Oral Anticoagulation For Deep Venous Thrombosis and Pulmonary Embolism Robby Ferrante WNE Pharmacy Candidate Oral Anticoagulation For Deep Venous Thrombosis and Pulmonary Embolism

Objectives Review the clotting cascade and the effect of various anticoagulants on this cascade Discuss oral anticoagulants that are used to treat DVT/PE. Analyze the use of these agents and their place in DVT/PE therapy.

Deep Venous Thrombosis Deep vein thrombosis (DVT) occurs when a blood clot forms in one or more deep veins Symptoms usually occur in legs Can cause leg pain or swelling May occur without any symptoms. Common causes: Immobility Traumatic Injury Surgery Obesity Prolonged travel Pregnancy Thrombophilia May be excluded by a D-dimer test before imaging is performed. D-dimer is a fibrin degradation product, fibrinolysis product

Pulmonary Embolism1 Blockage of 1+ pulmonary arteries by a substance that has traveled from elsewhere in the body Causes impaired blood flow Increased pressure in the right ventricle Symptoms Dyspnea Acute chest pain Increased heart rate Cough Abnormal breathing sounds Low blood pressure Cardiac arrest 00,000 to 600,000 (1 to 2 per 1,000, and in those over 80 years of age, as high as 1 in 100) each year in the United States. Estimates suggest that 60,000-100,000 Americans die of DVT/PE (also called venous thromboembolism). According to CDC

Prophylactic Treatment2 Generally, parenteral heparins or warfarin are used prophylactically. NOAC are becoming more commonly used as warfarin use is decreasing Prophaylactically for: Atrial Fibrillation CHADS2 score Previous DVT Prior to surgery in elderly patients

Clotting Cascade Intrinsic Pathway: Extrinsic Pathway: Trauma inside the vascular system Factors XII, XI, IX, VIII Slower Extrinsic Pathway: External trauma Factor VII Quicker http://mrcpandme.blogspot.com/2010/09/mrcp-revision-battle-142-clotting.html

Warfarin Warfarin sodium is an anticoagulant that works by blocking the regeneration of vitamin K(1) epoxide, thus inhibiting synthesis of vitamin K-dependent clotting factors which include factors 2, 7, 9 and 10, and the anticoagulant proteins C and S  -S 4-6 hrs N 24 hours O 48-72 hours T 60 hours (3 days) http://journal.publications.chestnet.org/data/Journals/CHEST/22073/zcb1060816760001.jpeg

Warfarin3 Vitamin K antagonists are the standard treatment therapy. Relative risk reduction of ~85% vs placebo Recurrence risk of ~3% Major bleeding risk ~2.1% during first 6 months There are critiques of warfarin therapy: Monitoring Small therapeutic window Effect of diet Multiple drug interactions

Direct Thrombin Inhibitor MOA: Potent, competitive, and reversible direct inhibitor of free and clot- associated thrombin Only one oral agent Dabigatran (Pradaxa) Indicated for DVT treatment and prophylaxis

Dabigatran4 Dose for DVT/PE prophylaxis: Administration: CrCl > 30 mL/min 150 mg Orally, twice a day CrCl 15-30 mL/min 75 mg Orally, twice a day Administration: Must be swallowed whole Not to be used in NG tube Keep in original container (120 days) For

Dabigatran ADME Absorption Distribution Metabolism Excretion Tmax = 1-6 hours Food does not effect bioavailability Distribution ~ 35% protein bound Metabolism Prodrug hydrolyzed by the liver Hepatic metabolism and PGP substrate Excretion Renal excretion (80%) Dialyzable T ½ = 12-17 hours

Dabigatran Black Box Warning: Premature discontinuation increases risk of thrombotic event. Epidural or spinal hematomas may occur in patients undergoing neuraxial anesthesia.

Re-Cover Trial5 2539 patients in randomized double blind noninferiority trial 150 mg Dabigatran BID 30/1274 (2.4%) had recurrent VT 20 patients had major bleed Warfarin; INR 2-3 27/1265 (2.1%) had recurrent VT 24 patients with major bleed Interesting observation: INR randomization D/C 9.0% dabi, 6.8% warfarin

Factor Xa Inhibitors Oral Options: Rivaroxaban (Xarelto) Apixaban (Apixaban) Edoxaban (Only in Japan) Will not discuss edoxaban

Factor Xa Inhibitors A: Tmax 2-4 hours D: 92%-95% protein bound Rivaroxaban Apixaban A: Tmax 2-4 hours D: 92%-95% protein bound M: Hepatic E: Renal 66% Non dialyzable T ½ - 5 - 11.7 hours A: Tmax 3-4 hours D: 87% Protein Bound M: Hepatic (Mainly 3A4) E: Fecal (majority) Renal 27% Non dialyzable T ½ - 6.8 hours (2.5 mg) T ½ - 15.2 hours (5 mg)

Factor Xa Inhibitors DVT/PE Treatment Post operative Prophylaxis Rivaroxaban6 Apixaban7 DVT/PE Treatment 15 mg PO BID for 21 days Then 20 mg PO Daily Take With food Post operative Prophylaxis Hip Repair 10 mg PO Daily 6-10 hours after surgery for 35 days DVT/PE Treatment 10 mg PO BID for 7 days Then 5 mg PO BID DVT/PE Prophylaxis 2.5 PO BID Post Operative Prophylaxis 2.5 mg PO BID 12-24 hours after surgery for 35 days

EINSTEIN VT8 and DVT9 3449 and 4832 Patients with acute DVT Rivaroxaban 15 mg BID for 3 weeks, then 20 mg PO QD Neither study displayed significant primary outcomes DVT study: 36 events vs 51 events Slight increase in nonfatal bleed PE study: 50 events vs 44 events Increase in major bleed in the standard therapy Double blind randomized event driven PE: 26 vs 52

Amplify Study10 5395 patients involved in the study with acute VT Apixaban 10 mg BID for 7 days, then 5 mg BID Primary Endpoiont – recurrent VT or VT related death. 59 events vs 71 events (2.3% vs 2.7%) Clinically relevant Major Bleeding 1.8% vs 0.6% All Bleeds 4.3% vs 9.7%

Thank You Nadine! Warfarin Dabigatran Rivaroxaban Apixaban   Warfarin Dabigatran Rivaroxaban Apixaban Indication Prophylaxis and treatment of VTE, Cardiac valve replacement, Prevention of stroke in atrial fibrillation Prevention and treatment of VTE, Prevention of stroke in nonvalvular atrial fibrillation Prevention and treatment of VTE, Nonvalvular atrial fibrillation Prevention and treatment of venous thromboembolism, Nonvalvular atrial fibrillation Dosing frequency Once daily BID Dosing Adjustments Based on INR Renal dose adjust Reduce dose if 2 or more factors: >80y/o, Weight < 60kg, Scr >1.5 Onset 3-5 days 2-3 hours 2.5-4 hours 3-4 hours Metabolism Hepatic Monitoring INR Not required Pregnancy X C B DDI 3A4/ 2C9 No dose adjustment 3A4 Contraindication Bleeding Creatinine clearance <15 mL/min , Hemodialysis dependent Contraindicated in those with a creatinine clearance <15 mL/min N/A Antidote Vitamin K None ADE Dyspesia, GI bleeding Thank you! A couple things I didn’t mention, Preg cat apix = B

Meta-Analysis (NOAC vs VKA)3 International Society in Thrombosis and Haemostasis 24455 patients with accute VTE All Phase iii trials, met Cochrane Collaboration’s tool for assessing risk of bias. Einstein studies showed most bias risk

Meta-Analysis Efficacy Recurrent VTE had best RR with 88%

Meta-Analysis Safety NNT for non-major bleed - 56

Conclusion Almost all comparisons between NOACs and VKAs were relatively similar Few significant differences Depending on patient factors, NOACs are a viable option and have proven to be non-inferior while also potentially reducing bleeding risk.

References 1.) Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) Data and Statistics. Atlanta Georgia. Center of Disease Control and Prevention. Published 8 June, 2012. www.cdc.gov/ncbddd/dvt/data.html 2.) Kirley K, Oato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012; 5(5): 615-21 3.) Van Der Hulle J, Koolman J, Den Exter PL, et al. Effectiveness and Safety of Novel Oral Anticoagulants as Compared With Vitamin K Antagonists in the Treatment of Acute Symptomatic Venous Thromboembolism: A Systematic review and Meta-Analysis. J Thromb Haemost 2014; 12: 320-8 4.) 1. Product Information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (Per FDA), Ridgefield, CT, 2012. 5.) Sam Schulman, M.D., Clive Kearon, M.D., Ajay K. Kakkar, M.D., et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med 2009; 361:2342-2352

References 6.) Product Information: XARELTO(R) oral tablets, rivaroxaban oral tablets. Janssen Pharmaceuticals, Inc. (per manufacturer), Titusville, NJ, 2012. 7). Product Information: ELIQUIS(R) oral tablets , apixaban oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2014 8.) The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363:2499-2510 9.) The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism.N Engl J Med 2012; 366:1287-1297 10.) Giancarlo Agnelli, M.D., Harry R. Buller, M.D., Ph.D., Alexander Cohen, M.D., et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013; 369:799-808

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