Technician Objectives. Pharmacist Objectives. Replacing Warfarin. Gaps in Practice. Target-Specific Anticoagulants: Clinical Update and

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1 Target-Specific Anticoagulants: Clinical Update and Considerations Erika Hellenbart, PharmD, BCPS September 13,2014 Target-Specific Anticoagulants: Clinical Update and Considerations Erika Hellenbart, PharmD, BCPS September 13,2014 I have no personal or financial conflict of interest to disclose Pharmacist Objectives Discuss the most recent evidence for the targetspecific oral anticoagulants Describe the benefits and limitations of each agent and select the optimal agent for a given patient situation Choose an appropriate perioperative anticoagulation management plan while considering patient specific factors Technician Objectives Identify the FDA labeled indications for the targetspecific oral anticoagulants Recognize the benefits and limitations of each target-specific oral anticoagulant Replacing Warfarin Frequent monitoring requiring clinic visits Variable dosing Genetics Age Race Gender Weight Interactions with drugs, diet, and diseases Perioperative management Long on and offset Bleeding risk Gaps in Practice Three oral anticoagulants have been approved since 2010 A fourth is under review What s in a name? Novel oral anticoagulants (NOACs) Non-vitamin K Anticoagulants (NoVOACs) Target-specific oral anticoagulants (TSOACs) Direct thrombin inhibitors (DTIs) AND direct factor Xa inhibitors 1

2 Gaps in Practice Limited evidence in special populations or scenarios Cancer Chronic kidney disease Antiphospholipid p p syndrome Perioperative management Guidance mostly from extrapolations, case reports, or sub-group analysis Pharmacists will play vital role in the appropriate selection and monitoring of these agents XII Anticoagulant Mechanisms Intrinsic System (surface contact) XI XIIa IX VIII XIa X V VIIIa XIa II Va Xa Fibrinogen Extrinsic System (tissue damage) VIIa Thrombin IIa Tissue Factor Fibrin VII Vitamin K antagonists Factor Xa inhibitors Direct thrombin inhibitors LMWH Target-Specific Oral Anticoagulants Stroke prevention in nonvalvular AF Dabigatran Rivaroxaban Apixaban Edoxaban RE-LY ROCKET-AF AVERROES ARISTOTLE ENGAGE AF-TIMI 48 VTE prophylaxis RE-MOBILIZE RECORD 3 ADVANCE 1 STARS E3 in TKA RE-MODEL RECORD 4 ADVANCE 2 VTE prophylaxis in THA AcuteVTE treatment ExtendedVTE treatment RE-NOVATE RE-NOVATE II RE-COVER RE-MEDY RE-SONATE RECORD 1 RECORD 2 EINSTEIN DVT EINSTEIN PE EINSTEIN EXT ADVANCE 3 STARS J-5 AMPLIFY AMPLIFY EXT HOKUSAI-VTE Target-Specific Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Stroke prevention in nonvalvular AF 1 Efficacy: Superior Non-inferior Superior (150mg) 1 Safety: Similar Similar Superior Acute VTE treatment 1 Efficacy: Non-inferior Non-inferior Non-inferior 1 Safety: Similar Similar Superior Connolly SJ, et al. N Engl J Med. 2009;361(1): Patel MR, et al. N Engl J Med. 2011;265: Granger CB, et al. N Engl J Med. 2011;365: Schulman S, et al. N Engl J Med. 2009;361(24): Bauersachs R, et al. N Engl J Med. 2010; 363(26): Buller HR, et al. N Engl J Med. 2012;366(14): Agnelli G, et al. N Engl J Med. 2013;369(9): Target-specific Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Stroke prevention in nonvalvular AF October 2010 November 2011 December mg BID 75mg BID if CrCl 15-30mL/min 20mg daily with evening meal 15mg daily with evening meal if CrCl 15-50mL/min 5mg BID -Use if ESRD or dialysis 2.5mg BID if any 2 of: Age > 80 years Body weight < 60kg SCr > 1.5 mg/dl VTE prophylaxis in No FDAindication July 2011 March 2014 TKA/THA 10mg daily for 12 days (knee) or 35 days (hip) 2.5mg BID for 12 days (knee) or 35 days (hip) VTE treatment April 2014 November 2012 No FDA indication 150mg BID after 5-10 days of parenteral anticoagulation No recs if CrCl < 30mL/min 15mg BID for 21 days then 20mg daily with food Avoid if CrCl < 30mL/min 10mg BID for 10 days then 5mg daily Mechanism Comparative Pharmacokinetic Properties Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor Direct factor Xa inhibitor Bioavailability (%) mg: % 20mg: 66% (increased with food) Tmax (hr) Protein binding (%) CYP or P-gp Substrate P-gp only P-gp CYP 3A4 CYP 2J2 Direct factor Xa inhibitor 50 P-gp CYP 3A4 Elimination Renal (80%) Renal (66%) Renal (27%); Fecal Half-life (hr) in elderly 2

3 Initial TSOAC Selection No head-to-head studies Indirect comparisons have been conducted and published largely for AF trials No significant ifi differences in efficacy endpoints Apixaban generally associated with less bleeding Patient specific factors can make one agent preferable to another Adherence Initial TSOAC Selection Daily vs. BID dosing Dabigatran: GI side effects and storage of capsules Rivaroxaban: 15mg and 20mg dose must be taken with food History of non-adherence with warfarin Initial TSOAC Selection: Age Average age for AF trials was years Percentage over 75 years: Dabigatran: 40% Rivaroxaban 44% Apixaban 31% Increased rates in primary efficacy and safety endpoints with increasing age Initial TSOAC Selection: Age Effect vs. warfarin for age > 75 yr vs. < 75 yr Dabigatran 150mg (RE-LY) Rivaroxaban (ROCKET AF) Apixaban (ARISTOTLE) Percent > 75 yr 40% 44% 31% Stroke or systemic Similar Similar N/A embolism Bleeding Increased: Increased: N/A - Major bleeding - Major or CRNM - Extracranial bleeding Similar: Similar: - Intracranial - Major bleeding - GI - Intracranial Eikelboom JW, et al. Circulation. 2011;123(21): Halpern JL, et al. Circulation. 2014;130(2): Halvorsen S, et al. Eur Heart J. 2014; 35(28): Initial TSOAC Selection: Renal Impairment Extent of Renal Elimination Primary Nonvalvular AF 75mg BID* -if CrCl 15-30mL/min -consider if CrCl 30-50mL/min and on dronedarone or ketoconazole VTE Treatment No recs for CrCl <30mL/min Avoid if CrCl <50mL/min and on P-gp inhibitors Dabigatran Riva- roxaban Significant 15mg daily* -if CrCl 15-50mL/min 50mL/min Avoid if CrCl <30mL/min Apixaban Minor 5mg BID* -if ESRD or on dialysis No FDA indication * Not clinically studied 2.5mg BID -if 2 of: age > 80 years; body weight <60kg; SCr > 1.5mg/dL -if used with strong dual inhibitors of CYP 3A4 and P-gp (contraindicated if already on 2.5mg BID dose) -if ESRD or on dialysis and either age > 80 years or weight <60kg Apixaban and ESRD Package insert updated 2013 Patients with ESRD with or without hemodialysis were not studied in clinical efficacy and safety studies. dosing recommendation for patients with nonvalvular atrial fibrillation is based on pharmacokinetic i and pharmacodynamic (anti- Factor Xa activity) data in subjects with ESRD maintained on dialysis. ESRD patients maintained with hemodialysis 5mg BID 2.5mg BID if also with one of the following: Age > 80 years or body weight 60 kg 3

4 Initial TSOAC Selection: Drug Interactions Dabigatran Rivaroxaban Apixaban P-gp Substrate Yes Yes Yes CYP Substrate t No CYP 3A4 CYP 3A4 CYP 2J2 Elimination Renal (80%) Renal (66%) Renal (27%); Fecal Initial TSOAC Selection: Drug Interactions CYP 3A4 P-gp Inducer Inhibitor Inducer Inhibitor Rifampin Clarithromycin Rifampin Quinidine Carbamazepine Itraconazole Carbamazepine Amiodarone Phenytoin Ketoconazole Phenytoin Dronedarone St. John s Wort Amiodarone St. John s Wort Diltiazem Dronedarone Verapamil Fluconazole Ritonavir Verapamil Clarithromycin Diltiazem Ritonavir Strong: concomitant use is not recommended Moderate: dose adjustments may be required Drug Interactions: Dabigatran AVOID P-gp inducers (rifampin) CrCl ml/min AND P-gp inhibitor 75mg BID if CrCl 30-50mL/min AND P-gp inhibitor (dronedarone, ketoconazole) No dose adjustment for other P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) Per PI: Should not be extrapolated to other P-gp inhibitors Drug Interactions: Rivaroxaban AVOID Strong CYP 3A4 and P-gp inducers (carbamazepine, rifampin, phenytoin, St. John s Wort) Strong CYP 3A4 and P-gp inhibitors (ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, conivaptan) Drug Interactions: Rivaroxaban AVOID CrCl 15-80mL/min and taking moderate CYP 3A4 and P-gp inhibitors amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin unless benefits justifies potential risks ik Increased AUC with combined P-gp and weak or moderate CYP 3A4 inhibitors Did NOT show increase in bleeding with CrCl 30 to < 50mL/min in ROCKET AF [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)] amiodarone, diltiazem, verapamil, chloramphenicol,cimetidine, and erythromycin Drug Interactions: Apixaban AVOID Strong CYP 3A4 AND P-gp inducers (rifampin, carbamazepine, phenytoin, St. John s Wort) 25mg 2.5mg BID if taking both strong CYP 3A4 AND P-gp inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) AVOID if already on 2.5mg dose NO discussion of moderate inhibitors 4

5 Pharmacodynamic Drug Interactions Perioperative Management All TSOACs Increased risk of bleeding with co-administration of: Antiplatelet agents Fb Fibrinolytics Heparin Aspirin Chronic NSAIDs AVOID unless benefits outweigh risks Pre-operative Timing of last dose before surgery Thromboembolic risk Bleeding risk Clearance of TSOAC Age Drug interactions Renal function Post-operative Timing of first dose after surgery Thromboembolic risk Bleeding risk Ability to take oral medications Type of surgery and medication absorption (Ex. bowel surgery) Thromboembolic Risk Indication for anticoagulation therapy Risk Atrial Fibrillation Mechanical Heart Valve Venous Thromboembolism Low (<5% annual risk) Moderate (5-10% annual risk) High (>10% annual risk) - CHADS 2 score 0-2 with no prior stroke or TIA - Bileaflet aortic valve prosthesis without AF and no other risk factors for stroke - CHADS 2 score Bileaflet aortic valve prosthesis and > 1 of the following: AF, prior stroke or TIA, HTN, DM, CHF, age > 75 yrs - CHADS 2 score Recent stroke or TIA (<3 months) - Rheumatic valvular heart disease Douketis JD, et al. Chest. 2012;141:e326S-50S - Any mitral valve prosthesis - Any older aortic valve prosthesis (caged-ball or tilting disc) - Recent stroke or TIA (<6 months) -VTE occurring >12 months ago with no other risk factors -VTE within previous 3-12 months - Non-severe thrombophilia (heterozygous factor V Leiden or prothrombin gene mutation) - Recurrent VTE - Active cancer (treated within 6 months or palliative) - Recent VTE (<3 months) - Severe thrombophilia (protein C, protein S, or antithrombin deficiency; antiphospholipid antibodies; multiple abnormalities) Stroke Risk Assessment CHADS 2 (ACCP) Risk Factor Points CHF 1 HTN 1 Age > 75 years 1 Diabetes 1 Stroke or TIA 2 Maximum Score 6 Score Risk 0 Low 1 Intermediate 2 High CHADS 2 VASc (ESC & AHA/ACC/HRS) Risk Factor Points CHF/LV dysfunction 1 HTN 1 Age > 75 years 2 Diabetes 1 Stroke, TIA, VTE 2 Vascular disease 1 (MI, PAD, aortic plaque) Age years 1 Female sex 1 Maximum Score 9 Gage BF, et al. JAMA. 2001;285: Lip GY, et al. Chest. 2010;137: Patient Bleeding Risk Assessment Procedure Bleeding Risk Assessment HAS-BLED Patient specific Endorsed by ESC Score Risk 0 Low 1-2 Moderate > 3 High Pisters R, et al. Chest. 2010;138: Risk Factor Points HTN; SBP > 160mmHg 1 Abnormal renal or liver function 1 for each Stroke 1 Bleeding history or predisposition 1 Labile INRs (if on warfarin) 1 Elderly: age > 65 years 1 Drugs: antiplatelet or NSAID use 1 Excess alcohol (> 8 units/week) 1 Maximum Score 9 Low Risk (2-day major bleed risk of 0-2%) Abdominal hernia repair Abdominal hysterectomy Cataract surgery Cholecystectomy Colonoscopy Cutaneous biopsies Dilation and curettage Dental extractions GI endoscopy + biopsy Pacemaker & cardiac defibrillator insertion High Risk (2-day major bleed risk of 2-4%) Abdominal aortic aneurysm repair Any surgery lasting > 45 minutes Major cardiac surgery (heart valve replacement & CABG) Major orthopedic surgery (joint replacement) Transurethral prostate resection Neurosurgical procedures Polypectomy, variceal treatment Major vascular surgery Spyropoulos AC, et al. Dis Mon. 2005;51:

6 Factors Affecting Metabolism and Half-Life Drug interactions Increase or decrease metabolism Age Decreased hepatic blood flow Decreased metabolic activity Renal function Decreases with age Increases half-life Renal Function and Half-Life Decreasing renal function increases half-life Must be considered when stopping pre-operatively Dabigatran Rivaroxaban Apixaban CrCl (ml/min) Half-life (hours) > to < to < < Schulman S, et al. Blood. 2012;119(13): Connolly G, et al. J ThrombThrombolysis. 2013;36(2): Nutescu E. Am J Health-Syst Pharm. 2013;70:S3-11 Preoperative Package Labeling Dabigatran CrCl > 50mL/min: 1-2 days prior to procedure CrCl < 50mL/min: 3-5 days prior to procedure Consider longer times for major surgery or spinal puncture Rivaroxaban Stop at least 24 hours prior to procedure Consider bridging with LMWH if unable to take oral medications Apixaban Moderate to high bleeding risk surgery: stop at least 48 hours prior to procedure Low bleeding risk or non-critical location: stop at least 24 hours prior to procedure Preoperative Management Last dose prior to surgery* CrCl (ml/min) Low bleeding risk surgery High bleeding risk surgery Dabigatran > 80 1 day 2 days 50 to < days 2-3 days 30 to < days 4-5 days < days 5-6 days Rivaroxaban & Apixaban > 80 1 day 2 days 50 to < days 2-3 days 30 to < days 3-4 days < 30 3 days 4 days *Consider earlier discontinuation if patient is also on one or more moderate CYP 3A4 or P-gp inhibitors or inducers Heidbuchel H, et al. Europace. 2013;15(5): Schulman S, et al. Blood. 2012;119(13): Nutescu E. Am J Health-Syst Pharm. 2013;70:S3-11 Postoperative Management Timing of first dose after surgery Minor surgery: hours Major surgery: hours Adequate hemostasis is achieved Consider half dose of TSOAC for first dose Use of heparin (UFH or LMWH) may be necessary Boxed warning: administer another anticoagulant as discontinuation increases risk of thrombotic events Patient unable to take oral medications Postoperative bowel paralysis First TSOAC dose at time UFH infusion is stopped or at time of next LMWH dose Heidbuchel H, et al. Europace. 2013;15(5): Schulman S, et al. Blood. 2012;119(13): Nutescu E. Am J Health-Syst Pharm. 2013;70:S3-11 Measurement of TSOACs No routine monitoring Monitor bleeding and renal function as appropriate Ability to measure drug effect can be useful Serious bleeding or thrombotic events Urgent surgery Renal or hepatic dysfunction Overdose Adherence Must know timing of last dose Maximal (peak) concentration ~2-3 hours Trough ~12-24 hours 6

7 Measurement of TSOACs Direct thrombin inhibitors: dabigatran Qualitative assessment: aptt Trough > 2x ULN suggests excessive bleeding risk Quantitative assessment: Ecarin clotting time (ECT) Not readily available Trough > 3x ULN suggests excessive bleeding risk Diluted thrombin time (dtt) Dependent on meter and thrombin lot Trough >200 ng/ml or > 65 s suggests increased risk of bleeding No data on cut-off dtt to confirm safe surgery Heidbuchel H, et al. Europace. 2013;15(5): Measurement of TSOACs Factor Xa inhibitor: rivaroxaban and edoxaban Qualitative assessment: PT Concentration-dependent prolongation Varying sensitivity of reagent Assay-specific specific calibrators and curves required Not useful for apixaban Quantitative assessment: Chromogenic Anti-FXa Assays and calibrators assess plasma concentrations No data on peak or trough level associated with bleeding or thromboembolic risk No data yet for apixaban Do NOT use INR Heidbuchel H, et al. Europace. 2013;15(5): Reversal Interventions No antidotes for any TSOAC Withhold anticoagulant Half-life of ~12 hrs Activated charcoal if last dose within 2 hours Can repeat 6 hours after last dose with FXa inhibitors Supportive measures Local hemostatic measures Fluid replacement RBC and/or platelets if necessary Consider dialysis with dabigatran Consider PCCs if life-threatening bleeding Heidbuchel H, et al. Europace. 2013;15(5): Bleeding Rates and Risk Factors: Dabigatran Pooled data from 5 phase III trials Similar bleeding rates compared to warfarin Dabigatran 150mg (n=399) vs. warfarin (n=421) Risk factors for bleeding: Older age Lower CrCl ASA use NSAID use Majeed A, et al. Circulation. 2013; 128(21): (mean 75.3 vs yrs; P<0.0001) (median 53 vs. 62 ml/min; P<0.0001) (30.9 vs. 24.6%; P=0.026) (24.6 vs. 8.4%; P=0.023) Outcomes After Major Bleeding: Dabigatran Shorter ICU stay with dabigatran (1.6 vs. 2.7 nights; P=0.01) Increased treatment with blood transfusions vs. plasma Trend toward reduced risk of death following bleed at 30 days Mortality Dabigatran Warfarin PValue 7 days (%) days (%) Majeed A, et al. Circulation. 2013; 128(21): Bleeding Rates and Risk Factors: Rivaroxaban ROCKET AF trial Rivaroxaban n (%) Warfarin n (%) HR (95% CI) PValue Primary safety 1,475 (14.91) 1,449 (14.52) endpoint ( ) Major bleeding 395 (3.60) 386 (3.45) ( ) Death* 27 (0.24) 55 (0.48) ( ) Intracranial* 55 (0.77) 84 (1.18) N/A <0.05 * Major bleeding subgroups Goodman SG, et al. JACC. 2014; 63(9):

8 Bleeding Rates and Risk Factors: Rivaroxaban Risk factors for bleeding Older age (median 75 vs. 73 yrs; P<0.0001) History of GI bleeding (7.8 vs. 3.3%; P<0.0001) ASA use (42.3 vs. 36.2%; P<0.0001) 0001 Lower CrCl (63 vs. 68mL/min; P<0.0001) Less likely to be female (34.3 vs. 40.0%; P=0.0017) Prior stroke or TIA (46.2 vs. 52.7%; P=0.0004) Goodman SG, et al. JACC. 2014; 63(9): Bleeding Rates and Risk Factors: Apixaban ARISTOTLE trial Apixaban (n) Warfarin (n) HR (95% CI) PValue Major bleeding <0.001 ( ) Death within < days* ( ) Intracranial* ( ) * Major bleeding subgroups <0.001 Major extracranial hemorrhage led to significantly fewer hospitalizations, transfusions, and surgical interventions than with warfarin Hylek EM, et al. JACC. 2014; 63(20): Bleeding Rates and Risk Factors: Apixaban Risk factors for bleeding Older age (74 vs. 70 yrs; P<0.001) Prior clinically relevant bleeding (23.6 vs. 16.4%; P<0.001) Prior stroke or TIA (23.8 vs. 19.2%; P=0.001) CrCl < 80 ml/min (72.7 vs. 57.9%; P<0.001) ASA use (32.2 vs. 24.1%; P<0.001) NSAID use (13.0 vs. 8.3%; P<0.001) Hylek EM, et al. JACC. 2014; 63(20): Other Considerations Comorbidities Cancer Antiphospholipid syndrome CAD with or without PCI Mechanical valves Pregnancy and lactation Patient adherence Current TTR if currently on warfarin Cost IDPA: warfarin and rivaroxaban preferred (PA required) Patient preference Following thorough education of risks and benefits of options Conclusion New evidence will continue to emerge regarding optimal use of TSOACs Pharmacists will play vital role: Initial i selection Patient education Provider education Patient monitoring Target-Specific Anticoagulants: Clinical Update and Considerations Erika Hellenbart, PharmD, BCPS September 13,2014 8

9 Target Specific Anticoagulants: Clinical Update and Considerations Technician Post Test Questions Erika Hellenbart, PharmD, BCPS 1. Which of the following have recently been approved by the FDA for non valvular atrial fibrillation? a. Dabigatran, rivaroxaban, warfarin b. Rivaroxaban, apixaban, edoxaban c. Dabigatran, rivaroxaban, apixaban d. Rivaroxaban, apixaban, enoxaparin 2. The only target specific oral anticoagulant with an FDA approved indication for nonvalvular atrial fibrillation, prophylaxis of venous thromboembolism following orthopedic surgery, and treatment of venous thromboembolism is: a. Dabigatran b. Rivaroxaban c. Apixaban d. Warfarin 3. All of the following are advantages to the target specific oral anticoagulants over warfarin EXCEPT: a. Fixed dosing b. Fewer drug and diet interactions c. Shorter on and off set d. Ability to measure drug level or effect 4. Which of the following should not be used in a patient with a history of GERD? a. Dabigatran b. Rivaroxaban c. Apixaban d. Warfarin Key: 1. C; 2. B; 3. D; 4. A

10 Target Specific Anticoagulants: Clinical Update and Considerations Erika Hellenbart, PharmD, BCPS 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(1): Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;265: Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365: Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24): Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010; 363(26): Buller HR, Prins MH, Lensing AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14): Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9): Pradaxa (dabigatran etexilate mesylate) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014 April. g%20information/pis/pradaxa/pradaxa.pdf (accessed 2014 Aug 5) 9. Xarelto (rivaroxaban) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014 March. (accessed 2014 Aug 5) 10. Eliquis (apixaban) prescribing information. Princeton, NJ: Bristol Myers Squibb Company March. (accessed 2014 Aug 5) 11. 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(21): Halpern JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014;130(2): Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014; 35(28): Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9 th Ed:

11 American College of Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012; 141(2)(Suppl): e326s e350s 15. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke. JAMA. 2001; 285: Lip GY, Nieuwlaat R, Pisters R, Lane DA, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factorbased approach: the Euro heart survey on atrial fibrillation. CHEST. 2010; 137(2): Pisters R, Lane DA, Nieuwlaat R, et al. A novel user friendly score (HAS BLED) to assess 1 year risk of major bleeding in patients with atrial fibrillation: the Euro heart survey. CHEST. 2010; 138(5): Spyropoulos AC. Perioperative bridging therapy for the at risk patient on chronic anticoagulation. Dis Mon. 2005; 51: Schulman S and Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012;119(13): Connolly G and Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOAC s. J Thromb Thrombolysis. 2013;36(2): Nutescu E. Oral anticoagulant therapies: balancing the risks. Am J Health Syst Pharm. 2013;70:S Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of the new oral anticoagulants in patients with non valvular atrial fibrillation. Europace. 2013;15(5): Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013; 128(21): Goodman SG, Wojdyla DM, Piccini JP, et al. Factors associated with major bleeding events. JACC. 2014; 63(9): Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin. JACC. 2014; 63(20):2141 7