Anticoagulant Review Morning Report – April 25, 2018 Sydney N. Kutter, Pharm.D. PGY1 Pharmacy Practice Resident Central Texas Veterans Health Care System

Rivaroxaban (Xarelto) Anticoagulants Warfarin (Coumadin) Edoxaban (Savaysa) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis)

Warfarin Review

Warfarin - Dosing Highly individualized – tailored based on bleeding risk, indication, goal range, interactions, etc. Initiation between 2.5-10mg daily Lower doses for elderly age, genetic polymorphism, alcohol or tobacco usage, change in diet, interacting medications, sickness, etc. Adjusted based on INR result

Warfarin Initial Dosing – VA PBM Algorithm

Warfarin Maintenance Dosing – VA PBM Algorithm

Drug Interactions Increase INR Decrease INR Alcohol Drugs Certain juices Sickness Vitamin K Nutritional shakes Liver Green tea

Drug/Drug Interactions Increase INR Decrease INR Antibiotics Amiodarone Prednisone Acetaminophen/NSAIDs Statins Phenytoin Omeprazole Herbals/OTCs Antibiotics Carbamazepine Rifampin Butalbital

Drug/Drug Interactions - Antibiotics Increase INR Decrease INR Metronidazole Bactrim Doxycycline Fluoroquinolones Macrolides B-lactams Cloxacillin Dicloxacillin Nafcillin

DOAC Review Direct Oral Anticoagulants

DOAC Review Drug VTE Dose AF Dose Notes Apixaban (Eliquis) Factor Xa Inhibitor 10mg BID x 7 days, then 5mg BID 5mg BID Preferred in those with history of GI bleeding Rivaroxaban (Xarelto) 15mg BID x 21 days, then 20 mg daily 20mg daily Take doses > 10mg with meal Edoxaban (Savaysa) 60mg daily After 5-10 days of parenteral anticoagulation Cheapest Dabigatran (Pradaxa) Thrombin Inhibitor 150mg BID Store in original container, discard after 4 months HOKUSAI-VTE Investigators. N Engl J Med. 2013;369:1406-1415. ENGAGE AF-TIMI 48 Investigators. N Engl J Med. 2013; 369:2093-2104. RE-COVER Investigators. N Engl J Med. 2009; 361:2342-2352. RE-LY Investigators. N Engl J Med. 2009; 361:1139-1151. AMPLIFY Investigators. N Engl J Med. 2013;369(9):799-808. ARISTOTLE Investigators. N Engl J Med. 2011;365:981-992. EINSTEIN Investigators. N Engl J Med. 2010;363:2499-2510. ROCKET AF Investigators. N Engl J Med. 2011;365:883-891.

DOAC Renal Elimination Apixaban ~27% Rivaroxaban ~35% Edoxaban ~50% Dabigatran ~80% ESC Scientific Document Group. Europace. 2017;19(11):1757-1758.

Edoxaban Contraindicated in patients with AF if CrCl > 95 ml/min https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf

Dabigatran Dyspepsia AUC decreases by ~30% in patients taking a PPI No impact on clinical outcomes? Compliance issues – must store in original container Reversal agent https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf

Rivaroxaban Take doses > 10 mg with evening meal Increased absorption https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf

Apixaban Recommended in patients at increased risk for bleeding Prior history of GIB On DAPT Age > 75 Clinical judgement https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf

DOAC Effect on INR INR not monitored if on DOAC therapy Can increase INR, though not a safety or efficacy measure

General DOAC Considerations - Reversal Reversal agent Dabigatran – Idarucizumab (Praxbind) Rivaroxaban Apixaban Edoxaban Under development Andexanet alfa – reversal agent for all Factor Xa inhibitors Ciraparantag – universal antidote No specific antidote, suggest using 4F-PCC, FFP Pollack, et al. N Engl J Med. 2015;373(6):511-20. ANNEXA-4 Investigators. N Engl J Med. 2016;375(12):1131-41. Ansell, et al. Thromb Haemost. 2017;117(2):238-245

General DOAC Considerations - Obesity Not recommended The ISTH 2016 guideline suggests avoiding the use of direct oral anticoagulants in patients with a BMI > 40 kg/m2 or weight > 120 kg due to the lack of clinical data in this population. Subgroup analysis of obese patients from the pivotal phase 3 DOAC trials suggests that DOACs generally appear to be safe and effective; however, data are limited. Martin, et al. J Thromb Haemost. 2016;14(6):1308-13. https://www.pbm.va.gov/apps/VANationalFormulary/GetFile.aspx

General DOAC Considerations - Obesity VA PBM recommends that when a DOAC is being considered in such patients: “A shared decision making approach should be utilized with information provided on the limited data regarding the efficacy and safety of these agents in extremes of body weight and recommendations of some groups against use in this situation."

General DOAC Considerations - Valves Mechanical valves excluded from all landmark trials Bioprosthetic valves Minimally included in apixaban and edoxaban AF trials ARISTOTLE (apixaban) N = 82 (1.7%) ENGAGE-AF (edoxaban) N = 191 (6.8%) No significant difference between groups with or without valvular heart disease ESC Scientific Document Group. Europace. 2017;19(11):1757-1758.

General DOAC Considerations - Cancer Minimally studied in DOACs Subgroups included in landmark trials Studied edoxaban in HOKUSAI VTE Cancer trial (2018) LMWH versus edoxaban (n=1046) Primary outcome – composite of recurrent VTE or major bleeding 12 months after randomization Edoxaban Primary Outcome: 12.8% VTE: 7.9% Bleeding: 6.9% LMWH Primary Outcome: 13.5% VTE: 11.3% Bleeding: 4% HOKUSAI VTE Cancer Investigators. N Engl J Med. 2018;378(7):615-624.

RE-VERSE AD Study IDARUCIZUMAB (PRAXBIND)

RE-VERSE AD Multicenter, prospective, observational trial Sponsored by the Boehringer Ingelheim Objective Examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran Idarucizumab is a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that observed with thrombin Pollack, et al. N Engl J Med. 2015;373(6):511-20.

RE-VERSE AD Group B Group A N = 39 N = 51 Uncontrollable or life-threatening bleeding Group B N = 39 Surgical or invasive procedure that couldn’t be delayed 8 hours Pollack, et al. N Engl J Med. 2015;373(6):511-20.

RE-VERSE AD - Treatment 5 grams of idarucizumab Two 50ml boluses (each containing 2.5 grams) No more than 15 minutes apart Could repeat if necessary Primary outcome Maximum percentage reversal of dabigatran Dilute thrombin time or ecarin clotting time 5 grams Calculated to reverse the total body load of dabigatran that was associated with the 99th percentile of the dabigatran levels measured in the RE-LY trial DTT or ECT chosen because they are highly correlated with the concentrations of unbound dabigatran Pollack, et al. N Engl J Med. 2015;373(6):511-20.

RE-VERSE AD - Results Median maximum percentage reversal was 100% 95% CI (100 to 100) Concentrations of dabigatran remained below 20ng/ml at 24 hours in 79% of patients Hemostasis restored at 11.4 hours in Group A Pollack, et al. N Engl J Med. 2015;373(6):511-20.

RE-VERSE AD - Limitations No control group Mortality can’t be extrapolated Adverse events? Primary outcome – lab versus clinical ? 22 patients had DTT that were WNL at initiation of study? Lack of flow diagram Pollack, et al. N Engl J Med. 2015;373(6):511-20.

Bottom Line DOACs can be complicated Don’t take studies at face value Perform thorough histories to determine appropriate agents Utilize pharmacy staff