Amiodarone (Cordarone® or Pacerone®)

Amiodarone is an anti-arrhythmic drug that decreases warfarin requirements. When estimating a dose, WarfarinDosing.org takes amiodarone into account, but that estimate that may be wrong, especially in patients taking large amiodarone doses (i.e., ≥ 600 mg/day).

Azoles

"Azoles" are a class of anti-fungal drugs that include ketoconazole, fluconazole, itraconazole, etc. Azoles decrease warfarin requirements. When estimating a dose, WarfarinDosing.org takes azoles into account, but that dose reduction is an estimate so an alternative anticoagulant may be safer. Metronidazole is an antibiotic that also decreases warfarin requirements significantly.

Baseline INR

Prior to beginning warfarin, the baseline INR should be around 1.0.  Baseline INR values
> 1.2 may indicate prior warfarin use, liver disease, or malnutrition--conditions that can decrease warfarin requirements, but are not accounted for in the dosing algorithms.

CALU Genotype

The CALU gene codes for Calumenin, which regulates vitamin K 2,3-epoxide reductase complex subunit 1. CALU rs339097 is associated with a 14% increased warfarin dose per G allele.( Voora D et al ).

CYP2C9 genotype

CYP2C9 stands for cytochrome P450, subfamily IIC, polypeptide 9. CYP2C9 is an enzyme that metabolizes S-warfarin. Patients who have 1 copy of the CYP2C9*2 SNP (i.e, CYP2C9*1/*2) are slow metabolizers of S-warfarin; patients who are homozygous for CYP2C9*2 (denoted as CYP2C9*2/*2) or who carry at least 1 copy of the CYP2C9*3, CYP2C9*5 or CYP2C9*6 SNP are very slow metabolizers. To help prevent overdose, WarfarinDosing.org decreases the estimated warfarin dose (after an initial loading dose) in slow an very slow metabolizers.

CYP4F2 genotype

Cytochrome P450 family 4, subfamily F, polypeptide 2 (CYP4F2) appears to be an oxidase of vitamin K1 (and also vitamin E) (McDonald MG et al 2009). Carriers of CYP4F2 V433M (rs2108622 C>T) have reduced function, resulting in approximately an 8% increase in warfarin dose (Caldwell M. et al 2008).

GGCX genotype

Gamma-glutamyl carboxylase resides in the endoplasmic reticulum where it oxidizes vitamin K 2,3-epoxide, which then activates clotting factors II, VII, IX, and X ( Rieder M et al, 2007). GGCX rs11676382 is associated with a 6% reduced warfarin dose per G allele (King C et al. 2010).

Indication

The reason that warfarin therapy is prescribed. For patients with multiple indications, select the condition with the highest target INR or longest duration of warfarin therapy.

INR

INR stands for International Normalized Ratio.  For most conditions the target INR is around 2.5, but higher INR values are recommend in some conditions (e.g. prosthetic mitral valves).

Liver Disease

Liver disease should be marked yes in patients with any of the following:  hepatic cirrhosis, a two-fold elevation of any liver transaminase, or an albumin < 3.6 (even if the low albumin is from another cause).  Liver transaminases include AST (aspartate aminotransferase, also called serum glutamic-oxaloacetic transaminase) and ALT (alanine transaminase, also called serum glutamate pyruvate transaminase).   When estimating an initial dose, WarfarinDosing.org does not take liver disease into account quantitatively but provides a warning that liver disease may predispose to an elevated INR response.

Mini-Loading dose

An initial warfarin dose that exceeds the estimated therapeutic dose.  To decrease the delay inherent in waiting for a therapeutic INR, WarfarinDosing.org recommends 1 or 2 mini-loading doses in slow metabolizers— i.e., patients who carry the CYP2C9*2, CYP2C9*3, CYP2C9*5, and/or CYP2C9*6 allele. To have the INR rise quickly, WarfarinDosing.org also calculates ~50% more than this estimate for the initial 1 or 2 days.

A hemorrhage requiring transfusion of 2 or more units of packed red blood cells (RBCs*) or a hemorrhage into a critical location: intracranial, subdural, epidural, intraocular, retroperitoneal, or pericardial.
*Does not include RBCs transfused during elective surgery.

S-warfarin

The more active half of commercial warfarin (Coumadin^TM and others).

Smokes

On WarfarinDosing.org, smokes refers to daily use of any tobacco (cigarettes, pipes, cigars, and chewing tobacco) or nicotine product (e.g. nicotine gum or patch).

SNP

SNP stands for Single Nucleotide Polymorphism.  SNPs are common genetic variants.  WarfarinDosing.org does not tailor the warfarin dose to rare genetic variants.

Statin/HMG CoA Reductase Inhibitor

Statins, or hydroxy methylglutaryl-coenzyme A reductase inhibitors, are a class of drugs that lower LDL cholesterol and may have other cardiovascular benefits. When taken with warfarin, statins (except for pravastatin) can decrease warfarin requirements. WarfarinDosing.org takes statins into account after the 3^rd warfarin dose, but not before that dose.

"Sulfa" antibiotics

"Sulfa" stands for sulfonamide antibiotics, which are sold as Septra®, Bactrim®, Cotrim®, and Sulfatrim®. They decrease warfarin requirements. When estimating a dose, WarfarinDosing.org takes sulfa antibiotics into account, but that dose reduction is an estimate that may be wrong.

VKORC1 -1639/ 3673 genotype

VKORC1 stands for Vitamin K epoxide reductase, complex 1 gene.  Warfarin inhibits the product of this gene (VKOR), a key enzyme in the vitamin K cycle.  WarfarinDosing.org tailors the estimated dose to a promoter SNP (often call 3673), which is located -1639 nucleotide base pairs upstream from the ATG start codon in the VKORC1 gene. Patients who have the AA genotype (or AA haplotype) are the most warfarin sensitive and therefore often require lower warfarin doses.  The VKORC1-1639/3673 A allele is in strong linkage disequilibrium with the VKORC1 1173 T and VKORC1 6853 C alleles.