warfarin (Coumadin, Panwarfin, Jantoven)

Introduction

Tradenames: Coumadin, Panwarfin. (warfarin sodium)

* (see direct oral anticoagulant (DOAC) for safety vs warfarin)

Indications

• hypercoagulability
• prophylaxis for venous thromboembolism
• atrial fibrillation
  • prevention of embolic stroke
• treatment of deep vein thrombosis (DVT)
  • pulmonary embolism
• acute myocardial infarction (AMI)
• transient ischemic attacks (TIA) due to cardiac emboli
• prosthetic heart valves
• may reduce risk of cancer in patients with atrial fibrillation or atrial flutter
  • all cancers (RR=0.62)
  • prostate cancer (RR= 0.60), lung cancer (RR=0.39)
  • breast cancer (RR=0.72), colon cancer (RR=0.71)
  • risk reductions less in warfarin users in general

Contraindications

• active bleeding, prior hemorrhage
• pregnancy
  • exception seems to be mechanical heart valve
  • safe during lactation
• renal insufficiency
  • seems beneficial for patients with atrial fibrillation & mild-moderate renal failure
  • may cause more harm than benefit in patients with atrial fibrillation & end-stage renal disease
• predisposition to falls
  • high risk of falls may not be an absolute contraindication
• barriers to adherence
• alcohol or drug abuse
• warfarin resistance
• does not lower the risk for catheter-related thromboses in patients with cancer
• also see warfarin & surgery
• preventing embolic stroke in patients with ESRD

Caution:

• anticoagulation with warfarin can be difficult in patients with underlying vitamin K deficiency
  • INR may be supersensitive to warfarin dose
• use caution in patients with malignancy (see adverse effects)

pregnancy category = x

safety in lactation = +

Benefit/risk

• number needed to treat non-valvular atrial fibrillation
  • 25 for 1.5 years to prevent 1 stroke
  • 42 for 1.5 years to prevent 1 death
• number needed to harm
  • 25 for 1.5 years for major hemorrhage
    • 384 for 1.5 years for intracranial hemorrhage
• number needed to treat (NNT) with warfarin vs aspirin
  • 60 for 1.9 years to prevent 1 stroke
  • 360 for 1.9 years to prevent systemic embolism
• number needed to harm with warfarin vs aspirin
  • 167 for 1.9 years for fatal hemorrhagic stroke
  • 25 for 1.9 years for hemorrhage requiring hospitalization

Dosage

• load 5-10 mg PO QD for 1-2 days, then adjust dose to target: INR: 2-3 standard therapy, but indication-dependent (2-10 mg PO QD) (see protocol for warfarin anticoagulation)
• supplement with 100-200 ug/day of vitamin K1 (phytonadione, phylloquinone) if unstable INR

* long-term low-intensity anticoagulation INR 1.5-2.0 (after 3 months of standard therapy) not recommended

Tabs: 1, 2, 2.5, 5, 7, 10 mg.

Pharmacokinetics

• well absorbed from the GI tract
• 97% of the drug is bound to plasma proteins, primarily albumin
• full anticoagulation is achieved 3-7 days after initiation of therapy (even with therapeutic INR)
• because prothrombin 1/2 life is 24 hours, anticoagulation is not achieved until 24-48 hours after reaching therapeutic INR; the early rise in INR is due to a decrease in factor V (1/2life 5 hours)
• effective 1/2life is 20-6- hours
• metabolized in the liver by CYP1A2, CYP2C9, CYP2C19, CYP3A4
• polymorphisms in VKORC1 associated with warfarin resistance
• polymorphisms in CYP2C9 & VKORC1, account for ~40% of the variability in warfarin responses
• moderate to severe renal impairment may be associated with a reduction in warfarin dose requirements

elimination via liver

1/2life = 22-52 hours

protein binding = 99 %

Monitor

• international normalized ratio (INR)
  • point of care testing (fingerstick) for home testing may be useful for patients with stable INR
• see protocol for warfarin anticoagulation
• check INR within 3 days after starting antibiotic
• because of long 1/2life, full impact of dose change is not manifested for 7-10 days
• 25% of warfarin recipients achieve stability of INR within 6 months based; of these patients, 30% with stable INR in subsequent year

Adverse effects

• not common (1-10%)
  • alopecia, stomach cramps, nausea, vomiting, diarrhea, leukopenia
• uncommon (< 1%)
  • mouth ulcers, renal damage, discolored toes (blue toe syndrome), hepatotoxicity, skin rash, agranulocytosis, anorexia
• epidermal necrosis
  • occurs in 1st week of therapy
  • commonly involves adipose areas: breast, hips, abdomen
  • associated with depletion of protein C & hypercoagulable state
• other
  • bleeding, especially GI bleeding
    • 6 fold increased risk of intracerebral hemorrhage
      • risk of intracranial hemorrhage in elderly (> 75 years of age) 1.8% (higher than with dabigatran 0.6%)
    • risk of major hemorrhage 13.1 events/100 patient years in elderly >= 80 vs 4.75 in patients < 80
    • risk of major hemorrhage ranges from 0.4% per year to 17% per year depending upon risk factors
    • major risk factors include:
      • anemia (blood hemoglobin < 13 g/dL men, < 12 g/dL women)
      • severe renal disease
      • age >= 75 years
      • prior hemorrhage
      • hypertension
    • risk of bleed is inversely associated with renal function in older patients starting warfarin for atrial fibrillation
    • scoring systems no better than physician clinical judgment in predicting major hemorrhage
    • when to restart anticoagulation after GI blood is controversial
      • study suggests after resolution of GI bleed, especially in patients with malignancy
  • long-term use may increased the risk of bone fracture
  • teratogenic
  • heavy menstrual bleeding
  • hemorrhage from postovulatory cysts
  • sensation of cold
  • progression of DVT to limb ischemia & gangrene in patients with cancer-associated hypercoagulability
    • thrombin generation coupled with warfarin-induced decreases in protein C & protein S may result in massive thrombosis
  • may cause skin necrosis & thrombosis in patients with protein C deficiency
  • may paradoxically increase risk of ischemic stroke during initiation of therapy by inhibition of endogenous anticoagulants
    • 50% decrease in protein C activity with warfarin initiation leads to hypercoagulable state, exp with discontinuation of heparin
• heart disease, liver disease, kidney disease, cancer, anemia & history of stroke are risk factors for adverse events in patients who receive warfarin

Toxicity:

bleeding

• hold warfarin administration until therapeutic INR & cessation of bleeding
  • in most cases, warfarin can be safely restarted within one week of a GI bleed
• vitamin K 1 mg IV in 15-20 mL of normal saline or 2.5-5.0 mg PO for minor bleeding or INR > 10#*
• for INR 5-10*, in the absence of bleeding, withhold warfarin
  • vitamin K is not necessary, controversial
• life-threatening hemorrhage
  • 4-factor prothrombin complex concentrate 25-50 units/kg
    • small volume, no need for thawing or ABO typing
    • in combination with 5-10 mg of IV vitamin K
    • treatment of choice
  • factor prothrombin complex in combination with 2 units of fresh frozen plasma or recombinant factor VIIa 25-90 ug/kg IV +/- vitamin K
  • fresh frozen plasma (FFP) alone may be an option if prothrombin complex & recombinant factor VIIa are unavailable
  • FFP alone may be associated with lower risk of thrombosis (requires thawing & ABO typing)

* Also see risk factors for persistently elevated INR

# vitamin K 2.5 mg PO as effective as 1 mg IV; PO & IV more effective than SC;

* ref suggests INR of 10 prior to vitamin K

* vitamin K reverses INR increase associated with warfarin overdose in a short time period - consider superwarfarin if reversal is prolonged

• drug adverse effects of antithrombotic agent(s)

Drug interactions

(also see prothrombin time)

• AMIODARONE, METRONIDAZOLE, TRIMETHOPRIM/SULFAMETHOXAZOLE (BACTRIM): significant increase in anticoagulant effect
• agents that may increase effect of warfarin:
  • antibiotics alter intestinal flora that synthesize vitamin K
    • ciprofloxacin & other quinolones
    • some cephalosporins (cefamandole, cefotetan, cefmetazole, cefoperazone)
    • amoxicillin
    • erythromycin & other macrolides
    • sulfonamides, sulfamethoxazole/trimethoprim (see above)
    • antifungals: fluconazole, griseofulvin, ketoconazole, miconazole, voriconazole
    • isoniazid, rifampin
    • tetracycline
    • metronidazole (see above)
  • oral glucocorticoids (prednisone)
  • hypolipidemic agents
    • lovastatin, simvastatin (& presumably other statins, except perhaps pravastatin)
    • clofibrate, colestipol, cholestyramine, fenofibrate, gemfibrozil,
  • acute alcohol intoxication, disulfiram, acetaminophen
  • antiplatelet agents - aspirin, P2Y12 receptor inhibitors
  • NSAIDs, COX2 inhibitors, salicylates, phenylbutazone, sulfinpyrazone
  • acetaminophen (scheduled dosing, occasional dose ok)
  • dextrothyroxine, methimazole, propylthiouracil, thyroid hormones
  • thiazides, ethacrynic acid
  • allopurinol, aminoglutethimide, anabolic steroids, chloral hydrate, cimetidine, diltiazem, glutethimide, glucagon, mercaptopurine, ompeprazole, pentoxifylline, phenytoin, propafenone, propranolol, quinidine, quinine, tamoxifen, vitamin E
• agents that may decrease effect of warfarin:
  • chronic alcohol, aprepitant, barbiturates, carbamazepine, cholestyramine, estrogen-containing contraceptives, griseofulvin, 6-mercaptopurine, mesalamine, methimazole, nafcillin, rifabutin, rifampin, spironolactone, sucralfate, trazodone, vitamin K, dicloxacillin
• any drug which inhibits CYP1A2, CYP2C9, CYP2C19, CYP3A4 can increase warfarin levels
• any drug which induces CYP1A2, CYP2C9, CYP2C19, CYP3A4 can diminish warfarin levels
• also see dietary interactions with warfarin

• drug interaction(s) of oral anticoagulants with selective serotonin reuptake inhibitor (SSRI)
• drug interaction(s) of aspirin, clopidogrel & warfarin
• drug interaction(s) of sulfonylureas with warfarin
• drug interaction(s) of trimethoprim/sulfamethoxazole with warfarin
• drug interaction(s) of antibiotics with warfarin
• drug interaction(s) of glucocorticoids with warfarin
• drug interaction(s) of propranolol with warfarin
• drug interaction(s) of warfarin with Panax quinquefolius
• drug interaction(s) of warfarin with ginseng
• drug interaction(s) of warfarin with Hyperocum perforatum
• drug interaction(s) of warfarin with NSAIDs
• drug interaction(s) of warfarin with antiplatelet agents
• drug interaction(s) of warfarin with chondroitin sulfate
• drug interaction(s) of warfarin with glucosamine
• drug interaction(s) of Vaccinium macrocarpon with warfarin
• drug interaction(s) of aspirin, P2Y12 inhibitors & anticoagulants

Laboratory

• specimen: serum, plasma (EDTA)
• methods: HPLC, GLC, spectrophotometric
• interferences:
  • fluorometry & spectrophotometry are non-specific
  • dicumarol, thiopental, salicylate may interfere with spectrophotometric assays
• therapeutic level generally assessed by:
  • prothrombin time (PT)
  • international normalized ratio (INR)
• genetic testing (see warfarin sensitivity testing)
  • vitamin K epoxide reductase alleles (VKORC1 gene mutation)
  • CYP2C9 variants
    • CYP2C9*3 variant increases risk of major bleeding 14.2 vs 7.8%
  • does not improve INR control
  • not reimbursed by medicare
  • identifies patients more likely to bleed in the 1st 90 days of warfarin treatment, thus candidates for more exepnsive direct oral anticoagulant therapy
  • CYP4F2 enzyme activity (some labs do genetic testing)

Mechanism of action

• anticoagulant
• interferes with hepatic synthesis of vitamin K-dependent coagulation factors (facot II, factor VII, factor IX & factor X)
• anticoagulant activities are due to inhibition of factor II & factor X; inhibition of factor VII & factor IX do not prevent thrombosis

Management

• patient education:
  • patient compliance is crucial for safety & efficacy of anticoagulation with warfarin
  • patients should notify physician in the event of unusual bleeding, especially:
    • gums
    • nose
    • vagina
    • hematuria
    • melena
    • excessive bruising
  • female patients should inform physician of pregnancy plans
  • travel should be discussed with physician
• fluctuating INR
  • vitamin K supplementation 100-150 ug/day may help stabilize INR
• surgery
  • discontinue 5 days prior to elective or scheduled surgery
  • bridging therapy with LMW heparin in high-risk patients
    • use unfractionated heparin if eGFR < 15-20 mL/min
• proton pump inhibitor does not reduce risk of GI bleed nless antiplatelet agent coadministered

More general terms

• heterocyclic compound, 2 rings
• lactone
• ketone
• pharmaceutical anticoagulant

Additional terms

• anticoagulation
• dietary interactions with warfarin
• International normalized ratio (INR)
• perioperative anticoagulation
• protocol for warfarin anticoagulation
• risk factors for persistently elevated INR
• superwarfarin; rat poison
• warfarin resistance
• warfarin sensitivity testing (CYP2C8, CYP2C9, CYP4F2, VKORC1)
• warfarin-induced epidermal necrosis

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6691
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=31424
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=17464
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5683