Warfarin Management - Adult- Ambulatory Consensus Care Guideline Population/Problem: This guideline outlines the evidence for managing anticoagulation therapy with oral vitamin K antagonist (warfarin) for adult patients in the ambulatory setting. For dosing and monitoring of warfarin therapy it is recommended that standardized and validated decision support tools be used for most patients. Evidence has shown improved time in therapeutic INR range and clinical outcomes in patients managed by trained staff using standardized procedures and dosing decision support tools.1 Recommendations: 1. Indications for use, INR goals and duration of therapy are listed in Table 1 1.1. Alternative INR goals may be chosen when bleeding risk outweighs clotting risk as determined by the individual’s provider (UW Health GRADE very low-quality evidence, conditional recommendation). Table 1. Indications for use, INR Ranges, and Duration of Therapy Table 1. Target INR Ranges and Duration of Therapy Indication INR Goal (Range) Duration Evidence Grading Thrombophilia with Thromboembolic Event1-3 Antiphospholipid Syndrome 2.5 (2-3) Indefinite ACCP Grade 2B Homozygous Factor V Leiden 2.5 (2-3) Indefinite Protein C, S or Anti-Thrombin deficiency 2.5 (2-3) Indefinite Atrial Fibrillation (AF)/Atrial Flutter4-6 Note: additional management information is available UW Health Atrial Fibrillation Guidelines Prior stroke, transient ischemic attack (TIA) 2.5 (2-3) Indefinite AHA/ACC/HRS Grade IA For AF: CHA2DS2-VASc score of 2 or greater in men or 3 or greater in women 2.5 (2-3) Indefinite AHA/ACC/HRS Grade IA (Table continues on next page) Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 1. Target INR Ranges and Duration of Therapy (cont) Indication INR Goal (Range) Duration Evidence Grading Atrial Fibrillation (AF)/Atrial Flutter (cont.)4-6 For AF: CHA2DS2-VASc score of 1 or greater in men or 2 or greater in women 2.5 (2-3) Indefinite AHA/ACC/HRS Grade IIb, C-LD Pre-cardioversion (AF or atrial flutter >48 hours or unknown duration) regardless of CHA2DS2VASc score 2.5 (2-3) At least 3-weeks unless the need for immediate cardioversion AHA/ACC/HRS Grade IB Post-cardioversion to normal sinus rhythm 2.5 (2-3) At least 4-weeks AHA/ACC/HRS Grade IB Cerebral Venous Thrombosis (CVT)3,7,8 Cerebral venous thrombosis (CVT) 2.5 (2-3) 3-6 months ACCP Grade 2B Provoked CVT associated with a transient risk factor (e.g., pregnancy, dehydration, infection) 2.5 (2-3) 3-6 months AHA/ASA Grade IIb, C Unprovoked CVT 2.5 (2-3) 6-12 months AHA/ASA Grade IIb, C Recurrent CVT, VTE after CVT, or first CVT with severe thrombophilia 2.5 (2-3) Indefinite AHA/ASA Grade IIb, C Venous Thromboembolism (VTE)9,10 Note: additional management information is available UW Health VTE Diagnosis and Treatment Guideline Deep Vein Thrombosis (DVT) or pulmonary embolism (PE) 2.5 (2-3) At least 3 months Individualize the duration based upon provoked events, risk factors for thrombosis and bleeding. Valve Surgical Replacement – Bioprosthetic11,12 Aortic or Mitral Aspirin 75 mg to 100 mg per day is reasonable in all patients with a bioprosthetic aortic or mitral valve. AHA/ACC IIa, B Aortic or Mitral with low risk of bleeding 2.5 (2-3) 3 to 6 months AHA/ACC IIa, B-NR Valve Surgical Replacement – Mechanical11-13 Aortic bileaflet or current-generation single-tilting disk and no risk factors for thromboembolism 2.5 (2-3) Chronic AHA/ACC IB Aortic with additional risk factors for thromboembolic events (AF, previous thromboembolism, LV dysfunction, or hypercoagulable conditions) or an older-generation mechanical AVR (such as ball-in- cage) 3 (2.5-3.5) Chronic AHA/ACC IB Mitral 3 (2.5-3.5) Chronic AHA/ACC IB Tricuspid 3 (2.5-3.5) Chronic AHA/ACC IB Dual Aortic and Mitral Valve 3 (2.5 -3.5) Chronic AHA/ACC IB On-X Aortic 2.5 (2-3) 3 months After 3 months consider decrease the INR goal to 1.5- 2.0 (in conjunction with aspirin 81mg daily) AHA/ACC IIb, B-R On-X Mitral 3 (2.5-3.5) Chronic AHA/ACC IB Aspirin 75 mg to 100 mg daily is recommended in addition to anticoagulation with warfarin in patients with a mechanical valve prosthesis. AHA/ACC IA Anticoagulant therapy with oral direct thrombin inhibitors or anti-Xa agents should not be used in patients with mechanical valve prostheses. AHA/ACC III:Harm Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions (Table continues on next page) Table 1. Target INR Ranges and Duration of Therapy (cont) Indication INR Goal (Range) Duration Evidence Grading Transcatheter Aortic Valve Replacement (TAVR)12,14 Guideline Pivotal Trials (Placement of Aortic Transcatheter Valve Trial [PARTNER] and US CoreValve15-17 American College of Cardiology/American Heart Association Guidelines 201712 European Society of Cardiology/ European Association for Cardiothoracic Surgery Guidelines 201718 First 3 to 6 months Aspirin plus clopidogrel for first 3 or 6 mo followed by monotherapy Clopidogrel 75mg daily for the first 6 months in addition to lifelong aspirin 75-100mg (AHA/ACC IIb, C) Low-dose aspirin plus P2Y12 inhibitor for 3 to 6 months followed by lifelong single antiplatelet therapy in patients without indication for oral anticoagulation (ESC/EACTS IIb, C) Lifelong treatment If vitamin K antagonist is indicated, aspirin plus warfarin (without clopidogrel) Warfarin with an INR of 2.5 (2-3) for at least 3 months in patients with low bleeding risk (AHA/ACC IIb,B) Lifelong oral anticoagulants for patients with indication (ESC/EACTS IC) Orthopedic Surgery19 Indication INR Goal (Range) Duration Total Knee or Hip Arthroplasty* 1.8-2.2 10-14 days INR goal per surgeon Hip Fracture Surgery* 1.8-2.2 10-14 days INR goal per surgeon Trauma Surgery* 1.8-2.2 35 days INR goal per surgeon * If other indication for anticoagulation exist - INR goal should be clarified Patient Assessment 2. Patients should be assessed for risk factors that may make them more sensitive to the effects of warfarin. If multiple high sensitivity risk factors are present then a lower initiation dose or reduced maintenance dose may be needed.20 (UW Health GRADE high quality evidence, strong recommendation) (see Table 2) Table 2. Warfarin sensitivity factors Increases sensitivity (usually require lower doses) • Baseline (pre-warfarin) PT/INR (e.g., greater than 1.4) • Advanced age (e.g., 60 years of age or older)21-30 • Underweight (e.g., BMI less than 18kg/m2)29,31,32 • Nutritional status (e.g., malnourished, low vitamin K intake/stores) • Genetic factors (e.g., CYP2C9, VKORC1 phenotypes) • Drug-drug interactions • Hypoalbuminemia33,34 • Ethnicity (Asian)30,35,36 • Liver disease30,37 • Thyroid Disease (e.g., hyperthyroidism, Graves’ disease)38-41 • Heart Failure42,43 • Febrile illness • Prolonged vomiting and diarrhea • Cannabinoids • Alcohol • Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions (Table continues on next page) Table 2. Warfarin sensitivity factors (cont) Decrease warfarin sensitivity (may require higher doses) • Enteral feedings • High-vitamin K intake • Drug interactions • Chewing tobacco 3. The HAS-BLED score can assist with predicting the risk of major bleeding in warfarin patients.44 (UW Health GRADE moderate quality evidence, strong recommendation) 3.1 This score should not automatically exclude patients from receiving warfarin if clinically indicated. It should be used to identify modifiable risk factors that can be corrected to decrease risk. (UW Health GRADE moderate quality evidence, strong recommendation) Table 3: HAS-BLED Score44 Factors Points Scoring Hypertension (SBP >160 mmHg) 1 Score = 0-1: Low risk Score = 2: Moderate risk Score ≥3: High risk High bleed risk considerations: - Optimize blood pressure control - Check INRs frequently - Utilize anticoagulation clinic - Focus on fall prevention - Utilize direct oral anticoagulants Abnormal lab values - Creatinine >2.26 mg/dL - Bilirubin >2x the upper limit of normal (ULN) and AST/ALT/AP >3x ULN 1 Stroke history 1 Bleeding history or predisposition 1 Labile INRs: Time in Therapeutic Range <60% 1 Elderly: > 65 years 1 Drugs - EtOH abuse - ASA or NSAID use 1 4. Initial warfarin dosing should be tailored based on baseline INR, patient bleed risk, potential sensitivity to warfarin (see Table 2), indication, goal INR range and if potential drug interactions are present20 (UW Health GRADE high quality evidence, strong recommendation) 5. If therapeutic anticoagulation is needed immediately, patients should receive another form of anticoagulation such as LMWH until they are therapeutic on warfarin for 24-48 hours7,20 (UW Health GRADE high quality evidence, strong recommendation) 6. Prior to making a dose adjustment, assess for missed doses, recent INR trends, changes in diet and activity level, potential drug interactions, symptoms of bleeding or clotting, pregnancy status and other changes that may affect INR level as described in Appendix A. Patient Assessment Tool1,20 (UW Health GRADE moderate quality evidence, strong recommendation) 6.1 Pregnant patients should not take warfarin and should be transitioned to an alternative anticoagulant (e.g. low molecular weight heparin) (UW Health GRADE high quality evidence, strong recommendation) Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 4. Warfarin Initiation (Week 1) with INR Goal 2-345 Day Therapy INR Value Dose Adjustment Day 1 5 mg daily (2.5 mg daily if high sensitivity to warfarin identified) In 2-3 days after initiation < 1.5 1.5-1.9 2.0-2.5 > 2.5 5 – 7.5 mg daily 2.5 - 5 mg daily 1 - 2.5 mg daily Hold and recheck INR next day In additional 2-3 days after last INR check < 1.5 1.5-1.9 2.0-3.0 > 3.0 7.5 – 10 mg daily 5 – 10 mg daily 2.5 – 5 mg daily Hold warfarin, recheck in 1-2 days *If patient is started on 2.5 mg then target lower warfarin dose adjustments to avoid overshooting INR goal Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 5. Warfarin Maintenance Dosing Protocol with INR Goal 1.5-2.045 INR less than 1.5 INR 1.5 – 2.0 INR 2.1 – 3.0 INR 3.1 – 3.9 INR 4.0-4.9 INR 5.0-8.9 INR greater than or equal to 9.0 Increase weekly dose 5% No Change Decrease weekly dose 5% Half dose x 1 and Decrease weekly dose 10% Hold 1 dose Decrease weekly dose by 10-20% Order required Consider: Hold 2-3 doses, when able recheck INR before resuming warfarin Decrease weekly dose 10-20%; Check HCT or Hgb Contact MD for urgent patient evaluation Table 6. Warfarin Maintenance Dosing Protocol with INR Goal 2-345 INR less than 1.5 INR 1.5 - 1.9 INR 2.0 - 3.0 INR 3.1- 3.9 INR 4.0-4.9 INR 5.0- 8.9 INR greater than or equal to 9.0 Extra Dose Increase weekly dose 10-20% Increase weekly dose 5-10% No change Decrease weekly dose 5-10% Hold 1 dose Decrease weekly dose 10% Order required Consider: Hold 2-3 doses, when able recheck INR before resuming warfarin Decrease weekly dose 10-20% Check HCT or Hgb Contact MD for urgent patient evaluation Table 7. Warfarin Maintenance Dosing Protocol with INR Goal 2.5-3.545 INR less than 1.9 INR 1.9 - 2.4 INR 2.5 - 3.5 INR 3.6 - 4.5 INR 4.6-4.9 INR 5.0- 8.9 INR greater than or equal to 9.0 Extra Dose Increase weekly dose 10-20% Increase weekly dose 5-10% No change Decrease weekly dose 5-10% Hold 1 dose Decrease weekly dose 10% Order required Consider: Hold 1-2 doses, when able recheck INR before resuming warfarin Decrease weekly dose 10-20% Check HCT or Hgb Contact MD for urgent patient evaluation Table 8. Warfarin Dosing Pearls (UW Health GRADE low quality evidence, conditional recommendation) INR range without a dosing table Use same concept of adjusting the weekly dose by 5-10% based on the INR result INR minimally out of range If there is a transient reason for INR to be out of range (e.g. missed dose) or patient previously stable with unknown reason to be out of range, then may consider rechallenging the dose before making a weekly dose adjustment. Recheck the INR in 1-2 weeks. Considerations for extra doses An extra dose can be either an extra partial dose or extra full dose based on the INR and patient’s known response to warfarin. The extra dose should not be included in the weekly dose adjustment Considerations for held doses A held dose should not be included in the weekly dose adjustment Point of Care (POC) INR If the INR is above 3.9, a repeat venipuncture is required to verify INR Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions INR < 2.0 AND mechanical valve with an INR goal of 2.5-3.5 Consider bridging with a low molecular weight heparin or as directed per the periprocedural guidelines Variations in INR Daily low dose vitamin K supplement should not be used to improve INR control Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Laboratory Monitoring1,20 (UW Health GRADE low quality evidence, conditional recommendation) Table 9. Laboratory monitoring recommendations for warfarin Baseline Within the past 30 days • Baseline INR • Pregnancy test* *Pregnancy test is not needed if: 1. Are postmenopausal (12 months of amenorrhea in a woman > 45 years old in the absence of other biological or physiological causes) 2. Had a hysterectomy or bilateral salpingo-oophorectomy 3. Have ovarian failure 4. Had a bilateral tubal ligation or other surgical sterilization procedure 5. Are known to be pregnant 6. Have had a miscarriage or abortion in the last 7 days 7. Have given birth within the past 4 weeks Within the past 90 days • Hemoglobin • Platelet count • Annually • Hemoglobin • Platelet count • Frequency of INR Monitoring After Initiation of Warfarin1,20,46,47 (UW Health GRADE low quality evidence, conditional recommendation) Initial INR •INR should be resulted before starting Every 2-3 days •Until INR therapeutic x 2 Every week •Until INR therapeutic x 2 Every 2 weeks •Until INR therapeutic x 2 Every 4 weeks • Can consider increasing interval after 3 months on same dose Every 6-8 weeks Every 8- 12 weeks Weekly dose adjusted by 5%  Weekly dose adjusted by 10%  Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Patient Assessment 7. Any significant signs or symptoms of major bleeding or clotting should be referred to a primary care provider or urgent care/emergency department for evaluation. Common signs and symptoms are listed in Table 10. (UW Health GRADE high quality evidence, strong recommendation). Table 10. Common Signs and Symptoms of Major Bleeding and Clotting9,48 Signs and Symptoms of Bleeding Signs and Symptoms of Clotting Blood in sputum Chest or unilateral leg pain Bloody emesis (bright red or coffee ground-like) Unilateral lower extremity swelling Blood in urine or stool (enough to color toilet water) Warm, red or discolored skin of lower extremity Bleeding that has not resolved or slowed within 10 minutes Elevated heart rate (HR > 100 bpm) Shortness of breath Coughing or coughing up blood Drug Interactions 8. Most drug interactions with warfarin will start to have an effect within 3-5 days of concomitant therapy. In general, it is recommended to check an INR 3-4 days after starting a medication that has the potential to interact with warfarin. If the INR is affected at that time, then a dose adjustment can be made. There are some notable exceptions to this that are listed in Table 11. Table 11. Dose adjustment recommendations for common/significant warfarin – drug interactions Medication INR check after starting Adjustment Amiodarone Every 7 days Target a 25-50% weekly dose reduction over 2-4 weeks Rifampin Every 7 days Target a 50% weekly dose increase over 2 weeks Fluconazole 2 – 3 days Target a 30% weekly dose decrease Metronidazole 2 – 3 days Target a 30% weekly dose decrease Sulfamethoxazole/ Trimethoprim 2 days Target a 30% weekly dose decrease Should reduce dose prior to starting medication to avoid critical INR elevation (UW Health GRADE moderate quality evidence, strong recommendation) Tables 12 and 13 outline potential drug-drug, drug-food, and drug-herb interactions. Bolded medications are considered significant interactions. The tables are not all inclusive. Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 12. Medications, Dietary Supplements and Food that INCREASE INR or Bleeding Risk1,20,30,49 Drug Class Known Interaction Probable Interaction Possible Interaction Unlikely Interaction Anti-Infective Ciprofloxacin Erythromycin Fluconazole* Isoniazid Metronidazole* Miconazole Miconazole Vaginal Suppository Moxifloxacin Sulfamethoxazole* Voriconazole Amoxicillin/clavulanate Azithromycin Clarithromycin Itraconazole Ketoconazole Levofloxacin Ritonavir Tetracycline Amoxicillin Chloramphenicol Darunavir Daptomycin Etravirine Ivermectin Nitrofurantoin Norfloxacin Ofloxacin Saquinavir Telithromycin Terbinafine Cefotetan Cefazolin Tigecycline Cardiovascular Amiodarone* Clofibrate Diltiazem Fenofibrate Propafenone Propranolol Aspirin Fluvastatin Quinidine Ropinirole Simvastatin Disopyramide Gemfibrozil Metolazone Analgesics, Anti- Inflammatory Piroxicam Acetaminophen Aspririn Celecoxib Tramadol Indomethacin Propoxyphene Sulindac Tolmentin Topical Salicylates Methylprednisolo ne Nabumetone CNS Drugs Alcohol Citalopram Entacapone Sertraline Disulfiram Chloral hydrate Fluvoxamine Phenytoin Felbamate Diazepam Fluoxetine Quetiapine GI Drugs and Food Cimetidine Mango Omeprazole Grapefruit Orlistat Herbal Supplement Fenugreek Feverfew Fish Oil Ginkgo Quilinggao Dandelion Danshen Don Quai Lycium PC-SPES Red or Sweet Clover Capsicum Forskolin* Garlic Ginger Turmeric Other Anabolic Steroids Capecitabine Zileuton Fluorouracil Gemcitabine Levamisole Paclitaxel Tamoxifen Tolterodine Acarbose Cyclophosphamide Danazol Iphosphamide Trastuzumab Etoposide Carboplatin Levonorgestrel *Indicates significant interaction Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 13. Medications, Dietary Supplements and Food that DECREASE INR1,20,30,49 Drug Class Known Interaction Probable Interaction Possible Interaction Unlikely Interaction Anti-Infective Griseofulvin Nafcillin Ribavirin Rifampin* Dicloxacillin Ritonovir Rifapentine Terbinafine Nelfinavir Nevirapine Cloxacillin Rifaximin Teicoplanin Cardiovascular Cholestyramine Bosentan Telmisartan Furosemide Analgesics, Anti- Inflammatory Mesalamine Azathioprine Sulfasalazine CNS Drugs Barbiturates Carbamazepine Chlordiazepoxide Propofol GI Drugs and Food High content vitamin K food Avocado Soy milk Sucralfate Sushi containing seaweed Herbal Supplement Alfalfa Ginseng Multivitamin St. John’s Wort Parsley Chewing Tobacco Co-Enzyme Q10 Yarrow Licorice Green Tea Other Mercaptopurine Chelation Therapy Influenza vaccine Raloxifene Cyclosporine Etretinate Ubidecarenone *Indicates significant interaction Dietary Interactions Fluctuating levels of vitamin K from both external dietary sources and internal gastrointestinal sources can significantly alter the INR. Increased dietary intake of vitamin K from either food sources or nutritional supplement sources can reduce the effectiveness of warfarin and decrease the INR. Since warfarin is a high protein bound drug with up to 99% of the drug bound to plasma proteins, patients who are malnourished with low albumin levels will have higher concentrations of unbound drug and may experience faster INR response. Conversely, patients receiving enteral nutrition will have more bound drug due to the high protein concentration in these products.20,30,50-52 9. Promote consistent intake of dietary vitamin K and not avoidance1 (UW Health GRADE high quality evidence, strong recommendation) 10. For enteral nutrition hold the tube feed 1 hour before and 1 hour after warfarin administration.50,52 (UW Health GRADE moderate quality evidence, strong recommendation) 10.1 If unable to hold enteral nutrition, increase warfarin dose until a therapeutic INR is achieved.52 (UW Health GRADE low quality evidence, conditional recommendation) 10.2 If on cycled tube feeding, administer warfarin at a time when tube feeds are off.52,53 (UW Health GRADE moderate quality evidence, strong recommendation) 11. A significant decrease (> 50%) in total dietary intake for >3 days may cause an increase in INR. Warfarin Reversal For information on reversing the effects of warfarin, see “Antithrombotic Reversal- Adult- Inpatient- Clinical Practice Guideline” Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Disclaimer Consensus care models assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Name: Anne Rose, PharmD - Pharmacy Phone Number: (608) 263-9738 Email Address: arose@uwhealth.org Contact for Changes: Name: Philip Trapskin, PharmD, BCPS – Drug Policy Phone Number: (608) 265-0341 Email Address: ptrapskin@uwhealth.org Guideline Author(s): Anne Rose, PharmD – Pharmacy Erin Robinson, PharmD, CACP – Anticoagulation Clinic Workgroup Members: Matthew Wolff, MD – Anticoagulation Clinic Vanessa Grapsas, PharmD, CACP – Anticoagulation Clinic Christi Albert, PharmD, BCPS – Anticoagulation Clinic Shelly Van Note, PharmD, CACP – Anticoagulation Clinic Reviewer(s): David Yang, MD – Lab Committee Approval(s): Inpatient Anticoagulation Committee: December 2019 Ambulatory Anticoagulation Committee: November 2010; June 2012; May 2013; September 2015; January 2020; April 2021; April 2022 UW Health Pharmacy and Therapeutics: December 2010; July 2012; June 2013; October 2015; May 2021; May 2022 Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Table 1. GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Very Low The true effect is likely to be substantially different from the estimated effect. Table 2. GRADE Ratings for Recommendations for or Against Practice Strong (S) Generally, should be performed (i.e., the net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision.) Conditional (C) May be reasonable to perform (i.e., may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented.) Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Collateral Tools & Resources The following collateral tools and resources support staff execution and performance of the evidence-based model recommendations in everyday clinical practice. Metrics • Time within therapeutic INR range (%): goal > 70% • % of patients with critical INR results Patient Resources 1. Health Facts For You #6900: Warfarin (Coumadin, Jantoven) 2. Health Facts For You #322: Food-Drug Interactions: Coumadin & Warfarin Diet Interactions 3. Health Facts For You #6915: Heparin (Unfractionated and Low Molecular Weight) Policies 1. UWHC Policy #2.3.1 Anticoagulation Monitoring by UW Anticoagulation Clinic Pharmacists 2. UW Health Policy #7.98 Entering Test Results into UW Health Link (EPIC) Protocols Initiation and Management of Warfarin – Adult -Ambulatory [7] Reporting Workbench Reports Anticoagulation Responsible Pool [7364099] AC Clinic Outreach Report [7594473] Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions References 1. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-e184S. 2. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;379(13):1290. 3. Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):53S-70S. 4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-267. 5. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019;74(1):104-132. 6. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e531S-e575S. 7. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e601S-e636S. 8. Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-1192. 9. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e496S. 10. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. 11. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e576S-e600S. 12. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(25):CIR.000000000000. 13. Puskas JD, Gerdisch M, Nichols D, et al. Anticoagulation and Antiplatelet Strategies After On-X Mechanical Aortic Valve Replacement. J Am Coll Cardiol. 2018;71(24):2717- 2726. Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions 14. Saito Y, Nazif T, Baumbach A, et al. Adjunctive Antithrombotic Therapy for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement. JAMA Cardiol. 2019. 15. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198. 16. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597- 1607. 17. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370(19):1790-1798. 18. Falk V, Baumgartner H, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur J Cardiothorac Surg. 2017;52(4):616-664. 19. Johanson NA, Lachiewicz PF, Lieberman JR, et al. American academy of orthopaedic surgeons clinical practice guideline on. Prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Bone Joint Surg Am. 2009;91(7):1756-1757. 20. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. 21. Britt RP, James AH, Raskino CL, Thompson SG. Factors affecting the precision of warfarin treatment. J Clin Pathol. 1992;45(11):1003-1006. 22. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med. 1992;116(11):901-904. 23. Shendre A, Parmar GM, Dillon C, Beasley TM, Limdi NA. Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage. Pharmacotherapy. 2018;38(6):588-596. 24. Shepherd AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol. 1977;4(3):315-320. 25. Kamali F, Khan TI, King BP, et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther. 2004;75(3):204-212. 26. Gladman JR, Dolan G. Effect of age upon the induction and maintenance of anticoagulation with warfarin. Postgrad Med J. 1995;71(833):153-155. 27. Dobrzanski S, Duncan SE, Harkiss A, Wardlaw A. Age and weight as determinants of warfarin requirements. J Clin Hosp Pharm. 1983;8(1):75-77. 28. Redwood M, Taylor C, Bain BJ, Matthews JH. The association of age with dosage requirement for warfarin. Age Ageing. 1991;20(3):217-220. 29. Wilke RA, Berg RL, Vidaillet HJ, Caldwell MD, Burmester JK, Hillman MA. Impact of age, CYP2C9 genotype and concomitant medication on the rate of rise for prothrombin time during the first 30 days of warfarin therapy. Clin Med Res. 2005;3(4):207-213. 30. Warfarin (Coumadin®) [prescribing information]. Brisol-Meyers Squibb, Inc.; Princeton, NJ. 2010. 31. Wallace JL, Reaves AB, Tolley EA, et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis. 2013;36(1):96-101. 32. Mueller JA, Patel T, Halawa A, Dumitrascu A, Dawson NL. Warfarin dosing and body mass index. Ann Pharmacother. 2014;48(5):584-588. 33. Abdelhafiz AH, Myint MP, Tayek JA, Wheeldon NM. Anemia, hypoalbuminemia, and renal impairment as predictors of bleeding complications in patients receiving anticoagulation therapy for nonvalvular atrial fibrillation: a secondary analysis. Clin Ther. 2009;31(7):1534-1539. Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions 34. Yoshizawa M, Hayashi H, Tashiro Y, et al. Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res. 2009;124(2):161-166. 35. Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother. 2005;39(6):1008-1012. 36. Zhang H, De T, Zhong Y, Perera MA. The advantages and challenges of diversity in Pharmacogenomics: Can minority populations bring us closer to implementation? Clinical Pharmacology & Therapeutics. 2019. 37. Qamar A, Vaduganathan M, Greenberger NJ, Giugliano RP. Oral Anticoagulation in Patients With Liver Disease. J Am Coll Cardiol. 2018;71(19):2162-2175. 38. Howard-Thompson A, Luckey A, George C, Choby BA, Self TH. Graves’ Disease and Treatment Effects on Warfarin Anticoagulation. Case Reports in Medicine. 2014;2014:1- 6. 39. Busenbark LA, Cushnie SA. Effect of Graves' disease and methimazole on warfarin anticoagulation. Ann Pharmacother. 2006;40(6):1200-1203. 40. Kellett HA, Sawers JS, Boulton FE, Cholerton S, Park BK, Toft AD. Problems of anticoagulation with warfarin in hyperthyroidism. Q J Med. 1986;58(225):43-51. 41. Self TH, Straughn AB, Weisburst MR. Effect of hyperthyroidism on hypoprothrombinemic response to warfarin. Am J Hosp Pharm. 1976;33(4):387-389. 42. Self TH, Reaves AB, Oliphant CS, Sands C. Does heart failure exacerbation increase response to warfarin? A critical review of the literature. Curr Med Res Opin. 2006;22(11):2089-2094. 43. del Campo M, Roberts G. Changes in Warfarin Sensitivity During Decompensated Heart Failure and Chronic Obstructive Pulmonary Disease. Ann Pharmacother. 2015;49(9):962-968. 44. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100. 45. Rose AE, Robinson EN, Premo JA, Hauschild LJ, Trapskin PJ, McBride AM. Improving Warfarin Management Within the Medical Home: A Health-System Approach. Am J Med. 2017;130(3):365 e367-365 e312. 46. Margolis AR, Porter AL, Staresinic CE, Ray CA. Impact of an extended International Normalized Ratio follow-up interval on healthcare use among veteran patients on stable warfarin doses. Am J Health Syst Pharm. 2019;76(22):1848-1852. 47. Barnes GD, Kong X, Cole D, et al. Extended International Normalized Ratio testing intervals for warfarin-treated patients. J Thromb Haemost. 2018;16(7):1307-1312. 48. Dupras D, Bluhm J, Felty C, et al. Institute for Clinical Systems Improvement Venous Thromboembolism Diagnosis and Treatment Health Care Guideline. 2013; http://sicoa.net/old/pdf/ICSI_Venous_Thromboembolism_Diagnosis_and_Treatment_feb 2013.pdf. Accessed May 5, 2021. 49. Nutescu EA, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf. 2006;5(3):433-451. 50. Dickerson RN, Garmon WM, Kuhl DA, Minard G, Brown RO. Vitamin K-independent warfarin resistance after concurrent administration of warfarin and continuous enteral nutrition. Pharmacotherapy. 2008;28(3):308-313. 51. Klang M, Graham D, McLymont V. Warfarin bioavailability with feeding tubes and enteral formula. JPEN J Parenter Enteral Nutr. 2010;34(3):300-304. 52. Dickerson RN. Warfarin Resistance and Enteral Tube Feeding: An Old Problem With a New Solution. 2008;43(6):520-524. https://doi.org/10.1310/hpj4306-520. 53. Petretich DA. Reversal of osmolite-warfarin interaction by changing warfarin administration time. Clin Pharm. 1990;9(2):93. Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 05/2022 Effective 5/19/2022. Contact CCKM@uwhealth.org for previous versions Collateral Tools & Resources References