Teddie Gould, Pharm. D, BCPS

Transcription

1 Teddie Gould, Pharm. D, BCPS Associate Professor of Pharmacy Practice College of Pharmacy, Idaho State University Clinical Pharmacist, Pocatello Cardiology

2 Financial Disclosure Statement I have no relevant financial interests with respect to this subject.

3 Learning Objectives for Pharmacists Discuss dabigatran, rivaroxaban and apixaban with regard to pharmacodynamics, pharmacokinetics, dosing, and patient selection Recognize three areas of uncertainty with regard to these new agents Recommend appropriate follow-up for patients newly started on these agents

4 Learning Objectives for Technicians List the brand and generic names of three new oral anticoagulants List two advantages of these new agents over warfarin List two disadvantages of these new agents as compared to warfarin

5 New agents to be discussed Dabigatran (Pradaxa ) FDA approved October 2010 Oral direct thrombin inhibitor Rivaroxaban (Xarelto ) FDA approved July 2011 Oral direct factor Xa inhibitor Apixaban (Eliquis ) FDA approved December 2012 Oral direct factor Xa inhibitor

6 New agents make up what % of your current OAC prescriptions A. < 10% B % C % D. > 50%

7 Which agent if any is on your formulary? A. None B. Dabigatran C. Rivaroxaban D. Apixaban E. More than one

8 I regularly see patients on AC therapy in my practice: A. Yes B. No

9 Approved indications All 3 have been FDA approved for stroke prevention in atrial fibrillation (AF) All 3 have been studied for VTE prophylaxis in orthopedic surgery; rivaroxaban approved All three have been studied for acute VTE and secondary prophylaxis; rivaroxaban approved Studies for use in other conditions, either completed or ongoing; will likely result in new indications VTE = venous thromboembolism

10 Warfarin - the good side Our primary oral anticoagulant since 1954 Well studied for numerous indications Specific antidote is vitamin K Anticoagulant effects correlate well with INR Once daily dosing Long half-life Missing a dose generally doesn t result in serious consequence Low acquisition cost

11 Warfarin - the bad side Significant inter- and intra-patient variability Genetics Drug-drug, drug-food, drug-disease interactions Increased risk of bleeding with excessive alcohol Slow onset of action, requires bridging Requires routine monitoring of INR Patients who should receive anticoagulant therapy often don t because of concerns with safety

12 Mechanisms of action Warfarin Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013;52:69-82.

13 Potential advantages of new agents compared to warfarin Rapid onset of action Fixed dosing Lack of need for routine coagulation monitoring No dietary interactions Fewer drug and disease interactions

14 Dabigatran - Indications FDA approved for prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation Also studied for VTE prophylaxis in total hip and knee replacement Secondary VTE prophylaxis after acute VTE and for extended treatment Prevention of stroke and systemic embolism in patients with bileaflet mechanical valve Contraindicated with mechanical prosthetic valve VTE = venous thromboembolism

15 Dabigatran in atrial fibrillation RE-LY trial N = 18,113 Dabigatran 150 mg BID Warfarin adjusted TTR 64% Stroke or systemic embolism P value 1.1% / year 1.69% / year P<0.001 for superiority Major bleeding 3.11% / year 3.36% / year P=0.31 Hemorrhagic stroke 0.10% / year 0.38% / year P<0.001 All cause mortality 3.64% / year 4.13% / year P=0.051 TTR = time in therapeutic range of for warfarin Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:

16 Dabigatran - Pharmacokinetics Prodrug - activated by esterases in plasma and liver Poorly absorbed, ph dependent, formulated with tartaric acid, not influenced by food Time to peak level 1-3 hours Protein binding 35% (allows it to be dialyzed) Renal excretion - 80% unchanged Half-life hours with normal renal function 28 hours with severe renal impairment (CrCl <30 ml/min)

17 Dabigatran - Pharmacokinetics cont. Not metabolized by CYP450 Substrate of P-glycoprotein (P-gp) Cellular efflux pump present in numerous tissues including the intestinal mucosa Inhibition can increase drug absorption Induction can decrease absorption Many drugs that inhibit or induce P-gp have similar effects on CYP450 CYP450 = cytochrome P450 enzyme system

18 Dabigatran - Drug interactions Caution with other agents impacting hemostasis Avoid with strong P-gp inducers (rifampin) Consider dose reduction in patients on strong inhibitors along plus poor renal function Completely avoid P-gp inhibitors if CrCl <30 ml/min (verapamil, amiodarone, ketoconazole, dronedarone) DDI with proton pump inhibitors judged not to be clinically significant FDA defines as an increase in exposure of >150% Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2012

19 Comment on DDI studies Limited number of patients Results reported as mean increase in AUC or Cmax Patients vary in their response Studies don t include patient outcomes Several drugs increased median AUC, but did not meet threshold for being labeled significant interaction Labeling varies between countries

20 Dabigatran - Dosing Standard dose is 150 mg BID with or without food CrCl ml/min: consider 75 mg BID if on dronedarone or ketoconazole CrCl ml/min: 75 mg BID Based on pharmacokinetic modeling Patients with CrCl <30 ml/min excluded in RE-LY CrCl <15 ml/min or on dialysis: not recommended Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2012

21 Dabigatran - Side effects Bleeding Higher risk >75 yo, renal dysfunction, low body wt Based on the RE-LY trial Same risk of major bleeding as with warfarin Less intracranial hemorrhage than warfarin More GI bleeding than warfarin Dyspepsia 11.5% vs. 5.8% with warfarin More drop outs in dabigatran groups (16% vs. 10%) Increased risk of myocardial infarction (MI)? Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:

22 Statistics on dabigatran and MI Incidence of myocardial infarction RE-LY trial 89 patients on dabigatran; 63 patients on warfarin 0.74% vs 0.53 %; P=0.048 Reanalysis of RE-LY trial including silent MI data 0.81% dabigatran; 0.64% warfarin; P=0.12 Meta-analysis of 7 trials (Uchino & Hernandez) 1.19% dabigatran; 0.79% control; RR 1.33; P=0.03 Incidence of ACS in the RE-MEDY trial 0.9% dabigatran vs 0.2% warfarin; P= 0.02 MI = myocardial infarction; ACS = acute coronary syndrome (MI, unstable angina)

23 Dabigatran - specific counseling info Taking with food may stomach upset Do not crush, chew or break capsules Keep in original container (no pill boxes) Discard bottles 4 months after opening Note: dabigatran needs to be dispensed in its original container

24 Rivaroxaban - Indications FDA approved for: Preventing stroke and systemic embolism in atrial fibrillation VTE prophylaxis in hip and knee replacement Acute treatment of DVT and PE Preventing recurrence of DVT or PE beyond 6 months Also studied for: Reducing cardiovascular events after ACS VTE prophylaxis in medical patients DVT = deep vein thrombosis; PE = pulmonary embolism; ACS = acute coronary syndrome

25 Rivaroxaban in atrial fibrillation ROCKET-AF N=14,264 Rivaroxaban 20 mg QD Warfarin adjusted TTR 55% P value Stroke or systemic embolism Clinically relevant bleeding Intracranial hemorrhage 1.7% / year 2.2% / year P<0.001 for noninferiority 14.9% / year 14.5% / year P= % / year 0.7% / year P=0.02 Fatal bleeding 0.2% / year 0.5% / year P=0.003 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:

26 Rivaroxaban for VTE prophylaxis in hip replacement - RECORD1 N=4541 Rivaroxaban 10 mg QD x 35 days Enoxaparin 40 mg SC daily x 35 days P value Total VTE and all cause mortality 1.1% 3.7% P<0.001 Major bleeding 0.3% 0.1% P=0.18 Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008:358:

27 Rivaroxaban for VTE prophylaxis in knee replacement - RECORD 4 N=3148 Rivaroxaban 10 mg QD x days Total VTE and all cause mortality Enoxaparin 30 mg SC q 12 hours x days P value 6.9% 10.1% P= Major bleeding 0.7% 0.3% P= Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet 2009;373:

28 Rivaroxaban for treatment of acute DVT EINSTEIN-DVT N=3449 Rivaroxaban 15 mg BID x 21 days followed by 20 mg QD Enoxaparin 1 mg/kg SC q 12 hours followed by VKA P Value Recurrent VTE 2.1% 3.0% P<0.001 for noninferiority Clinically relevant bleeding 8.1% 8.1% P=0.77 DVT = deep vein thrombosis; VKA = vitamin K antagonist (warfarin or acenocoumarol) The EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:

29 Rivaroxaban for treatment of acute PE EINSTEIN-PE N=4832 Rivaroxaban 15 mg BID x 21 days followed by 20 mg QD Enoxaparin 1 mg/kg SC q 12 hours followed by VKA P Value Recurrent VTE 2.1% 1.8% P=0.003 for noninferiority Clinically relevant bleeding 10.3% 11.4% P=0.23 PE = pulmonary embolus; VKA = vitamin K antagonist (warfarin or acenocoumarol) The EINSTEIN-PE investigators. Oral rivaroxaban for symptomatic pulmonary embolism. N Engl J Med 2012;366:

30 Rivaroxaban for extended VTE prevention EINSTEIN-EXT N=1196 Rivaroxaban 20 mg QD Placebo P Value Recurrent VTE 1.3% 7.1% P<0.001 for superiority Major bleeding 0.7%% 0% P=0.11 The EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:

31 Rivaroxaban - Pharmacokinetics 80% bioavailability Food increases absorption Time to peak level 2-4 hours Half-life 5-9 hours in young healthy patients hours in elderly patients Protein binding >90% (not likely dialyzed)

32 Rivaroxaban - Pharmacokinetics cont. Renal excretion - 36 % unchanged Patients with CrCl <30 ml/min excluded from ROCKET- AF Metabolized by CYP 3A4 and CYP 2J2 No major active metabolites Substrate of P-glycoprotein

33 Rivaroxaban - Drug interactions Caution with other agents impacting hemostasis Avoid use with drugs that are strong dual inducers or inhibitors of CYP 3A4 and P-gp Examples of combined strong inducers: Rifampin, phenytoin, carbamazepine, St. John s wort, Examples of combined strong inhibitors: Ketoconazole, itraconazole, ritonavir Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;2012.

34 Rivaroxaban Dosing Indication Dosage Atrial fibrillation CrCl >50 ml/min 20 mg QD w/evening meal CrCl ml/min 15 mg QD w/evening meal CrCl <15 ml/min Avoid Treatment DVT/PE 15 mg BID with food x 21 days followed by 20 mg QD with food for remaining treatment Secondary prevention DVT/PE 20 mg QD with food CrCl <30 ml/min Avoid VTE prophylaxis hip replacement 10 mg QD for 35 days with or without food VTE prophylaxis knee replacement 10 mg QD for 12 days with or without food VTE prophylaxis hip or knee replacement CrCl <30 ml/min Avoid Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;2012.

35 Rivaroxaban - Side effects Bleeding Based on the ROCKET-AF trial Same risk of major bleeding as with warfarin Less intracranial hemorrhage than warfarin More GI bleed than warfarin Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:

36 Apixaban - Indications FDA approved for prophylaxis of stroke and systemic embolism in nonvalvular AF Also studied for: VTE prophylaxis in total hip and knee replacement VTE prophylaxis in medical patients Acute treatment of DVT and PE Secondary VTE prophylaxis after acute VTE and for extended treatment Reducing cardiovascular events after ACS

37 Apixaban in atrial fibrillation ARISTOTLE N=18,201 Apixaban 5 mg BID Warfarin adjusted TTR 62.2% P value Stroke or systemic embolism 1.27% / year 1.60% / year P=0.01 for superiority Major bleeding 2.13% / year 3.09% / year P<0.001 Hemorrhagic stroke 0.24% / year 0.47% / year P<0.001 All cause mortality 3.52% / year 3.94% / year P=0.047 Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981.

38 Apixaban in atrial fibrillation AVERROES N=5599 Apixaban 5 mg BID Aspirin mg QD P value Stroke or systemic embolism 1.6% / year 3.7% / year P<0.001 Major bleeding 1.4% / year 1.2% / year P=0.57 Hemorrhagic stroke 0.2% / year 0.3% / year P=0.45 Connolly SJ, Eikelboom J, Joyner C, et al, for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:

39 Apixaban - Pharmacokinetics 50% bioavailability Absorption not affected by food Time to peak 1-3 hours Protein binding 87% (not likely dialyzed) Renal excretion 25 % unchanged Patients with Crcl <25 ml/min excluded in ARISTOTLE Metabolized by CYP 3A4 No major active metabolites Substrate of P-glycoprotein (P-gp)

40 Apixaban - Drug interactions Caution with other agents impacting hemostasis Reduce dose or avoid with drugs that are strong dual inhibitors of CYP 3A4 and P-gp Examples of dual strong inhibitors: Ketoconazole, itraconazole, ritonavir, clarithromycin Avoid with drugs that are dual inducers Rifampin, phenytoin, carbamazepine, St. John s wort, Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;2012.

41 Apixaban - Dosing Standard dose is 5 mg BID with or without food Decrease dose to 2.5 mg BID if: Patient meets 2 or more of the following criteria: <60 kg, age > 80 yo, scr >1.5 mg/dl Given with strong CYP3A4/P-gp inhibitor Avoid combination with strong CYP3A4/P-gp inhibitor if already on 2.5 mg BID Not recommended for CrCl <15 ml/min or on dialysis Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;2012.

42 Apixaban - Side effects Bleeding Based on ARISTOTLE Less major bleeding than with warfarin Less intracranial hemorrhage than warfarin Same incidence of GI bleeding Based on AVERROES Same bleeding risk as aspirin Based on AMPLIFY-EXT Similar to placebo Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368: (AMPLIFY-EXT)

43 Unresolved issues with NOAC No head-to-head trials amongst the new agents Short duration of follow up Impact of noncompliance in real world How to best quantify their effects on coagulation Prior to emergency procedures In the case of hemorrhage In the case of potential DDI Extreme weights How we reverse their effects NOAC = new oral anticoagulant agents

44 Measuring anticoagulant effect with new oral anticoagulants Not required for routine dose adjustment Would be nice to know in the following situations Prior to emergency procedures In case of hemorrhage In case of potential DDI To verify compliance With major organ dysfunction Extremes in body weight

45 Measuring effects cont. Ideal test Adequate sensitivity Linear correlation between dose and anticoagulant effect throughout the dosing range and beyond Has been calibrated for specific agent Standardized between labs and reagents Therapeutic ranges established Generally available None of current tests suitable for quantifying

46 Current options for measurement Dabigatran aptt detects anticoagulant (AC) effect More sensitive than PT but correlation not linear and some difference between reagents DOES interfere with INR interpretation Ecarin clotting (ECT) time has linear relation, but not generally available and not well standardized Thrombin clotting time (TCT) detects AC effect, but too sensitive Dilute TCT good sensitivity, may not be available

47 Current options for measuring cont. Rivaroxaban PT can detect AC effect, but differs between reagents and some not sensitive to low conc Do not use INR, calibrated for warfarin, variability Trying to develop an ISI to use with rivaroxaban Drug specific chromogenic anti-xa assays have good correlation, but not generally available and require standardization

48 Current options for measuring cont. Apixaban PT better than aptt but lacks adequate sensitivity Dilute PT (dpt) more sensitive, if available HepTest (clot-based anti-xa assay used for LMWH) shown to be as sensitive as dpt, if available Drug specific chromogenic anti-xa assays have good correlation, but not generally available and require standardization Normal coag results probably means no AC effect Work with your laboratory

49 Options for reversing effects No specific antidotes at this time Little to no patient data: Animal data (rats, baboons, rabbits) In vitro studies Limited info from healthy human volunteers Few case reports in bleeding patients Reversal of bleeding and reversing affects on coagulation assays not necessarily the same

50 Options for reversing effects cont. Activated charcoal within 2-3 hr if overdose General supportive care Fluids, PRBC, local measures, surgical intervention Discontinue and allow effects to wear off Dialysis is an option for dabigatran 60% removal over 2 hours Various blood factor products PRBC = packed red blood cells

51 Blood factor products available in US Fresh frozen plasma (FFP) - all coagulation factors rfviia (NovoSeven ) - activated factor VIIa 3-factor prothrombin complex concentrates (PCC) Bebulin VH and Profilnine SD Contain inactive factors II, IX and X Activated PCC FEIBA - activated factors II, VII, IX and X Not all PPCs with published data available in US Off-label use Risk of prothrombotic effect with rfviia and apcc

52 Suggested management of acute bleeding in patients taking novel oral anticoagulants Siegal DM, and Crowther MA. Eur Heart J 2013;34: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oup.com

53 Mancl EE, Crawford and Voils SA. Contemporary anticoagulation reversal: focus on direct thrombin inhibitors and factor Xa inhibitors. J Pharm Pract 2013;26:43-51.

54 Options for reversal cont. Dosing for factor concentrates not well-defined Monoclonal antibody being developed for neutralizing dabigatran Recombinant antidote being developed for factor Xa inhibitors - PRT CE program available through ASHP Emerging Treatment Options for the Reversal of Oral Anticoagulant Therapy for 2.0 CEUs

55 What the 2012 Chest guidelines say Atrial fibrillation For patients in whom anticoagulant therapy (AC) is favored, we suggest dabigatran 150 mg BID rather than adjusted-dose VKA (2B) VTE prophylaxis in hip or knee surgery Recommend use of one of the following for a minimum of days: LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH, adjusted dose vitamin K or aspirin (1B) Suggest LMWH in preference to other agents (2B)

56 What the 2012 Chest guidelines say cont. Treatment of DVT/PE Under initial treatment, new agents not mentioned Under choice of AC for long-term therapy, rivaroxaban and dabigatran are listed, but other agents suggested over them Executive Summary: Antithrombotic Therapy and Prevention of thrombosis, 9 th ed. American College of Chest Physicians Evidence-Based Practice Guidelines. Chest 2012;141(2)(Suppl)

57 December 2012 AHA/ASA recommendations for AF All 3 agents are considered alternatives Warfarin - Class I; level of evidence A Dabigatran - Class I; level of evidence B Apixaban - Class I; level of evidence B Rivaroxaban - Class IIa; level of evidence B

58 December 2012 AHA/ASA recommendations for AF cont. Selection should be individualized based on Patient risks Cost Tolerability Drug interactions Patient preference Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:

59 Where are we REALLY? Rapid transition phase Management of thrombosis likely to change dramatically once the unknowns are worked out In the meantime, increased ability to individualize therapy for each patient

60 Selection considerations Dabigatran Rivaroxaban Apixaban Compliance BID QD BID Baseline scr/crcl Bleeding risk Age >75 Screen for DDI Under/over weight Patient preference Ability to pay Hx GI bleed Dyspepsia

61 Education & follow up Patient education is crucial Importance of taking/not stopping on their own Duration of therapy Keeping track/not missing doses/what to do if miss Signs and symptoms of bleeding/thrombosis, what to do/who to call Letting other providers know/carry ID Contact patient periodically to follow up Monitoring should include renal function, CBC

62 New oral agents - recap Advantages Rapid onset Fixed dose No routine monitoring No dietary interactions Fewer drug and disease interactions New way to manage thrombotic disorders Can individualize therapy Potential for better safety and efficacy Unknowns/disadvantages How to measure How to reverse Impact of DDI Impact of noncompliance/bid dosing No head-to-head comparisons Limited experience beyond controlled trials Narrower range of indications PK in major organ dysfunction Cost

63 Dabigatran Rivaroxaban Apixaban The changing landscape of oral anticoagulant therapy

64 Which of the following should be obtained prior to prescribing NOACs? A. Renal function B. Thyroid function C. INR Pharmacist Assessment Question

65 Which of the following is dosed once daily for atrial fibrillation? A. Dabigatran B. Rivaroxaban C. Apixaban D. More than one of the above Pharmacist Assessment Question

66 Which of the following AF patients might benefit from a NOAC over warfarin? A. 82 yo female, CrCl = 24 B. 54 yo male w/bipolar disorder on carbamazepine C. 65 yo male, chronic binge drinker Pharmacist Assessment Question

67 Which of the following pairs is incorrect? A. Rivaroxaban/Xarelto B. Apixaban/Effient C. Dabigatran/Pradaxa Technician Assessment Question

68 Which is an advantage of NOACs over warfarin? A. Effects can easily be quantified B. Faster onset of action C. Not renally excreted Technician Assessment Question

69 Which is a disadvantage of NOACs compared to warfarin? A. Routine coagulation monitoring required B. More drug interactions C. No antidote Technician Assessment Question

70 References Review articles 1) Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy 2011;31: ) Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin k antagonists. Clin Pharmacokinet. 2013;52: ) Dubuske, LM. The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Safety 2005;28: ) Poulson BK, Grove EL and Husted SE. New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. Drugs 2012; 72: ) Hellwig T and Gulseth M. New oral therapies for the prevention and treatment of venous thromboembolism. Am J Health-Syst Pharm 2013;70: Guidelines 1) Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy. Antithrombotic Therapy and Prevention of Thrombosis 9 th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest 2012;141(2)(Suppl):e44S-e88S. 2) You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation. Antithrombotic Therapy and Prevention of Thrombosis 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2)(Suppl): e531s-e575s.

71 References cont. 3) Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Antithrombotic Therapy and Prevention of Thrombosis 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2)(Suppl): e419s-e494s. 4) Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients. Antithrombotic Therapy and Prevention of Thrombosis 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2)(Suppl):e278S-e325S. 5) Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43: Clinical trials 1) Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial. Circulation 2011;123: [RE-LY] 2) Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368: [RE-MEDY and RE-SONATE]

72 References cont. 3) Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368: [AMPLIFY-EXT] 4) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: [RE-LY] 5) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified results in the RE-LY trial. N Engl J Med 2010;636: ) 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. [ATLAS ACS 2 TIMI 51] 7) Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: [ROCKET-AF] 8) Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008:358: [RECORD1] 9) Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet 2009;373: [RECORD 4] 10) The EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: [EINSTEIN-DVT and EINSTEIN-EXT] 11) Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365: [ARISTOTLE]

73 References cont. 12) Connolly SJ, Eikelboom J, Joyner C, et al, for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: [AVERROES] 13) Eikelboom JW, Wallentin L, Connolly SJ. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011;123: ) The EINSTEIN-PE investigators. Oral rivaroxaban for symptomatic pulmonary embolism. N Engl J Med 2012;366: [EINSTEIN-PE] Side Effects 1) Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012;172: Laboratory monitoring and reversal 1) Miyares MA, Davis K. Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm 2012;69:

74 References 2) Mancl EE, Crawford AN and Voils SA. Contemporary anticoagulation reversal focus on direct thrombin inhibitors and factor Xa inhibitors. J Pharm Pract 2013; 26: [Reversal algorithm] 3) Tripodi A. The laboratory and the new oral anticoagulants. Clin Chem 2013; 59: ) Konkle BA. Monitoring target specific anticoagulants. J Thromb Thrombolysis Epub 2013 Feb 5. 5) Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematology 2012;87:S ) Siegal DM and Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013;34: [Reversal algorithm]