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.
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.
Reduce warfarin dose in CYP2C9 poor and intermediate metabolizers (PM and IM) and patients with CYP2C9*1/*3, *2/*3, *2/*2 or *3/*3 genotype. The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT.
Patients with the VKORC1 rs9923231 TT genotype (-1639 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 rs9923231 CT genotype (-1639 AG genotype).
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.
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.
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. 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.
| Level of Evidence | Level 1A |
|---|---|
| Type | Dosage |
| Variant | rs12777823 |
| Variant | Annotation |
|---|---|
| AA | Patients with the rs12777823 AA genotype may require a lower dose of warfarin in African Americans as compared to patients with the GG genotype. Other genetic and clinical factors may also influence warfarin dosage. |
| AG | Patients with the rs12777823 AG genotype may require a lower dose of warfarin in African Americans as compared to patients with the GG genotype. Other genetic and clinical factors may also influence warfarin dosage. |
| GG | Patients with the rs12777823 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 warfarin dosage. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs9923231 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs9923231 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 warfarin dose requirement. |
| CT | Patients with the rs9923231 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 warfarin dose requirement. |
| TT | Patients with the rs9923231 TT genotype may require a decreased dose of warfarin as compared to patients with the CC or CT genotype. Other genetic and clinical factors may also influence warfarin dose requirement. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Dosage |
| Genes | CYP4F2 |
| Variant | rs2108622 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs2108622 CC genotype may have decreased warfarin dosage requirements as compared to patients with the CT or TT genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dosage requirements. |
| CT | Patients with the rs2108622 CT genotype may have increased warfarin dosage requirements as compared to patients with the CC genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dosage requirements. |
| TT | Patients with the rs2108622 TT genotype may have increased warfarin dosage requirements as compared to patients with the CC or CT genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dosage requirements. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Toxicity |
| Genes | CYP2C9 |
| Phenotypes | over-anticoagulation |
| Variant | CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C9*1 allele is assigned as a normal function allele by CPIC. 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 or no function allele. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| *2 | The CYP2C9*2 allele is assigned as a decreased function allele by CPIC. Patients with CYP2C9*2 in combination with another normal, decreased, or no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| *3 | The CYP2C9*3 allele is assigned as a no function allele by CPIC. Patients with CYP2C9*3 in combination with another normal, decreased, or no function allele may have increased risk of over-anticoagulation when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| *5 | The CYP2C9*5 allele is assigned as a decreased function allele by CPIC. Patients with CYP2C9*5 in combination with another normal, decreased, or 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 | The CYP2C9*6 allele is assigned as a no function allele by CPIC. Patients with CYP2C9*6 in combination with another normal, decreased, or 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 | The CYP2C9*11 allele is assigned as a decreased function allele by CPIC. Patients with CYP2C9*11 in combination with another normal, decreased, or 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. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Toxicity |
| Genes | CYP2C9 |
| Phenotypes | Hemorrhage |
| Variant | CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C9*1 allele is assigned as a normal function allele by CPIC. 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 or no function allele. Other genetic and clinical factors may also influence the risk of warfarin-induced bleeding. |
| *2 | The CYP2C9*2 allele is assigned as a decreased function allele by CPIC. 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. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk of warfarin-induced bleeding. |
| *3 | The CYP2C9*3 allele is assigned as a no function allele by CPIC. 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. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the risk of warfarin-induced bleeding. |
| *5 | The CYP2C9*5 allele is assigned as a decreased function allele by CPIC. 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 warfarin-induced bleeding. |
| *6 | The CYP2C9*6 allele is assigned as a no function allele by CPIC. 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 warfarin-induced bleeding. |
| *11 | The CYP2C9*11 allele is assigned as a decreased function allele by CPIC. 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 warfarin-induced bleeding. |
| Level of Evidence | Level 1A |
|---|---|
| Type | Dosage |
| Genes | CYP2C9 |
| Phenotypes | Cardiovascular Disease |
| Variant | CYP2C9*1, CYP2C9*11, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*6, CYP2C9*8 |
| Variant | Annotation |
|---|---|
| *1 | The CYP2C9*1 allele is assigned as a normal function allele by CPIC. Patients carrying the 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 or no function allele. Other genetic and clinical factors may also influence warfarin dose. |
| *2 | The CYP2C9*2 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C9*2 allele in combination with a normal, decreased, or no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence warfarin dose. |
| *3 | The CYP2C9*3 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C9*3 allele in combination with a normal, decreased, or no function allele may require a lower dose of warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence warfarin dose. |
| *4 | The CYP2C9*4 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C9*4 allele in combination with a normal, decreased, or 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 warfarin dose. |
| *5 | The CYP2C9*5 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C9*5 allele in combination with a normal, decreased, or 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 warfarin dose. |
| *6 | The CYP2C9*6 allele is assigned as a no function allele by CPIC. Patients carrying the CYP2C9*6 allele in combination with a normal, decreased, or 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 warfarin dose. |
| *8 | The CYP2C9*8 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C9*8 allele in combination with a normal, decreased, or 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 warfarin dose. |
| *11 | The CYP2C9*11 allele is assigned as a decreased function allele by CPIC. Patients carrying the CYP2C9*11 allele in combination with a normal, decreased, or 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 warfarin dose. |
| Level of Evidence | Level 1B |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs7294 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs7294 CC genotype may require a lower dose of warfarin as compared to patients with the CT or TT genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dose requirements. |
| CT | Patients with the rs7294 CT genotype may require a higher dose of warfarin as compared to patients with the CC genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dose requirements. |
| TT | Patients with the rs7294 TT genotype may require a higher dose as compared to patients with the CC genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also affect warfarin dose requirements. |
| Level of Evidence | Level 1B |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs2359612 |
| Variant | Annotation |
|---|---|
| AA | Patients with the rs2359612 AA genotype may require a decreased dose of warfarin as compared to patients with the GG genotype. Other genetic and clinical factors may also influence dose of warfarin. |
| AG | Patients with the rs2359612 AG genotype may require a decreased dose of warfarin as compared to patients with the GG genotype. Other genetic and clinical factors may also influence dose of warfarin. |
| GG | Patients with the rs2359612 GG genotype may require an increased dose of warfarin as compared to patients with the AG or AA genotype. Other genetic and clinical factors may also influence dose of warfarin. |
| Level of Evidence | Level 1B |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs8050894 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs8050894 CC genotype may require a higher dose of warfarin as compared to patients with the CG or GG genotype. Other genetic and clinical factors may also influence warfarin dosage requirements. |
| CG | Patients with the rs8050894 CG genotype may require a lower dose of warfarin as compared to patients with the CC genotype. Other genetic and clinical factors may also influence warfarin dosage requirements. |
| GG | Patients with the rs8050894 GG genotype may require a lower dose of warfarin as compared to patients with the CC genotype. Other genetic and clinical factors may also influence warfarin dosage requirements. |
| Level of Evidence | Level 1B |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs9934438 |
| Variant | Annotation |
|---|---|
| AA | Patients with the rs9934438 AA genotype may require a lower dose of warfarin as compared to patients with the AG or GG genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence warfarin dose requirements. |
| AG | Patients with the rs9934438 AG genotype may require a lower dose of warfarin as compared to patients with the GG genotype, and a higher dose as compared to patients with the AA genotype. However, conflicting evidence has been reported. Other clinical and genetic factors may also influence warfarin dose requirements. |
| GG | Patients with the rs9934438 GG genotype may require higher dose of warfarin as compared to patients with the AG or AA genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence warfarin dose requirements. |
| Level of Evidence | Level 1B |
|---|---|
| Type | Toxicity |
| Genes | VKORC1 |
| Phenotypes | over-anticoagulation |
| Variant | rs9923231 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs9923231 CC genotype may have decreased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype TT or CT. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| CT | Patients with the rs9923231 CT genotype may have increased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| TT | Patients with the rs9923231 TT genotype may have increased risk of over-anticoagulation when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the toxicity to warfarin. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs2884737 |
| Variant | Annotation |
|---|---|
| AA | Patients with the rs2884737 AA genotype may require higher dose of warfarin as compared to patients with the CC genotype. Other clinical and genetic factors may also influence warfarin dosage requirements. |
| AC | Patients with the rs2884737 AC genotype may require higher dose of warfarin as compared to patients with the CC genotype. Other clinical and genetic factors may also influence warfarin dosage requirements. |
| CC | Patients with the rs2884737 CC genotype may require lower dose of warfarin as compared to patients with the AA genotype. Other clinical and genetic factors may also influence warfarin dosage requirements. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Dosage |
| Genes | VKORC1 |
| Variant | rs61742245 |
| Variant | Annotation |
|---|---|
| AA | Patients with the rs61742245 AA genotype may require an increased dose of warfarin as compared to patients with the CC genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the dose of warfarin. |
| AC | Patients with the rs61742245 AC genotype may require an increased dose of warfarin as compared to patients with the CC genotype. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the dose of warfarin. |
| CC | Patients with the rs61742245 CC genotype may have require a decreased dose of warfarin as compared to patients with the AA or AC genotypes. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the dose of warfarin. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Efficacy |
| Genes | VKORC1 |
| Phenotypes | time to therapeutic inr |
| Variant | rs9923231 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs9923231 CC genotype may require longer time to therapeutic INR when treated with warfarin as compared with patients with genotype TT or CT. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| CT | Patients with the rs9923231 CT genotype may require shorter time to therapeutic INR when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| TT | Patients with the rs9923231 TT genotype may require shorter time to therapeutic INR when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Efficacy |
| Genes | VKORC1 |
| Phenotypes | time in therapeutic range |
| Variant | rs9923231 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs9923231 CC genotype may spent more time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype TT or CT. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| CT | Patients with the rs9923231 CT genotype may spent less time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| TT | Patients with the rs9923231 TT genotype may spent less time in INR therapeutic range (TTR) when treated with warfarin as compared with patients with genotype CC. However, conflicting evidence has been reported. Other genetic and clinical factors may also influence the response to warfarin. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Toxicity |
| Genes | VKORC1 |
| Phenotypes | Hemorrhage |
| Variant | rs9923231 |
| Variant | Annotation |
|---|---|
| CC | Patients with the rs9923231 CC genotype may have a decreased risk of bleeding when treated with warfarin as compared to patients with the CT or TT genotypes. However, conflicting evidence has been reported. Other clinical and genetic factors may also influence risk of warfarin-induced bleeding. |
| CT | Patients with the rs9923231 CT genotype may have an increased risk of bleeding when treated with warfarin as compared to patients with the CC genotypes. However, conflicting evidence has been reported. Other clinical and genetic factors may also influence risk of warfarin-induced bleeding. |
| TT | Patients with the rs9923231 TT genotype may have an increased risk of bleeding when treated with warfarin as compared to the CC genotypes. However, conflicting evidence has been reported. Other clinical and genetic factors may also influence risk of warfarin-induced bleeding. |
| Level of Evidence | Level 2A |
|---|---|
| Type | Efficacy |
| Genes | CYP2C9 |
| Phenotypes | Atrial Fibrillation, Heart valve replacement |
| Variant | CYP2C9*1, CYP2C9*13, CYP2C9*14, CYP2C9*2, CYP2C9*3 |
| Variant | Annotation |
|---|---|
| *1 | Patients with CYP2C9*1 allele in combination with another normal function allele may require less time to achieve stable dose when treated with warfarin as compared to patients carrying two decreased or no function alleles or a normal or decreased function allele in combination with a no function allele. However, conflicting evidence has been reported. Other genetic or clinical factors may also influence the time to achieve warfarin stable dose. |
| *2 | Patients with CYP2C9*2 allele in combination with a normal, decreased or no function allele may require more time to achieve stable dose when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic or clinical factors may also influence the time to achieve warfarin stable dose. |
| *3 | Patients with CYP2C9*3 allele in combination with a normal, decreased or no function allele may require more time to achieve stable dose when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic or clinical factors may also influence the time to achieve warfarin stable dose. |
| *13 | Patients with CYP2C9*13 allele in combination with a normal function allele may require more time to achieve stable dose when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic or clinical factors may also influence the time to achieve warfarin stable dose. |
| *14 | Patients with CYP2C9*14 allele in combination with a normal function allele may require more time to achieve stable dose when treated with warfarin as compared to patients with two normal function alleles. However, conflicting evidence has been reported. Other genetic or clinical factors may also influence the time to achieve warfarin stable dose. |
Clinical annotations with lower levels of evidence are available.