Anticoagulation in the Inpatient Setting AIMS Morning Report October 7, 2015 Lindsay Waddington, PharmD PGY1 Pharmacy Practice Resident

Objectives Recall mechanism of action for anticoagulants Recognize when to adjust dosing for anticoagulant agents (e.g. weight, renal function) Select optimal anticoagulant agent based on patient specific factors

Clotting Cascade http://www.passmed.co.uk/haemostasis.html Stock image/vs making own and adding drugs

Review of Formulary Agents MECHANISM OF ACTION MONITORING Warfarin (Coumadin®) Vitamin K antagonist INR, liver function, nutrition (Vitamin K) Dabigatran (Pradaxa®) Direct Thrombin (factor IIa) Inhibitor Renal function (CrCl 30) Rivaroxaban (Xarelto®) Factor Xa Inhibitor Renal function (Tx: CrCl 30, NVAF: CrCl 50), hepatic function Apixaban (Eliquis®) Age, weight, SCr Fondaparinux (Atrixa®) Renal function (CrCl 50, 30), weight Enoxaparin (Lovenox®) Inhibition of Factor Xa and Factor IIa, enhancing antithrombin III Factor Xa Level , Renal function (CrCl 30) Unfractionated Heparin Potentiates antithrombin III (inactivates thrombin) aPTT WARFARIN – inhibits formation of vit K clotting factors…..what are they?.... II, VII, IX, X and proteins C + S ½ life ~40 hours = steady state in 120 hours or 5 days – full therapeutic effect in 5-7 days. Metabolized via CYP2C9, 1A2, 3A4, 2C19 – numerous drug interactions. Severe/end-stage renal disease warfarin is anticoagulant of choice (AHA/ACC/HRS jan 2014) DABIGATRAN – BID dosing, 150mg usual, 75mg if CrCl 15-30 (RE-LY) Red flags - >/= 80 years old CrCl 30mL/min CrCrl <30 and hemodialysis excluded from trials RIVAROXABAN – CYP3A4, 3A5, 2J2 >15mg/day with food NVAF: CrCl 15-50 reduce to 15mg (ROCKET, RECORD) APIXABAN – CYP3A4, pgp, compliance BID dosing (ARISTOTLE, AVERROES) SCr >1.5 but less than 2.5  excluded from studies 2 criteria of the 3 FONDAPARINUX - Fondaparinux prophylaxis 2.5mg (>50kg only), treatment <50kg 5mg/day, 7.5mg if 50-100, >100kg then use 10mg LOVENOX – monitor with Factor Xa level (referred to as heparin level in Sunrise) HEPARIN – aPTT 1.5-2.5 normal – dependent upon lab/institution **Monitor signs/symptoms of bleeding/CBC for all agents**

Endoxaban (Savaysa®) FDA approved Oct 2014 and Jan 2015 60mg once daily (treatment) Adjust for weight <60kg Adjust for CrCl <50mL/min Contraindicated for CrCl <15mL/min or >95mL/min in atrial fibrillation

Clinical cases

Case 1: “I’m too sick to get out of bed” 72yo F needs DVT prophylaxis Prophylaxis Planned vs. emergent

Case 1: “I’m too sick to get out of bed” 72yo F needs DVT prophylaxis (enoxaparin) Standard dose for prophylaxis 40mg daily Weight? 42kg : enoxaparin 30mg daily 142kg: enoxaparin 30mg twice daily Renal function? Adjust if CrCl <30mL/min Past medical history? Therapeutic dose of anticoagulation, drug allergies Prophylaxis

Case 1: “I’m too sick to get out of bed” Bleed risk? Anemia, patient status, pertinent labs Thrombus risk? Previous venous thromboembolism, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, known thrombophilic disorder Pertinent labs INR, CBC

Prophylactic Enoxaparin at St. Vincent Weight <40kg Heparin 5000 units SQ BID Weight 40kg - 50kg CrCl <30mL/min CrCl >30mL/min Enoxaparin 30mg SQ daily Weight 50kg - 120kg Enoxaparin 40mg SQ daily Weight 120kg - 180kg Enoxaparin 30mg SQ BID Weight >180kg Enoxaparin 40mg SQ BID Specifically for medical patients with severely restricted mobility during acute illness Treatment dosing of lovenox – 1mg/kg/dose Q12 or 1.5 mg/kg daily

Case 2 “What’s your OR look like?” 45yo M with a home dose of rivaroxaban 20mg daily with evening meal Scheduled for a procedure (low bleeding risk) on Friday How do you manage anticoagulation? Hold at least 24 hours prior to surgery Hold at least 24 hours if high risk of bleed hold 2 days No reversal agent, utilize blood products Reaches peak plasma conc in 2-4 hours No need to bridge, if NPO post surgery switch to parenteral Minor surgery ~2 half lives, major surgery 4-5 ½ lives anticoag

Stopping Anticoagulants for Planned Surgery Drug ½ Life When to stop Warfarin (Coumadin®) 40 hours 5 days prior (or administer vit K dependent upon surgery Dabigatran (Pradaxa®) 12-17 hours (longer with renal impairment) CrCl >50mL/min 2 days CrCl <50mL/min 5 days Rivaroxaban (Xarelto®) 5-9 hours (longer in elderly) At least 24 hours prior to surgery Apixaban (Eliqis®) 8-15 hours Fondaparinux (Atrixa®) 17-21 hours Enoxaparin (Lovenox®) 2-4 times standard heparin/based on Xa activity 12 hours prior for prophylactic doses 24 hours prior for treatment doses Unfractionated Heparin 60-90 minutes 4-6 hours prior “in patients who require temporary interruption of a VKA before surgery, we recommend stopping VKAs approximately 5 days before surgery COMPARED to shorter time before surgery” “In patients who require temporary interruption of a VKA before surgery, we recommend resuming VKA approximately 12 to 24 hours after surgery when there is adequate hemostasis VERSUS later resumption of VKA” In patients with a mechanical heart valve, afib, or VTE at high risk for thromboembolism - bridge instead of no bridge low risk for thromboembolism – no bridge Minor derm, dental (may stop 2-3 days prior), cataract – continue VKA – utilize local hemostasis, continue ASA ASA - should be held 7-10 days prior if you want it cleared Clopidogrel/prasugrel stop 5-7 days prior Stopping UFH 4 to 6 hours before surgery Therapeutic lovenox stop 24 hour instead of 12 hours prior resume 48-72 hours post Xarelto ½ life 11-13 hours in elderly

Case 3: “I’ve been taking this dose of warfarin longer than you’ve been alive” 59yo M MRSA cellulitis (oral agent to better transition home) Home medication: Warfarin 5mg daily Antibiotic to cover MRSA outpatient Sulfamethoxazole-trimethoprim Doxycycline Clindamycin (polypharm) warfarin What antibiotic covers MRSA outpatient? Bactrim Clindamycin Doxycycline (Linezolid) (Minocycline?)

Warfarin Warfarin drug interactions ABC’s A: Antimicrobials in general B: Bactrim C: Ciprofloxacin (all flouroquinolones) D: Diflucan (all azole antifungals) E: Erythromycin (all macrolides) F: Flagyl Avoid NSAIDS Herbals/Vitamin K intake CYP Enzymes (Phenytoin, Rifampin, Amiodarone) Alcohol Bolded drugs empirically reduce warfarin dose “G”’s - ginko, ginseng, ginger, green tea

Key Points Anticoagulant agents are adjusted based on weight and renal function Adjusting and/or holding therapy around surgery is drug specific and procedure specific Medications and disease states can also influence anticoagulation

References Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2 Suppl): 7S-47S January et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. JACC. 2014; 64(21):2246-80 Siegal D, Yudin J, Kaatz S et al. Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists: Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates. Circulation. 2012; 126:1630-39 Coumadin® (warfarin sodium) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011. Pradaxa® (dabigatran)[package insert]. Ridgefield, CT: Boehringer Ingelhein; 2015. Xarelto ® (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2015 Eliquis ® (apixaban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. Arixtra ® (fondaparinux injection) [package insert]. Mississauga, ON: GlaxoSmithKline Inc.; 2013 Lovenox (enoxaparin) [package insert]. Bridgewater, NJ: Sanofi-Aventis LLC; 2013.  Savaysa® (edoxaban) [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2015. Heparin sodium for injection [package insert]. Kirkland, QC: Pfizer, Inc.; 2014. Stroke guidelines Periprocedural heparin bridging in patients receiving vitamin K antagonists : AHA 2014 AHA/ACC/HRS Guideline