Disclosure: Dr. Smith has no actual or potential conflict of interest associated with this presentation.

Disclosure: Dr. Smith has no actual or potential conflict of interest associated with this presentation. Michael Smith, Pharm. D., BCPS, CACP Pharmacy Clinical Manager William Backus Hospital You were just diagnosed with atrial fibrillation. What drug are you going to use? A. Dabigatran B. Rivaroxaban C. Warfarin D. Um, no thanks, I don t want to bleed to death! One snowy morning in February, 1933, Ed Carlson, a farmer from Deer Park, Wisconsin, came into Karl Paul Link's laboratory carrying a milk can full of blood that refused to coagulate. Outside he had a small heap of spoiled sweet clover hay and a dead heifer freezing in the back of his truck. http://www.warf.org/about/index.jsp?cid=26&scid=34 1

Discuss the mechanism of action, indications, contraindications and adverse effects. Discuss the available monitoring and reversibility of these agents. Identify patients that may benefit from the new agents and those that may not. Ideal Anticoagulant Oral and Injectable Rapid onset/off Effective on venous and arterial thrombosis Rapidly reversible No monitoring necessary, but possible No drug interactions No or predictable effects of renal/hepatic disease Intrinsic system Extrinsic system (surface contact) (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII Unfractionated heparin 2,3 VIII VIIIa X Low molecular-weight heparins 2,3 Xa Vitamin K antagonists 4 V Va Direct thrombin inhibitors 4,5 II IIa (Thrombin) Factor Xa inhibitors 4,5 Fibrinogen Fibrin Dabigatran Rivaroxaban Apixaban Medical MAGELLAN ADOPT Prophylaxis THA RE NOVATE RECORD I RECORD II ADVANCE 3 TKA VTE Treatment RE MOBILIZE RE MODEL RE MEDY RE COVER RE SONATE RECORD III RECORD IV EINSTEIN DVT EINSTEIN PE EINSTEIN EXT ADVANCE 1 ADVANCE 2 AMPLIFY AMPLIFY EXT 1. Adapted from Petitou M et al. Nature. 1991;350(6319 suppl):30-33. 2. Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 3. Hirsh J et al. Chest. 2001;119(1 suppl):64s-94s. 4. Nutescu EA et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5. Bauer KA. J Thromb Thrombolysis. 2006;21:67-72. 9 Atrial Fibrillation Acute Coronary Syndrome Heart Valve replacement Dabigatran Rivaroxaban Apixaban RE LY ROCKET ARISTOTLE RE DEEM (phase II) RE ALIGN (phase II) ATLAS TIMI 46 ATLAS TIMI 51 APPRAISE (phase II) Direct thrombin inhibitor (DTI) Indication: Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Dose For CrCl>30 ml/min: 150mg BID For CrCl 15 30ml/min: 75mg BID 80% renal elimination Prescribing information, Boehringer Ingelheim Pharmaceuticals, 2012 2

RE LY trial 18,113 patients with atrial fibrilliation, unblinded warfarin use, 110mg or 150mg dabigatran, non inferiority, TTR = 64%. 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 trail. Lancet. 2010 Sep 18;376(9745):975-83 Outcome (%/yr) Dabigatran Warfarin Relative Risk P value Stroke or systemic embolism 1.11 1.69 0.66 (0.53 0.82) 0.01 Death from any cause 3.64 4.13 0.88 (0.77 1.0) 0.051 Major Bleeding 3.11 3.36 0.93 (0.81 1.07) 0.31 Anything bad 6.91 7.64 0.91 (0.82 1.00) 0.04 Conelly, SJ. N Engl J Med 2009;361:1139-51. Warnings and Precautions Dabigatran therapy should be temporarily discontinued before invasive or surgical procedures to decrease bleeding risk. Dabigatran should be discontinued 1 to 2 days (if CrCl is 50 ml/min or greater) or 3 to 5 days (if CrCl is less than 50 ml/min) before invasive or surgical procedures. Consider a longer period without the drug in patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port. P glycoprotein (PgP) inducers and inhibitors may affect dabigatran pharmacokinetics. Coadministration of rifampin, a PgP inducer, should be avoided because it reduces dabigatran exposure. AUC increase with amiodarone (12%), quinidine (53%), verapamil (23%), ketoconazole (150%). Adverse Drug Reactions The most common adverse reactions, occurring in at least 15% of patients receiving dabigatran to reduce the risk of stroke in atrial fibrillation, are gastritis like symptoms (35% with dabigatran and 24% with warfarin) and bleeding. In the RE LY study, major bleeding occurred in 3.3% of patients treated with dabigatran and 3.6% of patients treated with warfarin. Bleeding of any kind occurred in 16.6% of patients treated with dabigatran and 18.4% of patients treated with warfarin. Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83 Prescribing information, Boehringer Ingelheim Pharmaceuticals, 2012 FDA Drug Safety Communication: Safety review of post market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate) 12 7 2011: The U.S. Food and Drug Administration (FDA) is evaluating post marketing reports of serious bleeding events in patients taking Pradaxa (dabigatran etexilate mesylate). Pradaxa is a blood thinning (anticoagulant) medication used to reduce the risk of stroke in patients with non valvular atrial fibrillation (AF), the most common type of heart rhythm abnormality. Is renal function to blame? Renal Function CrCl (ml/min) Increase in AUC Increase in C max T1/2 (h) Normal 80 1 X 1 X 13 Mild 50 80 1.5 X 1.1 X 15 Moderate 30 50 3.2 X 1.7 X 18 Severe* 15 30 6.3 X 2.1 X 27 Patients with severe renal impairment were not studied in RE LY. Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modeling 75 mg dose was never clinically studied! Prescribing information, Boehringer Ingelheim Pharmaceuticals, 2012 3

Never mind... FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa 11 02 2012 The U.S. Food and Drug Administration (FDA) has evaluated new information about the risk of serious bleeding associated with use of the anticoagulants (blood thinners) dabigatran (Pradaxa) and warfarin (Coumadin, Jantoven, and generics). Following the approval of Pradaxa, FDA received a large number of post marketing reports of bleeding among Pradaxa users. As a result, FDA investigated the actual rates of gastrointestinal bleeding (occurring in the stomach and intestines) and intracranial hemorrhage (a type of bleeding in the brain) for new users of Pradaxa compared to new users of warfarin. The results of this Mini Sentinel assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE LY trial) Direct factor Xa inhibitor Half life 5 9hrs Dose 10mg, 15mg, 20mg depending on indication, point in therapy, and renal function. 65% renal elimination Healthcare professionals who prescribe Pradaxa should carefully follow the dosing recommendations in the drug label, especially for patients with renal impairment (when kidneys don t function normally) to reduce the risk of bleeding. Prescribing information, Janssen Pharmaceuticals, 2011 Indication To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery. For the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reduction in the risk of recurrence of DVT and of PE Dosage For patients with CrCl >50 ml/min: 20 mg orally, once daily with the evening meal For patients with CrCl 15 50 ml/min: 15 mg orally, once daily with the evening meal Hip: 10 mg orally, once daily for 35 days Knee: 10 mg orally, once daily for 12 days 15 mg orally twice daily with food for the first 21 days for the initial treatment. After the initial treatment period, 20 mg orally once daily for the remaining treatment period. ROCKET AF trial 14,264 patients, double blind, Rivaroxaban 20mg daily vs warfarin, non inferiority, 55% TTR Outcome (%/yr) Rivaroxaban Warfarin Hazard ratio P value Stroke or systemic 2.1 2.1 0.88 (0.75 1.03) <0.00 embolism Death from any cause 4.5 4.9 0.92 (0.82 1.03) 0.15 Major Bleeding 3.6 3.4 1.04 (0.90 1.20) 0.58 Anything bad?? Prescribing information, Janssen Pharmaceuticals, 2011 Patel MR. N Engl J Med 2009;361:1139-51. RECORD trials Randomized, double blind, thromboprophylaxis of orthopedic surgery Rivaroxaban 10mg PO Daily vs Enoxaparin; rivaroxaban started 6 8hrs after surgery RECORD-1 RECORD-2 RECORD-3 RECORD-4 Population THR n=4541 THR n=2509 TKA n=2531 TKA n=3148 Comparator Enoxaparin 40mg Daily Enoxaparin 40mg Daily Enoxaparin 40mg Daily Enoxaparin 30mg BID Duration 35 days Riva- 35 days Enox- 10 days 14 days 14 days VTE events Major Bleeding 1.1% Rivarox 3.7% Enox 0.3% Rivarox 0.1% Enox 2% Rivarox 9.3% Enox 9.6% Rivarox 18.9% Enox <0.1% 0.6% Rivarox 0.5% Enox 6.9% Rivarox 10.1% Enox 0.7% Rivarox 0.3% Enox Eriksson NEJM. 2008;358:2765-277 Kakkar Lancet. 2008;372:31-39 Lassan NEJM. 2008;358:2776-2786 Turpie Lancet. 2009;373(9676):1673-80 EINSTEIN DVT and EINSTEIN PE trials Treatment of VTE and the long term prevention of VTE. Open label, non inferiority study. Patients received rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily for 3, 6, or 12 months, or Enoxaparin 1 mg/kg twice daily followed by warfarin or an acenocoumarol dose adjusted to an international normalized ratio (INR) of 2 to 3 for 3, 6, or 12 months. DVT TTR 57.7%; PE TTR 62.7% Outcome % Rivaroxaban Warfarin Hazard Ratio P value DVT RecurrentVTE 2.1 3.0 0.68 (0.44 1.04) <0.001 DVT Bleeding 8.1 8.1 PE RecurrentVTE 2.1 1.8 1.12 (0.75 1.68) 0.003 PE Bleeding 10.3 11.4 0.90 (0.76 1.07) 0.23 N Engl J Med 2010;363:2499-510. N Engl J Med 2012;366:1287-97. 4

Contraindications: Rivaroxaban therapy is contraindicated in patients with known allergy to rivaroxaban or any of the product ingredients, and in patients with active major bleeding. Warnings and Precautions: Avoid the use of in patients with CrCl <15 ml/min since drug exposure is increased. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE and Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use in patients with CrCl <30 ml/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient Population. Drug Interactions: Rivaroxaban is a substrate of CYP3A4/5, P glycoprotein (P gp); concomitant use of rivaroxaban with combined P gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan) should be avoided. Concomitant use of rivaroxaban with combined P gp and weak or moderate CYP3A4 inhibitors (eg, erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine) should be avoided in patients with renal impairment, unless the benefit outweighs the bleeding risk. Concomitant use of rivaroxaban with combined P gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John s wort) should be avoided, or consideration given to use of an increased rivaroxaban dose. Administration with rifampicin resulted in a 50% reduction in rivaroxaban AUC and a 22% reduction in the rivaroxaban Cmax, with accompanying reductions in rivaroxaban effects. Prescribing information, Janssen Pharmaceuticals, 2011 ROCKET AF Discussion Event rates were similar at 30 days and 1 year after withdrawal, suggesting that the mechanism of events did not involve hypercoagulability early after withdrawal of rivaroxaban. Events occurring at the end of the study were probably related to increased difficulty in achieving the transition from blinded trial therapy to the open label use of a vitamin K antagonist when the patient had previously been assigned to the rivaroxaban group, since presumably many patients who had previously been assigned to the warfarin group would have already had a therapeutic INR. Prescribing information, Janssen Pharmaceuticals, 2011 Patel MR. N Engl J Med 2009;361:1139-51. Rivaroxaban is rapidly replacing warfarin and enoxaparin to reduce the risk of pulmonary and venous thromboembolism after hip and knee surgery. When we examined the reports, we found that the primary event was not hemorrhage, as with other anticoagulants. Instead, the largest category of events (158 cases, 44.4% of the total) was serious thrombus, most often pulmonary embolism the very event rivaroxaban is intended to prevent. As might be expected, there were also numerous reports of hemorrhage (121 cases, 34% of the total). Direct factor Xa inhibitor Indication: To reduce the risk of stroke and systemic embolism in patients with nonvlvular atrial fibrillation.* Dose: 5mg BID Renal elimination 25% * Proposed indication Press release, Bristol-Myers Squibb, 9/26/2012 5

FDA decision due on 3/28/12, 3/17/13 Originally granted a priority review by the FDA A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. ARISTOTLE Trial 18,201 patients, double blind, apixaban 5mg BID vs warfarin, non inferiority, 62.2% TTR Outcome (%/yr) Apixaban Warfarin Hazard ratio P value Stroke or systemic embolism 1.27 1.60 0.79 (0.66 0.45) 0.01* Death from any cause 3.52 3.94 0.89 (0.80 0.998).047 Major Bleeding 2.13 3.09 0.69 (0.60.80) <0.001 Anything bad 6.13 7.2 0.85 (0.78 0.92) <0.001 Press release, Bristol-Myers Squibb, 9/26/2012 *p value for superiority! Granger CB. N Engl J Med. 2011;365(11):981-92 Warnings, precautions, side effects. Metabolized by CYP 3A4 TBD You were just diagnosed with atrial fibrillation. What drug are you going to use? A. Dabigatran B. Rivaroxaban C. Apixaban D. Warfarin. Um, no thanks, I don t want to bleed to death! You feel that A. The ability to monitor a drug is important B. Warfarin monitoring is too troublesome C. They didn t monitor in the trials, it s not necessary, so what s the big deal? D. Hey, we re past the halfway point! May be important for: Compliance determination Determining why treatment fails Drug interactions/hepatic/renal issues Hemorrhagic events Emergent surgical needs 6

Assay Dabigatran Rivaroxaban Apixaban PT Not really Sensitive Sensitive aptt Sensitive Not really Not really PT and aptt do not respond in a linear or predictable fashion. They are useful for testing for the presence of the drug in the plasma. Not for determination of the extent of anticoagulation. Caution when trying to test INR with concurrent warfarin use. Other tests are being developed Miyares MA. AJHP 2012;69:1473-84-356 Warfarin Decreases production of factors II, VII, IX, X To reverse Vitamin K to overcome competitive inhibition ~4 hours Fresh frozen plasma (FFP) contains all coagulation factors in dilute amounts. Complex concentrates (PCC) contain various coagulation factors. Intrinsic system Extrinsic system (surface contact) (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII Unfractionated heparin 2,3 VIII VIIIa X Low molecular-weight heparins 2,3 Xa Vitamin K antagonists 4 V Va Direct thrombin inhibitors 4,5 II IIa (Thrombin) Factor Xa inhibitors 4,5 Fibrinogen Fibrin 1. Adapted from Petitou M et al. Nature. 1991;350(6319 suppl):30-33. 2. Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 3. Hirsh J et al. Chest. 2001;119(1 suppl):64s-94s. 4. Nutescu EA et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5. Bauer KA. J Thromb Thrombolysis. 2006;21:67-72. 39 Prothrombin Complex Concentrates 3 Factor PCC (Bebulin VH, Profilnine SD) Contain factors II, IX, X 4 Factor PCC Available as Feiba NF in the US II, IX, X and activated VII These products are all unique with respect to concentrations of factors and considered not interchangeable. Consider external validity Clinical trials have been done either in animal models or healthy human volunteers. Mixed results with end points. Normalization of coagulation markers Normalization of bleeding time Human trials of PCCs have used agents not available in the US. Apixaban Dabigatran Rivaroxaban Oral activated No data In vitro No data Charcoal Hemodialysis No data Human volunteers No data Hemoperfusion No data In vitro No data w/charcoal Fresh frozen plasma No data Mouse No data Activated factor VIIa No data Rat Rat and Baboon 3 factor PCC No data No data No data 4 factor PCC No data Human volunteers and rats Human volunteers Katz S, Kouides PA, Garcia DA, et al. Am J Hematol. 2012;87:S141-s145. 7

Apixaban Dabigatran Rivaroxaban Oral activated Yes Yes Yes Charcoal Hemodialysis No Yes No Hemoperfusion Possible Yes Possible w/charcoal Fresh frozen plasma No No No Activated factor VIIa Unclear Unclear Unclear 3 factor PCC Unclear Unclear Unclear 4 factor PCC Possible Possible Possible Panel s conclusions PCC: The use of either 3 factor or 4 factor PCCs have the potential to increase the risk of thrombosis. There have been no studies evaluating the effect of PCCs on bleeding in humans receiving the new oral anticoagulants. Whether use of PCCs will be effective to stop critical bleeding or reverse the anticoagulant effects of the new agents enough to safely proceed with emergent surgery is not established but seems, given the current state of information, to be a reasonable approach in dire clinical situations in the opinion of several of the authors. Importantly, however, consensus was not reached regarding PCC, as two authors felt that PCC cannot be recommended at this time due to absence of data. Katz S, Kouides PA, Garcia DA, et al. Am J Hematol. 2012;87:S141-s145. Katz S, Kouides PA, Garcia DA, et al. Am J Hematol. 2012;87:S141-s145. With respect to reversibility, you feel A. Keep those drugs away from me until a reversal agent is available. B. Risk of severe hemorrhage is low (and possibly lower than warfarin), I m comfortable with the new agents. Things to consider: Efficacy/Safety Compliance Cost Management NEWER ORAL ANTICOAGULANTS SHOULD BE USED AS FIRST LINE AGENTS TO PREVENT THROMBOEMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION AND RISK FACTORS FOR STROKE OR THROMBOEMBOLISM Warfarin monitoring and adverse reactions are an enormous burden to the healthcare system. Convenience may lead to improved adherence and persistence. Decreased hemorrhagic stroke and intracranial bleeding. Trend towards improved mortality. Granger CB, Armaganijan LV. Circulation. 2012;125:159-164. NEWER ORAL ANTICOAGULANTS SHOULD NOT BE USED AS FIRST LINE AGENTS TO PREVENT THROMBOEMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION. RE LY trial was open label with a 21% dropout rate for dabigatran and increased major GI bleeding and MI. Vanishing difference in relative efficacy as warfarin management improved. ROCKET AF trial had only a 57.8% TTR. Increased risk with poor adherence and no consistent follow up. Drug interactions? Ansell, J. Circulation. 2012;125:165-170. Many patient factors to consider to determine which is most appropriate. Anticoagulation management service available Efficacy likely equal Poor compliance Warfarin likely better Economic issues Rx cost least with warfarin, but what about monitoring? Monitoring beneficial renal/hepatic disease, many medications/interactions Possible with warfarin High risk of bleeding events reversibility vs decreased bleeding risk What about those having poor response to warfarin? What s the problem? 8

You were just diagnosed with atrial fibrillation. What drug are you going to use? A. Dabigatran B. Rivaroxaban C. Apixaban D. Warfarin Um, are we done yet? 9