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warfarin (Coumadin, Panwarfin, Jantoven)

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 [59] - 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 [59] Contraindications: 1) active bleeding, prior hemorrhage 2) pregnancy - exception seems to be mechanical heart valve [6] - safe during lactation [6] 3) renal insufficiency a) seems beneficial for patients with atrial fibrillation & mild-moderate renal failure b) may cause more harm than benefit in patients with atrial fibrillation & end-stage renal disease [40] 4) predisposition to falls - high risk of falls may not be an absolute contraindication [41] 5) barriers to adherence 6) alcohol or drug abuse 7) warfarin resistance 8) does not lower the risk for catheter-related thromboses in patients with cancer [19] 9) also see warfarin & surgery 10) preventing embolic stroke in patients with ESRD [55] Caution: - anticoagulation with warfarin can be difficult in patients with underlying vitamin K deficiency - INR may be supersensitive to warfarin dose [6] - use caution in patients with malignancy (see adverse effects) [49] Benefit/risk: - number needed to treat non-valvular atrial fibrillation [47] - 25 for 1.5 years to prevent 1 stroke - 42 for 1.5 years to prevent 1 death - number needed to harm [47] - 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 [48] - 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 [21,22] * long-term low-intensity anticoagulation INR 1.5-2.0 (after 3 months of standard therapy) not recommended [54] Tabs: 1, 2, 2.5, 5, 7, 10 mg. Pharmacokinetics: 1) well absorbed from the GI tract 2) 97% of the drug is bound to plasma proteins, primarily albumin 3) full anticoagulation is achieved 3-7 days after initiation of therapy (even with therapeutic INR) [11] 4) 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) 5) effective 1/2life is 20-6- hours [6] 6) metabolized in the liver by CYP1A2, CYP2C9, CYP2C19, CYP3A4 7) polymorphisms in VKORC1 associated with warfarin resistance 8) polymorphisms in CYP2C9 & VKORC1, account for ~40% of the variability in warfarin responses [46] 9) moderate to severe renal impairment may be associated with a reduction in warfarin dose requirements [24] Monitor: - international normalized ratio (INR) - point of care testing (fingerstick) for home testing may be useful for patients with stable INR [23] - 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 [6] - 25% of warfarin recipients achieve stability of INR within 6 months based; of these patients, 30% with stable INR in subsequent year [57] Adverse effects: 1) not common (1-10%) - alopecia, stomach cramps, nausea, vomiting, diarrhea, leukopenia 2) 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 [6] - associated with depletion of protein C & hypercoagulable state 3) other a) bleeding, especially GI bleeding - 6 fold increased risk of intracerebral hemorrhage [13,15] - risk of intracranial hemorrhage in elderly (> 75 years of age) 1.8% [42] (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 [18] - risk of major hemorrhage ranges from 0.4% per year to 17% per year depending upon risk factors [30] - major risk factors include: [30] - 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 [44] - scoring systems no better than physician clinical judgment in predicting major hemorrhage [31] - when to restart anticoagulation after GI blood is controversial - study suggests after resolution of GI bleed, especially in patients with malignancy [43] b) long-term use may increased the risk of bone fracture [5] c) teratogenic d) heavy menstrual bleeding e) hemorrhage from postovulatory cysts f) sensation of cold [9] g) progression of DVT to limb ischemia & gangrene in patients with cancer-associated hypercoagulability [49] - thrombin generation coupled with warfarin-induced decreases in protein C & protein S may result in massive thrombosis [49] h) may cause skin necrosis & thrombosis in patients with protein C deficiency i) may paradoxically increase risk of ischemic stroke during initiation of therapy by inhibition of endogenous anticoagulants [38] - 50% decrease in protein C activity with warfarin initiation leads to hypercoagulable state, exp with discontinuation of heparin [6] 4) heart disease, liver disease, kidney disease, cancer, anemia & history of stroke are risk factors for adverse events in patients who receive warfarin [6] Toxicity: bleeding [13,14] 1) hold warfarin administration until therapeutic INR & cessation of bleeding - in most cases, warfarin can be safely restarted within one week of a GI bleed [29] 2) 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#* [6] 3) for INR 5-10*, in the absence of bleeding, withhold warfarin - vitamin K is not necessary [6,63], controversial [20] 4) life-threatening hemorrhage a) 4-factor prothrombin complex concentrate 25-50 units/kg - small volume, no need for thawing or ABO typing [6] - in combination with 5-10 mg of IV vitamin K [61] - treatment of choice [6,61] b) factor prothrombin complex in combination with 2 units of fresh frozen plasma or recombinant factor VIIa 25-90 ug/kg IV +/- vitamin K [6,33] c) fresh frozen plasma (FFP) alone may be an option if prothrombin complex & recombinant factor VIIa are unavailable d) FFP alone may be associated with lower risk of thrombosis [6] (requires thawing & ABO typing) * Also see risk factors for persistently elevated INR # vitamin K 2.5 mg PO as effective as 1 mg IV [12]; PO & IV more effective than SC [14]; * ref [27] 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 [64] Drug interactions: (also see prothrombin time) [10] 1) AMIODARONE, METRONIDAZOLE, TRIMETHOPRIM/SULFAMETHOXAZOLE (BACTRIM): significant increase in anticoagulant effect 2) agents that may increase effect of warfarin: a) antibiotics alter intestinal flora that synthesize vitamin K 1] ciprofloxacin & other quinolones 2] some cephalosporins (cefamandole, cefotetan, cefmetazole, cefoperazone) 3] amoxicillin [39] 4] erythromycin & other macrolides 5] sulfonamides, sulfamethoxazole/trimethoprim (see above) 6] antifungals: fluconazole, griseofulvin, ketoconazole, miconazole, voriconazole [6,26] 7] isoniazid, rifampin 8] tetracycline 9] metronidazole (see above) b) oral glucocorticoids (prednisone) c) hypolipidemic agents 1] lovastatin, simvastatin (& presumably other statins, except perhaps pravastatin) 2] clofibrate, colestipol, cholestyramine, fenofibrate, gemfibrozil, d) acute alcohol intoxication, disulfiram, acetaminophen e) antiplatelet agents - aspirin, P2Y12 receptor inhibitors f) NSAIDs, COX2 inhibitors, salicylates, phenylbutazone, sulfinpyrazone g) acetaminophen (scheduled dosing, occasional dose ok) [56] h) dextrothyroxine, methimazole, propylthiouracil, thyroid hormones i) thiazides, ethacrynic acid j) allopurinol, aminoglutethimide, anabolic steroids, chloral hydrate, cimetidine, diltiazem, glutethimide, glucagon, mercaptopurine, ompeprazole, pentoxifylline, phenytoin, propafenone, propranolol, quinidine, quinine, tamoxifen, vitamin E [6] 3) 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 [6], dicloxacillin [50] 4) any drug which inhibits CYP1A2, CYP2C9, CYP2C19, CYP3A4 can increase warfarin levels 5) any drug which induces CYP1A2, CYP2C9, CYP2C19, CYP3A4 can diminish warfarin levels 6) also see dietary interactions with warfarin Laboratory: 1) specimen: serum, plasma (EDTA) 2) methods: HPLC, GLC, spectrophotometric 3) interferences: a) fluorometry & spectrophotometry are non-specific b) dicumarol, thiopental, salicylate may interfere with spectrophotometric assays 3) therapeutic level generally assessed by: a) prothrombin time (PT) b) international normalized ratio (INR) 4) 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 [36,37] - not reimbursed by medicare [46] - identifies patients more likely to bleed in the 1st 90 days of warfarin treatment, thus candidates for more exepnsive direct oral anticoagulant therapy [6] - CYP4F2 enzyme activity (some labs do genetic testing) Mechanism of action: 1) anticoagulant 2) interferes with hepatic synthesis of vitamin K-dependent coagulation factors (facot II, factor VII, factor IX & factor X) 3) anticoagulant activities are due to inhibition of factor II & factor X; inhibition of factor VII & factor IX do not prevent thrombosis [6] Management: 1) patient education: a) patient compliance is crucial for safety & efficacy of anticoagulation with warfarin b) patients should notify physician in the event of unusual bleeding, especially: - gums - nose - vagina - hematuria - melena - excessive bruising c) female patients should inform physician of pregnancy plans d) travel should be discussed with physician 2) fluctuating INR - vitamin K supplementation 100-150 ug/day may help stabilize INR [6,52] 3) surgery - discontinue 5 days prior to elective or scheduled surgery - bridging therapy with LMW heparin in high-risk patients [6,32] - use unfractionated heparin if eGFR < 15-20 mL/min 4) proton pump inhibitor does not reduce risk of GI bleed nless antiplatelet agent coadministered [58]

Interactions

drug interactions drug adverse effects of antithrombotic agent(s)

Related

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

General

heterocyclic compound, 2 rings ketone lactone pharmaceutical anticoagulant

Properties

MISC-INFO: elimination route LIVER 1/2life 22-52 HOURS therapeutic-range 1-10 UG/ML toxic-range >10 NG/ML protein-binding 99% pregnancy-category X safety in lactation +

Database Correlations

PUBCHEM correlations

References

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