What s new with DOACs? Defining place in therapy for edoxaban &

What s new with DOACs? Defining place in therapy for edoxaban & Use of DOACs in cardioversion Caitlin M. Gibson, PharmD, BCPS Assistant Professor, Department of Pharmacotherapy University of North Texas System College of Pharmacy Learning objectives Pharmacists Describe the literature supporting edoxaban use in atrial fibrillation, venous thromboembolism, and postoperative prophylaxis Identify patients who may benefit from edoxaban over other direct oral anticoagulants (DOACs) Describe the literature surrounding the use of DOACs in cardioversion Select an appropriate anticoagulant for use in the setting of cardioversion Technicians Describe indications for edoxaban List the appropriate dosing regimens for edoxaban for various indications Summarize appropriate anticoagulation regimens for cardioversion Abbreviations AF = atrial fibrillation CI = confidence interval CrCl = creatinine clearance DCCV = direct current cardioversion DOAC = direct acting oral anticoagulant HD = hemodialysis MI = myocardial infarction NVAF = nonvalvular AF SE = systemic embolism TIA = transient ischemic attack TEE = transesophageal echocardiogram VKA = vitamin K antagonist VTE = venous thromboembolism 1

Outline Edoxaban vs. other DOACs DOACs in cardioversion Summary Defining place in therapy for edoxaban DOACs Rapid acting, target specific oral anticoagulants Frequently used for: Prevention of stroke and systemic embolism in non valvular atrial fibrillation (NVAF) Off label: cardioversion Treatment (& prolonged treatment/secondary prevention) of venous thromboembolism (VTE) Post operative thromboprophylaxis after hip & knee replacement surgery 2

Edoxaban Pharmacokinetics & availability Dosage forms Onset Half life Excretion Metabolism FDA approved indications 15mg, 30mg, & 60mg tablets 1 2 hours 10 14 hours 50% renal P glycoprotein Prevention of stroke and systemic embolism in NVAF Treatment of VTE Edoxaban for VTE treatment Hokusai VTE Design Patients Interventions Outcomes Symptomatic recurrent VTE Randomized, placebo controlled trial over 3 12 months N = 4,921 with acute, symptomatic VTE Unfractionated heparin edoxaban 60mg vs. Edoxaban Warfarin Significance 3.2% 3.5% HR 0.89, 95% CI 0.70 1.13, p<0.001 for noninferiority Bleeding 8.5% 10.3% HR 0.81, 95% CI 0.71 0.94, p=0.004 for superiority N Eng J Med 2013;369:1406 15. Edoxaban for NVAF ENGAGE AF TIMI 48 Design Patients Interventions Randomized, double blind, placebo controlled trial N = 21,105 with moderate to high risk NVAF Edoxaban 60mg vs. edoxaban 30mg vs. Edoxaban 60mg Warfarin Significance Outcomes Stroke or SE 1.18% / yr 1.50% / yr HR 0.79, 97.5% CI 0.63 0.99, p<0.001 for non inferiority Major bleeding 2.75% / yr 3.43% / yr HR 0.80, 95% CI 0.71 0.91, p=0.001 for superiority N Eng J Med 2013;369:2093 2104. 3

Lessons from ENGAGE AF-TIMI 48 REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CRCL > 95 ML/MIN: edoxaban should not be used in patients with CrCL > 95 ml/min. In the ENGAGE AF TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 ml/min had an increased rate of ischemic stroke with edoxaban 60 mg once daily compared to patients treated with. In these patients another anticoagulant should be used Edoxaban adverse events Bleeding Anemia Liver enzyme elevations Rash Reversal Prothrombin complex concentrates Recombinant factor VIIa Andexanet alfa Intravenous modified factor Xa decoy protein Phase III ongoing Ciraparantag Small molecule which binds DOACs, heparin, and fondaparinux Phase II ongoing 4

Comparison to other agents Drug class Reversal agents Dosing frequency Direct thrombin inhibitor Idarucizumab Ciraparantag Factor Xa inhibitor Andexanet alfa Ciraparantag Factor Xa inhibitor Andexanet alfa Ciraparantag Factor Xa inhibitor Andexanet alfa Ciraparantag Twice daily Once daily Twice daily Once daily Time to peak 1 hour 2 4 hours 3 4 hours 1 2 hours Half life 12 17 hours 5 13 hours 12 hours 10 14 hours Dialyzable? Yes No No No Drug interactions P glycoprotein P glycoprotein CYP 3A4 P glycoprotein CYP 3A4 P glycoprotein Comparison: Acute VTE treatment Approved? Yes Yes Yes Yes 15 mg BID WC x21 days 10 mg BID x7 60mg PO daily Dose 150mg BID 20mg daily WC days 5mg BID (30mg if 60 kg) Renal adjustment Efficacy vs Major bleeding vs Anticoagulation req d prior? CrCl 30 or on HD: No rec. CrCl <30 or on HD: Avoid SCr >2.5 or CrCl <25: No rec. CrCl 15 50: 30mg PO daily CrCl <15: Avoid HD: No rec. Non inferior Non inferior Non inferior Non inferior Similar Similar Reduced Reduced Yes heparin x5 10 days No No Yes heparin x5 10 days N Eng J Med. 2011; 15:365:981 92; N Eng J Med. 2013;369:2093 2104; N Eng J Med. 2011;365:883 91; N Eng J Med. 2009;361:1139 51 Comparison: 2 o VTE prevention Approved? Yes Yes Yes No Dose 150 mg PO twice daily 20 mg PO daily with food 2.5 mg PO twice daily N/A Renal adjustment CrCl 30 or on HD: No rec. CrCl <30 or on HD: Avoid SCr >2.5 or CrCl <25: No rec. N/A Efficacy vs placebo Major bleeding vs placebo Superior (noninferior vs. ) Similar (reduced vs. ) Superior Superior N/A Similar Similar N/A N Eng J Med. 2013;368:709 18; N Eng J Med. 2013;368:699 708; N Eng J Med. 2010;363:2499 2510 5

Comparison: NVAF Approved? Yes Yes Yes Yes Dose 150 mg PO BID 20 mg PO WC 5 mg PO BID 60 mg PO daily Renal adjustment Efficacy vs Major bleeding vs CrCl 15 30: 75 mg twice daily CrCl <15 or on HD: No rec. CrCl 15 50: 15 mg PO daily with evening meal CrCl <15 or on HD: No rec. If 2: age 80 years, weight 60kg, SCr 1.5 adjust to 2.5mg BID HD: 5mg PO BID; if age 80 or weight 60 adjust to 2.5 mg BID CrCl >95: Boxed warning, avoid CrCl 15 50: 30mg daily CrCl <15: Avoid HD: No rec. Superior Non inferior Superior Non inferior Similar Similar Reduced Reduced N Eng J Med. 2013;369:2093 2104; N Eng J Med. 2011;365:883 91; N Eng J Med. 2011; 15:365:981 92; N Eng J Med. 2009;361:1139 51 Comparison: Post-operative DVT prophylaxis Approved? Hip Hip & knee Hip & knee No Dose 220mg daily 10mg daily 2.5mg BID N/A Renal adjustment Efficacy vs enoxaparin Major bleeding vs enoxaparin CrCl 30 or on HD: No rec. CrCl 30 50: Use with caution CrCl <30 or on HD: Avoid CrCl <30: No rec. N/A Non inferior Superior Superior N/A Similar Similar Similar N/A N Eng J Med. 2008;358:2776 86; N Eng J Med. 2008;358:2765 75; N Eng J Med. 2010;363:2487 98; Lancet. 2010;375:807 15; J Thromb Haemost. 2007;5:2178 85; Lancet. 2007;370:949 56 Edoxaban and renal function Renal function Recommendation CrCl > 95 ml/min CrCl 51 95 ml/min CrCl 15 50 ml/min CrCl <15 ml/min Hemodialysis Avoid in NVAF 60mg PO daily 30mg PO daily Avoid No recommendation in package insert In a study of 28 patients, edoxaban serum concentrations were not affected by HD; similar drug exposure in both arms 6

Question #1 RR is an 81yo female with a PMH of atrial fibrillation. She has not been able to maintain her INR within therapeutic range, and her physician wishes to switch her to a DOAC. She weighs 54kg and her CrCl is 102 ml/min. Her home meds include metoprolol tartrate twice daily (she struggles to remember her morning dose) and atorvastatin 40mg PO HS. Which DOAC is the best choice? A) Apixaban 5mg PO BID B) Edoxaban 60mg PO daily C) Dabigatran 150mg BID D) Rivaroxaban 20mg PO with evening meal Edoxaban take home points Once daily dosing No antidote Must use heparin first for VTE Avoid CrCl >95 in NVAF Weight impacts dosing in VTE Not for 2 o prophylaxis of VTE Not for postoperative DVT prophylaxis Consider for cardioversion Use of DOACs in cardioversion 7

Atrial fibrillation Treatment Most common sustained cardiac arrhythmia 2% prevalence Rate control Atrial fibrillation Rhythm control Stroke prevention Anticoagulation Cardioversion Maintenance Chemical Electrical Cardioversion & stroke Without anticoagulation, cardioversion 5 7% risk of stroke or systemic embolism With VKA therapy, cardioversion 0.7 0.8% risk Guideline recommendations: 3 weeks of anticoagulation prior to cardioversion 4 weeks of anticoagulation after cardioversion Circulation 2011;123:131 136. Anticoagulation & cardioversion >48h duration or unknown: anticoagulate Anticoagulate during procedure Highest risk 0 72h Anticoagulation recommended for 4 weeks after cardioversion Days -21-2 0 3 10 28 Chronic management <48h duration or <48h since TEE: optional High risk for embolism for 10 days after cardioversion Consider patient risk factors 8

Current guideline recommendations Guideline Publication Year Recommendation CHEST Guidelines for Antithrombotic Therapy for Atrial Fibrillation 2012 DOACs may be suitable before TEE guided cardioversion; dabigatran is recommended by name DOACs are not recommended for AF <48h duration DOACs (dabigatran) are recommended after cardioversion AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation 2014 Dabigatran, rivaroxaban, or apixaban is reasonable for 3 weeks before and 4 weeks after cardioversion Retrospective studies Trial Patients Drugs % TEE* RE LY post hoc Circulation 2011;123:131 6 ARISTOTLE post hoc J Am Coll Cardiol 2014;63:1082 7 ROCKET AF post hoc J Am Coll Cardiol 2013;61:1998 2006 ENGAGE AF TIMI 48 post hoc Clin Cardiol 2016;39:345 6 N = 1983 ~82% DCCV N = 743? DCCV N = 375 + 85 ablations 48.2% DCCV N = 632 100% DCCV Dabigatran vs. Apixaban vs. Rivaroxaban vs. Edoxaban vs. 24.1% vs. 13.3%* 32.5% vs. 30.1% Stroke or SE (DOAC vs VKA) 0.30% vs. 0.60% 0% vs. 0%? 1.9% vs. 1.9%? 0%vs. 0% *Statistically significant difference Prospective studies Trial Patients Drugs % TEE Primary endpoint Results: short vs. standard X VeRT Eur Heart J 2014;35:3346 55 N = 1504 97.6% DCCV Rivaroxaban vs. VKA ± heparin 43.7% vs. 21.4% Stroke, TIA, MI, peripheral embolism, CV death 0.51% vs. 1.02%, p>0.05 ENSURE AF Lancet 2016;388:1995 2003 N = 2199 100% DCCV Edoxaban vs. + enoxaparin ~54% vs. ~62% Stroke, systemic embolism, MI, CV death 0.46% vs. 1.0%, p>0.05 9

Question #2 Which of the following agents have been studied in the setting of cardioversion in prospective, randomized controlled trials? A) dabigatran B) rivaroxaban C) apixaban D) edoxaban Time & cost Basto et al: retrospective chart review from 2010 2015 Veterans with plan for elective cardioversion (n=68) Excluded emergent and chemical cardioversion Dabigatran (56%) vs. (44%) Time to cardioversion was 35 days in dabigatran group vs. 67 days in the group (p<0.01) Costs: Dabigatran Warfarin Significance Medication $141.90 $4.83 P < 0.01 Total costs $193.20 $183.50 P < 0.01 J Atr Fibrillation 2016;8:45 47. Take home points: a balancing act Safe in renal impairment Antidote Cost Warfarin Monitoring available No bridging No monitoring ±Antidote DOACs Prospective data Delay to cardioversion 10