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Warfarin Management - Adult - Ambulatory

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Warfarin Management - Adult -
Ambulatory
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 4
METHODOLOGY ...................................................................................................................... 5
DEFINITIONS ............................................................................................................................ 5
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS .............................................................................................................. 5
UW HEALTH IMPLEMENTATION ............................................................................................14
APPENDIX A ............................................................................................................................16
REFERENCES .........................................................................................................................15
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

CPG Contact for Content:
Name: Anne Rose, PharmD - Pharmacy
Phone Number: (608) 263 -9738
Email Address: arose@uwhealth.org
CPG Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS – Drug Policy Program
Phone Number: (608) 263 -1328
Email Address: ptrapskin@uwhealth.org
Guideline Author(s):
Anne Rose, PharmD – Anticoagulation Stewardship Program
Coordinating Team Members:
David Ciske, MD – Anticoagulation Clinic/Internal Medicine
Erin Robinson, PharmD, CACP – Anticoagulation Clinic
David Queoff, MD – Family Medicine
Review Individuals/Bodies:
Teresa Darcy, MD – Clinical Pathology
Ambulatory Anticoagulation Committee
Committee Approvals/Dates:
UW Health Ambulatory Anticoagulation Committee: November 2010; June 2012; May
2013; September 2015
UW Health Pharmacy and Therapeutics: December 2010; July 2012; June 2013 ;
October 2015
Release Date: October 2015 | Next Review Date: October 2018
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Executive Summary
Guideline Overview
This guideline outlines the evidence for managing anticoagulation therapy with oral
vitamin K antagonist (warfarin). Evidence is based on recommendations from the
Antithrombotic Therapy and Prevention of Thrombosis, 9 th edition: American College of
Chest Physicians Clinical Practice Guidelines. It provides recommendations for how to
initiate, dose adjust and monitor warfarin therapy in the ambulatory setting .
Key Practice Recommendations
1. Initial warfarin dosing should be tailored based on patient bleed risk, potential
sensitivity to warfarin, indication, goal INR range, and if potential drug interactions
are present.
2. Maintenance warfarin dose adjustments should be based on current INR results and
trends and patient assessment of any missed doses, drug interactions, dietary intake
or supplements, documentation of bleeding, or other changes that may affect the
INR.
3. Table 5, 6 and 7 provide recommendations for warfarin dosing for INR goals of 1.5-
2.0, 2-3 and 2.5 -3.5.
Companion Documents
1. Warfarin Management – Adult – Inpatient Clinical Practice Guideline
2. Atrial Fibrillation – Adult – Inpatient/Ambulatory Clinical Practice Guideline
3. Antithrombotics in Non-Valvular Atrial Fibrillation – Adult – Inpatient/Ambulatory
Clinical Practice Guideline
4. HealthDecision
TM Atrial Fibrillation Risk Stratification Tool
5. Indications for Blood Product Transfusion – Adult – Inpatient/Ambulatory Guideline
Pertinent UW Health Policies & Procedures
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)
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)
4. Health Facts For You #6115: Stopping Anticoagulation and Antiplatelet Therapy
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Scope
Disease/Condition(s):
This guideline will apply to any disease or condition requiring anticoagulation with oral vitamin K
antagonist (warfarin) therapy
Clinical Specialty:
Internal Medicine
Family Practice
Cardiology
Hematology
Pharmacy
Nursing
Intended Users:
Physicians
Advanced Practice Providers
Pharmacists
Nurses
Objective(s):
To provide a strategy for the management of warfarin therapy in ambulatory adult patients using
a standardized process while offering an individualized assessment.
Target Population:
Adult patients being initiated and maintained on warfarin therapy in the clinic setting.
Interventions and Practices Considered:
This guideline provides strategies and recommendations designed to assist clinicians in
developing warfarin management plans. It begins with providing recommendations for target
INR ranges based on indication for use. It focuses on how to dose warfarin based on individual
patient risk factors, INR response, drug interactions, and dietary interactions.
Major Outcomes Considered:
Thromboembolic events while initiating and maintaining warfarin therapy
Hemorrhagic events while initiating and maintaining warfarin therapy
Need for reversal agents in the event of a bleeding event or emergent surgery/procedure.
Guideline Metrics:
Metrics will include time within target INR range, sub and supratherapeutic INR values, critical
INR values, appropriate dose adjustments based on drug and dietary interactions while
receiving warfarin therapy.
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Methodology
Methods Used to Collect/Select the Evidence:
(1) completing a comprehensive literature search of electronic databases; (2) conducting an in-
depth review of relevant abstracts and articles; (3) conducting thoughtful discussion and
interpretation of findings; (4) ranking strength of evidence underlying the current
recommendations that are made.
Methods Used to Assess the Quality and Strength of the Evidence:
A similar grading system for the recommendations from the American College of Chest
Physicians was utilized.
Rating Scheme for the Strength of the Evidence:
For all other recommendations a modified Grading of Recommendations Assessment,
Development and Evaluation (GRADE) developed by the American Heart Association and
American College of Cardiology (Figure 1.) has been used to assess the Quality and Strength of
the Evidence in this Clinical Practice Guideline. 1
Definitions
1. Baseline INR – an INR resulted within the previous 30 days prior to initiating warfarin
2. Current INR – an INR reported on the same calendar date as the scheduled warfarin dose
Introduction
This guideline outlines the evidence for managing anticoagulation therapy with oral vitamin K
antagonist (warfarin). 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. 2
Warfarin works by inhibiting the reduction of vitamin K epoxide and limiting the activation of
vitamin K dependant clotting factors: II, VII, IX and X. It also inhibits the synthesis of
anticoagulant proteins C, S and Z. When administered orally warfarin is rapidly and completely
absorbed. It is highly protein bound and metabolized by the cytochrome P450 (CYP) enzyme
2C9, 1A2 and 3A4. The half-life of warfarin is 36-42 hours. 3
This guideline provides recommendations that are based on the evidence outlined from the
Antithrombotic Therapy and Prevention of Thrombosis 9 th edition: American College of Chest
Physicians Clinical Practice Guidelines (CHEST). 2-8
Recommendations
1. INR goals and duration of therapy listed in Table 1 are recommended by the CHEST
guidelines.2-8 (Class I, Level B)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

1.1. Exceptions include orthopedic surgery INR goals which are recommendations provided
by UW Health Orthopedic surgeon consensus and based on the American Association
of Orthopedic Surgeons clinical guideline on Prevention of Symptomatic Pulmonary
Embolism in Patients Undergoing Total Hip or Knee Arthroplasty 9 (Class IIb, Level C)
1.2. Alternative INR goals may be chosen for specific patients when bleeding risk outweighs
clotting risk and will be determined by the individual’s provider (Class IIb, Level C)
Table 1. Indications for Antithrombotics, INR Ranges, and Duration of Therapy 2-10
Indication INR
(Range)
Duration Comments
Thrombophilia with Thromboembolic Event2
Antiphospholipid Syndrome 2.5 (2 -3) Chronic
Homozygous Factor V Leiden 2.5 (2 -3) Chronic
Deficiency of Protein C, S or Anti -
Thrombin
2.5 (2 -3) Chronic
Atrial Fibrillation (AF)/ Atrial Flutter4
CHA2DS 2VASc = 0; Low stroke
risk
None May choose aspirin 75 -3 25 mg
daily
CHA2DS 2 VASc ≥ 1;
Intermediate/High stroke risk
2.5 (2 -3) Chronic Anticoagulation CI: aspirin 75 -325
mg and clopidogrel 75 mg daily
Pre -cardioversion (AF or flutter
>48 hours)
2.5 (2 -3) 3 weeks
Post -cardioversion (in NSR) 2.5 (2 -3) 4 weeks
Ischemic Stroke5
Non -cardioembolic stroke or TIA None Chronic Use antiplatelet therapy
Cardioembolic stroke or TIA
-With warfarin CI None Chronic Aspirin 81 -325 mg daily
-With cerebral venous sinus
thrombosis
2.5 (2 -3) 3 -6 months
- With patent foramen ovale None Chronic Use antiplatelet therapy

Thromboembolism (DVT, PE) symptomatic or asymptomatic6
Provoked VTE event 2.5 (2 -3) 3 months
Unprovoked : 1st VTE event
- Proximal or Distal DVT 2.5 (2 -3) 3 months After 3 months evaluate risk -
benefit for extended therapy
- PE 2.5 (2 -3) > 3 months After 3 months evaluate risk -
benefit for extended therapy
Unprovoked : 2nd VTE event
- DVT or PE 2.5 (2 -3) > 3 months Consider chronic
With malignancy 2.5 (2 -3) > 3 months LMWH preferred over warfarin
Consider chronic
Acute Upper Extremity DVT
- Associated with central
venous catheter that was
removed
2.5 (2 -3) 3 months
- Associated with central
venous catheter that was
NOT removed
2.5 (2 -3) Extended Continue anticoagulation until
catheter removed
- Not associated with a central
venous catheter
2.5 (2 -3) 3 months
Spontaneous superficial vein
thrombosis
None 45 days Prophylaxis LMWH or
Fondaparinux
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Valvular Disease7
Rheumatic mitral valve disease
- Left atrial diameter < 55 mm None
- With AF, left atrial thrombus,
or left atrial diameter > 55 mm
2.5 (2 -3) Chronic
Valve Repair
Aortic None Aspirin 81 mg daily
Mitral None 3 months Antiplatelet therapy
Valve Replacement - Bioprosthetic
Aortic or TAVI* None Antiplatelet therapy
Mitral 2.5 (2 -3) 3 months Followed by aspirin 81 mg daily
* If other indication for anticoagulation exist – see specific indication for therapy recommendations
Valve Replacement - Mechanical
Aortic 2.5 (2 -3) Chronic Low bleed risk: add aspirin 81 mg
Mitral 3 (2.5 -3.5) Chronic Low bleed risk: add aspirin 81 mg
Dual Aortic and Mitral Valve 3 (2.5 -3.5) Chronic Low bleed risk: add aspirin 81 mg
Orthopedic Surgery8,9
Total Knee or Hip Arthroplasty* 1.8 -2.2 10-14 days INR goal per UWHC Orthopedics
Hip Fracture Surgery * 1.8 -2.2 10-14 days INR goal per UWHC Orthopedics
Trauma Surgery * 1.8 -2.2 35 days INR goal per UWHC Orthopedics
* If other indication for anticoagulation exist - INR goal should be clarified
AF- atrial fibrillation ; CAD – coronary artery disease; CI- contraindications; DVT- deep vein thrombosis; LMWH- low molecular
weight heparin; NSR- normal sinus rhythm; PE- pulmonary embolism; TIA- transient ischemic attack; TAVI - transcatether aortic
valve transplantation; VTE – venous thromboembolism
Patient Assessment
2. Before initiating warfarin therapy the patient should be assessed for risk factors that may
increase their risk for bleeding, thromboembolic events and for risk factors that may impact
the sensitivity of the response to warfarin.2,3 (Class I, Level C)
3. There are various clinical tools available to assess a patient’s bleeding risk, however, the
HAS -BLED score has been shown to accurately predict the risk of major bleeding in patients
receiving antithrombotic therapy. 10 (Class IIb, Level A)
3 .1 It stratifies patients as low, moderate or high bleed risk
3 .2 This score should not automatically exclude patients from receiving anticoagulation if
clinically indicated, but instead should be used to identify modifiable risk factors that
can be corrected (ex. uncontrollable hypertension) (Class IIb, Level C)
3 .3 Table 2 outlines the HAS-BLED score and bleeding classification 10
Table 2: HAS -BLED Score 10 (Class IIb, Level A)
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
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
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Bleeding history or predisposition 1 - Check INRs frequently
- Utilize anticoagulation clinic
- Focus on fall prevention
- Utilize direct oral anticoagulants
Labile INRs: Time in Therapeutic
Range <60% 1
Elderly: > 65 years 1
Drugs
- EtOH abuse
- ASA or NSAID use
1
4 . Patients with multiple high sensitivity risk factors may require a lower initiation dose and
reduced maintenance doses2,3,10 (Class IIb, Level C)
4 .1 Examples of these risk factors are included in Table 3
Table 3. Factors for Identifying Warfarin Sensitive Patients 2,3,10 (Class I, Level C)
Increased Warfarin Sensitivity
Increased INR Response Increased Bleeding Risk
Baseline INR ≥ 1.5 Current antiplatelet therapy
Age > 65 Thrombocytopenia: platelet <75 K/uL
Actual body weight < 45 kg or actual < ideal Significant hepatic disease:
cirrhosis or total bilirubin.>2.4 mg/dL
Malnourished/ NPO >3 days Alcohol abuse history
Hypoalbuminemia <2 g/dl End stage renal disease
Chronic diarrhea GI bleed within past 30 days
Significant drug interactions Surgery within past 2 weeks
Decompensated heart failure Intracranial bleed within past 30 days
Initial Warfarin Dosing
5. Initial dosing should be tailored based on patient bleed risk, potential sensitivity to warfarin,
indication for anticoagulation, goal INR range and if potential drug interactions are present 3
(Class I, Level C)
6. A baseline INR should be resulted prior to initiating warfarin therapy 3 (Class I, Level C)
7 . A dose larger than the anticipated maintenance dose (loading dose) of warfarin is
inappropriate and should not be used in most patients 2 (Class IIb, Level C)
7 .1 In healthy patients with a PE or DVT warfarin 10 mg for the first 2 days may be
considered followed by dosing based on INR measurements 2 (Class IIb, Level C)
8. Prior to making a dose adjustment assess for any missed doses, drug interactions, diet,
documentation of bleeding, or other changes that may affect INR 2,3 (Class I, Level C)
8 .1 Table 4 should be utilized for warfarin dose adjustments within the first week of
therapy (Class IIb, Level C)
8.2 Warfarin should be adjusted based on current INR measurements 2,3 (Class I, Level C)
9. If appropriate, patients should receive another form of anticoagulation such as LMWH for at
least 5 days and until they are therapeutic on warfarin for 24-48 hours 3 ,6 (Class I, Level B)
Table 4. Warfarin Initiation (Week 1) with INR Goal 2-3 (Class IIb, Level C)
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
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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
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
Maintenance Warfarin Dosing
10. Warfarin should be adjusted based on current INR measurements and assessment of any
missed doses, recent INR trends, changes in diet and activity level, potential drug
interactions, symptoms of bleeding or clotting and other changes that may affect INR level
as described in Appendix A. Patient Assessment Tool 2,3 (Class I, Level C)
10.1. INRs minimally above or below therapeutic range by ≤ 0.5 in patients previously
stable or if there is a specific reason for the INR to be out of range (ex. missed dose),
then no dosing change may be needed. Recommend to continue current dose and
test INR in 1-2 weeks. 2 (Class IIa, Level C)
11. Tables 5-7 should be utilized for warfarin dose adjustments after at least 7 days of therapy
11.1 For INR ranges that do not have a corresponding dosing table, the same principles
of adjusting the weekly dose by approximately 10% for an out of range INR should
be uses. (Class IIb, Level C)
11.2 Daily low dose vitamin K supplement should not be used to improve INR control 2
(Class IIa, Level C)
12. Prior to cardioversion procedure the INR must remain within goal for 30 days. 4 If an INR is
trending downward consider increasing the warfarin dose to prevent a subtherapeutic INR
(Class IIb, Level C)
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Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

Table 5. Warfarin Maintenance Dosing Protocol with INR Goal 1.5-2.0 (Class IIb, Level C)
INR ≤ 1.2 INR 1.3 -1.4 INR 1.5 - 2.0 INR 2.1 – 3.0 INR 3.1 - 4.0* INR 4.1 -5.0* INR 5.1 -9.0* INR > 9.0
Increase
weekly dose
10%
Increase
weekly dose
5%
No change Decrease
weekly dose
5%
Consider half
dose x 1 and
Decrease
weekly dose
10%
Hold 1 dose
Decrease
weekly dose
by 10 -20%
MD order required
Consider:
Hold 2 doses
Decrease weekly
dose 10-20%
Check Hct
Contact MD for
urgent patient
evaluation
Table 6. Warfarin Maintenance Dosing Protocol with INR Goal 2-3 (Class IIb, Level C)
INR < 1.5 INR 1.5 - 1.9 INR 2.0 - 3.0 INR 3.1 - 4.0* INR 4.1 -5.0* INR 5.1 - 9.0* INR > 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%
MD order required
Consider:
Hold 2 doses
Decrease weekly dose
10-20%
Check Hct
Contact MD for
urgent patient
evaluation
Table 7. Warfarin Maintenance Dosing Protocol with INR Goal 2.5-3.5 (Class IIb, Level C)
INR < 1.9 ŧ INR 1.9 - 2.4 ŧ INR 2.5 - 3.5 INR 3.6 - 4.5* INR 4.6 -5.0* INR 5.1 - 9.0* INR > 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%
MD order required
Consider:
Hold 2 doses
Decrease weekly dose
10-20%
Check Hct
Contact MD for
urgent patient
evaluation
* If the INR is above the specified range for accuracy per point of care (POC) device, a repeat venipuncture is required to verify INR
ŧ If the INR < 2.0 and the patient has a mechanical valve then bridge therapy with a low molecular weight heparin should be considered
13. If an extra dose or hold dose is recommended:
13.1 A partial-full extra or partial–full held dose can be utilized based on INR and patient’s sensitivity to
warfarin.(Class IIb, Level C)
13.2 The extra or held dose should not be included in the weekly dose adjustment unless the total weekly
dose is > 50 mg per week as a small percentage change can greatly impact the INR. (Class IIb, level C)
14. If warfarin is dosed at > 50 mg per week then smaller weekly dose adjustments should be targeted (ex. 5%)
(Class IIb, level C )
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11
Laboratory Monitoring 2,3
15. INR
15.1 A baseline INR must be resulted prior to the first dose of warfarin (Class I, Level A)
15.2 Upon discharge from the hospital an INR should be obtained within 2- 4 days for
newly initiated warfarin or if there were changes that could affect the INR. (Class I,
Level C)
15.3 If bridging warfarin with low molecular weight heparin may consider checking the
INR within 1-2 days if the INR is close to the therapeutic range (i.e. 1.7-1.9). (Class
I, Level C)
15.4 If there were no changes then the INR may be checked at the next scheduled INR
visit. (Class I, Level C)
15.5 Table 8 outlines recommendations for monitoring the INR when initiating warfarin
therapy
15.6 Table 9 outlines recommendations for monitoring the INR during maintenance
warfarin therapy.
16. Hematocrit, platelet, ALT, total bilirubin, and serum creatinine should be resulted within
the preceding 3 months and periodically thereafter per physician discretion (Class IIb,
Level C)
17. For women of child bearing age a pregnancy test is recommended before initiating warfarin
(Class IIb, Level C)
Table 8. Frequency of INR Monitoring After Initiation of Warfarin (Class IIb, Level C)
INR Check
Every 2 – 3 days Until INR within therapeutic range on 2 consecutive INR
checks
Then every week Until INR within therapeutic range on 2 consecutive INR
checks
Then every 2 weeks Until INR within therapeutic range on 2 consecutive INR
checks
Then every 4 weeks When dose is stable check monthly
Table 9. Frequency of INR Monitoring for Maintenance of Warfarin (Class IIb, Level C)
INR Check
After 1 week If start/stop interacting medication, change in diet, change in
activity level or other change that could affect INR
Every 1 -2 weeks If dose needed adjustment by 5 -10%
Every 4 weeks If patient maintained on same stable dose < 6 months
Every 6 -8 weeks If patient maintained on same stable dose for at least 6
months
Symptomatic Monitoring
18. At each encounter for INR monitoring patients should be assessed for signs and
symptoms of bleeding and clotting as well as any change that could affect the INR
result2,3. (Class I, Level C)
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12
18.1 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.
Table 10. Common Signs and Symptoms of Major Bleeding and Clotting 6,11 (Class I, Level C)
Signs and Symptoms of Bleeding Signs and Symptoms of Clotting
Blood in urine or stool (enough to color toilet
water)
Chest or unilateral leg pain
Blood in sputum Shortness of breath
Bloody emesis (bright red or coffee ground -like) Elevated heart rate (HR > 100 bpm)
Bleeding that has not resolved or slowed within
10 minutes
Unilateral lower extremity swelling
Drug Interactions
Most drug interactions with warfarin will start to have an effect within 3-5 days of concomitant
therapy. There are some notable exceptions which include amiodarone, carbamazepine, and
rifampin which have a delayed effect after 7-14 days of dual therapy. 2,3 ,12,13 Tables 11 and 12
outline potential drug-drug, drug-food, and drug-herb interactions. Bolded medications are
considered significant interactions. This table is not all inclusive.
19. For most drug interactions with warfarin it is recommended to either increase or decrease
(based on expected INR response) the weekly dose by 30% (Class IIb, Level C)
19.1 For amiodarone target a 50% reduction in weekly maintenance dose for warfarin
after 7-14 days of dual therapy 12 or if initiating warfarin start at 2.5 mg dose (Class
IIb, Level C)
19.2 For rifampin target a 50% increase in weekly maintenance dose for warfarin after 7-
14 days of dual therapy. 12 (Class IIb, Level C)
Table 11. Medications, Dietary Supplements and F ood that INCREASE INR or Bleeding Risk .2,3,12,13
(Class I, Level C)
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
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13
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
Table 12. Medications, Dietary Supplements and Food that DECREASE INR .2,3,12,13 (Class I,
Level C)
Drug Class Known
Interaction
Probable Interaction Possible
Interaction
Unlikely
Interaction
Anti-Infective Griseofulv in
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
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

14
Dietary Interactions
Patients on long term warfarin therapy can be sensitive to the fluctuating levels of vitamin K
from both external dietary sources and internal gastrointestinal sources. 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. 3,12, 14 -16
20. Promote consistent intake of dietary vitamin K and not avoidance 3 (Class I, Level C)
21. For enteral nutrition hold the tube feed 1 hour before and 1 hour after warfarin
administration14,16 (Class IIa, Level B)
21.1 If unable to hold enteral nutrition, increase warfarin dose until a therapeutic INR is
achieved16 (Class IIb, Level B)
22.2 If on cycled tube feeding, administer warfarin at a time when tube feeds are off 16,17
(Class IIa, Level B)
Warfarin Reversal
The treatment for warfarin reversal should be based on the indication for use, location of bleed,
severity of bleed and the extent of INR elevation. Guidelines for reversal of warfarin are available
within the UW Health Adult Procoagulant Therapy for Treatment of Non-Hemophiliac Bleeding
Clinical Practice Guideline. 2,3
http://www.uwhealth.org/files/uwhealth/docs/anticoagulation/Procoagulant_Guideline.pdf
UW Health Implementation
Potential Benefits:
This guideline will provide a resource for standardizing the approach to warfarin management
for an individual patient. Individualization of a warfarin management plan should result in lower
incidence of supra-therapeutic and critical INR results, minimize the risk for bleeding events and
provide guidance for managing drug and dietary interactions.
Potential Harms:
Warfarin is a complex medication that requires close monitoring to prevent adverse events.
While significant bleeding more commonly occurs when the INR is above the therapeutic range,
it, may also occur when the INR is within or slightly below target INR range. Bleeding is the
most common adverse event of warfarin for which to monitor. Additionally, if the INR remains
sub-therapeutic for an extended time there is the risk for thromboembolic events.
Qualifying Statements
Despite providing recommendations to manage many common scenarios, there may be
external factors that can influence the INR and dosing of warfarin that are not provided in this
guideline. Since standardization of warfarin management is unrealistic, clinical judgement
should be used when indicated to prevent unwanted adverse events
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
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15
Implementation Plan/Tools
Recommendations provided in this guideline will be disseminated to staff through a variety of
venues including newsletters, clinic inservices and additional tools as described below:
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
2. Guideline will also be posted on UW Health Anticoagulation Website:
www.uwhealth.org/anticoagulation
3. Online class and quarterly live training program on use of the Warfarin Management
Guideline and Protocol will contain updates
4. Links to this guideline will be included in the Warfarin Management Protocol
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and
treatment of patients. This Clinical Practice 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.
References
1. Tricoci P, Allen J, Kramer J, et al. Scientific evidence underlying the ACC/AHA Clinical Practice
Guidelines. JAMA. 2009;301(8):831 -841.
2. Holbrook A, Schulman S, Witt D, et al. Evidence Based Management of Anticoagulant Therapy:
Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest
Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:e152s-184s.
3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral Anticoagulant Therapy: Antithrombotic Therapy
and Prevention of Thrombosis, 9 th ed. American College of Chest Physicians Evidence Based
Clinical Practice Guidelines. CHEST. 2012;141:e44s-88s.
4. You J, Singer D, Howard P, et al. Antithrombotic Therapy for Atrial Fibrillation: Antithrombotic
Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest Physicians Evidence
Based Clinical Practice Guidelines. CHEST. 2012;141:e531s-575s.
5. Lansberg M, O’Donnell M, Khatri P, et al. Antithrombotic and Thrombolytic Therapy for Ischemic
Stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest
Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:601s -636s.
6. Kearon C, Akl E, Comerota A, et al. Antithrombotic Therapy for VTE Disease : Antithrombotic
Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest Physicians Evidence
Based Clinical Practice Guidelines. CHEST. 2012;141: 419s-494s.
7. Whitlock R, Sun J, Fremes S, et al. Antithrombotic and Thrombolytic Therapy for Valvular
Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of
Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:576s -600s.
8. Falck-Ytter Y, Francis C, Johanson N, et al. Prevention of VTE in Orthopedic Sugery Patients :
Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest
Physicians Evidence Based Clinical Practice Guidelines. CHEST. 2012;141:278s -325s.
9. American Academy of Orthopaedic Surgeons Clinical Practice Guideline of prevention of
symptomatic pulmonary embolism in patients undergoing total hip of knee arthroplasty.
Rosemont (IL): American Academy of Orthopaedic Surgeons (AAOS); 2007.63 p.
10. Pisters R, Lane DA, Nueuwlaat R, de Vos CB, Crijns HJ. A novel user-friendly score (HAS -BLED)
to assess 1-year risk of major bleeding in atrial fibrillation: the euro heart survey. CHEST.
2010;138(5):1093 -1100.
11. Dupras D, Bluhm J, Felty C, et al (2013) Institute for clinical systems improvement: venous
thromboembolism diagnosis and treatment. Available via http://bit.ly/VTE0113 . Accessed March
10, 2015
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
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12. Product Information: COUMADIN(R) oral tablets, intravenous injection, warfarin sodium oral
tablets, intravenous injection. Bristol -Myers Squibb Company, Pri nceton, NJ, 2010
13. Nutescu EA, Shapiro NL, Ibrahim S, et al (2006) Warfarin and its interactions with food, herbs
and other dietary supplements. Expert Opin Drug Saf 5(3):433 -51.
14. 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.
15. Klang M, Graham D, McLymont V. Warfarin bioavailability with feeding tubes and enteral
nutrition. JPEN J Parenter Enteral Nutr. 2010;34(3):300 -304
16. Dickerson, RN. Warfarin resistance and enteral tube feeding: an old problem with a new solution.
Hosp Pharm. 2008;43(6): 520 -524
17. Petretich DA. Reversal of osmolite warfarin interaction by changing warfarin administration time.
Clin Pharm. 1990;9(2):93
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Appendix A. Ambulatory Warfarin Management – Adults – CPG
Warfarin Management Dosing Tool
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org

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Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 10/2015CCKM@uwhealth.org