Purpose
To provide details about warfarin use

Indication
Maintenance anticoagulation. Warfarin should be avoided in infants < 12 months of age (with the exception of infants with mechanical heart valves) and shouldn’t be used for initial therapy of heparin induced thrombocytopenia (HIT). Warfarin is teratogenic and contraindicated in pregnancy (except in pregnant women with mechanical heart valves who are at high risk of thromboembolism).

USE

Dosage Forms
Warfarin is available as oral tablet.

Tablets

1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Initiating Therapy

• Minimum Monitoring Requirements:
  • PT-INR monitoring
    • Inpatient
      • Baseline PT/INR within 48 hours prior to initiating warfarin therapy or continuing therapy from home/outside healthcare setting
      • PT/INR will be monitored daily until the warfarin dose is stable. Anticipate that full effect of a dose change will be seen after ~3 days
      • Once the warfarin dose is stable, PT/INR monitoring may decrease to twice weekly
  • Prior to initiation of therapy, but no longer than 48 hours before, the following labs should also be checked: CBC, coagulation profile (PT, PTT, fibrinogen activity), hepatic function panel, creatinine, urine pregnancy if applicable
  • For patients with baseline prolonged INR, use of FX or FII clot-based activity is needed. FII activity of 20-40%, and FX activity of ~13-23% correlate with an INR of 2-3. If chromogenic FX activity indicated, can be sent with ~20-43% chromogenic FX activity correlating with INR of 2-3%.
  • CBC should be monitored weekly while on warfarin therapy inpatient.
  • INR should still be obtained with each Emergency Department or admission encounter.
• Administration:
  • Warfarin doses are routinely given at the same time daily.
  • Doses should be rounded to the nearest ½ tablet strength (0.5 mg, as smallest formulation available is 1 mg tablet).
  • Patients should preferably be taking goal nutritional regimen prior to starting warfarin to prevent the INR from increasing to critically high levels
  • Prescribe doses as combinations of available tablet strengths whenever possible.
• Safety Precautions
  Renal impairment: Consider adjusting the initiation dose for severe renal impairment. Patients with renal failure have an increased risk of bleeding complications
• Hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis and cirrhosis (due to decreased production of vitamin K-dependent clotting factors).
• Drug-Drug interactions:
  • Hepatic metabolism primarily via CYP2C9
  • Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants
  • Consult pharmacy if questions with drug-drug interactions
• Drug-Food interactions:
  • The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K.
  • Vitamin E may increase warfarin effect.
  • Cranberry juice may increase warfarin effect.

Pharmacokinetics

Time to peak	~4 h
Protein binding	99%
Elimination half-life	~40 h. Highly variable among individuals
Excretion	Primary as metabolites renally
Metabolism	Hepatic metabolism, primarily through the CYP2C9 enzyme

Dosing

• It is recommended that all thrombosis patients receive initial anticoagulation with UFH or LMWH before starting warfarin therapy. Warfarin therapy may be started on day 1 or 2 of UFH/LMWH therapy. UFH/LMWH therapy should be continued for a minimum length of 5 days.
• The loading period is 3-5 days for most patients before a stable maintenance phase is achieved.
• For most thrombosis patients, maintain INR of 2-3. Aim for INR of 2.5-3.5 for patients who develop recurrent thromboembolic events while on therapeutic INR of 2-3.
• Cardiac patients who have mechanical heart valves, shunts, or conduits are at high risk for thrombosis and stroke. Suggested INR goals based on valve/conduit type are:

Valve/Conduit	INR Goal	Antiplatelet therapy
Mechanical bileaflet or current generation single-tilting disc AVR, and no additional risk factors for thromboembolism	2-3 Bridge with therapeutic LMWH (or UFH as alternative agent)	Addition of aspirin 81 mg PO daily is at discretion of primary team
Mechanical AVR with additional thromboembolic risk factors, or older-generation mechanical AVR	2.5-3.5 Bridge with therapeutic LMWH (or UFH as alternative agent)	Addition of aspirin 81 mg PO daily is at discretion of primary team
Mechanical MVR or TVR	2.5-3.5 Bridge with therapeutic LMWH (or UFH as alternative agent)	Aspirin 81 mg PO daily
Bioprosthetic MVR in patients at low risk for bleeding	2.0-3.0 Bridge with therapeutic LMWH (or UFH as alternative agent)	Continue warfarin for 3 months post-operatively. Aspirin 81 mg PO daily is reasonable in all patients with any valve prosthesis.
Bioprosthetic TVR	2.0-3.0 Bridge with therapeutic LMWH (or UFH as alternative agent)	Continue warfarin for 3 months post-operatively + aspirin 81 mg PO daily indefinitely.
On-X valve in mitral position and no additional risk factors for thromboembolism	2.5-3.5 Bridge with therapeutic LMWH (or UFH as alternative agent)	Aspirin 81 mg PO daily
On-X valve in aortic position and no additional risk factors for thromboembolism	1.5-2.5 Bridge with therapeutic LMWH (or UFH as alternative agent)	Aspirin 81 mg PO daily
CorMatrix/CardioCel valves, valved conduits	1.5-2.5 with risk factors Bridge with therapeutic LMWH (or UFH as alternative agent)	Aspirin 81 mg PO daily
Homografts, valve repairs, or RV-PA conduits unless under research study	N/A	Aspirin 3 – 5 mg/kg/day up to 81 mg PO daily
Bioprosthetic AVR/PVR	N/A	Aspirin 81 mg PO daily
Bioprosthetic AVR with high risk for thromboembolism (arrhythmia, low EF, prior thrombus or embolic even, known or suspected thrombophilia etc.)	2.0-3.0 Bridge with therapeutic LMWH (or UFH as alternative agent)	Continue warfarin for 3 months + aspirin 81 mg PO daily. May consider continuing warfarin lifelong with a target INR of 1.5-2.5 if low risk for bleeding.
Transcatheter pulmonary valve	N/A	Aspirin 3-5 mg/kg/day up to 325 mg PO daily for 6 months postoperatively, then decrease to aspirin 81 mg PO daily indefinitely.

Risk factors for thromboembolism include prior thrombus or embolic event, known or suspected thrombophilia, arrhythmia, low EF.

Loading Dose for Treatment of Thrombosis

• For treatment of thrombosis, the usual loading dose is 0.2 mg/kg enterally as a single daily dose (as long as the baseline INR is 1-1.3), with maximum dose of 5-10 mg. Reduce dose to 0.1 mg/kg enterally in patients with liver dysfunction AND baseline INR >1.3, severe renal dysfunction (e.g. hemodialysis), or post-Fontan (max 5 mg).
• Loading dose period is 3-5 days for most patients before stable maintenance phase achieved.
• The dose adjustments below are to avoid overshooting the INR.
  • Obtain initial INR on day 3 after two doses (unless patient is at high risk of bleeding, malnourished, NPO, post-operative, or with elevated baseline INRs, then check sooner), and daily on day 4, 5, and 6, or, at least every-other-day until 2 consecutive therapeutic INR are obtained on 2 separate days. On average, the INR should increase by a minimum of 0.2 per day to achieve therapeutic target INR by 5 to 7 days (time to achieve warfarin steady state).
  • Ideally when the INR is greater than 2 for two consecutive days, the UFH/LMWH may be discontinued. Usually the INR decreases by a small percentage the following day (Exception: the practitioner may choose to discontinue UFH/LMWH after a single therapeutic INR if patient cannot obtain daily INRs).
• Loading dose Days 2-4

INR Range	Adjustment
1.1-1.3	Repeat initial dose
1.4-3.0	50% initial dose
3.1-3.5	25% initial dose
>3.5	Hold until INR <3.5 then restart at 50% less than previous dose

Maintenance Dose for Treatment of Thrombosis

• Once 2 consecutive therapeutic INR are obtained on 2 separate days, thereafter, check 2x/week for 1-2 weeks, then 1x/week for 1-2 weeks, then qMonthly and with dose changes. An INR should always be measured within 5 to 7 days after initiating a new dose. Consider increased monitoring in the following:
  • <2 years of age due to age and potential for drug-nutrient interactions with formula and/or breast milk
  • Complex gastrointestinal disorder, complex diet, or changes/initiation of other medications that could interact with warfarin.
  • Being evaluated in the Emergency Department, even if INR checked within the previous 24 hours.
  • Admitted to the hospital, regardless of reason.
  • Within 3-4 days of hospital discharge
• While making dose adjustments, it is recommended to calculate the cumulative dose for the entire week and make changes to that dose.
• The following INR adjustments are for medically stable patients already established on long-term maintenance therapy. Medically unstable patients or those completing the loading protocol (above) may respond differently. Close daily monitoring with individualized dose adjustment of such patients is essential until they are clearly established on maintenance therapy.
• Maintenance dose Days ≥5

INR Goal 1.5-2.5		INR Goal 2.0-3.0		INR Goal 2.5-3.5
1.1-1.4	Check for compliance. If compliant, increase weekly dose by 10-20%	1.1-1.4	Check for compliance. If compliant, increase weekly dose by 20%	1.1-1.9	Check for compliance. If compliant, increase weekly dose by 20%
1.5-2.5	No change	1.5-1.9	Increase weekly dose by 10%	2-2.4	Increase weekly dose by 10%
2.6-3.0	Decrease weekly dose by 10%	2.0-3.0	No change	2.5-3.5	No change
3.1-3.5	Decrease weekly dose by 20%	3.1-3.7	Decrease weekly dose by 10%	3.6-3.7	No change if last 2 INRs were in range AND no increased risk of hemorrhage; otherwise decrease weekly dose by 5-10%
3.6-4.0	Administer next dose at 50% previous dose, then decrease weekly dose by 20-25% of maintenance dose	3.8-4.5	Administer next dose at 50% of previous dose, then decrease weekly dose by 20-25% of previous maintenance dose	3.8-4.2	Decrease weekly dose by 5-10%
>4	Hold until INR < 2.5, then decrease weekly dose by 25-50%	>4.5	Hold until INR < 3.5, then decrease weekly dose by 25-50% previous dose.	4.3-5.0	Administer next dose at 50% previous dose, then decrease weekly dose by 20-25% previous maintenance dose.
				>5.0	Hold until INR <3.5, decrease weekly dose by 25-50% of previous maintenance dose

Perioperative Management

• Decision making regarding whether warfarin needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. If it is indicated, warfarin should be held 5-7 days prior to procedure for complete reversal.
• Bridge with another anticoagulant once INR is at lower end of target (e.g., when INR <2 for patient with INR goal of 2-3).
  • If bridging with enoxaparin, consider holding the enoxaparin for 24-48 hours prior to procedure.
  • If bridging with continuous heparin infusion, consider holding the infusion 4-6 hours prior to procedure.
• Restart warfarin and enoxaparin after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionist.
• Continue enoxaparin or continuous heparin until INR in therapeutic range.

Low – Intermediate risk of thromboembolism

Stop warfarin therapy 5 days before surgery. Initiate treatment-dose LMWH 2 days before surgery (the morning immediately following the second held warfarin dose) No reversal of warfarin is necessary for most surgeries if the INR is < 1.5. Obtain INR 12 to 24 hours prior to surgery to confirm INR within normal limit

High risk of thromboembolism

Stop warfarin 5 days before surgery. Initiate treatment-dose LMWH 3 days before surgery (the morning immediately following the first held warfarin dose). For patients at very high risk for thromboembolic events, consider UFH to provide the least amount of time off anticoagulation prior to surgery. Discontinue UFH approximately 4-6 hours prior to surgery with the expectation that the anticoagulant effect will have worn off at the time of surgery. Obtain INR 12 to 24 hours prior to surgery to confirm INR within normal limits

• Low risk of thromboembolism includes no recent (> 3 months) venous thromboembolism, atrial fibrillation without a history of stroke or other risk factors, or bileaflet mechanical cardiac valve in aortic position.
• High risk of thromboembolism includes recent (3 months) history of venous thromboembolism, mechanical cardiac valve in mitral position, or old model of cardiac valve (ball/cage).

Bleeding Precautions & Warnings

• While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
• Try to avoid IM injections, lumbar punctures, arterial punctures. Apply pressure after venipuncture until bleeding has ceased.

Reversal Information
Vitamin K is the antidote to warfarin. It is preferably administered PO or IV; the subcutaneous route may lead to erratic and unpredictable absorption, and the IM route may lead to hematoma development. Vitamin K may be administered alone or in addition to fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC; Kcentra).

• Pharmacokinetics of Vitamin K:
  • Onset: 6-10 hr (PO); 1-2 hr (IV)
  • Peak effect: 24-48 hr (PO); 12-14 hr (IV)
• No bleeding:
  • If rapid reversal not required, hold warfarin for 24 hours and repeat INR.
  • If rapid reversal is required and patient will require warfarin in the near future, give vitamin K 30 mcg/kg/dose PO (max dose: 0.5-2 mg PO) with the expectation that a reduction of INR will occur in 24 hours
  • If rapid reversal is required and no near future warfarin required, give vitamin K 2-5 mg PO with the expectation that a reduction of INR will occur in 24 hours.
  • DO NOT GIVE VITAMIN K TO PATIENTS WITH CARDIAC VALVES, SHUNTS OR CONDUITS; Consult IHTC/cardiac surgeon/cardiologist on call.
• With non-life threatening bleeding:
  • Give vitamin K 0.5-2 mg PO with FFP 20 mL/kg with the expectation that a reduction of INR will occur in 24 hours
  • DO NOT GIVE VITAMIN K TO PATIENTS WITH CARDIAC VALVES, SHUNTS OR CONDUITS; Consult IHTC/cardiac surgeon/cardiologist on call.
    • If necessary to reverse bleeding before contacting IHTC/cardiac surgeon/cardiologist use judicious aliquots of FFP (5-10 ml/kg) to prevent thrombosis.
• With life-threatening bleeding or emergent surgical procedure:
  • Give vitamin K 5-10 mg IV over 10-20 minutes and FFP (20 mL/kg) or KCentra
    • Kcentra may be used in adolescents instead of FFP with standard dose of 25-50 FIX units/kg depending on INR.
      • Dosing:
        • INR 2 to < 4 = 25 FIX units/kg (max dose 2500 IU)
        • INR 4 to 6 = 35 FIX units/kg (max dose 3500 IU)
        • INR > 6 = 50 FIX units/kg (max dose 5000 IU)
      • Don’t exceed stated maximum dose for patient’s weighing > 100 kg.
      • Kcentra is contraindicated in DIC and known HIT.
      • Repeat dosing isn’t recommended and not supported by clinical trials.
      • Vitamin K should be administered following KCentra administration.
      • KCentra should be infused at room temperature at a rate of 0.12 ml/kg/min, up to the maximum rate of 8.4 ml/min. Blood should not enter the syringe being used for administration, as fibrin clots may form. Do not mix with other medications. Administer through a separate infusion line.
      • Time to clinical effect is 30 minutes, with a duration of > 12 hours
    • Vitamin K (1 to 2 mg slow IV) can be repeated every 12 hours depending on the INR. Consider higher vitamin K doses if INR not appropriately decreasing.
  • DO NOT GIVE VITAMIN K TO PATIENTS WITH CARDIAC VALVES, SHUNTS OR CONDUITS; Consult IHTC/cardiac surgeon/cardiologist on call.
    • If necessary to reverse bleeding before contacting IHTC/cardiac surgeon/cardiologist use judicious aliquots of FFP (5-10 ml/kg) to prevent thrombosis.
  • Recombinant factor VIIa (Novoseven) can be considered if patient not responding to vitamin K and KCentra administration (i.e., severe bleeding continues).
• For non-cardiac cases, consult hematology to help guide decision making on reversal agent of choice.

Critical site bleeds: Intracranial hemorrhage, including intraparenchymal, subdural, epidural, and subarachnoid hemorrhages; Other CNS hemorrhage, including intraocular, intra- or extra-axial spinal hemorrhages; Pericardial tamponade; Airway, including posterior epistaxis; Hemothorax, intraabdominal bleeding, and retroperitoneal hemorrhage; Extremity bleeds, including intramuscular and intraarticular bleeding concerning for compartment syndrome, bleeding associated with hemodynamic instability, bleeding in a noncompressible vessel (e.g., subclavian)

Transition Information

• The patient should be on a bridge anticoagulant (i.e. heparin or enoxaparin) at the same time to avoid warfarin induced skin necrosis or other thrombotic complications. See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to warfarin.
• Continue the bridge anticoagulant until INR is within therapeutic range.
• See table for switching from warfarin to another anticoagulant:

From	To	Action
Warfarin	LMWH	Stop warfarin and start LMWH on the 3rd day of holding warfarin. Patients with higher clotting risk may be started on LMWH immediately upon discontinuation of warfarin.
	UFH	Stop warfarin and start UFH on the 3rd day of holding warfarin or when INR </= 2.0
	Apixaban, Dabigatran	Stop warfarin and start apixaban or dabigatran when INR is <2
	Edoxaban	Stop warfarin and start edoxaban when INR is ≤2.5
	Rivaroxaban	Stop warfarin and start rivaroxaban when INR is <3

Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women. Females of childbearing age must be counseled that warfarin is teratogenic and contraindicated during pregnancy and referred for appropriate contraception if needed.

Patient Education and Ongoing Management
Discharging IHTC physician/APP is responsible for ensuring adequate follow-up for anticoagulation management has been scheduled prior to patient leaving the hospital.

References
1.     Bristol-Myers Squibb. Coumadin (warfarin sulfate) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf. Revised October 2011. Accessed September 2023.
Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo) [Prescribing information]; San Francisco, CA: Portola Pharmaceuticals; February 2023.

2.     Monagle, P.; Chan, A.K.C.; Goldenberg, N.A.; Ichord, R.N.; Journeycake, J.M.; NowakGottl, U.; and Vesely, S.K. Antithrombotic therapy in neonates and children: antithrombobotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012: 141(2)(Suppl): e737s-e801s.

3.     Warfarin. Pediatric and Neonatal Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed September 2023.

4.     Ageno W., Gallus A.S., Wittkowsky A., Crowther M., Hylek E.M., and 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.

5.     Kcentra: In: DrugDex® Drug Evaluations. Thomson Reuters (healthcare) Inc. Available from http://www.thomsonhc.com. Accessed September 2023.

6.     University of California, San Diego, Rady Children’s Hospital Warfarin Procedure 2019.

7.     Cincinnati Children’s Anticoagulation and Thrombolytic Therapy Subcommittee Warfarin Clinical Guidelines 2019.

8.     Whitlock RP, Sun JC, Fremes SE, et al. 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.

9.     Otto CM, Nishimura RA, Bonow RO et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143:e72- e227

10.  SickKids Handbook for Pediatric Thrombosis and Haemostasis, Edition 1