Information on warfarin

PGx Dosing Guidelines

Annotation of CPIC Guideline for warfarin and CYP2C9,CYP4F2,VKORC1

The updated guideline for pharmacogenetics-guided warfarin dosing is published by the Clinical Pharmacogenetics Implementation Consortium. The recommendations for dosing are for adult and pediatric patients that are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.

Annotation of CPNDS Guideline for warfarin and CYP2C9

The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) clinical recommendation group has published guidelines for the use of pharmacogenetic testing for variants in VKORC1 and CYP2C9 in adult and pediatric patients with an indication for warfarin. They recommend testing for the VKORC1 SNP -1639G>A (rs9923231) and the CYP2C9 alleles *2 and *3 in order to better guide warfarin dosage.

Annotation of DPWG Guideline for warfarin and VKORC1

Patients with the VKORC1 -1639 (rs9923231) AA genotype should be given 60% of the standard initial dose of warfarin. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. There are no recommendation for patients with the VKORC1 -1639 AG genotype.

Annotation of PRO Guideline for acenocoumarol,fluindione,warfarin and CYP2C9,VKORC1

Testing for VKORC1/CYP2C9 genotype is advisable to determine the optimal dose and to orient the prescription to an alternative therapeutic option such as a direct-action oral anticoagulant before initiating vitamin K antagonists (VKA) treatment. Testing is also advisable to explain an hemorrhagic event or VKA resistance after treatment initiation.

PGx Drug Labels

Annotation of FDA Label for warfarin and CYP2C9,PROC,PROS1,VKORC1

On FDA Biomarker List - see whole list on FDA website
Actionable PGx - see definitions

Warfarin (COUMADIN) is an anticoagulant used as a prophylaxis and to treat venous thrombosis, pulmonary embolism, thromboembolic complications from atrial fibrillation and cardiac valve replacement, and to reduce the recurrence of myocardial infarction. Pharmacogenomics-related dosing information for CYP2C9 and VKORC1 variants is provided within the label. The drug label notes that deficiency in protein C (PROC) or protein S (PROS1) have been associated with tissue necrosis following warfarin administration.

Drug labels from sources other than the FDA are available.

PGx Annotations

Clinical Annotation for rs12777823; warfarin (level 1A Dosage)

Level of Evidence Level 1A
Type Dosage
Biogeographical Group African American/Afro-Caribbean
Variant rs12777823
Variant Annotation
AA Patients with the AA genotype may require a lower dose of warfarin (may require a dose reduction of 9·34 mg/week) in African Americans as compared to patients with the GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
AG Patients with the AG genotype may require a lower dose of warfarin (may require a dose reduction of 6·92 mg/week) in African Americans as compared to patients with the GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
GG Patients with the GG genotype may require a higher dose of warfarin in African Americans as compared to patients with the AA or AG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

Clinical Annotation for rs9923231 (VKORC1); warfarin (level 1A Dosage)

Level of Evidence Level 1A
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Variant rs9923231
Variant Annotation
CC Patients with the CC genotype may require an increased dose of warfarin as compared to patients with the CT or TT genotype. Other genetic and clinical factors may also influence a patient's warfarin dose requirement.
CT Patients with the CT genotype may require a decreased dose of warfarin as compared to patients with the CC genotype or an increased dose as compared to patients with the TT genotype. Other genetic and clinical factors may also influence a patient's warfarin dose requirement.
TT Patients with the TT genotype may require a decerased dose of warfarin as compared to patients with the CC or CT genotype. Other genetic and clinical factors may also influence a patient's warfarin dose requirement.

Clinical Annotation for CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6; warfarin; over-anticoagulation (level 1A Toxicity/ADR)

Level of Evidence Level 1A
Type Toxicity/ADR
Genes CYP2C9
Phenotypes over-anticoagulation
Biogeographical Group Mixed Population
Variant CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6
Variant Annotation
*1 Patients carrying CYP2C9*1 allele in combination with another normal function allele may have decreased risk of over-anticoagulation when treated with warfarin as compared to patients carrying at least one copy of a decreased function or no function allele. Other genetic and clinical factors may also influence the toxicity to warfarin.
*2 Patients with CYP2C9*2 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the toxicity to warfarin.
*3 Patients with CYP2C9*3 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the toxicity to warfarin.
*5 Patients with CYP2C9*5 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the toxicity to warfarin.
*6 Patients with CYP2C9*6 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the toxicity to warfarin.
*11 Patients with CYP2C9*11 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the toxicity to warfarin.

Clinical Annotation for CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6; warfarin; Hemorrhage (level 1A Toxicity/ADR)

Level of Evidence Level 1A
Type Toxicity/ADR
Genes CYP2C9
Phenotypes Hemorrhage
Biogeographical Group Mixed Population
Variant CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6
Variant Annotation
*1 Patients carrying CYP2C9*1 allele in combination with another normal function allele may have a decreased risk of bleeding when treated with warfarin as compared to patients carrying at least one copy of a decreased function or no function allele. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.
*2 Patients with CYP2C9*2 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of bleeding when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.
*3 Patients with CYP2C9*3 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of bleeding when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.
*5 Patients with CYP2C9*5 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of bleeding when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.
*6 Patients with CYP2C9*6 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of bleeding when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.
*11 Patients with CYP2C9*11 in combination with another normal function allele, a decreased function allele, or a no function allele may have increased risk of bleeding when treated with warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence the risk of bleeding in patients administered warfarin.

Clinical Annotation for CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*6, CYP2C9*8; warfarin; Cardiovascular Diseases and Heart Diseases (level 1A Dosage)

Level of Evidence Level 1A
Type Dosage
Genes CYP2C9
Phenotypes Cardiovascular Diseases, Heart Diseases
Biogeographical Group Mixed Population
Variant CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*6, CYP2C9*8
Variant Annotation
*1 Patients carrying CYP2C9*1 allele in combination with another normal function allele may require a higher dose of warfarin as compared to patients carrying at least one copy of a decreased function or no function allele. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*2 Patients carrying CYP2C9*2 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*3 Patients carrying CYP2C9*3 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*4 Patients carrying CYP2C9*4 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*5 Patients carrying CYP2C9*5 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*6 Patients carrying CYP2C9*6 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*8 Patients carrying CYP2C9*8 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
*11 Patients carrying CYP2C9*11 allele in combination with another normal function allele, a decreased function allele, or a no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

Clinical Annotation for CYP4F2*1, CYP4F2*3; warfarin; Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Thromboembolism and venous thromboembolism (level 1A Dosage)

Level of Evidence Level 1A
Type Dosage
Genes CYP4F2
Phenotypes Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Thromboembolism, venous thromboembolism
Biogeographical Group Mixed Population
Biogeographical Notes Studies include White, Black or African American, Asian, Hispanic or Latino and Mixed populations.
Variant CYP4F2*1, CYP4F2*3
Variant Annotation
*1 Patients carrying the *1 allele (rs2108622 C) in combination with another *1 allele may have decreased warfarin dosage requirements as compared to patients with *3/*3 or *1/*3, while patients carrying the *1 allele in combination with a *3 allele may have decreased warfarin dosage requirements as compared to patients with two *3 alleles. Other genetic and clinical factors may also affect a patient's warfarin dosage requirements.
*3 Patients carrying the *3 allele (rs2108622 T) in combination with another *3 allele may have increased warfarin dosage requirements as compared to patients with *1/*1 or *1/*3, while patients carrying the *3 allele in combination with *1 allele may have increased warfarin dosage requirements as compared to patients with *1/*1. Other genetic and clinical factors may also affect a patient's warfarin dosage requirements.

Clinical Annotation for rs7294 (VKORC1); warfarin (level 1B Dosage)

Level of Evidence Level 1B
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Biogeographical Notes White, Asian, Black, Mixed Population
Variant rs7294
Variant Annotation
CC Patients with the CC genotype who are treated with warfarin may require a lower dose as compared to patients with the TC or TT genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
CT Patients with the CT genotype who are treated with warfarin may require a higher dose as compared to patients with the CC genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
TT Patients with the TT genotype who are treated with warfarin may require a higher dose as compared to patients with the CC genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

Clinical Annotation for rs9934438 (VKORC1); warfarin; Arteriosclerosis, Heart Diseases, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Pulmonary Embolism, Stroke, Thromboembolism, venous thromboembolism and Venous Thrombosis (level 1B Dosage)

Level of Evidence Level 1B
Type Dosage
Genes VKORC1
Phenotypes Arteriosclerosis, Heart Diseases, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Pulmonary Embolism, Stroke, Thromboembolism, venous thromboembolism, Venous Thrombosis
Biogeographical Group Mixed Population
Biogeographical Notes White,Black or African American, Asian
Variant rs9934438
Variant Annotation
AA Patients with the AA genotype who are treated with warfarin may require a lower dose as compared to patients with the AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
AG Patients with the AG genotype who are treated with warfarin may require a lower dose as compared to patients with the GG genotype, and a higher dose as compared to patients with the AA genotype. Other clinical and genetic factors may also influence a patient’s required dose of warfarin.
GG Patients with the GG genotype who are treated with warfarin may require higher dose as compared to patients with the AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

Clinical Annotation for rs4917639 (CYP2C9); warfarin (level 2A Dosage)

Level of Evidence Level 2A
Type Dosage
Genes CYP2C9
Biogeographical Group Mixed Population
Biogeographical Notes White, Asian
Variant rs4917639
Variant Annotation
AA Patients with the AA genotype may require increased dose of warfarin as compared to patients with the CC or CA genotype. Other clinical or genetic factors may also influence warfarin dose.
CA Patients with the CA genotype may require decreased dose of warfarin as compared to patients with the AA genotype. Other clinical or genetic factors may also influence warfarin dose.
CC Patients with the CC genotype may require decreased dose of warfarin as compared to patients with the AA genotype. Other clinical or genetic factors may also influence warfarin dose.

Clinical Annotation for rs2884737 (VKORC1); warfarin (level 2A Dosage)

Level of Evidence Level 2A
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Biogeographical Notes white, black, South Indian
Variant rs2884737
Variant Annotation
AA Patients with the AA genotype may require higher dose of warfarin as compared to patients with the CC genotype. Other clinical and genetic factors may also influence a patient's warfarin dose.
AC Patients with the AC genotype may require higher dose of warfarin as compared to patients with the CC genotype. Other clinical and genetic factors may also influence a patient's warfarin dose.
CC Patients with the CC genotype may require lower dose of warfarin as compared to patients with the AA genotype. Other clinical and genetic factors may also influence a patient's warfarin dose.

Clinical Annotation for rs9923231 (VKORC1); warfarin; time to therapeutic inr (level 2A Efficacy)

Level of Evidence Level 2A
Type Efficacy
Genes VKORC1
Phenotypes time to therapeutic inr
Biogeographical Group Mixed Population
Variant rs9923231
Variant Annotation
CC Patients with genotype CC may require longer time to therapeutic INR when treated with warfarin as compared with patients with genotype TT or CT. Other genetic and clinical factors may also influence the response to warfarin.
CT Patients with genotype CT may require shorter time to therapeutic INR when treated with warfarin as compared with patients with genotype CC. Other genetic and clinical factors may also influence the response to warfarin.
TT Patients with genotype TT may require shorter time to therapeutic INR when treated with warfarin as compared with patients with genotype CC. Other genetic and clinical factors may also influence the response to warfarin.

Clinical Annotation for rs9923231 (VKORC1); warfarin; Hemorrhage (level 2A Toxicity/ADR)

Level of Evidence Level 2A
Type Toxicity/ADR
Genes VKORC1
Phenotypes Hemorrhage
Biogeographical Group Mixed Population
Variant rs9923231
Variant Annotation
CC Patients with the CC genotype who are treated with warfarin may have a decreased risk of Hemorrhage as compared to the CT or TT genotypes. Other clinical and genetic factors may also influence risk of hemorrhage in patients administered warfarin.
CT Patients with the CT genotype who are treated with warfarin may have an increased risk of Hemorrhage as compared to the CC genotypes. Other clinical and genetic factors may also influence risk of hemorrhage in patients administered warfarin.
TT Patients with the TT genotype who are treated with warfarin or acenocoumarol may have an increased risk of Hemorrhage as compared to the CC genotypes. Other clinical and genetic factors may also influence risk of hemorrhage in patients administered warfarin.

Clinical Annotation for rs9923231 (VKORC1); warfarin; time in therapeutic range (level 2A Efficacy)

Level of Evidence Level 2A
Type Efficacy
Genes VKORC1
Phenotypes time in therapeutic range
Biogeographical Group Mixed Population
Variant rs9923231
Variant Annotation
CC Patients with the CC genotype may spent more time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype TT or CT. Contradictory findings have also been reported. Other genetic and clinical factors may also influence the response to warfarin.
CT Patients with the CT genotype may spent less time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype CC. Contradictory findings have also been reported. Other genetic and clinical factors may also influence the response to warfarin.
TT Patients with the TT genotype may spent less time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype CC. Contradictory findings have also been reported. Other genetic and clinical factors may also influence the response to warfarin.

Clinical Annotation for rs2359612 (VKORC1); warfarin (level 2A Dosage)

Level of Evidence Level 2A
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Biogeographical Notes Asians, Black or Whites
Variant rs2359612
Variant Annotation
AA Patients with the AA genotype who are treated with warfarin may require a decreased dose as compared to patients with the GG genotype. Other genetic and clinical factors may also influence dose of warfarin.
AG Patients with the AG genotype who are treated with warfarin may require a decreased dose as compared to patients with the GG genotype. Other genetic and clinical factors may also influence dose of warfarin.
GG Patients with the GG genotype who are treated with warfarin may require an increased dose as compared to patients with the AG or AA genotype. Other genetic and clinical factors may also influence dose of warfarin.

Clinical Annotation for rs8050894 (VKORC1); warfarin (level 2A Dosage)

Level of Evidence Level 2A
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Biogeographical Notes Asians, Black or Whites
Variant rs8050894
Variant Annotation
CC Patients with the CC genotype who are treated with warfarin may require a higher dose as compared to patients with the CG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
CG Patients with the CG genotype who are treated with warfarin may require a lower dose as compared to patients with the CC genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.
GG Patients with the GG genotype who are treated with warfarin may require the lowest dose as compared to patients with the CC genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

Clinical Annotation for rs61742245 (VKORC1); warfarin (level 2A Dosage)

Level of Evidence Level 2A
Type Dosage
Genes VKORC1
Biogeographical Group Mixed Population
Variant rs61742245
Variant Annotation
AA Patients with the AA genotype may have increased dose of warfarin as compared to patients with genotype CC. Other genetic and clinical factors may also influence the dose of warfarin.
AC Patients with the AC genotype may have increased dose of warfarin as compared to patients with genotype CC. Other genetic and clinical factors may also influence the dose of warfarin.
CC Patients with the CC genotype may have decreased dose of warfarin as compared to patients with genotype AA or AC. Other genetic and clinical factors may also influence the dose of warfarin.

Clinical Annotation for rs9923231 (VKORC1); warfarin; over-anticoagulation (level 2A Toxicity/ADR)

Level of Evidence Level 2A
Type Toxicity/ADR
Genes VKORC1
Phenotypes over-anticoagulation
Biogeographical Group Mixed Population
Variant rs9923231
Variant Annotation
CC Patients with the CC genotype may have decreased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype TT or CT. Other genetic and clinical factors may also influence the toxicity to warfarin.
CT Patients with the CT genotype may have increased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype CC. Other genetic and clinical factors may also influence the toxicity to warfarin.
TT Patients with the TT genotype may have increased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype CC. Other genetic and clinical factors may also influence the toxicity to warfarin.

Clinical annotations with lower levels of evidence are available.