imported>Chunbum Park |
imported>Robert Badgett |
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| ==Vitamin K antagonists== | | ==Vitamin K antagonists== |
| ===Warfarin=== | | ===Warfarin=== |
| ====Pharmacogenomics====
| | {{main|warfarin}} |
| Warfarin activity is determined partially by genetic factors. The American [[Food and Drug Administration]] "highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients" .<ref>{{cite web |url=http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html |title=FDA Approves Updated Warfarin (Coumadin) Prescribing Information |accessdate=2007-08-20 |format= |work=}}</ref>
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| =====VKORC1=====
| | Warfarin is a commonly used oral anticoagulant that interferes with the Vitamin K dependent coagulation co-factors. |
| [[Polymorphism (biology)|Polymorphism]]s in the ''[[vitamin K epoxide reductase]] complex 1 (VKORC1)'' gene explain 30% of the dose variation between patients<ref name="pmid15883587">{{cite journal |author=Wadelius M, Chen LY, Downes K, ''et al'' |title=Common VKORC1 and GGCX polymorphisms associated with warfarin dose |journal=Pharmacogenomics J. |volume=5 |issue=4 |pages=262-70 |year=2005 |pmid=15883587 |doi=10.1038/sj.tpj.6500313}}</ref>: particular mutations make VKORC1 less susceptible to suppression by warfarin<ref name="pmid14765194"/> There are a main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B).<ref name="pmid15930419">{{cite journal |author=Rieder MJ, Reiner AP, Gage BF, ''et al'' |title=Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose |journal=N. Engl. J. Med. |volume=352 |issue=22 |pages=2285-93 |year=2005 |pmid=15930419 |doi=10.1056/NEJMoa044503}}</ref> For the three combinations of the haplotypes, the mean daily maintenance dose of warfarin was:
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| * A/A: 2.7+/-0.2 mg
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| * A/B: 4.9+/-0.2 mg
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| * B/B: 6.2+/-0.3 mg
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| ''VKORC1'' polymorphisms also explain why [[African American]]s are relatively resistant to warfarin (higher proportion of group B haplotypes), while [[Asian American]]s are more sensitive (higher proportion of group A haplotypes).<ref name="pmid15930419"/>
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| =====CYP2C9=====
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| ''CYP2C9'' is an [[isozyme]] of [[cytochrome P450]]. Polymorphisms of CYP2C9 explain another 10% of variation in warfarin dosing<ref name="pmid15883587"/>, mainly among Caucasian patients as these variants are rare in African American and most Asian populations.<ref name="pmid15714076">{{cite journal |author=Sanderson S, Emery J, Higgins J |title=CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis |journal=Genet. Med. |volume=7 |issue=2 |pages=97-104 |year=2005 |pmid=15714076 |doi=}}</ref> A [[meta-analysis]] of mainly Caucasian patients found<ref name="pmid15714076"/>:
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| * CYP2C9*2 allele:
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| ** present in 12.2% of patients
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| ** mean reduction was in warfarin dose was 0.85 mg (17% reduction)
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| ** relative bleeding risk was 1.91
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| * CYP2C9*3 allele:
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| ** present in 7.9% of patients
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| ** mean reduction was in warfarin dose was 1.92 mg (37% reduction)
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| ** relative bleeding risk was 1.77
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| ====Dosage====
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| =====Loading regimens=====
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| Because of warfarin's poorly-predictable [[pharmacokinetics]], several researchers have proposed algorithms for commencing warfarin treatment:
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| * The Kovacs 10 mg algorithm was better than a 5 mg algorithm.<ref name="pmid12729425">{{cite journal |author=Kovacs MJ, Rodger M, Anderson DR, ''et al'' |title=Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial |journal=Ann. Intern. Med. |volume=138 |issue=9 |pages=714-9 |year=2003 |pmid=12729425 |doi=|url=http://annals.org/cgi/content/full/138/9/714}} ([http://annals.org/cgi/content/full/138/9/714/F1 summary of 10 mg algorithm])</ref> The 10 mg algorithm performed similarly to a pharmacogenetic-guided algorithm.<ref name="pmid17989110">{{cite journal |author=Anderson JL, Horne BD, Stevens SM, ''et al'' |title=Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation |journal=Circulation |volume=116 |issue=22 |pages=2563–70 |year=2007 |pmid=17989110 |doi=10.1161/CIRCULATIONAHA.107.737312 |issn=}}</ref>
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| * The Fennerty 10 mg regimen is for urgent anticoagulation<ref name="pmid3144365">{{cite journal |author=Fennerty A, Campbell IA, Routledge PA |title=Anticoagulants in venous thromboembolism |journal=BMJ |volume=297 |issue=6659 |pages=1285-8 |year=1988 |pmid=3144365 |doi= | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3144365}}</ref>
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| * The Tait 5 mg regimen is for "routine" (low-risk) anticoagulation ([http://www.blackwell-synergy.com/action/showPopup?citid=citart1&id=f1&doi=10.1046%2Fj.1365-2141.1998.00716.x summary])<ref name="pmid9633885">{{cite journal |author=Tait RC, Sefcick A |title=A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation |journal=Br. J. Haematol. |volume=101 |issue=3 |pages=450-4 |year=1998 |pmid=9633885 |doi=10.1046/j.1365-2141.1998.00716.x }}</ref>
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| * Millican ''et al'' derived an 8-value pharmacogenetic-based model from a cohort of orthopedic patients. The model included CYP29C and VKORC1 genotype results and predicted 80% of the variation in warfarin doses. It is awaiting validation in larger populations and has not been reproduced in those who require warfarin for other indications.<ref>{{cite journal |author=Millican E, Jacobsen-Lenzini PA, Milligan PE, ''et al'' |title=Genetic-based dosing in orthopaedic patients beginning warfarin therapy |journal= |volume=110 |issue=5 |pages=1511-5 |year=2007 |pmid=17387222 |doi=10.1182/blood-2007-01-069609}} [http://www.warfarindosing.org Online tool based on the study].</ref>
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| * A second pharmacogenetic-guided algorithm performed similarly to the Kovaks 10 mg algorithm.<ref name="pmid17989110">{{cite journal |author=Anderson JL, Horne BD, Stevens SM, ''et al'' |title=Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation |journal=Circulation |volume=116 |issue=22 |pages=2563–70 |year=2007 |pmid=17989110 |doi=10.1161/CIRCULATIONAHA.107.737312 |issn=}}</ref>
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| =====Adjusting the maintenance dose=====
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| Recommendations by the [[American College of Chest Physicians]]<ref name="pmid15383473"/> have been distilled to help manage dose adjustments.<ref>{{cite web |url=http://www.aafp.org/afp/20050515/pocform.html |title=Point-of-Care Guides - May 15, 2005 - American Family Physician |accessdate=2007-08-20 |format= |work=}}</ref>
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| ====Interactions and contraindications====
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| Some foodstuffs have also been reported to interact with warfarin.<ref name="pmid15911722">{{cite journal |author=Holbrook AM, Pereira JA, Labiris R, ''et al'' |title=Systematic overview of warfarin and its drug and food interactions |journal=Arch. Intern. Med. |volume=165 |issue=10 |pages=1095–106 |year=2005 |pmid=15911722 |doi=10.1001/archinte.165.10.1095}}</ref>
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| ====Adverse effects====
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| Patients aged 80 years or more may be especially susceptible to bleeding complications with a rate of 13 bleeds per 100 person-years.<ref name="pmid17515465">{{cite journal |author=Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S |title=Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation |journal=Circulation |volume=115 |issue=21 |pages=2689-96 |year=2007 |pmid=17515465 |doi=10.1161/CIRCULATIONAHA.106.653048}}PMID 17515465</ref>
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| ====Antagonism and reversal====
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| Details on reversing warfarin are provided in [[clinical practice guideline]]s from the [[American College of Chest Physicians]].<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S-233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S}} ([http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S/T6 summary])</ref>
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| For patients with an [[international normalized ratio]] (INR) between 4.5 and 10.0, 1 mg of oral vitamin K is effective.<ref name="pmid12186515">{{cite journal |author=Crowther MA, Douketis JD, Schnurr T, ''et al'' |title=Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251-4 |year=2002 |pmid=12186515 |doi=}}</ref>
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| ==Heparin== | | ==Heparin== |
