Warfarin response

Initial and Maintenance Dosing

The appropriate initial dosing of warfarin sodium tablets varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

• Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities
• Genetic factors (CYP2C9 and VKORC1 genotypes)

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.

Dosing Recommendations without Consideration of Genotype

If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium tablets is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance warfarin sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.Please review the complete therapeutic recommendations that are located here: (1)

VKORC1 CT: warfarin

NO action is required for this gene-drug interaction.

The genetic variation results in a reduction in the required dose and an increase in the risk of excessively severe inhibition of blood clotting during the first month of the treatment. However, the effect is small and CT is also the most common genotype, meaning that the standard treatment will primarily be based on patients with this genotype.

VKORC1 TT: warfarin

The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of excessively severe inhibition of blood clotting (INR >4) during the first month of the treatment.

Recommendation:

1. use 60% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica.

From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

CYP2C9 IM: warfarin

This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.

Recommendation:

1. use 65% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the \*2 and \*3 allele. If the activity of the reduced-activity alleles is comparable to the activity of \*2 or \*3, then the algorithm can be completed as if \*1/\*2 or \*1/\*3 is present. See https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

Modified dose algorithms have been developed for patients of African or (East) Asian heritage.

CYP2C9 PM: warfarin

This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk of bleeding.

Recommendation:

1. use 20% of the standard initial dose

The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. Algorithms for Caucasian patients usually contain only the \*2 and \*3 allele. If the activity of the reduced-activity alleles is comparable to the activity of \*2 or \*3, then the algorithm can be completed as if \*2 or \*3 is present. See https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm without genotype information can be used to calculate the dose.

Modified dose algorithms have been developed for patients of African or (East) Asian heritage.

CYP2C9*1/*2: warfarin

NO action is required for this gene-drug interaction.

Genetic variation may lead to a decrease in the required maintenance dose. However, there is insufficient evidence that this causes problems when therapy is initiated as usual.

Please review the complete therapeutic recommendations located here: (2, 3)

Non-African ancestry recommendation

In patients who self-identify as non-African ancestry, the recommendation is to:

1. Calculate warfarin dosing using a published pharmacogenetic algorithm, including genotype information for VKORC1-1639G>A and CYP2C9*2 and *3. In individuals with genotypes associated with CYP2C9 poor metabolism (e.g., CYP2C9 *2/*3, *3/*3) or both increased sensitivity (VKORC1-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant might be considered. The bulk of the literature informing these recommendations is in European and Asian ancestry populations, but consistent data exist for other non-African populations. These recommendations are graded as STRONG.
2. If a loading dose is to be utilized, the EU-PACT loading dose algorithm that incorporates genetic information could be used. This recommendation is OPTIONAL.
3. While CYP2C9*5, *6, *8, or *11 variant alleles are commonly referred to as African-specific alleles, they can occur among individuals who do not identify as, or know of their, African ancestry. If these variant alleles are detected, decrease calculated dose by 15–30% per variant allele or consider an alternative agent. Larger dose reductions might be needed in patients homozygous for variant alleles (i.e., 20–40%, e.g., CYP2C9*2/*5). This recommendation is graded as OPTIONAL.
4. If the CYP4F2*3 (i.e., c.1297A, p.433Met) allele is also detected, increase the dose by 5–10%. This recommendation is also considered OPTIONAL.
5. The data do not suggest an association between rs12777823 genotype and warfarin dose in non-African Americans, thus rs12777823 should not be considered in these individuals (even if available).

African ancestry recommendation

In patients of African ancestry, CYP2C9*5, *6, *8, *11 are important for warfarin dosing. If these genotypes are not available, warfarin should be dosed clinically without consideration for genotype. If CYP2C9*5, *6, *8, and *11 are known, then the recommendation is to:

1. Calculate warfarin dose using a validated pharmacogenetic algorithm, including genotype information for VKORC1 c.-1639G>A and CYP2C9*2 and *3;
2. If the individual carries a CYP2C9*5, *6, *8, or *11 variant allele(s), decrease calculated dose by 15–30%. Larger dose reductions might be needed in patients who carry two variant alleles (e.g., CYP2C9*5/*6) (i.e., 20–40% dose reduction).
3. In addition, rs12777823 is associated with warfarin dosing in African Americans (mainly originating from West Africa). Thus, in African Americans a dose reduction of 10–25% in those with rs12777823 A/G or A/A genotype is recommended. These recommendations are considered MODERATE.

In individuals with genotypes that predict CYP2C9 poor metabolism or who have increased warfarin sensitivity (VKORC1 c.-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant should be considered (see Supplemental Material for definitions of strength of recommendations). As noted above, for non-African ancestry, if a loading dose is to be used, the EU-PACT algorithm that incorporates genetic information could be used to calculate loading dose. This recommendation is OPTIONAL. The data do not support an impact on clinical phenotype for CYP4F2 on warfarin dosing in those of African ancestry and so no recommendation is made for use of CYP4F2 genotype data in blacks.

Please review the complete therapeutic recommendations, including recommendations for pediatric patients, located here: (4).