- Recent VTE (within 3 mo) - Severe thrombophilia: - CHADS 2 of 5 or 6 - Recent stroke or TIA (within 3 mo) - Rheumatic valvular heart disease

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1 GUIDELINE for PERIOPERATIVE MANAGEMENT OF ANTITHROMBOTIC THERAPY This document is intended as a guideline only and should not replace sound clinical judgment Bridging therapy is a complex process that usually requires expert level review. Consultation with a provider with experience in this area such as a benign hematologist, outpatient anticoagulation clinic, other specialty services or inpatient anticoagulation service is strongly recommended. Inpatient anticoagulation service Outpatient Coumadin Clinic Most of these CHEST 2012 recommendations are WEAK (i.e. 2C) because they are based on little or no high- quality evidence. Therefore, while we hope they will serve as a useful starting point, it is anticipated that clinical practice will deviate from these suggestions in many instances and these suggestions should never supercede the judgment of an experienced clinician who is best positioned to evaluate the risks and benefits of different strategies for an individual patient. Note: Peri- operative bridging is different from induction of anticoagulation for an acute thrombotic event. When bridging, it is not necessary to complete 5 full days of overlap therapy with warfarin and parenteral anticoagulant, as it is for an acute thrombotic event. The bridge may be discontinued once the INR is >2 even if that occurs before day 5. These guidelines pertain to elective procedures or those in which there is adequate time to implement recommended cessation periods. For all other situations (e.g. urgent or emergent surgery), providers are encouraged to collaborate with the inpatient effective peri- operative plan. I. Assessment of need for bridging versus no bridging in MAJOR procedures A. Perioperative management is assessed based on the risk of bleeding and risk of thromboembolism B. Recommendations for perioperative bridging are outlined below based on the most common indications for warfarin therapy and risk stratification for perioperative thrombosis RISK STRATUM MECHANICAL HEART VALVE ATRIAL FIBRILLATION VTE RECOMMEND High* (>10% annual risk of thrombo- embolism (TE)) Moderate (5-10% annual risk of TE) Low (<5% risk of TE) - Any mitral valve prosthesis - Any caged- ball or tilting disc aortic valve prosthesis - Recent stroke or TIA (within 6 mo) Bileaflet aortic valve prosthesis and one or more risk factors: - Atrial fibrillation - Prior stroke or TIA - Hypertension - Diabetes - Congestive heart failure - Age> 75 years Bileaflet aortic valve prosthesis without atrial fibrillation and no other risk factors for stroke - CHADS 2 of 5 or 6 - Recent stroke or TIA (within 3 mo) - Rheumatic valvular heart disease CHADS 2 of 3 or 4 CHADS 2 of 0 to 2 (assuming no prior stroke or TIA) CHADS 2 - Recent VTE (within 3 mo) - Severe thrombophilia: Protein C, protein S, or antithrombin deficiency Antiphospholipid antibodies Multiple abnormalities - VTE within the past 3-12 mo - Non- severe thrombophilia: Prothrombin gene mutation - Recurrent VTE - Active cancer (treated within 6 mo or palliative) Suggest bridging Assess need for bridging based on Heterozygous factor V Leiden patient- specific VTE >12 mo previous and no other risk factors and surgery related factors (see section D. below) Suggest no bridging

2 C. Patients may be also considered high thromboembolic risk* in the following scenarios and bridging should be considered - Prior stroke or TIA occurring >3 months before the planned surgery and a CHADS 2 score <5 - Prior thromboembolism during temporary interruption warfarin - Patient with remote ( > 1 year ago), severe VTE with resultant pulmonary hypertension - Surgery associated with an increased risk for stroke or other thromboembolism (i.e. cardiac valve replacement, carotid endarterectomy, major vascular surgery) NOTE: In the above patients at high risk for thromboembolism AND undergoing high- bleeding risk procedures (major cardiac surgery, carotid endarterectomy surgery), it is not unreasonable to consider no bridging D. Assessing need for bridging in moderate risk patients i. Consider bridging with surgeries/procedures associated with a low risk for bleeding (Appendix I) ii. Consider no bridging with surgeries /procedures associated with a high bleeding risk (Appendix II) II. PERI- OPERATIVE ANTICOAGULANT MANAGEMENT A. MAJOR procedures Assessment of bleeding risk and adequate post- operative hemostasis should be considered prior to anticoagulation re- initiation i. Traditional anticoagulants MEDICATION Warfarin** UFH LMWH TREATMENT DOSING PROPHYLACTIC DOSING Cessation Re- initiation Post- Op* Cessation Re- initiation Post- Op* 5 days (Grade 1C) 4 to 6 hours 24 hours*** Fondaparinux hours 12 to 24 hours after surgery (evening of or next morning) Low bleed risk surgery : hours High bleed risk surgery : hours Low bleed risk surgery : 24 hours High bleed risk surgery : hours Consider a shorter acting agent until the pt is tolerant to anticoagulation 5 days 12 to 24 hours after surgery 4 to 6 hours 30mg BID: 12 hours 40mg daily: 24 hours *Depending on surgical hemostasis UNMH RX webpage ***If using 1.5 mg/kg once daily, give ½ of dose 24 hours prior to procedure See appendices I and II

3 ii. Target specific oral anticoagulants a. Time of last dose ingested is important when considering duration of cessation prior to procedure - the number of doses suggested to be held in table below is based on 4-5 half- lives (t 1/2 ) of drug b. Should not be used concomitantly with warfarin at either prophylactic or treatment doses, as this has not been studied. If overlap therapy is needed, use UFH or enoxaparin Medication Cessation Re- Initiation Post- Op* DABIGATRAN Low bleeding risk procedure: (Pradaxa ) 1/ h) 150 mg BID Skip 2 doses RIVAROXABAN (Xarelto ) 20 mg PO daily APIXABAN (Eliquis ) 5 mg PO BID CrCl ml/min (t 1/ h): Skip 4 doses High bleeding risk procedure 1/ h) Skip 4 doses - CrCl ml/min(t 1/ h) Skip 6-8 doses More invasive procedures (e.g. major surgery, spinal puncture, placement of a spinal or epidural catheter or port) Consider longer period of cessation Low bleeding risk procedure: - 1/2 8-9h) Skip 1 dose - CrCl ml/min (t 1/2 9-10h) Skip 2 doses High bleeding risk procedure - 1/2 8-9h) Skip 2 doses - CrCl ml/min (t 1/2 9-10h) Skip 3 doses Low bleeding risk procedure: - 1/2 7-8h) Skip 2 doses - CrCl ml/min (t 1/ h) Skip 4 doses High bleeding risk procedure - 1/2 7-8h) Skip 4 doses APPLIES TO ALL TSOACs No specific information available Peak plasma concentrations reached Dabigatran: 1-2 hours Rivaroxaban: 2-4 hours Apixaban 3-4 hours Recommend re- initiating only if hemostasis is achieved, and hours after minor procedures hours after major procedures If TSOAC cannot be used post- procedure, consider initiation of parenteral agent If parenteral agent used as initial bridging therapy (e.g. UFH, LMWH), TSOAC therapy should be resumed At least 1 hour after discontinuation of UFH infusion At least 10 hours after last dose of LMWH Recommend consultation with anticoagulation service - CrCl ml/min (t 1/ h) Skip 6 doses *Depending on surgical hemostasis see appendices I and II aiming for mild- moderate residual anticoagulant effect (<12-25%) at surgery aiming for no or minimal residual anticoagulant effect (<3-6%) at surgery patients on rivaroxaban 15 mg po daily

4 B. MINOR procedures (dental/dermatologic/ophthalmologic) i. The following recommendations are for warfarin only a. There is currently no available evidence as to how to manage patients on new oral anticoagulants undergoing minor procedures. b. Recommend consultation with anticoagulation service PROCEDURE Minor dental procedures (Tooth extraction, endodontic procedures) Minor dermatologic procedures (Excision of basal and squamous cell skin cancers, actinic keratosis, premalignant or cancerous skin nevi) Minor ophthalmologic procedures (Cataract surgery) RECOMMENDATION Suggest continuing warfarin with co- administration of an oral prohemostatic agent* OR stopping warfarin 2 to 3 days before the procedure Suggest continuing warfarin around the time of the procedure and optimizing local hemostasis Suggest continuing warfarin around the time of the surgery *UNMH formulary agent is aminocaproic acid oral solution (Amicar); dose = 10mL by mouth q 6 hours x 2 days post- procedure III. ANTIPLATELET MANAGEMENT Collaboration with additional specialty services, such as cardiology, cardiothoracic surgery, neurology or anesthesia, is encouraged when deciding cessation options for antiplatelet therapy. As newer antiplatelet therapies emerge, the bleeding and thrombotic risks associated with individual antiplatelet agents should be uniquely considered. A. MAJOR procedures SURGERY Non- cardiac surgery CABG Patient with coronary stents having surgery RECOMMENDATIONS Moderate to high risk for cardiovascular events* OR on ASA for secondary prevention: suggest continuing asa and/or P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor)** EXCEPT for intracranial, middle ear, posterior chamber of eye, intramedullary spine and possibly transurethral prostatectomy (TURP) procedures which confer a very high risk of hemorrhagic complications Low risk for cardiovascular events or on ASA for primary prevention: suggest stopping ASA 7-10 days before surgery, clopidogrel/prasugrel 5-7 days before surgery or ticagrelor 5 days before surgery ASA monotherapy : suggest continuing ASA Dual antiplatelet therapy : - suggest continuing ASA around the time of surgery - suggest stopping clopidogrel/prasugrel 5 days before surgery, ticagrelor 3 days prior to surgery P2Y12 monotherapy: follow ASA monotherapy recommendations Recommend deferring surgery for at least 6 weeks after placement of a bare- metal stent and for at least 12 months after placement of a drug- eluting stent In patients who require surgery within 6 weeks of placement of a bare- metal stent or within 12 months of placement of a drug- eluting stent: suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy (CHEST 2012 Grade 2C) or at minimum, continuing ASA monotherapy if at all possible to avoid stent thrombosis (ACC/AHA 2007) * ischemic heart disease, compensated or prior CHF, diabetes, renal insufficiency or cerebrovascular disease ** a small minority of patients may have an indication for dual antiplatelet therapy despite not having a coronary stent

5 i. Re- initiation of antiplatelet therapy: a. If therapy has been interrupted, consider resuming antiplatelet therapy within 24 hours after surgery if hemostasis is achieved (a) Maximal antiplatelet effect occurs within minutes of administration of ASA B. MINOR procedures (dental/dermatologic/ophthalmologic) i. Low incidence of major bleeding when continuing aspirin therapy ii. Recommendation: In patients receiving ASA for the secondary prevention of cardiovascular disease, suggest continuing ASA around the time of the procedure. IV. OUTPATIENT TO INPATIENT MANAGEMENT A. All surgical patients on chronic anticoagulant therapy being seen pre- operatively in clinic need to have a clearly delineated peri- operative anticoagulant management strategy. B. Surgical provider should refer to algorithm below to identify appropriate resource for assistance: Patient on chronic anticoagulation needing invasive procedure YES UNMH Coumadin Clinic patient? NO NON- UNMH provider that manages the willing and able to develop bridging strategy? YES NO Contact UNMH Coumadin Clinic ( ) at least one week prior to procedure to have them assess need for bridging strategy Contact NON- UNMH provider that one week prior to procedure to have them assess need for bridging strategy Contact UNMH Inpatient Anticoagulation Service ( ) at least one week prior to procedure to have them assess need for bridging strategy C. See appendix III below for a general template for a warfarin patient who warrants bridging i. It is strongly recommended that a dosing template with specific instructions be filled out and given to patient at pre- operative clinic visit, along with any needed prescriptions, such as LMWH, etc. D. For newer oral anticoagulants (dabigatran, rivaroxaban, apixaban), see table above (target specific oral anticoagulants), refer to package insert or, preferably, consult with a more experienced provider. E. An electronic copy of the bridging plan should also be placed in Powerchart well before the procedure to provide guidance to inpatient providers.

6 The following appendices pertain only to anticoagulant therapy management. They do not pertain to antiplatelet therapies Appendix I: Surgeries and procedures associated with a low bleeding risk - Abdominal hernia repair - Abdominal hysterectomy - Axillary node dissection - Endoscopically- guided fine needle aspiration - Bronchoscopy + biopsy - Cataract and non- cataract eye surgery - Cholecystectomy - Dilatation and curettage - GI endoscopy +biopsy, enteroscopy, biliary/pancreatic stent without sphinecterotomy, endonosonography, without fine needle aspiration - Hydrocele repair - Noncoronary angiography - Simple dental extractions - Sternotomy wire removal - Bowel polypectomy - Bowel resection - Carpal tunnel repair - Central venous catheter removal - Cutaneous and bladder/prostate/thyroid/breast/lymph node biopsies - Endarterectomy or carotid bypass surgery - Hemorrhoidal surgery - Knee/Hip replacement and shoulder/foot/hand surgery and arthroscopy - Pacemaker and cardiac defibrillator insertion and electrophysiologic testing - Skin cancer excision Appendix II: Surgeries and procedures associated with a high bleeding risk - Urologic surgery and procedures consisting of transurethral prostate resection, bladder resection, or tumor ablation; nephrectomy; or kidney biopsy in part due to untreated tissue damage (after prostatectomy) and endogenous urokinase release - Pacemaker or ICD implantation in which separation of infraclavicular fascial layers and lack of suturing of unopposed tissues within the device pocket may predispose to hematoma development - Colonic polyp resection, typically of large (i.e. >1-2 cm long) sessile polyps, in which bleeding may occur at the transected stalk following hemostatic plug release - Surgery and procedures in highly vascular organs, such as the kidney, liver, and spleen - Bowel resection in which bleeding may occur at the bowel anastomosis site - Major surgery with extensive tissue injury (i.e. cancer surgery, joint arthroplasty, reconstructive plastic surgery) - Cardiac, intracranial, or spinal surgery, especially as small pericardial, intracerebral, or epidural bleeds can have serious clinical consequences - Any major operation (>45 minute duration) - Multiple tooth extractions

7 Appendix III: General bridging template for warfarin patient Days before procedure Date Warfarin INR LMWH* bridging agent - 5 none none none - 4 none none none - 3 none none LMWH - 2 none none LMWH - 1 none Check INR - Give mg Vit K PO if INR >1.6 LMWH in AM only (hold for 24 hours prior to procedure) procedure Resume home dose none none Continue home dose and adjust based on INR Continue home dose and adjust based on INR Continue home dose and adjust based on INR Check INR LMWH (start at least 24 hours post- procedure) Check INR Continue LMWH until INR >2 Check INR daily until >2 then PRN Continue LMWH until INR >2 * Need for and dosing intensity (prophylactic versus therapeutic) of LMWH should be determined by experienced provider

8 References 1. Martin MT, Kuchta AM, Nutescu EA. A clinician's guide to perioperative bridging for patients on oral anticoagulation. J Pharm Pract Aug;23(4): Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R. Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest Feb;141(2 Suppl):e326S- 50S. 3. Dabigatran etexilate (Pradaxa ) package insert. Available at Accessed 8/14/ Rivaroxaban (Xarelto ) package insert. Available at Accessed 8/14/ Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 12/ Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 11/ Eliquis [prescribing information]. Princeton, NJ: Bristol- Myers Squibb Company.; 12/ Miyares MA, Davis K. Newer oral anticoagulants: A review of laboratory monitoring options and reversal agents in the hemorrhagic patient. Am J Health Syst Pharm. 2012(69): e28- e Viles- Gonzalez JF, Fuster V, Halperin JL. New anticoagulants for prevention of stroke in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2011(22): Gerstein NS, Schulman PM, Gerstein WH, Petersen TR, Tawil I. Should more patients continue aspirin therapy perioperatively? Clinical impact of aspirin withdrawal syndrome. Ann Surg May; 255(5): Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation. 2007;116:e418 e499. Originated by: Pree Sarangarm, PharmD; Allison Burnett, PharmD Michael Carey, MD; Isaac Tawil, MD; Michael Chartrand, MD Approved by: