No more rat poison? New oral anticoagulants and perioperative considerations

1 No more rat poison? New oral anticoagulants and perioperative considerations Jerrold H. Levy, MD, FAHA, FCCM Professor Department of Anesthesiology/Critical Care Duke University School of Medicine Durham, North Carolina Introduction Anticoagulation is a critical aspect of perioperative management that includes venous thromboembolism (VTE) prophylaxis and stroke prevention in patients with atrial fibrillation (AF). The only oral agents until recently were the vitamin K antagonists (VKAs) such as warfarin.(1) The newer oral anticoagulants (NOACs) available include the direct thrombin inhibitor (DTI) dabigatran etexilate (Pradaxa, Boerhing-Ingelheim Pharma), and the direct factor Xa inhibitors, rivaroxaban (Xarelto, Johnson and Johnson/Bayer Schering Pharma) and the recently approved agent apixiban (Eliquis, Bristol Myers Squibb/Pfizer).(2,3) Advantages of these new agents include their rapid onset and predictable pharmacokinetics, so that routine coagulation monitoring is not required. However, monitoring may be relevant in certain clinical situations, where an assessment of the anticoagulation status is needed.(3) This presentation will examine NOACs, their pharmacokinetic profile, and perioperative management. Dabigatran Dabigatran is a rapid acting reversible DTI that is a prodrug that has a rapid onset of action, is administered twice a day, and doesn t require routine coagulation monitoring.(4) Dabigatran undergoes renal excretion with 80% of the drug entering the urine unchanged and its duration of action is prolonged with renal dysfunction. Dabigatran is the only drug that can be eliminated during hemodialysis.(5) Dabigatran is approved in the US, Canada and Europe for stroke prevention in patients with non-valvular AF based largely on the results of the RE-LY trial in which 150 mg of dabigatran twice-daily was superior to dose-adjusted warfarin with a similar rate of major bleeding.(6) In the US, a 75 mg BID is approved based on pharmokinetic and dynamic evaluations for patients with a CrCl 30-15 ml/min. In Canada and Europe it is also approved for VTE prophylaxis following total hip or knee replacement surgery, but not in the US.(7) Rivaroxaban Rivaroxaban is an oral, direct Factor Xa inhibitor that also has a rapid onset of action and is administered once a day. Following oral administration, peak plasma concentrations occur within 2-4 hours of administration with a half-life of 5-9 hours in healthy subjects.(4) Rivaroxaban clearance is also decreased in patients with renal impairment.(8) In patients with AF and moderate renal impairment, reduced doses of rivaroxaban (15 mg) compared to the recommended dose (20 mg) of warfarin was effective.(9) Due to high plasma protein binding (>90%), rivaroxaban can not be eliminated during hemodialysis. Rivaroxaban is approved in the US, Canada and Europe for VTE prophylaxis after hip or knee replacement surgery and for stroke prevention in patients with non-valvular AF. A double blind trial of 14,264 patients randomized to either rivaroxaban 20 mg daily with normal renal function or 15 mg with renal impairment compared to dose-adjusted warfarin demonstrated that rivaroxaban was non-inferior 1

2 to warfarin with no significant difference in major bleeding events.(10) Rivaroxaban was also recently approved for a wider indication including VTE and pulmonary embolus prophylaxis. Rivaroxaban has also been studied for acute coronary syndromes but is not currently approved for this indication.(11) Apixaban Apixaban is another oral, direct Factor Xa inhibitor similar to rivaroxaban just approved.(4) In patients treated with apixaban 2.5 mg twice daily, the risk of major bleeding appears not to be influenced by renal function.(12) For this reason, no dose adjustment is recommended in patients with mild or moderate renal impairment (CL CR 30-50 ml per min). Apixaban is approved in Canada and Europe for VTE prophylaxis after total hip and knee replacement surgery and recently approved in the US for stroke prevention with AF. The halflife in healthy subjects is 8-15 hours.(4) Apixaban was just approved in the US for this indication. In the ARISTOLE study, apixaban was superior to VKAs in preventing stroke with a decrease in bleeding complication, and a lower mortality.(13) Monitoring anticoagulation with the NOACs Although routine monitoring is not required, specific laboratory studies should be obtained in patients receiving these agents who develop an acute bleed, suspected overdose, or requiring emergency surgery.(3) For dabigatran, most of the routine coagulation assays will be prolonged except the PT/INR.(14) However, dabigatran can be best measured using the thrombin time (TT) or the HEMOCLOT direct thrombin inhibitor assay.(15) Other assays reported include the ecarin clotting time (ECT) although this test is not widely available. The HEMOCLOT assay is a diluted thrombin time that has a better correlation to plasma levels of dabigatran.(15) The partial thromboplastin time (PTT), can also be used; however, the relationship between dabigatran concentration and PTT is curvilinear, resulting in decreased precision of the assay as plasma dabigatran concentration increase (US Package Insert Feb 2012). Nonetheless, this provides reasonable alternative if other tests are not available.(3) Rivaroxaban and apixiban inhibit factor Xa in a similar manner to low molecular weight heparin but independently of antithrombin.(2) Rivaroxaban causes prolongation of PT in a concentration dependent fashion but the PT is not useful for measuring its pharmacodynamic effects.(16) More recently, a factor Xa assay has been developed and might provide the optimal method for determining the effect of rivaroxaban, but further studies are needed. (2,17,18) The PT/INR may only be slightly prolonged with these agents. Temporary Discontinuation Prior to Surgery For dabigatran, discontinuation should be based on creatinine clearance and the bleeding risk associated with the procedure.(3,19,20) The Working Group on perioperative hemostasis and the French Study Group on thrombosis and hemostasis, published recommendations about the perioperative management of NOACs.(21) For scheduled surgery or invasive procedures with low risk of bleeding, they recommend interruption 24h (~2 half-lives) before the procedure and to restart 24h after. In case of scheduled surgery or invasive procedures at moderate or high risk of bleeding, a 5 days interruption prior to surgery is recommended while treatment should be restarted according to the bleeding risk. A recent report evaluated bleeding rates from 7 days prior until 30 days following invasive procedures for patients receiving dabigatran.(22) From 2

3 4591 patients having at least one invasive procedure, dabigatran and warfarin were associated with similar rates of peri-procedural bleeding, including patients having urgent surgery.(22) Reversal of the Novel Anticoagulants and Management of Acute Bleeding Immediate reversal of anticoagulation is often needed in the bleeding patient or patient requiring emergency surgery.(3) Managing these patients is a challenge, but even warfarin and other VKA agents are not easily reversible with therapies available in the United States, such as vitamin K and/or fresh frozen plasma (FFP). Four component prothrombin complex concentrates (PCCs) is currently preferred in most European countries and recommended in recent guidelines for VKA.(21,23,24) For any significant bleeding event, initial measures should include hemodynamic and hemostatic resuscitation and attempts at local hemostatic control if possible.(3) Hemodialysis or hemoperfusion are other potential options for the emergent removal anticoagulants.(3) Rivaroxaban and apixaban are too highly protein-bound to be effectively removed by these methods, but dabigatran is an appropriate candidate for hemodialysis.(4) However, attempting to obtain vascular access or dialyze a bleeding patient in shock may not be possible.(25) Therefore, the use of procoagulant agents is important for a life threatening bleed. Recombinant factor VIIa (rfviia) is increasingly used off-label as a universal hemostatic and reversal agent. However, it has not been studied in humans for reversal of NOACs, and the results of studies in animal models are variable. PCCs are available in 3-factors (II, IX, X) and 4-factors (II, VII, IX, X) varieties that are procoagulant and enhance thrombin generation.(24) The 4-factor PCCs have activated and nonactivated forms and only 3-factor PCCs are available in the US.(26) Caution is required for off label use as all prothrombotic agents may have prothrombotic events. One report included 12 healthy men given dabigatran 150 mg twice-daily or rivaroxaban 20 mg twice-daily for 2.5 days, and subsequently received either a 50 IU/kg bolus of a 4-factor PCC or saline.(27) The PCC completely reversed both the PT prolongation and inhibition of endogenous thrombin potential associated with rivaroxaban. However, dabigatran associatedprolongations in the ECT, TT, PTT and endogenous thrombin potential lag time were not corrected by the administration of the PCC. In this study the PCC was actually administered to the volunteers. In an in vitro study, dabigatran and rivaroxaban reversal was determined from blood from 10 healthy volunteers randomized to receive rivaroxaban (20 mg) or dabigatran (150 mg). Anticoagulation reversal was tested in vitro using PCC, rfviia or FEIBA at different concentrations.(28) In rivaroxaban treated patients, PCC and FEIBA corrected thrombin generation, but rfviia only modified the kinetic parameters. In dabigatran treated patients, PCC increased thrombin generation as determined by area under the curve, but only rfviia and FEIBA corrected the altered lag-time.(28) A recent analysis compared the peri-procedural bleeding risk of patients in the RE-LY trial treated with dabigatran and warfarin by evaluating bleeding rates before until 30 days following invasive procedures from 4591 patients having at least one invasive procedure. In the report, 50.1% of patients received dabigatran (110 or 150), and 25.9% warfarin. The procedures were: pacemaker/ defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%) and joint replacement (6.2%). The last dose of dabigatran was given 49 (35-85) hours prior to the procedure; compared to 114 (87-144) hours in patients receiving warfarin. There was no significant difference in the rates of peri-procedural major bleeding between patients receiving dabigatran-110 (3.8%) or dabigatran- 3

4 150 (5.1%) or warfarin (4.6%). Summary The NOACs are important novel therapeutic anticoagulants that are currently increasing in use and will continue to require careful management when patients present in a perioperative setting. Active research is underway to determine the best methods to monitor and treat bleeding when it occurs, but unlike warfarin, spontaneous recovery will occur more rapidly without renal dysfunction due to the reversible inhibition that occurs. We have a recent review In Press in Anesthesiology that summarizes much of the current information.(3) References: 1. Eikelboom JW, Weitz JI. New anticoagulants. Circulation 2010;121:1523-32. 2. Levy JH, Key NS, Azran MS. Novel oral anticoagulants: implications in the perioperative setting. Anesthesiology 2010;113:726-45. 3. Levy JH, Faroni D, Spring JL et al. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting. Anesthesiology In Press. 4. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clinical pharmacokinetics 2009;48:1-22. 5. Wagner F, Peters H, Formella S, Clemens A. Effective elimination of dabigatran with hemodialysis: a phase I single center study in patients with end stage renal disease. Circulation 2011;124:12. 6. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2009;361:1139-51. 7. Ginsberg JS, Davidson BL, Comp PC et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1-9. 8. Kubitza D, Becka M, Mueck W et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. British journal of clinical pharmacology 2010;70:703-12. 9. Fox KA, Piccini JP, Wojdyla D et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011;32:2387-94. 10. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine 2011;365:883-91. 11. Mega JL, Braunwald E, Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19. 12. Leil TA, Feng Y, Zhang L et al. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther;88:375-82. 13. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. 14. van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med 2012;125:417-20. 15. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012;23:138-43. 16. Samama MM, Martinoli JL, LeFlem L et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2010;103:815-25. 17. Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011;43:682-92. 4

5 18. Samama MM, Amiral J, Guinet C et al. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010;104:1078-9. 19. Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallelgroup, single-centre study. Clinical pharmacokinetics 2010;49:259-68. 20. Huisman MV, Lip GY, Diener HC et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thrombosis and haemostasis 2012;107:838-47. 21. Sie P, Samama CM, Godier A et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: Thrombin or factor-xa inhibitors. Recommendations of the Working Group on perioperative haemostasis and the French Study Group on thrombosis and haemostasis. Arch Cardiovasc Dis 2011;104:669-76. 22. Healey JS, Eikelboom J, Douketis J et al. Peri-Procedural Bleeding and Thromboembolic Events with Dabigatran Compared to Warfarin: Results from the RE-LY Randomized Trial. Circulation 2012;126:343-48. 23. Garcia D. Rethinking warfarin reversal. Blood 2011;116:675-6. 24. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology 2008;109:918-26. 25. van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27. 26. Kaatz S, Kouides PA, Garcia DA et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. American journal of hematology 2012;87 Suppl 1:S141-5. 27. Eerenberg ES, Kamphuisen PW, Sijpkens MK et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9. 28. Marlu R, Hodaj E, Paris A et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217-24. 5