warfarin (Coumadin, Panwarfin, Jantoven)
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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)
- 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
- active bleeding, prior hemorrhage
- pregnancy
- exception seems to be mechanical heart valve[6]
- safe during lactation[6]
- 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[40]
- predisposition to falls
- high risk of falls may not be an absolute contraindication[41]
- barriers to adherence
- alcohol or drug abuse
- warfarin resistance
- does not lower the risk for catheter-related thromboses in patients with cancer[19]
- also see warfarin & surgery
- preventing embolic stroke in patients with ESRD[55]
Caution:
- anticoagulation with warfarin can be difficult in patients with underlying vitamin K deficiency
- 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
- 25 for 1.5 years for major hemorrhage
- number needed to treat (NNT) with warfarin vs aspirin
- 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
- 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)[11]
- 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[6]
- 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[46]
- moderate to severe renal impairment may be associated with a reduction in warfarin dose requirements[24]
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[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
- not common (1-10%)
- uncommon (< 1%)
- mouth ulcers, renal damage, discolored toes (blue toe syndrome), hepatotoxicity, skin rash, agranulocytosis, anorexia
- epidermal necrosis
- other
- 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]
- 6 fold increased risk of intracerebral hemorrhage[13][15]
- long-term use may increased the risk of bone fracture[5]
- teratogenic
- heavy menstrual bleeding
- hemorrhage from postovulatory cysts
- sensation of cold[9]
- 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]
- 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[38]
- 50% decrease in protein C activity with warfarin initiation leads to hypercoagulable state, exp with discontinuation of heparin[6]
- bleeding, especially GI bleeding
- heart disease, liver disease, kidney disease, cancer, anemia & history of stroke are risk factors for adverse events in patients who receive warfarin[6]
Toxicity:
- hold warfarin administration until therapeutic INR & cessation of bleeding
- 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]
- for INR 5-10*, in the absence of bleeding, withhold warfarin
- life-threatening hemorrhage
- 4-factor prothrombin complex concentrate 25-50 units/kg
- 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]
- 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[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]
- 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[39]
- erythromycin & other macrolides
- sulfonamides, sulfamethoxazole/trimethoprim (see above)
- antifungals: fluconazole, griseofulvin, ketoconazole, miconazole, voriconazole[6][26]
- 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)[56]
- 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[6]
- antibiotics alter intestinal flora that synthesize vitamin K
- 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]
- 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:
- genetic testing (see warfarin sensitivity testing)
- vitamin K epoxide reductase alleles (VKORC1 gene mutation)
- CYP2C9 variants
- 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
- 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[6]
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:
- female patients should inform physician of pregnancy plans
- travel should be discussed with physician
- fluctuating INR
- surgery
- discontinue 5 days prior to elective or scheduled surgery unless low-risk
- bridging therapy with LMW heparin in high-risk patients[6][32]
- not necessary to discontinue warfarin if low-risk procedure
- proton pump inhibitor does not reduce risk of GI bleed nless antiplatelet agent coadministered[58]
More general terms
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
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Clinical Guide to Laboratory Tests, 3rd edition, NW Tietz ed, WB Saunders, Philadelphia, 1995
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ 5.0 5.1 Prescriber's Letter 6(10):60, Oct, 1999
- ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018.
- ↑ Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 9.0 9.1 Prescriber's Letter 8(12):68 2001
- ↑ 10.0 10.1 Prescriber's Letter 9(3):14 2002
- ↑ 11.0 11.1 Prescriber's Letter 10(6):35 2003
- ↑ 12.0 12.1 Journal Watch 24(1):2, 2004 Lubetsky A et al Arch Intern Med 163:2469, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14609783
- ↑ 13.0 13.1 13.2 Goldstein JN et al, Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage Stroke 2006; 37:151 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16306465
- ↑ 14.0 14.1 14.2 DeZee KJ et al, Treatment of excessive anticoagulation with phytonadione (vitamin K): A meta-analysis. Arch Intern Med 2006; 166:391 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16505257
- ↑ 15.0 15.1 Flaherty ML et al, The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 2007, 68:116 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17210891
- ↑ Prescriber's Letter 14(4): 2007 Warfarin and Corticosteroid Interaction Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=230404&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Coumadin
- ↑ 18.0 18.1 Hylek EM et al, Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007, 115:2689 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17515465
Wyse DG Bleeding while starting anticoagulation for thromboembolism prophylaxis in elderly patients with atrial fibrillation: From bad to worse. Circulation 2007, 115:2684 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17533193 - ↑ 19.0 19.1 Young AM et al, Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial Lancet 2009 373:567-574 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19217991
- ↑ 20.0 20.1 Prescriber's Letter 16(4): 2009 How to Manage High INRs in Warfarin Patients Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250409&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 21.0 21.1 Prescriber's Letter 16(6): 2009 How to Manage High INRs in Warfarin Patients Use of Low-Dose Vitamin K Supplements to Stabilize INR PATIENT HANDOUT: What You Should Know About Your Diet and Warfarin COMMENTARY: Use of Low-Dose Vitamin K Supplements to Stabilize INR CHART: How to Manage High INRs in Warfarin Patients GUIDELINES: Pharmacology and Management of the Vitamin K Antagonists (ACCP, 8th edition, Summary) Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250604&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 22.0 22.1 Hirsh AJ et al, Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):160S-198S PMID: https://www.ncbi.nlm.nih.gov/pubmed/18574265
- ↑ 23.0 23.1 Matchar DB et al, Effect of Home Testing of International Normalized Ratio on Clinical Events N Engl J Med 2010 Oct 21; 363:1608. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20961244 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1002617
- ↑ 24.0 24.1 Limdi NA et al. Warfarin dosing in patients with impaired kidney function. Am J Kidney Dis 2010 Nov; 56:823 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/20709439 <Internet> http://dx.doi.org/10.1053/j.ajkd.2010.05.023
Limdi NA et al. Influence of kidney function on risk of supratherapeutic international normalized ratio-related hemorrhage in warfarin users: A prospective cohort study. Am J Kidney Dis 2015 May; 65:701 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25468385
Jun M, James MT, Manns BJ et al The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study. BMJ. 2015 Feb 3;350:h246 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25647223 - ↑ Wieloch M et al. Anticoagulation control in Sweden: Reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011 Sep 18; 32:2282 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21616951
- ↑ 26.0 26.1 Baillargeon J et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med 2012 Feb; 125:183. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22269622
- ↑ 27.0 27.1 Prescriber's Letter 19(5): 2012 CHART: How to Manage High INRs in Warfarin Patients GUIDELINES: Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012) Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280524&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Prescriber's Letter 19(6): 2012 COMMENTARY: Update on Warfarin Dosing and Monitoring WARFARIN DOSING: Warfarin Dose Calculator Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280617&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 29.0 29.1 Witt DM et al Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding. Arch Intern Med. Published online September 17, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22987143 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1358544
Brotman DJ and Jaffer AK Resuming Anticoagulation in the First Week Following Gastrointestinal Tract Hemorrhage: Should We Adopt a 4-Day Rule? Comment on "Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding" Arch Intern Med. Published online September 17, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22987255 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1358547 - ↑ 30.0 30.1 30.2 Fang MC et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am Coll Cardiol 2011 Jul 19; 58:395. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21757117
- ↑ 31.0 31.1 Donze J et al. Scores to predict major bleeding risk during oral anticoagulation therapy: A prospective validation study. Am J Med 2012 Nov; 125:1095. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22939362
- ↑ 32.0 32.1 Douketis JD, Spyropoulos AC, Spencer FA et al Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22315266 (corresponding NGC guideline withdrawn Dec 2017)
- ↑ 33.0 33.1 Holbrook A, Schulman S, Witt DM et al Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e152S-84S PMID: https://www.ncbi.nlm.nih.gov/pubmed/22315259 Free PMC Article (corresponding NGC guideline withdrawn Dec 2017)
Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb 15; 141:e419S PMID: https://www.ncbi.nlm.nih.gov/pubmed/22315268
corresponding NGC guideline updated Sept 2016
Kearon C et al Antithrombotic Therapy for VTE Disease: CHEST Guideline. Chest. January 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26867832 <Internet> http://journal.publications.chestnet.org/article.aspx?articleid=2479255 - ↑ Prescriber's Letter 20(10): 2013 ALGORITHM: How to Manage High INRs in Warfarin Patients CHART: Clotting Factors for Reversing Anticoagulants Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=291012&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Deprecated Reference
- ↑ 36.0 36.1 Kimmel SE et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013 Nov 19 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24251361 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1310669
- ↑ 37.0 37.1 Pirmohamed M et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013 Nov 19; <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24251363 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1311386
Verhoef TI et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013 Nov 19 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24251360 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1311388 - ↑ 38.0 38.1 Azoulay L et al Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J first published online December 18, 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24353282 <Internet> http://eurheartj.oxfordjournals.org/content/early/2013/12/15/eurheartj.eht499.full
- ↑ 39.0 39.1 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 40.0 40.1 Shah M et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014 Mar 18; 129:1196. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24452752 <Internet> http://circ.ahajournals.org/content/129/11/1196
Granger CB and Chertow GM. A pint of sweat will save a gallon of blood: A call for randomized trials of anticoagulation in end-stage renal disease. Circulation 2014 Mar 18; 129:1190 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24452751 <Internet> http://circ.ahajournals.org/content/129/11/1190 - ↑ 41.0 41.1 Donze J et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012 Aug; 125:773 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22840664
- ↑ 42.0 42.1 Orciari Herman A, Fairchild DG, Hefner EH Dabigatran Linked to More Bleeding Events Than Warfarin in Atrial Fibrillation. Physician's First Watch, Nov 4, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org
Hernandez I et al Risk of Bleeding With Dabigatran in Atrial Fibrillation. JAMA Intern Med. Published online November 03, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25365537 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1921753 - ↑ 43.0 43.1 Sengupta N et al. The risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: A prospective study. Am J Gastroenterol 2014 Dec 16 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25512338 <Internet> http://www.nature.com/ajg/journal/vaop/ncurrent/full/ajg2014398a.html
- ↑ 44.0 44.1 Jun M et al. The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: Population based observational study. BMJ 2015 Feb 3; 350:h246 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25647223
- ↑ Kawai VK, Cunningham A, Vear SI et al Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014 Dec;15(16):1973-83 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25521356
- ↑ 46.0 46.1 46.2 Mega JL et al. Genetics and the clinical response to warfarin and edoxaban: Findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015 Mar 10; [e-pub] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25769357 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961994-2/abstract
Wu AHB. Pharmacogenomic testing and response to warfarin. Lancet 2015 Mar 10 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25769360 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962219-4/abstract - ↑ 47.0 47.1 47.2 The NNT: Oral anticoagulants in non-valvular atrial fibrillation for primary stroke prevention (no prior stroke) http://www.thennt.com/nnt/warfarin-for-atrial-fibrillation-stroke-prevention/
Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001927. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16034869 - ↑ 48.0 48.1 The NNT: Oral anticoagulants versus antiplatelet agents in non-valvular atrial fibrillation for stroke prevention (and no prior stroke) http://www.thennt.com/nnt/warfarin-vs-aspirin-for-atrial-fibrillation-stroke-prevention/
Aguilar MI1, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006186. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17636831 - ↑ 49.0 49.1 49.2 49.3 Green D Limb Gangrene in Cancer Patients Receiving Warfarin. NEJM Journal Watch. June 4, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
Warkentin TE et al. Warfarin-induced venous limb ischemia/gangrene complicating cancer: A novel and clinically distinct syndrome. Blood 2015 May 15 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25979950 - ↑ 50.0 50.1 Pottegard A, Henriksen DP, Madsen KG et al Change in International Normalized Ratio Among Patients Treated With Dicloxacillin and Vitamin K Antagonists. JAMA. 2015;314(3):296-297. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26197191 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=2397825
- ↑ Sarode R, Milling TJ Jr, Refaai MA et al Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013 Sep 10;128(11):1234-43 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23935011
- ↑ 52.0 52.1 Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007 Mar 15;109(6):2419-23. Epub 2006 Nov 16. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17110451
- ↑ Ageno W, Gallus AS, Wittkowsky A et al Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e44S-88S PMID: https://www.ncbi.nlm.nih.gov/pubmed/22315269
- ↑ 54.0 54.1 Kearon C, Ginsberg JS, Kovacs MJ et al. Comparison of low-intensity warfarin therapy with conventional- intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349(7):631-639. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12917299
- ↑ 55.0 55.1 Dahal K et al. Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: A meta-analysis of observational studies. Chest 2016 Apr; 149:951 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26378611
- ↑ 56.0 56.1 Paauw DS Dangerous and Deadly Drug Combinations Medscape. June 30, 2016 http://www.medscape.com/features/slideshow/dangerous-drug-combinations
- ↑ 57.0 57.1 Pokorney SD, Simon DN, Thomas L et al. Stability of International Normalized Ratios in Patients Taking Long-term Warfarin Therapy.. JAMA 2016 Aug 9; 316:661 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27532922
- ↑ 58.0 58.1 Ray WA, Chung CP, Murray KT et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology 2016 Sep 14 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27639805
- ↑ 59.0 59.1 59.2 Haaland GS, Falk RS, Straume O et al Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. AMA Intern Med. 2017;177(12):1774-1780 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29114736 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2661703
- ↑ Crowther MA, Ageno W, Garcia D et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med 2009 Mar 5; 150:293. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19258557
- ↑ 61.0 61.1 61.2 Anderson I, Cifu AS. Management of Bleeding in Patients Taking Oral Anticoagulants. JAMA. 2018;319(19):2032-2033. May 15, 2018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29800198 https://jamanetwork.com/journals/jama/fullarticle/2681178
- ↑ Lee A, Crowther M. Practical issues with vitamin K antagonists: elevated INRs, low time-in-therapeutic range, and warfarin failure. J Thromb Thrombolysis. 2011 Apr;31(3):249-58. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21274594
- ↑ 63.0 63.1 Khatib R et al. Vitamin K for reversal of excessive vitamin K antagonist anticoagulation: A systematic review and meta-analysis. Blood Adv 2019 Mar 12; 3:789-796 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/30850385 Free PMC Article <Internet> http://www.bloodadvances.org/content/3/5/789?sso-checked=true
- ↑ 64.0 64.1 NEJM Knowledge+