New Anticoagulants! Thomas DeLoughery, MD FACP FAWM DIRECT THROMBIN INHIBITOR

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1 Thomas DeLoughery, MD FACP FAWM DIRECT THROMBIN INHIBITOR New Anticoagulants! Dabigatran Dosing: Therapy:150 mg (75 mg bid if CrCl 15-30, none if < 15) Prophylaxis 220mg or 110mg dday Drug-drug interaction rifampin (possible also - amiodarone, cyclosporin, clarithromycin, itraconazole, ketoconazole, ritonavir, saquinavir, tacrolimus or verapamil) Approved in Europe for DVT prevention 220 or 150mg daily Approved for stroke prevention in atrial fibrillation and RCT data for DVT treatment/prevention Renal clearance dose reduce if CrCl < 30 and contraindicated CrCl < 15 Effects aptt - can use to see if patient still has drug effect 1.5-2x hours after dose PeaceHealth Labs performs specific dabigatran level No specific antidote specific antibody in development Consider activated prothrombin complex concentrates (apcc) or PCC Can be dialyzed off FACTOR Xa INHIBITORS Rivaroxaban Dosing Therapy Atrial fibrillation 20 mg/day DVT 15mg x 3 wks then 20mg/day Prophylaxis 10mg qd Drug-drug interaction: CYP 3A4 agents (azole antifungals (except fluconazole) or HIV-protease inhibitors) Approved for DVT prevention RCT in DVT therapy and afib prophylaxis Renal clearance Contraindicated with CrCl < 15 Affect prothrombin time No specific antidote specific reversal agent in development PCC 50 units/kg may work Apixaban Dosing Therapy 5mg Prevention 2.5mg Potential CYP 3A4 drug-drug interaction Less dependence on renal clearance RCT in DVT prevention and Afib prophylaxis In trials for DVT therapy

2 Table One: New Anticoagulants Apixaban Betrixaban Dabigatran Edoxaban Rivaroxaban Action Anti-Xa Anti-Xa Anti-IIa Anti-Xa Anti-Xa Bioavailability 66% 47% 6.5% 45% % Onset to peak action (hours) Half-life (hours) Renal excretion ~ ~66 (%) Dose- 2.5 mg 150mg qd 10mg qd Prophylaxis 220mg qd Therapeutic 5mg 150mg 30mg, 60mg 20mg qd Drug Interaction CYP 3A4 none P-glycoprotein CYP 3A4 CYP 3A4 Table Two: Novel Anticoagulants in Prevention of Thrombosis in Total Knee Arthroplasty Number Comparator Days Total Thrombosis and Death Major Bleeding 220mg/D 150mg/day Enox 220mg/D 150mg/day Enox 1896 Enox 30mg * Enox 40mg qd R 10mg/day Enox R 10mg/day Enox 2531 Enox * mg/day 3148 Enox 30mg * A 2.5mg Enox A 2.5mb Enox 3195 Enox 30mg * Enox 40mg/Day * A = Apixaban D = Dabigatran Enox = Enoxaparin R = Rivaroxaban * = significant Table Three: Novel Anticoagulants in Prevention of Thrombosis in Total Hip Arthroplasty Number Comparator Days Total Thrombosis and Death Major Bleeding 220mg/D 150mg/day Enox 220mg/D 150mg/day Enox 3494 Enox 40mg/day R 10mg/day Enox R 10mg/day Enox 4541 Enox 40mg/day * Enox 40mg/day E * 9.3 < 0.1 < 0.1 R A 2.5mg Enox A 2.5mb Enox 5407 Enox 40mg/day * A = Apixaban D = Dabigatran Enox = Enoxaparin R = Rivaroxaban * = significant

3 Table Four: Novel Anticoagulants in Therapy of Acute Thrombosis N PE Initial Heparin % Cancer Age Recurrent Thrombosis/death Major Bleeding D150 Warf D150 Warf % Yes 4.6% 64% R 20mg/day+ Warf R20mg/day* Warf 14, No 6% 58% D = Dabigatran R = Rivaroxaban + = 15mg x 3 weeks then 20mg/day * = significant Table Five: Novel Anticoagulants in Prevention of Stroke in Atrial Fibrillation N Age CHADS2 ASA TRR Stroke & Embolism Major Bleeding D110 D150 Warf D110 D150 Warf 18, % 64% 1.53%/yr* 1.11%/yr 1.69%/yr 2.71%/yr* 3.11%/yr 3.36%/yr R 20mg/day Warf R20mg/day Warf 14, ? 58% 1.71%/yr 2.16%/yr 3.6%/yr 3.45%/yr A 5mg Aspirin A 5mg Aspirin % - 1.6%/yr 3.7%/yr 1.4%/yr 1.2%/yr A 5mg Warf A 5m Warf 18, % 66% 1.27%/yr* 1.60%/yr 2.13%/yr* 3.09%/yr A = Apixaban D = Dabigatran R = Rivaroxaban Warf = Warfarin * = significant Table Six: Intracranial Hemorrhages in Atrial Fibrillation Trials Stroke Results Intracranial bleeding Events/100 person RR Events/100 RR years person years Dabigatran ( ) ( ) Dabigatran ( ) ( ) Rivaroxaban ( ) ( ) Apixaban ( ) ( ) Apixaban ( ) ( ) REFERENCES General DeLoughery TG. Practical aspects of the oral new anticoagulants. Am J Hematol Jul;86(7): Apixaban Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van MW, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S. Apixaban in Patients with Atrial Fibrillation. N Engl J Med Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh

4 BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez- Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; the ARISTOTLE Committees and Investigators. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med Aug 27. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:p Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:p Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:p Dabigatran Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:p Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:p Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007;370:p Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:p 1-9. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:p Rivoraban Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:p Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:p Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S. 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:p Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:p Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; the ROCKET AF Investigators. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med Aug 10. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:p

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