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A New Era in Anticoagulation Management

Allyson Sarigianis, Pharm.D. October 19, 2013. A New Era in Anticoagulation Management. Objectives. Review current practice recommendations for prevention of stroke/systemic embolism in atrial fibrillation

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A New Era in Anticoagulation Management

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  1. Allyson Sarigianis, Pharm.D. October 19, 2013 A New Era in Anticoagulation Management

  2. Objectives • Review current practice recommendations for prevention of stroke/systemic embolism in atrial fibrillation • Compare and contrast pharmacology between warfarin and target specific oral anticoagulants (TSOACs) • Summarize the efficacy and safety of TSOACs for atrial fibrillation • Examine the differences between warfarin and TSOACs for atrial fibrillation • Identify future clinical implication for new era in anticoagulation management based on AT9 2012 Chest Guidelines

  3. Warfarin

  4. Warfarin

  5. Warfarin • Onset of action: • 5-7 days • May requiring bridging • Antidote: • Vitamin K, FFP, PRBC • Interactions: • Foods with high vitamin K content

  6. Warfarin • Medications • Amiodarone • Antiplatelets • Azoleantifungals (fluconazole) • 2nd/3rd-gen Cephalosporins • Fluoroquinolones (ciprofloxacin) • Griseofulvin • Isoniazid • Macrolides (clarithromycin) • Metronidazole • NSAIDs • Penicillins (nafcillin) • Prednisone • Rifampin • SSRIs • Sulfonamides (Bactrim) • Tetracyclines (Doxycycline ) • Herbals • Ginger • Gingko • Fenugreek • Chamomile • St. John’s Wort

  7. Warfarin • ADRs • Bleeding/Hemorrhage/Hematuria • Vasculitis • Dermatitis, pruritus, urticaria • Abdominal pain, N/V/D • Anemia • Skin necrosis, gangrene, “purple toes” syndrome

  8. Dabigatran (Pradaxa)

  9. Dabigatran • MOA: direct thrombin inhibitor which inhibits: • Both free and fibrin-bound thrombin • Cleavage of fibrinogen to fibrin • Activation of factors V, VIII, XI, and XIII • Thrombin-induced platelet aggregation

  10. Dabigatran

  11. Dabigatran • Monitoring • PPT • Onset: 1 hour, delayed by food • Antidote: None • ADRs • Bleeding (8% to 33%; major ≤ 6%) • Dyspepsia (11%)

  12. Dabigatran • Contraindications • Hypersensitivity to dabigatran or any component • Active bleeding • Warnings/Precautions • Bleeding • Renal impairment • Anticoagulants • Invasive/surgical invasions • P-gp inducers/inhibitors

  13. Dabigatran • Drug interactions • Category X: P-Gp inducers • Category D: Amiodarone, P-Gp inhibitors, quinidine, St. john’s Wort, verapamil • Category C: antacids, anticoagulants, antiplatelet agents, atorvastatin, dasantinib, ibritumonmab, NSAIDs, prostacyclin analogs, PPIs, salicylates, thrombolytic agents

  14. Dabigatran • FDA Bleeding Risk: [12-7-2011] • Evaluating post-marketing reports of serious bleeding • “Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies.”

  15. Dabigatran • ISMP Medication Safety Alert: Quarter Watch [01-12-12] • 932 serious adverse events for 1st quarter of 2011 • 120 deaths • 25 cases of permanent disability • 543 cases requiring hospitalization • 505 cases involved hemorrhage: elderly patients (Median age of 80) • 120 cases of hemorrhagic stroke 

  16. Dabigatran • FDA Drug Safety Communication: [11‐02‐2012] • “… FDA investigated the actual rates of gastrointestinal bleeding and intracranial hemorrhage for new users of [dabigatran] compared to new users of warfarin. The results of this Mini‐Sentinel assessment indicate that bleeding rates associated with new use of [dabigatran] do not appear to be higher than bleeding rates associated with new use of warfarin….”

  17. Dabigatran • FDA Drug Safety Communication: [12-19-2012] • “A clinical trial in Europe (the RE-ALIGN trial) was recently stopped because [dabigatran] users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin. There was also more bleeding after valve surgery in the [dabigatran] users than in the warfarin users [dabigatran] is not approved for patients with AF caused by heart valve problems. “

  18. Dabigatran

  19. Rivaroxaban (Xarelto)

  20. Rivaroxaban • MOA: selective/reversible direct inhibitor of factor Xa • Prevents the conversion of prothrombin to thrombin • Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin

  21. Rivaroxaban

  22. Rivaroxaban

  23. Rivaroxaban • Monitoring • Prothrombin time (PT) • CBC with differential • Renal/hepatic function • Onset: 2-4 hours • Antidote: None

  24. Rivaroxaban • ADRs • Pruritus (2%) • Bleeding • DVT prophylaxis: 6% [major: <1%] • Atrial fibrillation: 21% [major: 6%] • Thrombocytopenia (3%) • Increase in liver enzymes (7%-3%)

  25. Rivaroxaban • Contraindications • Hypersensitivity to rivaroxaban or any component • Active bleeding • Drug Interactions • Category X: P-Gp or 3A4 inhibitors/inducers • Category C: anticoagulants, antiplatelet agents, NSAIDs, salicylates

  26. Rivaroxaban • ISMP Medication Safety Alert: 10/4/2012 • Primary event: Thrombus • 158 cases, 44.4% of the total • Hemorrhage • 121 cases, 34% of the total

  27. Apixaban (Eliquis)

  28. Apixaban • MOA: oral direct Xa inhibitor • Dose: 5mg twice daily • Dose reduction to 2.5mg twice daily if 2+ of the following: • Age ≥80 years • Body weight ≤60kg • Scr ≥1.5mg/dl • AVOID in CrCl <15 ml/min

  29. Apixaban

  30. Apixaban • Monitoring • Minimal impact on the PT, INR, or aPTT • Factor Xainhibition • Onset: 3-4 hours • Antidote: None

  31. Clinical Evidence

  32. Guidelines

  33. ACC/AHA/HRS 2011 • Focused update recommendation: • Dabigatran is a useful alternative to warfarin for the prevention of stroke and systemic embolism in patients with paroxysmal to permanent AF and risk factors for stroke and systemic embolism • Do not have a prosthetic heart valve, hemodynamically significant valve disease, severe renal failure (CrCl < 15mL/min), or impaired liver disease • Alternative to warfarin for moderate-high risk patients: • Difficulty achieving therapeutic INRs • Inability obtaining regular bloodwork monitoring • Low risk for GI bleeding • Low risk for cardiovascular events

  34. AT9 2012 Chest • 2.1.8 • CHADS = 0 • No therapy rather than antithrombotic therapy (Grade 2B) • 2.1.9 • CHADS = 1 • Oral anticoagulation rather than no therapy (Grade 1B)

  35. AT9 2012 Chest • 2.1.10 • CHADS =2+ • Oral anticoagulation rather than no therapy (Grade 1A) • 2.1.11 • Dabigatran 150 mg twice daily rather than adjusted-dose VKA therapy (target INR range, 2.0-3.0) (Grade 2B)

  36. The Future

  37. Conclusions

  38. Comparison of agents

  39. Conclusions • Efficacy • superiority vs non- inferiority • ADRs • ACS / MI risk • Cost • Clinical guidelines

  40. References Antibiotic/Antifungal Drug Interactions and Warfarin. Pharmacist's Letter 2012; 28(1):280102. Connolly SJ, Ezekowitz MD, Yusuf S, et al. RELY Trial: Dabigatran versus warfarin in patients with atrial fibrillation. NEJM.2009; 361(12): 1139-51. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376: 975-83. Reversing Dabigatran and Rivaroxaban. Pharmacist's Letter 2011; 27(9):270912. Weitz JI. New oral anticoagulants in development. ThrombHaemost 2010; 103: 62–70. Institute of Safe Medication Practices. ISMP Medication Safety Alert, January 12, 2012. “Outpatient Anticoagulation Management” VA Medical Center: MCM 11-20. Updated August 2011. Dabigatran (Pradaxa®) National Drug Monograph, VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives, April 2011. “Dabigatran etexilate: drug information.” www.uptodate.com. Accessed 20 January , 2012. Rivaroxaban. Monograph. Medscape. Accessed 24 January, 2012. http://reference.medscape.com/drug/xarelto-rivaroxaban-999670#10 Patel MA, Mahaffey KE, Garg JY, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Eng J Med. 2011. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604. Lopes RD, Alexander JH, Al-Khatib SM, et al; ARISTOTLE Investigators. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159:331-9. Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of  AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010;159:348-53.  Comparison of Oral Antithrombotics. Pharmacist's Letter. 2012; 28(1):280102. DentaliF, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126:2381. Guyatt GH , Akl EA, Crowther M, et al. Antithrombotic Therapy and Prevention of Thrombosis.. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 2012; 141:7S-47S

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