Mechanism of Action

• Local fibrinolysis by binding to fibrin, converts entrapped plasminogen to plasmin

Pharmacokinetics

• Elimination Half-Life: ~40 hours. Highly variable among individuals
• Metabolism: Hepatic metabolism, primarily through the CYP2C9 enzyme
• Time to peak: ~4 hours
• Protein binding: 99%
• Excretion: Primary as metabolites renally

Dosing – Pediatric

• Maintenance anticoagulation. Warfarin is teratogenic and contraindicated in pregnancy (except in pregnant women with mechanical heart valves who are at high risk of thromboembolism).
• 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).

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.

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.

Monitoring

• PT
• APTT

* If previously on UFH reduce infusion rate 30 min prior to rt-PA. Increase UFH rate to full dose 30 min after completion of a 6-hr infusion of rt-PA.

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

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

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.