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The Changing Landscape of Anticoagulation

The Changing Landscape of Anticoagulation. William D. Cahoon, Jr., PharmD, BCPS Cardiology Clinical Pharmacist VCU Health System April 12, 2012. Objectives. Review dabigatran post-marketing safety data Evaluate cardiovascular data for novel oral anticoagulants

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The Changing Landscape of Anticoagulation

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  1. The Changing Landscape of Anticoagulation William D. Cahoon, Jr., PharmD, BCPS Cardiology Clinical Pharmacist VCU Health System April 12, 2012

  2. Objectives • Review dabigatran post-marketing safety data • Evaluate cardiovascular data for novel oral anticoagulants • Identify advantages and limitations of available agents • Discuss the practical management of oral anticoagulation

  3. Dabigatran

  4. Dabigatran Oral, direct thrombin inhibitor Activation: Hydrolysis Tmax: 1 hour T1/2: 12-17 hours Metabolism: Hydrolysis Renal excretion: 80% Dosing: Fixed, twice daily Monitoring: None required Annu Rev Med 2011;62:41-57

  5. Dabigatran – The First Non-Warfarin • Oral direct thrombin inhibitor with no monitoring • FDA approved October 2010 • RE-LY Trial demonstrated: • Dabigatran superior to warfarin for stroke prevention • Equivalent rates of major bleeding • By August 2011 dabigatran prescribed to 250,000 U.S. atrial fibrillation patients (~10%)

  6. Dabigatran Dosage and Administration • Note: Capsules cannot be opened, crushed, or chewed Pradaxa Package Insert

  7. ISMP Safety Alert - Dabigatran • 932 serious adverse events reported with dabigatran in the 1st quarter of 2011 • 505 cases involved hemorrhage • Hemorrhage in elderly (median age 80) • “FDA and manufacturer should reevaluate dosing in the elderly”

  8. Dabigatran Post-Marketing • FDA investigating post-marketing reports of serious bleeding • 260 fatal bleeding events worldwide • Prompted safety advisories in several countries • Labeling changes in US and Europe

  9. Dabigatran Labeling Changes Pradaxa Package Insert – Updated 1/2012

  10. New Zealand Dabigatran Experience • 7000 patients started treatment in first 2 months • Audit revealed 78 bleeding episodes; 12 major • Four contributing factors identified: • Prescriber error • Impaired renal function • Patient age • Lack of reversal agent N Engl J Med 2012;366(9):864-6

  11. Dabigatran and MI Signal • Meta-analysis revealed a significant 33% relative risk increase in MI or ACS (p=0.03) • Absolute risk increase was only 0.27% • RE-LY investigators found non-significant increase in MI with dabigatran • Risk may be due to warfarin comparator Arch Intern Med 2012; Published Online Circulation 2012;125:669-76.

  12. Warfarin Following MI • OASIS and WARIS II • Meta-analysis of warfarin plus aspirin • Associated with reduced risk of MI, stroke • Increase in major bleeding • Thienopyridines decreased uptake of warfarin for secondary ACS prevention Ann Intern Med 2005;143:241-50

  13. RE-DEEM • Purpose: Select the dabigatran dose that balances effectiveness and bleeding risk • Methods: Randomized, placebo-controlled trial of patients post myocardial infarction (MI) • Intervention: • Dabigatran 50, 75, 110, or 150 mg twice daily or placebo • Primary Outcome: Major or clinically relevant minor bleed • Secondary Outcome: Incidence of cardiovascular events Eur Heart J 2011;32:2781-9

  14. RE-DEEM Eur Heart J 2011;32:2781-9

  15. D-Fine Study • Purpose: Test a short course of dabigatran prior to PCI • Methods: Randomized, open-label trial of 50 patients • Intervention: • Dabigatran 110 or 150 mg twice daily or heparin (UFH) • Outcome: • 5 dabigatran patients required anticoagulation bail-out • UFH provided greater level of anticoagulation protection • Conclusion: Dabigatran may not provide sufficient anticoagulation to allow for elective PCI Eur Soc Cardiol Congress 2011

  16. Dabigatran Prior to PCI BOEHRINGER INGELHEIM PHARMACEUTICALS, INC DRUG INFORMATION UNIT Percutaneous Coronary Intervention (PCI): During PCI, the activated clotting time (ACT) was to be measured and heparin administered as needed according to usual practice Reference: Data on file. Boehringer Ingelheim, Ridgefield, CT. Clinical Trial Report 1160.26. Thromb Haemost 2010;103:1116-1127

  17. Dabigatran Post Procedure • Bridge therapy for AF patients typically unnecessary • Use of monitored anticoagulant (i.e. heparin) may be indicated in patients following major surgery Curr Pharm Des 2010;16:3436-3441

  18. No hepatic dose adjustment needed Close renal function monitoring required Caution in the elderly, low body weight Questionable signal of MI risk NOT on VCUHS patient assistance program (PAP); ~$152/mo, insurance coverage varies Dabigatran Considerations

  19. Novel Anticoagulants TF/VIIa X IX VIIIa IXa Xa II IIa Fibrinogen Fibrin

  20. Rivaroxaban

  21. Rivaroxaban Oral factor Xa inhibitor Activation: None Tmax: 2-4 hours T1/2: 5-9 hours Metabolism: Hepatic,CYP3A4 Renal excretion: 66% Dosing: Fixed, once daily Monitoring: None required Annu Rev Med 2011;62:41-57

  22. Rivaroxaban Dosage and Administration *Administer with evening meal Xarelto Package Insert

  23. ROCKET AF • Purpose: Compare rivaroxaban with warfarin for the prevention of stroke in nonvalvular atrial fibrillation (AF) • Methods: Double-blind, double-dummy non-inferiority (superiority) trial of moderate to high risk patients • Intervention: • Rivaroxaban 20 mg daily -or- • Warfarin (Target INR 2.5) • Primary Efficacy Outcome: Stroke or systemic embolism • Primary Safety Outcome: Major bleeding N Engl J Med 2011;365(10):883-91

  24. ROCKET AF N Engl J Med 2011;365(10):883-91

  25. ATLAS ACS 2-TIMI 51 • Purpose: Evaluate rivaroxaban as adjunctive therapy following recent ACS • Methods: Double-blind, placebo-controlled study of patients within 7 days post ACS • Intervention: • Rivaroxaban 2.5 mg twice daily • Rivaroxaban 5 mg twice daily • Placebo • Primary Outcome: Composite of death, MI, stroke N Engl J Med 2012;366(1):9-19

  26. ATLAS ACS 2-TIMI 51 • Primary Endpoint: Rivaroxaban 2.5 mg 9.1% vs. placebo 10.7% (HR 0.84, p=0.02) • Primary Endpoint: Rivaroxaban 5 mg 8.8% vs. placebo 10.7% (HR 0.85, p=0.03) N Engl J Med 2012;366(1):9-19

  27. ATLAS ACS 2-TIMI 51 • March 2012 - FDA granted priority review for the additional indication of reducing CV events post ACS N Engl J Med 2012;366(1):9-19

  28. X-PLORER • Purpose: Compare rivaroxaban with UFH as the primary anticoagulant in elective PCI • Intervention (Estimated enrollment 105 pts): • UFH 70-100 IU/kg bolus, ACT goal 250-300 sec • Rivaroxaban 10 mg single dose • Rivaroxaban 20 mg single dose • Rivaroxaban 10 mg plus UFH 50 IU/kg bolus • Primary Outcome: Thrombosis and ischemic events • Estimated study completion April 2012 www.clinicaltrials.gov accessed 3/2012

  29. Rivaroxaban Prior to PCI • Half-life 5-9 hours; once daily dosing • Activity does not correlate with aPTT or ACT *Consider longer drug free interval in renal impairment

  30. Rivaroxaban Post Procedure • Should be restarted as soon as adequate hemostasis established • If oral medication cannot be taken following procedure consider administering a parenteral anticoagulant Xarelto Package Insert

  31. Avoid in moderate-severe hepatic impairment Renal dose adjustment required Once daily dosing may improve compliance Potential “benefit” in ACS patients On VCUHS PAP program; ~$151/mo, insurance coverage varies Rivaroxaban Considerations

  32. Apixaban

  33. Apixaban Oral, factor Xa inhibitor Activation: None Tmax: 3-3.5 hours T1/2: 9-14 hours Metabolism: Hepatic,CYP3A4 Renal excretion: 25% Dosing: Fixed, twice daily Monitoring: None required Annu Rev Med 2011;62:41-57

  34. ARISTOTLE • Purpose: Compare apixaban with warfarin for the prevention of stroke or systemic embolism • Methods: Randomized, double-blind trial of patients with at least 1 risk factor for stroke • Intervention: • Apixaban 5 mg twice daily -or- • Warfarin (Target INR 2.0 - 3.0) • Primary Efficacy Outcome: Stroke or systemic embolism • Primary Safety Outcome: Major bleeding N Engl J Med 2011;365(11):981-92

  35. ARISTOTLE • FDA to review apixaban on June 28, 2012 N Engl J Med 2011;365(11):981-92

  36. APPRAISE-2 • Purpose: Evaluate the role of apixaban in patients with recent acute coronary syndromes (ACS) • Methods: Double-blind, parallel group trial of high risk ACS patients with mono or dual antiplatelet therapy • Intervention: • Apixaban 5 mg twice daily -or- • Placebo • Primary Outcome: Composite of cardiovascular death, MI, and ischemic stroke N Engl J Med 2011;365(8):699-708

  37. APPRAISE-2 • Stopped early by data safety monitoring board • Increase in major bleed events without reduction in recurrent ischemic events N Engl J Med 2011;365(8):699-708

  38. NOT FDA approved Hepatic dose adjustment may be necessary Renal dose adjustment unlikely Decreased bleed rates compared with warfarin Risk-benefit neutral in ACS Apixaban Considerations

  39. Choice of Agent

  40. Atrial Fibrillation Trial Comparison

  41. Characteristics of Novel Agents

  42. Patient Selection Novel anticoagulants may be most appropriate for: Unstable INRs on warfarin Difficulty or hardship with INR monitoring CrCl > 30 ml/min History of good medication compliance Patients < 75 years old Novel anticoagulants probably not the best choice for: Consistently therapeutic INRs on warfarin Renal dysfunction (dabigatran and rivaroxaban) History of significant GI disease or GI bleeding Medication non-compliance No prescription insurance / unable to afford co-pay

  43. Management of Bleeding Bleeding on Therapy Mild Moderate-Severe Life-Threatening Delay next dose or discontinue Symptomatic Treatment Compression Surgical intervention Fluid replacement Blood transfusion Charcoal (overdose) Dialysis (dabigatran) Consider rFVIIa or PCC Thromb Haemost 2010;103:1116-1127

  44. Bleeding Reversal • No reversal agents or antidotes exist • Vitamin K and protamine should be avoided • Clotting factor concentrates may be an option • Prothrombin Complex Concentrate 50 units/kg • FEIBA 50-100 units/kg • Factor VIIa 90 mcg/kg • Monitor for signs of clinical improvement

  45. Post-operative prophylaxis (orthopedic) Each agent has been evaluated in clinical trials Only rivaroxaban FDA approved for this indication DVT prophylaxis in medically ill Acute venous thromboembolism treatment Other Potential Indications Pharmacotherapy 2011;31(12):1175-91

  46. Notable Agents in Development • Edoxaban • Oral factor Xa inhibitor in phase III trials • ENGAGE AF TIMI 48 Trial • Otamixaban • IV, short-acting factor Xa inhibitor • Phase III TAO trial in early invasive ACS • plasma derived (pd)-factor Xa antidote • Potential antidote for factor Xa inhibitors • Preliminary trials showed dose dependent reversal Pharmacotherapy 2011;31(10):975-1016 Am J Hematol 2012; e-pub ahead of print

  47. Remaining Questions • Real world effectiveness vs. clinical trial efficacy • Market uptake of multiple novel oral anticoagulants • Safety of triple antithrombotic therapy • Safety with concomitant prasugrel or ticagrelor therapy • Management of bleeding and identification of antidote

  48. Summary: Oral Anticoagulants • Dabigatran associated with post-marketing bleed events • Rivaroxaban the first oral, factor Xa inhibitor to market • Clinical trials evaluating use in other cardiovascular indications (ACS, PCI) in addition to AF • Management of bleeding difficult as no antidote exists • Agent-specific characteristics to guide drug selection

  49. Questions?

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