Warfarin

 
FDA approved indications Prophylaxis and Treatment of Thromboembolic disorders, Stroke Prevention Atrial Fibrillation, DVT Prophylaxis, Prevention of Clots in Mechanical and Bioprosthetic Valves
Mechanism of action Inhibits vitamin K dependent clotting factors II, VII, IX, X
Onset of Action Initial 12-24 hours but full effects 5-7 days (because of the half-lives of the clotting factors (Factor II=60 hours, Factor XI=2 hours)
Metabolism Warfarin is a combination of two active isomers (R and S). S isomer is five times as potent as R.  S enantiomer is metabolized by the CYP2C9 enzyme of the cytochrome P450 system.

R enantiomer is metabolized by the 1A2 and 3A4 enzymes.

Dose 2.5-5 mg/day as a starting dose.  Lower starting dose for the elderly and Asian, higher dose for obese patients. Adjustments made by approximately 15% and may require varying doses by day.
Lab Monitoring/Adjustments INR (international normalized ratio) which is a reflection of the depletion of factors II, VI, IX.  INR should be monitored every  until therapeutic range has been achieved for 2 days then 2-3 times weekly for 1-2 weeks then less often depending upon stability.

If patient has a stable INR at a given dose then an INR can be checked less frequently (every 4-6 weeks).

Overlap therapy Depending upon the indication, treatment doses of low molecular weight heparin (LMWH- enoxaparin 1mg/kg BID SQ), fondaparinux (5mg, 7.5mg,10mg SQ daily) OR unfractionated heparin (UFH) continuous infusion based on protocol to achieve goal PTT should be used due to the time it takes to reach the goal INR.
Renal Adjustment None
Hepatic No adjustments, and the response may be enhanced. Monitor INR
Drug Interactions Patient to patient variability with interacting drugs.

There are numerous interactions via different mechanisms including increased anticoagulant effect (increased INR) such as trimethoprim/sulfamethoxazole, levofloxacin, decreased absorption as with cholestyramine,  Inhibition of  the cyclic inter-conversion of vitamin K as with cephalosporins.  Monitor closely with all interactions.

NSAIDs may increase INR and depending upon the NSAID they also affect platelets. Thus, avoid unless no other option.

Larger doses (2-4 grams/day) of acetaminophen for long durations can potentiate warfarin’s effect. But usual doses have no effect.

Food Interactions Vitamin K foods may decrease warfarin’s effect but it takes major changes to impact the dosing (i.e. NPO in a hospital).
Disease Interactions HF exacerbations, Hyperthyroidism, Hyper-metabolic states such as fever may increase warfarin’s effect by increasing catabolism of vitamin K clotting factors.
Ethanol Interaction Chronic alcohol ingestion causes a decrease in warfarin effect (induced warfarin metabolism)

Acute alcohol ingestion causes an increase in warfarin’s effect (decreasing warfarin’s metabolism).

Pregnancy Contraindicated and avoid use (change to LMWH when achieve pregnancy)
Withholding Therapy Depending upon the risk of clotting Vs bleeding (indication based) warfarin may be held days prior to the procedure. Overlap therapy may be used and stopped immediately prior to procedure (and re-start when bleeding risk minimal) if the clotting risk is high as with MVR.
Adverse Effects/Precautions Bleeding (see section below)

Tissue necrosis which is rare and typically occurs early in therapy

Spinal puncture (which could lead to hematoma and paralysis).  Avoid continuous epidural anesthesia if possible and INR should be less than 1.5 at the time of catheter removal

  Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)
FDA Approved Indications Reduction of risk of stroke and systemic embolism in non-valvular AFib

Treatment of DVT/PE in patients who have been treated with parenteral anticoagulation for 5-10 days

Reduction of recurrence of DVT and PE

Reduction of risk of stroke and systemic embolism in non-valvular AFib

Treatment of DVT and PE

Reduction in the recurrence of DVT and PE

Prophylaxis of DVT following hip and knee replacement surgery

Reduction of risk of stroke and systemic embolism in non-valvular AFib

Treatment of DVT/PE

Reduction in the risk of recurrence of DVT/PE

Prophylaxis of DVT following hip and knee replacement surgery

Reduction of risk of stroke and systemic embolism in non-valvular AFib

Treatment of DVT and PE in patients who have been treated with parenteral anticoagulation for 5-10 days

 

Mechanism of action Direct thrombin inhibitor Xa inhibitor Xa inhibitor Xa inhibitor
Dose (normal renal function thresholds as defined)  Greater than 30 ml/min

AFib:  150 mg BID

DVT/PE 150 mg BID

AFIB > 50ml/min 20mg daily with evening meal

Treatment of DVT/PE > 30 ml/min 15mg BID with food x 21 days than 20 mg QD with food

Hip/Knee replacement: 10mg daily (hip x 35d, knee x 12d)

SCr >1.5, < 80 yrs

> 60kg

AFIB 5 mg BID

Treatment of DVT/PE 10mg BID x 7 days then 5mg QD

Hip/Knee: 2.5 mg BID (hip x 35d, knee x 12 days)

Greater than 50 ml/min

AFib: 60 mg daily

Treatment of DVT/PE: 60 mg daily

Lab Monitoring None None None None
Renal Adjustments Stroke prevention AFIB: 15-30ml/min 75 mg BID, less than 15 ml/min not recommended

DVT/PE less than 30ml/min not recommended

Stroke Prevention AFIB: 15-50 ml/min 15mg QD

DVT/PE less than 30ml/min avoid use

If meet two of the criteria for AFIB: SCr >=1.5mg/dL, > 80yrs, <=60kg

2.5 mg BID

30-50ml/min: decrease dose by 50%

Not approved for CrCl > 95ml/min

Hepatic Adjustments No evidence Avoid in patients with child Pugh score B and C or any hepatic disease Not recommended in severe impairment No evidence
Time to max concentration 3 hours 2-4 hours 3-4 hours 1-2 hours
Half-life 12-17 hours 5-9 hours (young)

11-13 hours (elderly)

12 hours 10 hours
Drug Interactions Avoid with strong P-gp inducers (rifampin). Some Pgp inhibitors may be used but monitored closely (ketoconazole, verapamil, amiodarone, quinidine, clarithromycin) Avoid with strong Pgp inducers and CYP3A4 inducers (carbamazepine, phenytoin, rifampin, ketoconazole, itraconazole, indinavir, conivamptan) Avoid with strong Pgp inducers and CYP3A4 inducers (carbamazepine, phenytoin, rifampin, ketoconazole, itraconazole, indinavir, conivamptan). For patients on greater than 2.5 mg BID should be decreased by 50% with dual inhibitors of CYP3A4 and Pgp Avoid with strong Pgp inducers and CYP3A4 inducers (carbamazepine, phenytoin, rifampin, ketoconazole, itraconazole, indinavir, conivamptan).   Doses should be decreased by 50% if co-administered with strong inhibitors of Pgp
Converting from parenteral Start 0-2 hours before the time the next dose of the inj AC would have been due. Start at the time of the DC of the heparin drip Start 0-2 hours before the time the next dose of the inj AC would have been due. Start at the time of the DC of the heparin drip. Start at the time the next dose of inj AC would have been administered Start at the time the next dose of the inj AC would have been administered
Withholding treatment DC at least 1-2 days (CrCl >=50ml/min) or 3-5 days (CrCl<50ml/min) before invasive procedure Stop at least 24 hours before surgery or invasive procedure Stop at least 48 hours prior to invasive procedure. If a low risk of bleeding stop at least 24 hours prior No information available
Adverse Effects/Precautions Bleeding (see below)

Spinal hematoma and risk of paralysis with neuroaxial anesthesia and spinal puncture. See guidelines for appropriate approach during therapy.

Dabigatran: Indigestion, Edoxaban Increase in LFTs and patients with high CrCl (greater than 95ml/min) and increased risk of systemic embolism.

 

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