

• VTE prophylaxis in the acute setting ▫ Betrixaban • VTE prophylaxis post-op hip/knee replacement ▫ Apixaban ▫ Rivaroxaban • VTE treatment/secondary prophylaxis ▫ Apixaban ▫ Rivaroxaban ▫ Edoxaban ▫ Dabigatran

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Indications for

• Only for non-valvular atrial fibrillation ▫ Apixaban ▫ Rivaroxaban ▫ Edoxaban ▫ Dabigatran

Before we talk renal adjustments…

• Weight, Scr, and Age ▫ Apixaban

• Remember to calculate CrCl using ACTUAL body weight ▫ Dabigatran ▫ Edoxaban ▫ Rivaroxaban ▫ Betrixaban

Apixaban and Dabigatran Medication Indication Dose Renal adjustment

ApixabanMedication Non-IndicationValvular Afib 5Dose mg PO BID RenalAny 2 adjustmentof the following: Age ≥ 80 yo, wgt ≤ 60 kg, SCr ≥ 1.5 mg/dl = 2.5 Apixaban (Eliquis) Non-Valvular Afib 5 mg PO BID Anymg 2 PO of theBID* following: Age ≥ 80 yo, wgt ≤ 60 kg, SCr ≥ 1.5 mg/dl = 2.5 DVT/PE 10 mg PO BID x 7 days mgNo PO adjustment* BID* Then 5 mg PO BID x 6 months DVT/PE ~May10 mg decrease PO BID x to 7 days2.5 mg PO BID after 6 No adjustment * monthsThen 5 mgof full PO treatmentBID x 6 months dosage May decrease to 2.5 mg PO BID after 6 Post op hip replacement 2.5months mg BID of full x 35 treatment days dosage No adjustments, patients with CrCl < 30 ml/min were excluded from Post op hip 10 mg daily x 35 days CrCltrial< 30 ml/min = Avoid Post replacementop knee replacement 2.5 mg BID x 12days Drug interactions: DecreasePost dosage op knee 50% for dosage >10 2.5 mg mg daily PO xBID 10- AND14 days receiving concomitant clarithromycin,CrCl < 30 ml/min oral = Avoid ketoconazole, itraconazole, or ritonavir (dualreplacement strong CYP3A4 and P-gp inhiibtors) ~ AVOID use with above medications if pt is taking 2.5 mg BID or has 2 of following (age, SCR, wt) Drug interactions: For dosage > 2.5 mg PO BID AND receiving concomitant clarithromycin, oral ketoconazole, itraconazole, or ritonavir = decrease dose 50%. ~For dosage of 2.5 mg PO BID and receiving above medicaitons, avoid usage Dabigatran Non- Valvular Afib 150 mg PO BID CrCl 15-30 ml/min = 75 mg PO BID < 15 ml/min or ESRD = CI

DVT/PE 150 mg PO BID after 5- 10 days of < 30 ml/min = Avoid Dabigatran (Pradaxa) Non- Valvular Afib 150 mg PO BID CrCl 15-30 ml/min = 75 mg PO BID parenteral anticoagulant

Drug interactions afib: CrCl 30-50 ml/min and receiving oral ketoconazole or dronedarone = 75 mg< 15 BID. ml/min CrCl or15 ESRD-30 ml/min = CI and receiving concomitant P-gp inhibtor = AVOID Drug interactions DVT/PE: CrCl <50 ml/min and receiving concomitant P-gp inhibitor (amiodarone, clarithromycin, dronedarone, quinidine, verapamil, etc) = AVOID Drug interactions afib and DVT/PE: any P glycoprotein inducer (Rifampin) = AVOID * Patients with SCr > 2.5 mg/dl or CrCl < 25 ml/min were excluded from the trial

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Edoxaban, Rivaroxaban, and Betrixaban Medication Indication Dose Renal adjustment Edoxaban Non-Valvular Afib 60 mg daily CrCl > 95 ml/min = AVOID CrCl 15-50 ml/min = 30 mg daily CrCl < 15 ml/min = AVOID DVT/PE 60 mg PO daily after 5-10 days of CrCl 15-50 ml/min = 30 mg daily parenteral anticoagulation CrCl < 15 ml/min = AVOID Drug interactions: Concomitant verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, or oral ketoconazole= 30 mg daily Weight less than 60 kg = 30 mg daily Rivaroxaban Non-Valvular Afib 20 mg PO daily CrCl 15-50 ml/min = 15 mg daily CrCl < 15 ml/min or ESRD = CI DVT/PE 15 mg PO BID x 21 days CrCl < 30 ml/min = AVOID Then 20 mg PO daily with food Post op hip replacement 10 mg daily x 35 days CrCl < 30 ml/min = AVOID

Post op knee 10 mg daily x 12-14 days CrCl < 30 ml/min = AVOID replacement Drug interactions: Concomitant , , St John's Wort, idelalisib, conivaptan, ketoconazole, ritonavir/lopinavir, fluconazole, itraconazole, indinavir, carbamazepine, phenytoin, rifampin= AVOID Drug interactions: Renal dysfunction and concomitant erythromycin, clarithromycin, amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine= CAUTION USE Betrixaban VTE prophylaxis for Initial: 160 mg orally as a single dose, CrCl 15 - 30 mL/min = 80 mg X 1 dose, hospitalized patients at followed by 80 mg once daily at the same followed by 40 mg once daily for 35 to 42 risk time each day with food for 35 to 42 days days for VTE Drug interactions: Concomitant use of P-gp inhibitors = Reduce initial dose to 80 mg orally as a single dose, followed by 40 mg once daily for 35 to 42 days

What about hepatic impairment?

• Apixaban ▫ Mild impairment – Child-Pugh Class A  No adjustments ▫ Moderate impairment – Child-Pugh Class B  No adjustments provided – use with caution ▫ Severe impairment – Child-Pugh Class C  Use is not recommended • Dabigatran ▫ No dosage adjustments per manufacturer. In patients with moderate impairment, no changes in exposure or were observed in a study. • Edoxaban ▫ Mild impairment – Child-Pugh Class A  No adjustments ▫ Moderate to severe impairment – Child-Pugh Class B and C  Use is not recommended • Rivaroxaban ▫ Mild impairment – Child-Pugh Class A  No adjustments ▫ Moderate impairment – Child-Pugh Class B or C  Avoid use • Betrixaban ▫ Use is not recommended

Choosing the right medication

• Indication • Patient’s lifestyle • Compliance • Dosing complexity • Renal/Hepatic function • Age • Bleeding Risk • Cost

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Apixaban – Specific points

• Duration of therapy – orthopedic uses (knee - 12 days, hip - 35 days) • VTE –dose change at 1 week ▫ 10 mg BID X 7 days, then 5 mg BID • May crush tablets and place in 60 ml of D5W for immediate delivery down NG tube ▫ Can also mix with apple juice, applesauce, D5W, or water and give orally ▫ Stable for up to 4 hours

Dabigatran – Specific points • Initiation after 5-10 days of parenteral therapy (VTE) • Storage ▫ Do not store in pill organizer ▫ Must use within 4 months of opening bottle • Take with full glass of water • With or without food • Do not break, crush, chew, or open capsule • Side effects ▫ Stomach upset, indigestion

Edoxaban – Specific points

• Initiation of therapy ▫ VTE requires 5-10 days of parenteral therapy • Side effects can include rash • Take with or without food • Should not be used in patients who have a CrCl greater than 95 mL/min due to an increased risk of ischemic

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Rivaroxaban – Specific points • Duration of therapy – orthopedic uses (knee - 12-14 days, hip - 35 days) • VTE – dose change at 3 weeks • Take with food (for doses 15 mg or greater) • Crush or chew? ▫ May be crushed and mixed in applesauce immediately prior to usage ▫ NG tube – may be crushed and mixed in 50 ml of water. Administration should be followed by enteral feeding • Missed dosage of 15 mg BID ▫ Must get 30 mg in a day – two 15 mg doses can be given at once

Betrixaban

• Approved on June 23, 2017 • Only for use in the acute setting • Take at same time each day with food

APEX trial • Treatment groups ▫ Enoxaparin 40 mg daily vs. betrixaban 160 mg X 1, then 80 mg daily for 35-42 days ▫ Primary efficacy endpoint:  Composite of:  asymptomatic proximal DVT between day 32-47  Symptomatic proximal or distal DVT  Symptomatic non-fatal PE  Death from VTE ▫ Three cohorts:  Patients with elevated D-dimer  Patients with elevated D-dimer or age > 75  Entire trial population N Engl J Med 2016; 375: 534-44

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Results from APEX trial

• Primary end point, cohort 1 ▫ Did not show clinical significance (P = 0.054) ▫ Therefore the rest of the analyses were considered “exploratory” • Safety endpoints (betrixaban vs enoxaparin) ▫ Major bleeding  0.7% vs 0.6% (P = 0.55) ▫ Major or clinically relevant non-major bleeding  3.1% vs 1.6% (P = <0.001)

N Engl J Med 2016; 375: 534-44

Transitioning from warfarin to DOACs

• Discontinue warfarin, then … ▫ Dabigatran & Apixaban  Initiate when INR is below 2 ▫ Rivaroxaban:  Initiate when INR is below 3 ▫ Edoxaban:  Initiate when INR is below 2.5 ▫ Betrixaban:  No information available

Transitioning from Dabigatran to warfarin

Adjust the start time of warfarin based on the patient’s CrCl:

Recommended start of warfarin before discontinuing dabigatran

*Because dabigatran can increase INR, the INR will better reflect warfarin’s effect only after dabigatran has been stopped for at least 2 days.

Dabigatran [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. Accessed September 5, 2017.

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Transitioning from Factor Xa inhibitors to warfarin

• Discontinue factor Xa inhibitor and initiate a parenteral anticoagulant and warfarin at the time when the next factor Xa dose would have been administered • Continue parenteral anticoagulant until INR is therapeutic • Includes Rivaroxaban, Apixaban, and Edoxaban

Perioperative Management of DOACs7-11, a

Time of Last Dose Before Time of Last Dose Before Drugs and CrCl Minor Procedure Major Surgery Dabigatran >50 mL/min 1 day 2 days

30–50 mL/min 2 days 4 days

< 30 mL/min 4 days 5–6 days

Rivaroxaban, apixaban, or edoxaban >50 mL/min 1 day 2 days

30–50 mL/min 1–2 days 3–4 days

< 30 mL/min 2 days 4 days

DOAC Dabigatran Rivaroxaban - Apixaban Edoxaban Bleeding risk of invasive procedure LOW HIGH LOW HIGH LOW HIGH Bleeding risk Bleeding risk Bleeding Bleeding risk Bleeding risk Bleeding risk risk GIHP Preoperative CrCl ≥50 ml/min Last dose Last dose Last Last dose Last dose Last dose (Groupe interruption ≥ 24 h before 4 days before surgery dose 3 days before ≥ 24 h before 3 days before surgery d’Intérêt en No bridging CrCl >30 ml/min surgery Last dose ≥ 24 h surgery surgery Hémostase (except 5 days before surgery before Péri- patients with surgery opératoire) high risk of Very high risk Last dose 5 days before surgery TE) procedure Resumption LOW Bleeding Risk: after Resume minimum 6 h after invasive procedure or surgery invasive HIGH Bleeding Risk: procedure or Prophylactic dose of LMWH, UFH or minimum 6 h after invasive procedure or surgery if venous thromboprophylaxis is indicated surgery Therapeutic dose of DOACs when hemostasis is controlled (24-72 h) For neuraxial anesthesia with indwelling catheter: Resumption with LMWH or UFH until indwelling catheter is out Heidbuchel Preoperative CrCl ≥80 ml/min ≥ 24 h ≥ 48 h ≥ 24 h ≥ 48 h ≥ 24 h ≥ 48 h et al. interruption CrCl 50–80 ml/min ≥ 36 h ≥ 72 h ≥ 24 h ≥ 48 h ≥ 24 h ≥ 48 h No bridging CrCl 30–50 ml/min ≥ 48 h ≥ 96 h ≥ 24 h ≥ 48 h ≥ 24 h ≥ 48 h CrCl 15–30 ml/min Not Not indicated ≥ 36 h ≥ 48 h ≥ 36 h ≥ 48 h indicated CrCl <15 ml/min No official indication for use Resumption LOW Bleeding Risk: after • DOACs 6-8 h invasive HIGH Bleeding Risk: procedure or • Low TE risk ➔ resume DOACs 48-72 h after procedure surgery • High TE risk ➔ prophylactic or intermediate dose of LMWH 6-8 h after procedure, resume DOACs when hemostasis is controlled (48-72 h) Spyropoulos Preoperative CrCl >50 mL/min Last dose Last dose Last dose 2 days Last dose 3 days Last dose 2 days before Last dose 3 days before surgery et al. interruption 2 days 3 days before before surgery before surgery surgery No bridging before surgery surgery CrCl 30–50 mL/min Last dose Last dose 4– Last dose 2 days Last dose 3 days 3 days 5 days before before surgery before surgery before surgery surgery CrCl 15–29 mL/min Depends on patient Depends on and procedural factors patient and procedural factors Resumption LOW Bleeding Risk: after • DOACs 24 h invasive HIGH Bleeding Risk: procedure or • Low TE risk ➔ resume DOACs 48-72 h after procedure surgery • High TE risk ➔ consider a reduced dose of dabigatran (75 mg twice daily), rivaroxaban (10 mg once daily) or apixaban (2,5 mg twice daily) on the evening after surgery and on the following day (first postoperative day) after surgery. Dubois, V et al. Perioperative management of patients on direct oral anticoagulants. Thrombosis Journal 2017; 15:14.

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Drug Interactions

• Rivaroxaban, Apixaban, and Edoxaban ▫ Metabolized by CYP3A4 ▫ Substrate for P-glycoprotein

• Dabigatran ▫ Substrate for P-glycoprotein

Management of DOAC-related bleeding

• Idarucizumab ▫ Approved in 2015 under accelerated approval ▫ Humanized monoclonal antibody fragment ▫ Neutralizes the anticoagulant effect of dabigatran by binding to dabigatran and its acylglucuronide metabolites ▫ Indicated for life threatening bleeding or need for emergent surgery ▫ 5 g (administered via 2 vials) IV ▫ Dabigatran can be reinitiated 24 hours after administration ▫ Not compatible with other medications ▫ RE-VERSE AD trial  The anticoagulant effect of dabigatran was fully reversed in 88- 98% of patients at 4 hours following administration of idarucizumabThrombotic events occurred in 5 patients (n = 90)

Management of DOAC-related bleeding

• Andexanet alpha ▫ Binds factor Xa inhibitors ▫ ANNEXA – A and ANNEXA – R trials  Phase 3, Studied the reversal effects on apixaban and rivaroxaban in healthy volunteers  Anti–factor Xa activity was reduced by 94% and 92% respectively with andexanet vs. 21% and 18% with placebo  No major thrombotic adverse events reported ▫ ANNEXA-4  Ongoing Trial  Phase 3  Evaluating efficacy in patients with an acute major bleed  Estimated primary completion date – November 2022 ▫ A study of the PK/PD, safety, and tolerability in healthy subjects  Ongoing trial  Estimated primary completion date – September 2017

https://clinicaltrials.gov

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Management of DOAC-related bleeding • Ciraparantag ▫ Binds to edoxaban, rivaroxaban, apixaban, dabigatran, and LMWH/UFH ▫ Phase I trial  Evaluation of the Safety, Tolerability, and Pharmacodynamic Effects of a Double-Blind, Single Dose of Ciraparantag Administered Alone, and Following a Single Dose of Edoxaban  80 healthy participants  In patients receiving a single intravenous dose of PER977 (100 to 300 mg) 3 hours after the administration of edoxaban, the whole-blood clotting time decreased to within 10% above the baseline value in 10 minutes or less, whereas in patients receiving placebo, the time to reach that level was much longer (approximately 12 to 15 hours) ▫ Ongoing Study  Phase 2 Placebo-Controlled, Single-Site, Single-Blind Study of Rivaroxaban Reversal by Ciraparantag as Measured by whole blood clotting time  Estimated study completion date- December 2017

https://clinicaltrials.gov

CHEST guidelines 10th edition

• Summary: ▫ Risk reduction for recurrent VTE with all of the DOACs appears to be similar to the risk reduction with VKA ▫ Risk reduction for recurrent VTE among the different DOACs appears to be similar ▫ Risk of bleeding with the DOACs, and particularly intracranial bleeding, is less than with VKA therapy based on patients with atrial fibrillation  GI bleeding may be higher with dabigatran, rivaroxaban, and edoxaban than with VKA therapy, although this has not been seen in patients with VTE ▫ Risk of bleeding may be lower with apixaban than with the other DOACs ▫ Risk that a major bleed will be fatal appears to be no higher for DOACs than for VKA therapy ▫ Suggest that a DOAC is used in preference to VKA for the initial and long-term treatment of VTE in patients without cancer

Questions

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References 1. Apixaban. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; November 2015. Accessed March 24th, 2016. 2. Dabigatran. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; October 2015. Accessed March 24th, 2016. 3. Edoxaban. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; February 2015. Accessed March 24th, 2016. 4. Rivaroxaban. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; July 2015. Accessed March 24th, 2016. 5. Cohen, A et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375: 534-44. 6. Dubois, V et al. Perioperative management of patients on direct oral anticoagulants. Thrombosis Journal 2017; 15:14. 7. Nutescu EA, Dager WE, Kalus JS et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst Pharm. 2013; 70:1914-29. 8. Boehringer Ingelheim Pharmaceuticals. Pradaxa (dabigatran etexilate mesylate)prescribing information. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf (accessed 2016 Jan 7). 9. Bristol-Myers Squibb. Eliquis(apixaban) prescribing information.http://packageinserts.bms.com/pi/pi_eliquis.pdf (accessed 2015 Jul 30). 10. Daiichi Sankyo. Savaysa (edoxaban)prescribing information. http://dsi.com/prescribing- informationportlet/getPIContent?productName=Savaysa&inline=true (accessed 2015Jul 30). 11. Janssen Pharmaceuticals. Xarelto (rivaroxaban) prescribinginformation. www.xareltohcp.com/shared/product/xarelto/prescribinginformation.pdf (accessed 2015 Jul30). 12. Gulseth M. Overview of direct oral anticoagulant therapy reversal. Am J Health-Syst Pharm. 2016; 73(suppl 2):S5-13 13. Product Information: PRAXBIND(R) intravenous injection, idarucizumab intravenous injection. Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015. 14. Pollack C. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015; 373: 511-20. 15. Siegal D. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015; 373: 2413-24. 16. Connolly S. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016;375:1131-41. 17. Ansell J. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. N Eng J Med 2014; 371: 2141-2142. 18. Martin K, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH . J Thromb Haemost 2016; 14(6): 1308–1313.

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