1. Dodson Thompson, DO Northlakes Community Clinic Minong, WI

3. Apixaban(Eliquis): Approved in 2014 Rivaroxaban(Xarelto): Approved in 2011 Dabigatran(Pradaxa): Approved in 2010 Savaysa(Edoxaban): Approved in 2015

4. 65 y/o male with a history of aortic stenosis status post aortic valve replacement with a mechanical valve. Medications: Toprol XL 50mg daily Crestor 10mg daily Lisinopril 20mg daily. Warfarin 5mg to 7.5mg daily depending on his INR INR has been difficult to control and varies from being sub- therapeutic to super-therapeutic.

5. At his next office visit, he asks you if he can switch to one of the new anticoagulants that he has seen advertised on television? What do you tell him? a.) Yes, he can switch directly from Warfarin to a NOAC and never have to have his INR checked again. b.) No, because he has a mechanical valve, he has to continue taking Warfarin and having his INR checked.

6. 79 y/o female hospitalized with sudden onset of shortness of breath and subsequently diagnosed with pulmonary embolism. PMHx: hypertension Medications: Hydrochlorothiazide 25mg daily. Atenolol 50mg twice daily.

7. Patient was started on lovenox 80mg SQ twice daily and warfarin 5mg daily. INR prior to initiating the above medications was 1.0. Her INR after three days of anticoagulation is 1.3. She is reluctant to continue warfarin because of the monitoring parameters that it requires. You discuss NOACS with her. Can she: a.) stop lovenox and warfarin and start one of the NOACs on discharge? b.) continue lovenox and warfarin until her INR in 2.0 then change to a NOAC? c.) she is not a candidate for NOACs because they are only approved for treatment of non-valvular atrial fibrillation.

8. 73 y/o female with a history of atrial fibrillation diagnosed approximately five years ago. She is rate controlled on metoprolol and her INR has been amazingly stable. So much so, that she usually only presents to the clinic 4-5 times per year to have it checked. PMHx: Atrial fibrillation Hypertension Medications: Metoprolol 25mg daily HCTZ 25mg daily. Warfarin 3mg daily.

9. At her most recent visit, she asks you if it is possible to stop taking warfarin and take one of the new anticoagulants that does not require monitoring? What do you tell her? a.) Yes, she can take a NOAC that would not require INR monitoring. Luckily, that medication is not much more expensive than warfarin. You will write her a script today. b.) No, NOACs are considerably more expensive. The change probably is not worth it considering she only visits the office 3-4 times per year anyway.

10. Warfarin: Pharmacokinetics: ½ life averages 40 hours. 92% excreted by the kidneys. Inhibits vitamin K dependent coagulation factors II, IX, X as well as protein C and S. Clinical trials have shown a 64% reduction in stroke and a 26% reduction in all cause mortality when compared to placebo. Relative risk reduction for stroke of 39% when compared with aspirin. Effects of warfarin can be reversed with vitamin K or FFP. Vitamin K can take up to 48 hours to take affect. FFP has shown some degree of reversal in as little as 2 hours, but may take as much as 96 hours to fully reverse warfarin.

11. Apixaban(Eliquis): Pharmacokinetics: ½ life of 12 hours Peak plasma levels reached in 3-4 hours with a steady state plasma concentration achieved in 3 days. 27% excreted by the kidneys. Oral bioavailability of approximately 50%. Selectively blocks the active site of coagulation factor Xa Cost approximately $326/month

12. Apixaban(Eliquis): Dosing: VTE/Stroke prophylaxis: 5mg BID(decrease to 2.5mg BID if age>80 y/o, weight 1.5 DVT prophylaxis: 2.5mg BID DVT/PE treatment: 10mg BID for 7 days, then 5mg BID. Conversion from Warfarin: Start apixiban along with tapering doses of warfarin. Discontinue warfarin when INR<2.

13. Aristotle Trial: Patients had a diagnosis of atrial fibrillation or atrial flutter at the beginning of the trial. Patients also had at least one of the following risk factors stroke: Age of 75 y/o or older. Hx of previous stroke, TIA, or VTE. Symptomatic heart failure within the previous three months. Diabetes or hypertension requiring pharmacologic treatment.

14. Aristotle Trial: Primary efficacy outcome was the combined incidence of stroke or VTE. The primary outcome occurred in 212 of 9120(1.3%) patients in the Apixaban group versus 265 of 9081(1.6%) patients in the Warfarin group. RRR of 19% Patients in the Apixiban group had significantly decreased incidence of stroke 199 of 9120(1.2%) versus 250 of 9081(1.5%). RRR of 20%. Rates of hemorrhagic stroke were also reduced in the Apixaban group; 40 of 9120(0.24%) versus 78 of 9081(0.47%) Patients in the Apixiban group had a small reduction in the incidence of VTE; 15 of 9120(0.09%) versus 17 of 9081(0.10%) in the Warfarin group. RRR of

15. ARISTOTLE Trial: Primary safety outcome was major bleeding defined as clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2g/dL or transfusion of at least 2 units of PRBCs. Incidence of intracranial hemorrhage was decreased in the apixaban group 52 of 9088(0.33%) versus warfarin 122 of 9052(0.80%). Incidence of GI bleed was decreased in the apixaban group 105 of 9088(0.76%) versus warfarin 119 of 9052(0.86%)

16. AMPLIFY Trial: Apixiban for the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis as First Line Therapy. RCT comparing apixiban with subcutaneous enoxaparin and warfarin for the treatment of acute venous thromboembolism. Primary outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. Patients were assessed for primary outcome at weeks 2, 4, 8, 12, 16, 20 and 24 weeks after randomization and 30 days after the end of the treatment period.

17. AMPLIFY Trial: Patients: 18 y/o or older with objectively confirmed, symptomatic proximal deep vein thrombosis or pulmonary embolism(with or without DVT). Patients were excluded if they had received: More than two doses of once daily LMWH, fondaparinux, or a vitamin K antagonist. More than three doses of twice daily LMWH, or more than 36 hours of IV heparin.

18. AMPLIFY Trial: Patients in the Apixiban group received 10mg twice daily for seven days then 5mg twice daily for six months. Patients in the conventional treatment group received enoxaparin at 1mg/kg SQ every 12 hours for at least five days. Enoxaparin was discontinued when the INR reached 2. Warfarin was initiated concomitantly with enoxaparin and continued for six months. Warfarin dose was adjusted to maintain the INR between 2-3.

19. AMPLIFY Trial: Primary Efficacy Combined: Recurrent VTE occurred in 59 of 2609(2.3%) patients in the Apixiban group and 71 of 2635(2.7%) patients in the conventional therapy group. Relative risk reduction(RRR) of 15% Primary Efficacy for DVT: 38 of 1698(2.2%) patients in the apixiban group and 47 of 1736(2.7%) patients in the conventional group. Relative risk reduction of 19%.

20. AMPLIFY Trial: Primary Efficacy for pulmonary embolism: 21 of 900(2.3%) in the apixiban group and 23 of 886(2.6%) in the conventional therapy group. Relative risk reduction of 12%. Fatal pulmonary embolism occurred in one patient in the apixiban group and two patients in the conventional group. Rate of recurrent nonfatal pulmonary embolism was actually higher 27 of 2691(1.0%) patients in the apixiban group versus 23 of 2704(0.9%) patients in the conventional group.

21. AMPLIFY Trial: Major bleeding occurred in 15 of 2691(0.6%) patients in the apixiban group vs 49 of 2704(1.8%) patients in the conventional therapy group. Relative risk reduction of 67%. Intracranial hemorrhage occurred in 3(0.1%) of the patients in the apixiban group and 6(0.2%) of patients in the conventional group. Gastrointestinal bleeding occurred in 7(0.3%) of the patients in the apixiban group and 18(0.7%) of patients in the conventional group. Relative risk reduction of 57%.

22. Rivaroxaban(Xarelto): Pharmacokinitics: ½ life of 5-9 hours. Oral bioavailability of 80%. Peak plasma levels reached in 2-3 hours. Primarily metabolized by the liver. Selectively inhibits factor Xa Contraindicated in CrCl<30ml/min. Cost approximately $312/month.

23. Rivaroxaban(Xarelto): Dosing: VTE/stroke prophylaxis: 20mg QD. DVT prophylaxis: 10mg QD. DVT/PE treatment: 20mg QD. Conversion from Warfarin: Rivaroxaban can be started anytime the INR<3.

24. ROCKET AF Trial: Multicenter, randomized, double blind trial conducted in 45 countries. Recruited patients with nonvalvular atrial fibrillation at moderate to high risk for stroke, TIA or systemic embolism. Patients also had at least two of the following risk factors: Congestive heart failure w/ ejection fraction of 35% or less Hypertension Age > 75 Diabetes CHADS2 score of 2 or more

25. ROCKET AF Trial: Patients randomly assigned to receive rivaroxaban 20mg daily or adjusted dose warfarin with a target INR of 2-3. INR within therapeutic range 55% of time in the warfarin group. Primary efficacy endpoint was combination of stroke(either ischemic or hemorrhagic) and systemic VTE. Patient characteristics: Median age was 73 y/o 90% had a diagnosis of hypertension. 63% had a diagnosis of heart failure. 40% had a diagnosis of diabetes. 55% had experienced a previous stroke, VTE, or TIA. Median CHADS2 score was 3.

26. ROCKET AF Trial: Stroke or systemic embolism occurred in 188 of 6958(1.7%) patients in the rivaroxaban group and 241 of 7004(2.2%) patients in the warfarin group. Relative risk reduction for stroke or VTE of 22%. Any major, non-fatal bleeding including a decrease in hemoglobin >2g/dl or bleeding requiring transfusion was more common in the rivaroxaban group.(5.6% vs 5.4%) Intracranial hemorrhage occurred in 0.8% of the patients in the rivaroxaban group versus 1.2% in the warfarin group. Relative risk reduction of 33%

27. EINSTEIN-PE Trial: Randomized trial involving 4832 patients diagnosed with acute symptomatic pulmonary embolism with or without deep vein thrombosis. Rivroxaban 15mg twice daily for three weeks followed by 20mg once daily was compared with enoxaparin and adjusted dose warfarin for 3, 6, or 12 months. Eligible patients were at least 18 y/o with an objectively confirmed pulmonary embolism. Patients were deemed ineligible if they received a therapeutic dose of LMWH, fondaparinux or more than a single dose of warfarin prior to randomization.

28. EINSTEIN-PE Trial: Primary efficacy outcome was recurrence of symptomatic venous thromboembolism, defined as a composite of fatal or nonfatal pulmonary embolism. Primary safety outcome was the incidence of clinically relevant bleeding defined as: Decrease in hemoglobin of 2.0g/dl or more. Transfusion of two or more units of PRBC. Bleeding that was intracranial or retroperitoneal.

29. EINSTEIN-PE Trial: In the rivaroxaban group 50 of 2419(2.1%) patients suffered recurrent VTE compared with 44 of 2413(1.8%) in the standard therapy group. There were more people in the rivaroxaban group who suffered: Fatal PE: 2 vs 1 Nonfatal PE:22 vs 19 Recurrent DVT: 18 vs 17

30. EINSTEIN-PE Trial: There were 26(1.1%) major bleeding episodes in the rivaroxaban group vs 52(2.2) in the standard therapy group. Of those episodes, 2 were fatal in the rivaroxaban and 3 were fatal in the standard therapy group. There were 7(0.3%) episodes of nonfatal major bleeding in the rivaroxaban group versus 26(1.1%) in the standard therapy group. Intracranial bleeding: 1 vs 10 Retroperitoneal bleeding: 1 vs 7

31. Dabigatran(Pradaxa): Pharmacokinetics: ½ life of 12-17 hours. Minimal oral bioavailability, so it has to be administered as a prodrug, dabigatran etexilate. Peak plasma levels reached in 1-2 hours. Primarily excreted by the kidneys. Reversibly inhibits thrombin. Contraindicated if the CrCl<30ml/min, except for VTE/stroke prophylaxis. Cost approximately $325/month.

32. Dabigatran(Pradaxa): Dosing: VTE/stroke prophylaxis: 150mg BID(decrease to 75mg BID if CrCl 15-30ml/min). DVT/stroke prophylaxis: 150mg BID. DVT/PE treatment: 150mg BID.

33. Edoxaban(Savaysa): Pharmacokinetics: ½ life 10-14 hours. 50% excreted in the urine. Selectively blocks the active site of factor Xa. Contraindicated in patients with CrCl<15mL/min. Reduced efficacy in atrial fibrillation patients with a CrCl>95mL/min.(trials actually showed an increased risk of ischemic stroke when compared to warfarin in this population of patients) Cost approximately $288/month.

34. - Dosing: - VTE/stroke prophylaxis: 60mg QD. - DVT/PE treatment: 60mg QD.