Mom New Oral Anticoagulant (NOAC) Agent Guideline Working Group Testing Supportive Therapy Drug Dosing Management of New Oral Anticoagulant Agents in Alberta Health Services There are three new oral anticoagulant agents that are available as an alternative to warfarin and low molecular weight heparin therapy in certain circumstances. Dabigatran, a direct thrombin inhibitor, has been approved by Health Canada for stroke risk reduction in patients with non-valvular atrial fibrillation (AF). Rivaroxaban, a factor Xa inhibitor, has Health Canada approval for DVT prophylaxis following orthopedic surgery, stroke risk reduction in patients with non-valvular AF patients and for treatment of deep venous thrombosis (DVT) and pulmonary embolus. Apixaban, another factor Xa inhibitor, has been approved by Health Canada for orthopedic surgery prophylaxis and stroke risk reduction in patients with non valvular AF. Alberta Health Services (AHS) Drugs and Therapeutics Committee has approved Rivaroxaban for stroke risk reduction in AF and for orthopedic DVT/PE prophylaxis. Dabigatran has been approved for stroke prevention in AF patients. Apixaban is currently available in some surgical services facilities for prophylaxis after arthroplasty. These agents do not require routine monitoring of anticoagulation status and do not affect traditionally available coagulation monitoring methods in a consistent effect and dose-based fashion. There is currently, no reversal agent that can be employed that has been proven to completely reverse coagulopathy or control of bleeding or both. All three agents do require some degree of renal clearance, which can vary with acute and chronic kidney disease. The degree of renal clearance is least for Apixaban and greatest for Dabigatran. Patients may be placed on these agents in the community and come into the AHS setting in a variety of ways including: 1. Emergently with bleeding: Table 1a: Management of patients with bleeding on Dabigatran Patients on Dabigatran (Pradaxa) with Bleeding Minor Moderate Bleeding Major Bleeding Bleeding CBC, INR/PTT Creatinine Local therapy Hold Dabigatran CBC, INR/PTT creatinine fibrinogen Type and Screen Thrombin Time Local therapy/site control Transfusion Surgery/Intervention CBC, INR/PTT Creatinine Fibrinogen Cross-match Thrombin Time Local Therapy, Transfusion Surgery/intervention Consider platelet transfusion if antiplatelet agents are in use Hold Dabigatran Hold antiplatelet agents Reversal/Removal None Consider charcoal** if <2-4 hours post-dose Consider dialysis Procoagulant Agents None Tranexamic acid (10 mg/kg IV or 25 mg/kg PO)* Consider PCC 25-50u/kg or FEIBA 50 iu/kg, If no PCC/FEIBA to be given then administer Tranexamic acid (10 mg/kg IV)* Draft 3 04.23.2013 1 NOAC Guideline
Table 1b. Management of patients with bleeding, on Rivaroxaban/Apixaban Patients on Rivaroxaban (Xarelto) or Apixaban (Eliquis) with Bleeding Minor Bleeding Moderate Bleeding Major Bleeding Testing CBC, INR/PTT CBC, INR/PTT fibrinogen, T &S, Supportive Therapy Drug Dosing Local therapy Hold Rivaroxaban/ Apixaban Hold Antiplatelet Agents Local therapy, Transfusion, Surgery/Intervention Anti Xa level Local Therapy, Transfusion, Surgery/intervention, Consider platelet transfusion if recent antiplatelet agents Hold Rivaroxaban/Apixaban Hold antiplatelet agents Reversal None Consider charcoal**(no evidence for effectiveness) Not dialyzable Procoagulant agents None Tranexamic acid (10 mg/kg IV or 25 mg/kg PO)* Consider PCC 25-50 u/kg or rfviia 90 mg/kg If no PCC or rfviia to be given than administer Tranexamic acid (10 mg/kg IV)* *Urinary tract bleeding is a relative contraindication for Tranexamic acid, which can cause clot colic ; should not be used concomitantly with FEIBA or PCC **Major upper GI bleeding is a relative contraindication for activated charcoal 2. In need of emergent/urgent procedure: a. For patients admitted with need for emergent surgery, there is no potential for reversal prior to proceeding nor is there time to get results of coagulation testing. Reasonable to proceed with plan to transfuse as necessary and inform need for other products as time permits. This would include drawing blood for: CBC, INR, PTT, fibrinogen, thrombin time, anti-xa activity, type and screen, Creatinine b. For patients admitted with need for urgent surgery, reasonable to assess level of effect of the oral anticoagulant agent and depending on level of risk of bleeding either waiting until the effect is minimal or below detection prior to proceeding. c. Determining timing of expected reversal of effect. In general, the expected timing of reversal will primarily be affected by time from the last dosage of oral anticoagulant and renal function. Dabigatran s effect will be influenced more by renal dysfunction than that of rivaroxaban or abixaban. Draft 3 04.23.2013 2 NOAC Guideline
Table 2: Peri-procedural management of new anticoagulant agents: Initial Testing Testing Required CBC, INR/PT Type and screen Creatinine Procedure with low Bleeding Risk INR, PTT normal OK to proceed Procedure with Higher Bleeding Risk Thrombin time (Dabigatran) or anti Anti- Xa level (Rivaroxaban/Apixaban) Subsequent Testing Example of Procedure Thrombin time or AntiXa level Not needed unless current bleeding issues Colonoscopy Cardiac Cath Uncomplicated laparascopic procedure OK to proceed once thrombin time or Anti-Xa level normal Hip # Cardiac surgery Neurosurgery Major abdominal surgery Neuraxial blockade 3. Patients presenting for elective procedures: For patients who are presenting electively, ensuring that the oral anticoagulant has been held appropriately will depend on the type of procedure, bleeding risk and renal function. Patients should be seen in preoperative assessment clinic to ensure that this is determined. Anesthesia should be involved and informed of the presence of oral anticoagulant agents in order to plan for type of anesthesia to be used. For surgeries that require full reversal of anticoagulant effect, testing of INR/PTT the morning of surgery may not suffice and completion of urgent Thrombin Time or Anti-Xa activity levels may be required. For those procedures with standard risk of bleeding, demonstrating a normal INR/PTT on am of surgery should suffice. Table 3: Perioperative Guideline for Dabigatran from RELY study: Draft 3 04.23.2013 3 NOAC Guideline
Weitz J, et al, Circulation 2012; 126: 343 Schulman et al, Blood; 2012;119(13):3016-23 Schulman et al, Blood; 2012;119(13):3016-23 Curr Pharm Des 2010; 16(31):3436 3441 Draft 3 04.23.2013 4 NOAC Guideline
4. Patients presenting to hospital with other health issues: Patients on new oral anticoagulants will present to hospital with other acute medical issues and it is important that clinicians be aware of these agents and the impact of renal failure as well as indications and contraindications to use of these agents. In the setting of acute renal failure, it is important to consider the need to hold/discontinue the new oral anticoagulant. Patients may require other agents such as warfarin. In the setting of acute illness with inability to eat, bridging with heparin/low molecular weight heparin may be required until the gut is working. Should a patient present with an acute coronary syndrome, use of antiplatelet therapies in addition to the anticoagulant will be required. This will likely result in a temporary switch to a parenteral anticoagulant at standard acute coronary syndrome doses. Some agents have been found to cause significant drug interactions with new oral agents (Table 5). (Shulman et al, Blood 2012) Table 5: Significant drug interactions with new oral anticoagulant agents: Draft 3 04.23.2013 5 NOAC Guideline
References: 1. Jeff S. Healey, MD, MSc; John Eikelboom, MD; James Douketis, MD; Lars Wallentin, MD, PhD; Jonas Oldgren, MD, PhD; Sean Yang, MSc; Ellison Themeles, BA; Hein Heidbuchel, MD; Alvaro Avezum, MD; Paul Reilly, PhD; Stuart J. Connolly, MD; Salim Yusuf, MD, DPhil; Michael Ezekowitz, MB, ChB, DPhil; on behalf of the RE-LY Investigatorsl Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin:Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation. 2012;126:343-348 2. Sam Schulman and Mark A. Crowther; How I anticoagulate in 2012, new and old anticoagulant agents, and when and how to switch: Blood First Edition Paper, Blood; 2012;119(13):3016-23. 3. Van Ryn J, et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb and Haemost 2010; 103(6):1116-27 Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 7 (Suppl 1):107-10 4. Levy JH. Novel oral anticoagulants: implications in the perioperative setting. Anesthesiology 2010; 113(3):726-45 5. Van Ryn J et al. Successful reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood (ASH Annual Meeting Abstracts), Nov 2011; 118: 2316 6. Elise S. Eerenberg, MD; Pieter W. Kamphuisen, MD; Meertien K. Sijpkens, BSc; Joost C. Meijers, PhD; Harry R. Buller, MD; Marcel Levi, MD. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9 7. Weltermann, M. Brodmann, H. Domanovits, B. Eber, M. Gottsauner-Wolf, W. M. Halbmayer, J. M. Hiesmayr, P. A. Kyrle, F. Längle, F. X. Roithinger, H. Watzke, R. Windhager, C. Wolf, R. Zweiker Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management. Wien Klin Wochenschr (2012) 124:340 347 8. Joanne van Ryn; Joachim Stangier; Sebastian Haertter; Karl-Heinz Liesenfeld; Wolfgang Wienen; Martin Feuring; Andreas Clemens. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116 1127 9. Birgitta Salmela, M.D., Ph.D. Lotta Joutsi-Korhonen, M.D., Ph.D. Elina Armstrong, M.D., Ph.D. Riitta Lassila, M.D., Ph.D. Active Online Assessment of Patients Using New Oral Anticoagulants: Bleeding Risk, Compliance, and Coagulation Analysis, Semin Thromb Hemost 2012;38:23 30. 10. Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des 2010; 16(31):3436 3441. 11. Jeffrey I. Weitz, MD; Daniel J. Quinlan, MBBS; John W. Eikelboom, MBBS. Periprocedural management and approach to bleeding in patients taking Dabigatran. Circulation. 2012; 126:2428-2432. Prepared by: Elizabeth MacKay, MD, FRCPC, MPH Medical Director, Calgary Zone Anticoagulation Management Services New oral anticoagulant agent guideline working group members: Dr. Cathy Dorrington, Dr. Xiu Jiang, Dr. Eddy Lang, Jennifer Lowerison, Dr. Adnan Mansoor, Dr. Graham Pineo, Dr. Man -Chui Poon, Dr. Karen Valentine, Dr. Ken Butcher, Dr. Barry Finegan, Dr. Michael Hill, Dr Steven Meyer, Dr. Brent Mitchell, Dr Susan Nahirniak, Dr. Gustavo Nogareda, Dr Blair O Neill, Dr. Kenneth O Reilly, Dr. Bruce Ritchie, Dr. Artur Szkotak, Dr. Robert Welsh Draft 3 04.23.2013 6 NOAC Guideline