The New Kids on the Block: Oral Anticoagulants

The New Kids on the Block: Oral Anticoagulants Lauren E. Odum, PharmD, BCPS Clinical Assistant Professor UMKC School of Pharmacy at MU April 11, 2014

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Oral Anticoagulants Warfarin (Coumadin ) Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban next new oral anticoagulant?

Warfarin Cost Half-life Reversal agent Once daily Drug of choice in rheumatic heart disease, mitral stenosis, or prosthetic heart valves Can assess adherence Monitoring Doses change often Drug/drug interactions Drug/diet interactions Half-life

Dabigatran, Rivaroxaban, Apixaban Fixed doses No routine drug monitoring No diet limitations Few drug/drug interactions Half-life At least as effective as warfarin Cost No reversal agent Half-life Short trial durations Difficult to assess adherence

FDA Approved Indications Nonvalvular Atrial Fibrillation Thromboprophylaxis in Knee or Hip Replacement Treatment of DVT or PE Dabigatran Rivaroxaban Apixaban

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Nonvalvular Atrial Fibrillation References for Key Trials: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009;361:1139-1151. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011;365:981-992. Patel MR, Maheffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011;365:883-891.

Drug Key Studies Leading to FDA Approval for Nonvalvular Atrial Fibrillation RE-LY ROCKET-AF ARISTOTLE Dabigatran 110 or 150 mg BID Rivaroxaban 15 or 20 mg Qday Apixaban 2.5 or 5 mg BID Comparator Warfarin Warfarin Warfarin Sample size 18,113 14,264 18,201 Duration, median Mean or median age CHADS2 score, mean 2 years ~2 years 1.8 years 71 years 73 years 70 years 2.1 3.5 2.1

Key Studies Leading to FDA Approval for Nonvalvular Atrial Fibrillation RE-LY ROCKET-AF ARISTOTLE Drug Dabigatran Rivaroxaban Apixaban Time warfarin in therapeutic range 64% 55% 62.2% Stroke or systemic embolism vs warfarin/year 1.1% (150mg) vs 1.7% (RR 0.66, 95% CI 0.53-0.82, P<0.001) Superior 1.7% vs 2.2% (HR 0.79, 95% CI 0.66-0.96, P<0.001) Non-inferior 1.3% vs 1.6% (HR 0.79, 95% CI 0.66-0.95, P=0.01) Superior Major bleeding vs warfarin/year 3.1% vs 3.4%, P=Not significant 3.6% vs 3.4%, P=Not significant 2.1% vs 3.1%, P<0.001 ICH vs warfarin/year 0.1% vs 0.4%, P<0.001 0.5% vs 0.7%, P=0.02 0.2% vs 0.5%, P<0.001 RR=relative risk; CI=confidence interval; HR=hazard ratio

Dabigatran Additional Notes More gastrointestinal bleeds in dabigatran vs warfarin 1.51%/year vs 1.02%/year RR 1.50 (95% CI 1.19-1.89), P<0.001 More myocardial infarction in dabigatran vs warfarin 0.74%/year vs 0.53%/year RR 1.38 (95% CI 1.00-1.91), P=0.048 Rivaroxaban More gastrointestinal bleed in rivaroxaban vs warfarin 3.2% vs 2.2%, P<0.001 RR=relative risk; CI=confidence interval

Patients Excluded from the Trials for Nonvalvular Atrial Fibrillation RE-LY ROCKET-AF ARISTOTLE Drug Dabigatran Rivaroxaban Apixaban Excluded populations -Heart-valve disorder -CrCl <30 ml/min -Active liver disease -Pregnancy -Recent stroke (last 14 days or last 6 months if severe) -Heart-valve disorder -CrCl <30 ml/min -Taking ASA >100 mg/day -Taking ASA + clopidogrel -Heart-valve disorder -CrCl <25 ml/min or SCr >2.5 mg/dl -Taking ASA >165 mg/day -Taking ASA + clopidogrel -Recent stroke (last 14 days or last 3 months if severe)

DVT and PE Prophylaxis in Knee and Hip Surgery References for Key Trials: Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-2775. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31-39. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-2786. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009:361:594-604. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-815. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD 4): a randomised trial. Lancet 2009;373:1673-1680.

Key Studies Leading to FDA Approval for DVT and PE Prophylaxis in Knee and Hip Surgery RECORD 1-4 ADVANCE 1-3 Drug Rivaroxaban 10 mg daily Apixaban 2.5 mg BID Comparator Enoxaparin 40 mg qday (RECORD 1-hip RECORD 2-hip RECORD 3-knee), Enoxaparin 30 mg Q12h (RECORD 4-knee) Enoxaparin 30 mg Q12h (ADVANCE 1-knee), Enoxaparin 40 mg Qday (ADVANCE 2-knee), Enoxaparin 40 mg Qday (ADVANCE 3-hip) Duration Knee: 10-14 days Hip: 35 days Knee: 10-14 days Hip: 35 days Sample size RECORD 1 and 2-hip: 6579 RECORD 3 and 4-knee: 5580 ADVANCE 1 -knee: 3195 ADVANCE 2 -knee: 3057 ADVANCE 3 -hip: 5407

Key Studies Leading to FDA Approval for DVT and PE Prophylaxis in Knee and Hip Surgery RECORD 1-4 ADVANCE 1-3 Drug Rivaroxaban Apixaban Composite time to first DVT or PE recurrence (and also any death for apixaban trials) vs enoxaparin First major or nonmajor bleed vs enoxaparin RECORD 1 (hip), 2 (hip), and 3 (knee): Superior RECORD 4 (knee): Non-inferior All trials: No difference ADVANCE 1 (knee): Did not meet noninferiority ADVANCE 2 (knee): Superior ADVANCE 3 (hip): Superior ADVANCE 1 (knee): Less bleeds, P=0.03 ADVANCE 2 (knee): No difference ADVANCE 3 (hip): No difference

Patients Excluded from the Trials for DVT and PE Prophylaxis in Knee and Hip Surgery RECORD 1-4 ADVANCE 1-3 Drug Rivaroxaban Apixaban Excluded populations -Bilateral total hip replacement -CrCl <30 ml/min -Hepatitis or cirrhosis -CrCl <30 ml/min -AST or ALT >2X ULN -Total bilirubin 1.5X ULN ULN=upper limit of normal

DVT and PE References for Key Trials: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510. The EINSTEIN PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297.

Key Studies Leading to FDA Approval for DVT and PE Drug Comparator EINSTEIN DVT Rivaroxaban 15 mg BID with food X 3 weeks, then 20 mg qday with food Enoxaparin 1 mg/kg Q12 hrs + warfarin X 5 days, then warfarin INR 2-3 EINSTEIN PE Rivaroxaban 15 mg BID with food X 3 weeks, then 20 mg qday with food Enoxaparin 1 mg/kg Q12 hrs + warfarin X 5 days, then warfarin INR 2-3 Duration 3, 6, or 12 months 3, 6, or 12 months Sample size 3449 4832

Key Studies Leading to FDA Approval for DVT and PE EINSTEIN DVT EINSTEIN PE Drug Rivaroxaban Rivaroxaban Time warfarin was in therapeutic range Recurrent venous thromboembolism vs enox/warfarin 58% 63% 2.1% vs 3.0%, (HR 0.68, 95% CI, 0.44-1.04, P<0.001) Non-inferior 2.1% vs 1.8%, (HR 1.12, 95% CI, 0.75-1.68) Non-inferior Major or nonmajor bleed vs enox/warfarin 8.1% vs 8.1% (HR 0.97, 95% CI 0.76-1.22, P=0.77) No difference 10.3% vs 11.4% (HR 0.90, 95% CI 0.76-1.07, P=0.23) No difference HR=hazard ratio; CI=confidence interval

Patients Excluded from the Trials for DVT and PE EINSTEIN DVT and PE Drug Excluded populations Rivaroxaban -Thrombectomy or fibrinolytic -CrCl <30 ml/min -Significant liver disease -Active bleeding

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Mechanism of Action Warfarin Seven Nine two Ten RivaroXaban ApiXaban Dabigatran

Pharmacokinetics Dabigatran Rivaroxaban Apixaban Warfarin Bioavailability 3-7% 10 mg: 80-100% regardless of food 20 mg: 66% without food and higher with food 50% 95-100% P-gp substrate? Yes Yes Yes No Onset of action Rapid Rapid Rapid Slow Protein binding 35% 92-95% 87% 99% Cytochrome P450 metabolism? None 3A4/5 and 2J2 3A4 2C9 Renal elimination? Yes Yes Yes No (very little) T ½ (hrs) 12-17 5-9 12 20-60 P-gp=P-glycoprotein, T1/2=half-life

Dabigatran 75 and 150 mg Atrial fibrillation CrCl >30: 150 mg BID CrCl 15-30: 75 mg BID CrCl <15: AVOID CrCl=creatinine clearance in ml/min Rivaroxaban 10, 15, and 20 mg Dosing Atrial fibrillation CrCl >50: 20 mg qday with evening meal CrCl 15-50: 15 mg qday with evening meal CrCl <15: AVOID Knee/hip replacement CrCl >30: 10 mg qday with or without food X 12 days (knee) or 35 days (hip) CrCl <30: AVOID DVT/PE CrCl >30: 15 mg BID X21 days with food. Then 20 mg qday with food. CrCl <30: AVOID Apixaban 2.5 and 5 mg Atrial fibrillation 5 mg BID 2.5 mg BID if 2 or more of the following: 80 years, 60 kg, SCr 1.5 mg/dl On hemodialysis: 5 mg BID OR 2.5 mg BID if 80 years or 60 kg Knee/hip replacement 2.5 mg BID X 12 days (knee) or 35 days (hip)

Dosing Dabigatran Rivaroxaban Apixaban No recommendations for hepatic impairment dosing Child-Pugh B or C: AVOID Severe hepatic impairment: AVOID

Dosing: Take Home Points Doses vary depending on the indication! Rivaroxaban dose changes after 21 days for DVT/PE Take rivaroxaban with food for 15 and 20 mg Renal issues? Consider warfarin Look up renal dosing once CrCl <50 ml/min Look up dosing for apixaban if patient is elderly, underweight, or has poor renal function

Drug Interactions Clinically relevant interactions exist and may require dose modification or avoidance, especially in renal impairment P-gp inducers decrease efficacy of anticoagulant Ex. Rifampin, St. John s Wort AVOID dabigatran P-gp inhibitors increase bleed risk Ex. dronedarone, ketoconazole, clarithromycin, verapamil, amiodarone, quinidine AVOID dabigatran if CrCl <30 ml/min REDUCE dabigatran if CrCl <50 ml/min and taking dronedarone or ketoconazole P-gp=P-glycoprotein

Drug Interactions Combined P-gp and 3A4 inducers will decrease efficacy of anticoagulant Ex. carbamazepine, rifampin, phenytoin, St. John s Wort AVOID rivaroxaban and apixaban Combined P-gp and 3A4 inhibitors will increase bleed risk Ex. ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole, itraconazole AVOID rivaroxaban REDUCE apixaban Other anticoagulants, NSAIDS, and antiplatelets will increase bleed risk

Contraindications and Warnings Contraindications: Active bleeding Hypersensitivity Mechanical heart valves Warnings and precautions: Risk of bleeding Pregnancy category C (dabigatran and rivaroxaban) and B (apixaban) Avoid in breastfeeding Bioprosthetic heart valves Avoid lapse in therapy Spinal or epidural hematoma in patients undergoing spinal puncture or receiving neuraxial anesthesia for rivaroxaban and apixaban

Main Side Effects All drugs: Bleeding Dabigatran: DYSPEPSIA and GASTRITIS-like symptoms

Laboratory Monitoring for New Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Warfarin CBC prn Renal function prn Hepatic function prn CBC prn INR usually monthly or more

Cost Comparison to Patient Dabigatran 150 mg BID 30 day supply: $327.02 Rivaroxaban 10 or 20 mg Qday 30 day supply: $321.36 Apixaban 2.5 or 5 mg BID 30 day supply: $338.02 Enoxaparin 30 mg Q 12 hours for 12 to 35 days: ~$700 100 mg Q 12 hours for 10 days: $620.14 Warfarin 30 day supply: $4 Cost of labs Costco pharmacy web site. http://www2.costco.com/pharmacy/druginformation.aspx?p=1. Accessed March 2014.

Cost Comparison to Health Care Other costs: Cost of major bleed, especially intracranial Cost of drug monitoring New anticoagulants have shown costeffectiveness when compared to warfarin Unknown if new medications are still costeffective in patients who are well-controlled on warfarin Harrington AR, Armstrong EP, Nolan PE, Malone DC. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke 2013. Advance online publication doi: 10.1161/ STROKEAHA.111.000402.

Counseling Points All drugs: ADHERENCE and BLEED RISK Dabigatran GI ADRs are common full glass of water Do not open, break, chew, crush Keep in original container with closed lid at room temperature and remove only one capsule at a time Only open one bottle at a time and use within 4 months Do not take missed doses within 6 hours of one another Rivaroxaban Take a missed dose ASAP in the same day Take 15 and 20 mg doses with evening meal Apixaban Take a missed dose ASAP in the same day; do not double dose

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Converting Between Anticoagulants Warfarin to dabigatran Stop warfarin and start dabigatran when INR <2.0 Warfarin to rivaroxaban Stop warfarin and start rivaroxaban when INR <3.0 Warfarin to apixaban Stop warfarin and start apixaban when INR <2.0

Converting Between Anticoagulants Dabigatran to warfarin CrCl > 50 ml/min: Start warfarin 3 days before stopping dabigatran CrCl 30-50 ml/min: Start warfarin 2 days before stopping dabigatran CrCl 15-30 ml/min: Start warfarin 1 day before stopping dabigatran Rivaroxaban to warfarin Unclear Consider stopping rivaroxaban and starting parenteral agent plus warfarin at the time the next dose of rivaroxaban would be given Apixaban to warfarin Unclear Consider stopping apixaban and starting parenteral agent plus warfarin at the time the next dose of apixaban would be given

Converting Between Anticoagulants Parenteral/other anticoagulant besides warfarin to dabigatran or rivaroxaban Start dabigatran or rivaroxaban 0 to 2 hours before the time for the next parenteral dose or non-warfarin oral anticoagulant Start dabigatran or rivaroxaban at the time of stopping a continuously administered parenteral Parenteral/other anticoagulant besides warfarin to apixaban Discontinue one being taken and start the other at the next scheduled dose

Converting Between Anticoagulants Dabigatran to parenteral CrCl >30 ml/min: Wait 12 hours after last dose of dabigatran to start parenteral Rivaroxaban to parenteral or other anticoagulant besides warfarin Apixaban to parenteral or other anticoagulant besides warfarin Discontinue one being taken and start the other at the next scheduled dose CrCl<30 ml/min: Wait 24 hours after last dose of dabigatran to start parenteral

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Perioperative Care Dabigatran Rivaroxaban Apixaban CrCl >50 ml/min, hold 1-2 days prior to procedure CrCl < 50 ml/min, hold 3-5 days prior to procedure Consider longer for major bleed risk procedures Hold at least 24 hours before procedure Hold at least 24 to 48 hours before procedure depending on bleed risk of procedure

Objectives Be able to Understand the major trials leading to the FDA approval of the new oral anticoagulants Compare and contrast the new oral anticoagulants Convert the new oral anticoagulants to and from other anticoagulants Manage new oral anticoagulants during perioperative care Choose new oral anticoagulant therapy based on patientspecific factors

Choosing an Oral Anticoagulant Consider insurance coverage and cost to patient as well as patient preferences Options: Warfarin, dabigatran, apixaban, or rivaroxaban Adhere to FDA approved indications Nonvalvular atrial fibrillation: Warfarin, dabigatran, apixaban, or rivaroxaban Knee/hip replacement: Warfarin, apixaban, or rivaroxaban DVT/PE: Warfarin or rivaroxaban Other indication: Warfarin

Choosing an Oral Anticoagulant Heart valve or significant valvular disease Use warfarin Cancer-related thrombosis Use low molecular weight heparin Pregnancy Use low molecular weight heparin

Choosing an Oral Anticoagulant Poor kidney function Prefer warfarin>apixaban>rivaroxaban>dabigatran Gastrointestinal bleed Prefer warfarin or apixaban>rivaroxaban or dabigatran Dyspepsia/cannot swallow whole pills/needs pillbox/coronary artery disease Avoid dabigatran Feeding tube distal to stomach Prefer warfarin or apixaban

Choosing an Oral Anticoagulant Adherence problems: define reason Warfarin long half-life and can check INR but some may refuse due to labs and restrictions Dabigatran twice daily and cannot put in pillbox Apixaban twice daily Rivaroxaban- once daily but short half-life and must take with food for 15 and 20 mg doses

References Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009;361:1139-1151. Costco pharmacy web site. http://www2.costco.com/pharmacy/druginformation.aspx?p=1. Accessed March 2014. Coumadin prescribing information. http://packageinserts.bms.com/pi/pi_coumadin.pdf. Updated October 2011. Accessed March 2014. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510. The EINSTEIN PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297. Eliquis prescribing information. http://packageinserts.bms.com/pi/pi_eliquis.pdf. Updated March 2014. Accessed online March 2014. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-2775. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011;365:981-992. Harrington AR, Armstrong EP, Nolan PE, Malone DC. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke 2013. Advance online publication doi: 10.1161/ STROKEAHA.111.000402. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31-39.

References Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-2786. Lassen MR, Raskbo GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009:361:594-604. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-815. Patel MR, Maheffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011;365:883-891. Pradaxa prescribing information. http://bidocs.boehringeringelheim.com/biwebaccess/viewservlet.ser?docbase=renetnt&folderpath=/prescribing%20information/pis/pradaxa/prada xa.pdf. Updated December 2013. Accessed online March 2014. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD 4): a randomised trial. Lancet 2009;373:1673-1680. Xarelto prescribing information. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Updated March 2014. Accessed online March 2014.

The New Kids on the Block: Oral Anticoagulants Lauren E. Odum, PharmD, BCPS Clinical Assistant Professor UMKC School of Pharmacy at MU April 11, 2014