Target Specific Oral Anticoagulants (TSOACS) and Areas for Pharmacy Involvement

1 Target Specific Oral Anticoagulants (TSOACS) and Areas for Pharmacy Involvement Cindy Brucato, PharmD, BCACP Ohio Society of Health-System Pharmacists April 24, 2015

2 Disclosures I have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation

3 Learning Objectives Pharmacist Learning Objectives Review all TSOACS including new indications and dosing with a focus on edoxaban Identify key drug interactions with TSOACS Discuss role of pharmacists in the monitoring of these medications Technician Learning Objective Recognize all TSOACS and typical doses associated with each

4 Abbreviations TSOAC target specific oral anticoagulant CRNMB clinically relevant nonmajor bleeding OAC oral anticoagulant CrCl creatinine clearance scr serum creatinine AFib atrial fibrillation VTE venous thromboembolism DVT deep vein thrombosis PE pulmonary embolism PCP primary care provider ECG echocardiogram THR total hip replacement TKR total knee replacement CVA cerebrovascular accident (stroke) GI gastrointestinal CKD chronic kidney disease TTR time in therapeutic range P-gp P glycoprotein Wt weight INR International normalized ratio LMWH low molecular weight heparin UFH unfractionated heparin

5 Ideal Anticoagulants Oral Fixed doses Rapid onset and offset of action No renal or hepatic dose adjustments Predictable pharmacokinetics/dynamics No need for bridging Wide therapeutic window safety Minimal monitoring Minimal food or drug interactions Reversible/Antidote Cost -- affordable

6 TSOACS Direct Thrombin Inhibitor Dabigatran Direct Factor Xa Inhibitor Rivaroxaban Apixaban Edoxaban

Mechanism of Action 1 7

8 TSOACS Pharmacokinetics/dynamics MOA Property Dabigatran 2 Rivaroxaban 3 Apixaban 4 Edoxaban 5 Direct IIa inhibitor Direct Xa inhibitor Direct Xa inhibitor Direct Xa inhibitor Bioavailability 6-7% 80% 50% 62% Tmax 1.5hrs 2-4hrs 2-3hrs 1-2hrs T ½ 12-14hrs 9-13 hrs 8-15hrs 8-11hrs Protein binding 35% 90% 87% 55% Hepatic metabolism No Yes Yes Yes Drug interactions P-gp P-gp/CYP3A4 P-gp/CYP3A4 P-gp Renal elimination 80% 66% 27% 40% Renal dosing Yes Yes No? Yes Dialyzable Yes No No No Antidote No No No No

9 ENGAGE AF TIMI 48 6 Double-blinded, double-dummy trial (n=21,105) Documented AFib via ECG within the last 12 months and a CHADS2 score > 2 Adjusted warfarin (goal INR 2-3) Edoxaban 60mg once daily * Edoxaban 30mg once daily* *Dose was reduced by ½ for any ONE of the following: CrCl of 30-50ml/min, wt <60kg, concomitant use of potent P-gp inhibitor Primary Endpoint: Stroke or systemic embolic event Primary Safety Endpoint: Major bleeding

ENGAGE AF TIMI 48 Efficacy Outcomes 6 10

11 ENGAGE AF TIMI 48 Efficacy Outcomes 6 Outcome Primary efficacy Warfarin (n=7036) %/year Edoxaban 60mg (n=7035) %/year P-value Edoxaban 30mg (n=7034) %/year 1.8 1.57 0.08 2.04 0.1 Stroke 1.69 1.49 0.11 1.19 0.12 Ischemic Stroke Hemorrhagic Stroke Systemic Embolism All cause mortality Cardiovascular mortality P-value 1.25 1.25 0.97 1.77 <0.001 0.47 0.26 <0.001 0.16 <0.001 0.12 0.08 0.19 0.38 0.27 4.35 3.99 0.08 3.8 0.006 3.17 2.74 0.013 2.71 0.008

ENGAGE AF TIMI 48 Safety Outcomes 6 12

13 TSOACS for AFib Baseline Characteristics Dabigatran RE-LY 7 Rivaroxaban ROCKET AF 8 Apixaban ARISTOTLE 9 Edoxaban ENGAGE-AF 6 Number of patients 18,113 14,266 18,206 21,105 Mean Age 71 73 70 72 Mean CHADS2 score 2.2 3.5 2.1 2.8 CHADS2 score >2 32% 87% 30% 77% Prior CVA/TIA 20% 55% 19% 28% Mean TTR 64% Protocol managed 55% No protocol 62% Protocol managed 68% Protocol managed Design Open label Double blinded Double blinded Double blinded Bleeding Recorded throughout study Recorded throughout study Recorded for 2 days after end of therapy Recorded for 3 days after end of therapy

14 TSOACS for AFib Results 6-9 Stroke and systemic embolism prevention All TSOACS were non-inferior to warfarin Dabigatran and apixaban demonstrated superiority Hemorrhagic stroke events with all TSOACS vs. warfarin Ischemic stroke events with Dabigatran vs. warfarin Major bleeding events with apixaban and edoxaban vs. warfarin All cause mortality All TSOACS showed a decrease in all-cause mortality vs. warfarin; however, only apixaban showed a statistically significant decrease (p=0.01)

15 FDA Approved Dosing for AFib 6-9 Dabigatran CrCl > 30ml/min 150mg BID CrCl 15-30ml/min 75mg BID Rivaroxaban Apixaban Edoxaban CrCl >50ml/min 20mg daily with food CrCl 15-50ml/min 15mg daily with food 5mg BID unless 2 of the following conditions are met then 2.5mg BID scr >1.5 mg/dl, age >80yoa, wt<60kg CrCl 50-95ml/min 60mg daily CrCl 15-50ml/min, wt < 60kg, OR strong concurrent P-gp use 30mg daily

16 AHA/ACC/HRS 2014 Guidelines 10 Stroke Prevention in AFib Antithrombotic therapy should be guided by absolute risk of stroke, bleeding, and patient preference Warfarin in patients with AFib and mechanical heart valves CHA 2 DS 2 -VASc score > 2 oral anticoagulant therapy Warfarin goal INR 2-3 Direct thrombin inhibitor or factor Xa inhibitors Renal function should be evaluated prior to and re-evaluated at least annually with dabigatran, rivaroxaban, and apixaban For patients with CHA 2 DS 2 -VASc score > 2 and who have end stage CKD (CrCl <15ml/min) or are hemodialysis, it is reasonable to use warfarin Class I Level C Class I Level B Class I Level A Class I Level B Class I Level B Class IIa Level B

17 Assessment Question 1 Which TSOAC has the recommendation to avoid use in non-valvular atrial fibrillation patients with a CrCl > 95ml/min? A. Apixaban B. Dabigatran C. Edoxaban D. Rivaroxaban

18 Hokusai VTE 11 Edoxaban Placebo edoxaban Warfarin Placebo warfarin LMWH VTE R Day 1-5 Day 6-12 3 mo 6 mo 12 mo Edoxaban Dosing 60mg once daily 30mg once daily if CrCl 30-50ml/min, wt < 60kg, or strong P-gp inhibitor Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: clinically relevant bleeding

Hokusai VTE Primary Outcome 11 19

Hokusai VTE Safety Outcomes 11 20

21 Hokusai VTE Safety Outcomes 11 Event Edoxaban (n=4118) No. (%) Warfarin (n=4122) No. (%) Hazard Ratio (95% CI) P-Value Major Bleed 54 (1.4) 66 (1.6) 0.84 (0.59-1.21) 0.35 Fatal 2 (<0.1) 10 (0.2) Fatal intracranial 0 6 (0.1) Non-fatal intracranial 5 (0.1) 12 (0.3) CRNMB 298 (7.2) 368 (8.9) Combination major bleed and CRNMB 349 (8.5) 423 (10.3) 0.81 (0.71-0.94) 0.004

22 TSOACS for Treatment of VTE Baseline Characteristics Number of patients Dose of OAC Parenteral anticoagulant Dabigatran RE-COVER I & II 12-13 Rivaroxaban EINSTEIN DVT & PE 14-15 Apixaban AMPLIFY 16 Edoxaban HOKUSAI VTE 11 5107 4832 5365 8240 150mg BID vs. warfarin Yes Median 9 days 15mg BID x21 days then 20mg daily vs. warfarin No 10mg BID x7 days then 5mg BID vs. warfarin No 60mg daily vs. warfarin Yes Median 7 days

23 TSOACS for Treatment of VTE 11-16 Baseline Characteristics Dabigatran RE-COVER I & II Rivaroxaban EINSTEIN DVT & PE Apixaban AMPLIFY Edoxaban HOKUSAI VTE Mean age 55/57 56/58 57 56 Weight (kg) 85/81 82/83 84 82 CrCl 30-50ml/min NR/NR 6.8%/8.2% 5.7% 6.6% Active cancer 4.8%/3.9% 6.0%/4.6% 2.7% 2.5% VTE history 26%/18% 19%/20% 16% 18% DVT only 69%/68% 99%/0% 66% 60% PE only 21%/23% 0%/75% 25% 30% DVT + PE 10%/9% 1%/25% 9% 10%

24 TSOACS for Treatment of VTE 11-16 Efficacy and Safety Results Primary Efficacy outcome: All TSOACS showed non-inferiority vs. warfarin for symptomatic recurrent VTE None of the TSOACS demonstrated superiority to warfarin based on efficacy Primary Safety outcome: Rivaroxaban and Apixaban demonstrated significant decrease in the number of major bleeds vs. warfarin All TSOACS showed a significant decrease in CRNMB

25 FDA Approved Dosing for VTE 2-5 Dabigatran Minimum of 5 days parenteral anticoagulation CrCl > 30ml/min 150mg BID Rivaroxaban Apixaban Edoxaban CrCl > 30ml/min 15mg BID x21 days then 20mg daily 10mg BID x 7 days then 5mg BID Patients with CrCl < 25ml/min or scr > 2.5mg/dL were excluded from clinical trials Minimum of 5 days parenteral anticoagulation CrCl >50ml/min 60mg daily CrCl 15-50ml/min 30mg daily

26 Anticoagulation Strategies for VTE treatment Bridging LMWH/ Warfarin UFH/ Warfarin Switching OAC only LMWH/UFH to Dabigatran Rivaroxaban (21 days at high dose) LMWH/UFH to Edoxaban Apixaban (7 days at high dose)

27 Assessment Question 2 Which TSOACS must have 5-10 days of parenteral anticoagulation first when treating VTE? A. Apixaban B. Dabigatran C. Edoxaban D. A & C E. B & C

28 VTE Prophylaxis Post-Orthopedic Surgery THR Dabigatran RE-NOVATE 17 Rivaroxaban RECORD 1 18 Apixaban ADVANCE 3 19 Edoxaban 150mg or 220mg once daily Efficacy VTE rates -- non-inferior Safety similar rates of major bleeding 10mg once daily Efficacy VTE rates were significantly reduced Safety similar rates of major bleeding 2.5mg twice daily Efficacy VTE rates were significantly reduced Safety similar rates of major bleeding Not studied in this patient population

29 VTE Prophylaxis Post-Orthopedic Surgery TKR Dabigatran RE-MODEL 20 RE-MOBILIZE 21 Rivaroxaban RECORD 3 22 RECORD 4 23 Apixaban ADVANCE 2 24 ADVANCE 1 25 Edoxaban 150mg or 220mg once daily Efficacy VTE rate (1) vs. enoxaparin 40mg daily noninferior (2) vs. enoxaparin 30mg BID higher rates of VTE Safety similar rates of major bleeding 10mg once daily Efficacy VTE rates (1) vs. enoxaparin 40mg daily significantly reduced rates of VTE (2) vs. enoxaparin 30mg BID significantly reduced rates of VTE Safety similar rates of major bleeding 2.5mg twice daily Efficacy VTE rates (1) vs. enoxaparin 40mg daily significantly reduced rates of VTE (2) vs. enoxaparin 30mg BID non-inferior Safety similar rates of major bleeding Not studied in this patient population

30 VTE Prophylaxis Post-Orthopedic Surgery 2-5 Dabigatran Not FDA approved Rivaroxaban FDA approved for both THR and TKR 10mg once daily Apixaban FDA approved for both THR and TKR 2.5mg twice daily Edoxaban Not FDA approved Not studied

31 Roles of the pharmacist 26 Patient education Drug interactions Monitoring Appropriate selection of TSOAC based on patient specific factors

32 General Patient Education for TSOACS Indication Carry a medication alert card with you Do not stop taking without talking to your doctor Do not miss doses Handling missed doses May increase risk of bleeding Recognize signs or symptoms of bleeding May bruise more easily May take longer to stop bleeding Tell your health care providers about this medication and all of your medications You may need to stop this medication prior to procedures Do not take with other anticoagulants unless instructed to do so by your doctor

33 Unique Education for Each TSOAC 2-5 Dabigatran Rivaroxaban Apixaban Edoxaban Take with or without food Must be stored in original bottle. Do not use a pillbox. Only good for 4 months after bottle is opened. May cause GI upset or indigestion Take with food for doses >10mg For BID dosing in VTE take 2 doses at one time if dose is missed Take with or without food Take with or without food

34 Drug-Drug Interactions Dabigatran 2 Interacting Medication P-gp inducer rifampin P-gp inhibitor ketoconazole, dronedarone P-gp inhibitor amiodarone, verapamil, ketoconazole, dronedarone, diltiazem, clarithromycin Pharmacodynamic interaction aspirin, clopidogrel, ticagrelor, NSAIDS Action needed Avoid combination Increased risk of CVA If CrCl 30-50ml/min consider dose reduction to 75mg BID Increased risk of bleed If CrCl 15-30ml/min avoid use Increased risk of bleed Assess risk vs. benefit Increased risk of bleed

35 Drug-Drug Interactions Rivaroxaban 3 Interacting Medication Action needed Dual strong CYP3A4 and P-gp inducer rifampin, phenytoin, carbamazepine, St. John s wort Dual strong CYP3A4 and P-gp inhibitor conivaptan, HIV protease inhibitors, intraconazole, ketoconazole Dual weak to moderate CYP3A4 and P-gp inhibitor amiodarone, verapamil, diltiazem, erythromycin, dronedarone, cimetidine Pharmacodynamic interaction aspirin, clopidogrel, ticagrelor, NSAIDS Avoid combination Increased risk of CVA Avoid combination Increased risk of bleed If CrCl 15-80ml/min assess for risk vs. benefit. Concurrent use was allowed in clinical trials May increase risk of bleed Assess risk vs. benefit Increased risk of bleed

36 Drug-Drug Interactions Apixaban 4 Interacting Medication Action needed Dual strong CYP3A4 and P-gp inducer rifampin, phenytoin, carbamazepine, St. John s wort Dual strong CYP3A4 and P-gp inhibitor conivaptan, HIV protease inhibitors, intraconazole, ketoconazole Pharmacodynamic interaction aspirin, clopidogrel, ticagrelor, NSAIDS Avoid combination Increased risk of CVA If on apixaban 5mg BID, then decrease dose to 2.5mg BID. If on apixaban 2.5mg BID, then avoid use Increased risk of bleed Assess risk vs. benefit Increased risk of bleed

37 Drug-Drug Interactions Edoxaban 5 Interacting Medication P-gp inducer rifampin P-gp inhibitor For VTE verapamil, quinidine, azithromycin, clarithromycin, erythromycin, intraconazole, ketoconazole Pharmacodynamic interaction aspirin, clopidogrel, ticagrelor, NSAIDS Action needed Avoid combination Increased risk of CVA AFib No dose reduction needed VTE Decrease dose to 30mg daily Increased risk of bleed Assess risk vs. benefit Increased risk of bleed

38 TSOAC Selection 2-5 Prior to initiation Drug interactions Assess age, wt, renal and hepatic function Assess for history of bleed Review pertinent labs Patient education Affordability Assess for interactions with P-gp transporter or CYP enzymes Assess for concurrent medications which may increase bleed risk Follow-up Adherence Monitor for adverse drug reactions Monitor CBC, renal and hepatic function

39 Inappropriate Patients for TSOACS Poor renal function CrCl < 15min/min CrCl < 30ml/min(?) Severe hepatic dysfunction Mechanical heart valve Special populations: pregnancy/lactation/pediatrics Non-adherence Currently stable on warfarin Concurrent therapy with potent P-gp and CYP3A4 inducers or inhibitors Hemodynamically unstable

40 Considerations in CKD Patients 2-5 % Renal Clearance Rivaroxaban 66% Dabigatran 80% Edoxaban 40% Apixaban 27%

41 TSOAC Differentiation for AFib 6-9 Characteristics Preferred Agent Rationale Age >75 years CrCl >95ml/min CrCl 30-50 ml/min CrCl 25-30 ml/min Apixaban Edoxaban Any except Edoxaban Apixaban Apixaban major bleeding with dabigatran GI bleed with rivaroxaban risk of stroke with edoxaban risk of major bleeding Only agent studied at this CrCl Adherence concerns Rivaroxaban/Edoxaban Only administered once daily High bleed risk Apixaban/ Edoxaban risk of major bleeding History of GI bleed High risk of stroke with a low risk of bleed Edoxaban Apixaban risk of GI bleeding No risk of GI bleed Dabigatran in ischemic stroke vs. warfarin History of dyspepsia Direct Xa inhibitor Dabigatran associated with dyspepsia

42 TSOAC Bleeding Profile for AFib 6-9 Effect RE-LY Dabigatran 150mg daily ROCKET-AF Rivaroxaban ARISTOTLE Apixaban ENGAGE-AF Edoxaban 150mg Intracranial hemorrhage Major Bleeding GI Bleeding

43 TSOAC Differentiation for VTE 11-16 Characteristics Preferred Agent Rationale CrCl 25-30ml/min Apixaban Only TSOAC studied Weight < 60kg Edoxaban Apixaban (?) Reduced dose studied Active cancer LMWH Small % of patients in clinical trials Adherence concerns Increased bleed risk Edoxaban Rivaroxaban (?) Apixaban Rivaroxaban Once daily Decreased risk of major bleed Prior MI Any Factor Xa inhibitor Dabigatran associated with MI Chronic NSAID use Apixaban Clinical trial allowed use Concurrent clopidogrel Rivaroxaban Clinical trial allowed use

44 Monitoring of TSOACs 26 Adherence Thromboembolism Bleeding Side effects Drug interactions Labs Serum creatinine Hemoglobin Hematocrit LFTs

45 Pharmacist Driven Services Inpatient Services Aid in appropriate selection of TSOAC Review for correct dosing and drug interactions Outpatient Services Focus on transitions of care Education Affordability One-on-one appointments Shared medical appointments

46 Patient Case #1 History of Present Illness: RS is a 25year old female diagnosed with a DVT. Pt is 6 weeks post-partum. Pt is not breast feeding. No history of miscarriages. While in the hospital, a thrombophilia panel was sent out. Results received in outpatient setting homozygous for Factor V Leiden. HAS-BLED score = 1 for anemia Past Medical History: none Family History: no history of thrombosis or thrombophilia Social History: Denies tobacco, alcohol, and illicit drug use Treatment Plan: Lovenox 1mg/kg every 12 hours and dose adjusted warfarin with goal INR 2-3. Treatment changed to apixaban 5mg BID after appointment and discussion with PCP 2weeks later

47 Special Populations Thrombophilias16, 27-29 Patients with thrombophilias/prothrombotic genotypes Apixaban Warfarin Placebo AMPLIFY 2.8% 2.2% N/A AMPLIFY -EXT 3.8% 3.2% 4.3% Patients with known Factor V Leiden, prothrombin gene mutation, antithrombin deficiency, activated protein C resistance, protein C deficiency, protein S deficiency, hyperhomocysteinemia (MTHFR), dysfibrinogenemia, hypoplasminogenenmia, dysplasminogenemia, and antiphospholipid syndrome were excluded.

48 Patient Case #2 History of Present Illness: JR is a 53year old male diagnosed with a PE. Pt had a bioprosthetic AVR 3 years ago and has not required OAC. Home medications: aspirin 81mg daily, metformin 1000mg BID, sitagliplitin 100mg daily, lisinopril 20mg daily, HCTZ 25mg daily, and atorvastatin 40mg daily Past Medical History: bioprosthetic AVR, HTN, DLD, and T2DM Family History: no history of thrombosis or thrombophilia Social History: Denies tobacco, alcohol, and illicit drug use Treatment Plan: Apixaban 10mg BID for 7 days then 5mg BID

49 Special Populations -- Valve Replacement 30 Dabigatran RE-ALIGN Trail Prosthetic mechanical valves 68% aortic valve 28% mitral valve 4% aortic and mitral valves Trial was stopped after enrollment of 252 patients (required 405 for power) Time to first thrombotic event HR 1.94 (95% CI 0.64 5.86) p=0.24 Time to first bleeding event HF 2.45 (95% CI 1.23 4.86) p=0.01

50 Special Populations Valve Replacement Apixaban 9,16,24-25,28,31 Did not evaluate use of apixaban in patients with prosthetic mechanical or bioprosthetic heart valves Patients with prosthetic mechanical heart valves were excluded from ARISTOTLE, AVERROES, ADVANCE-1, ADVANCE-2, ADVANCE-3, AMPLIFY, and AMPLIFY-EXT Rivaroxaban 8,14-15 Did not evaluate use of rivaroxaban in patients with prosthetic mechanical heart valves Patients with prosthetic mechanical heart valves were excluded from ROCKET-AF, EINSTEIN-DVT, EINSTEIN-PE

51 Assessment Question 3 Which TSOAC is least renally cleared? A. Apixaban B. Dabigatran C. Edoxaban D. Rivaroxaban

52 Assessment Question 4 Which TSOACS are contraindicated if a patient is on a dual strong CYP3A4 and strong P-gp inhibitor? A. Dabigatran B. Edoxaban C. Rivaroxaban D. Apixaban E. C & D

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55 References 21. Ginsberg JS, Davidson BL, Comp PC, et al; for RE-MOBILIZE Investigators. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009 Jan; 24(1):1-9. 22. Lassen MR, Ageno W, Borris LC, et al; for RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786. 23. Turpie AG, Lassen MR, Davidson BL, et al; for RECORD 4 Invesitgators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009 May 16;373(9676):1673-1680. 24. Lassen MR, Raskob GE, Gallus A, et al; for ADVANCE2 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE2): a randomised double-blind trial. Lancet. 2010;375:807-815. 25. Lassen MR, Raskob GE, Gallus A, et al; for ADVANCE 1 Investigators. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604. 26. Testa S, Paoletti O, Zimmermann A, et al. The role of anticoagulation clinics in the era of new oral anticoagulation. Thrombosis. 2012. 27. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism (supplementary appendix). N Engl J Med. 2013;369:799-808. 28. Agnelli G, Buller HR, Cohen A, et al; for the AMPLIFY-EXT Investigators. Apixaban forextended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. 29. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism (supplementary appendix). N Engl J Med. 2013;368(8):699-708. 30. Eikelboom JW, Connolly SJ, Brueckmann M, et al; for RE-ALIGN Invesitgators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.

56 Target Specific Oral Anticoagulants (TSOACS) and Areas for Pharmacy Involvement Cindy Brucato, PharmD, BCACP Ohio Society of Health-System Pharmacists April 24, 2015