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Study: Race Influences Warfarin Dose

Authors take first step toward race-specific algorithms for personalized therapy

A new study has demonstrated that clinical and genetic factors affecting dose requirements for warfarin vary by race. The findings, published online in Blood, suggest race-specific equations to help clinicians better calculate warfarin dosage.

Warfarin is the most widely used anticoagulant for the prevention of stroke and for the treatment of blood clots. Determining the optimal warfarin dose to prevent clots while avoiding dangerous bleeding is difficult. To ensure that a safe balance is achieved, patients taking warfarin must regularly visit their doctors for blood tests.

Investigators have identified several factors that affect how the body breaks down warfarin and that consequently influence dose requirements. These factors include the presence of genes that help the body break down warfarin (CYP2C9) and help to activate clotting (VKORC1).

While researchers agree that clinical and genetic factors affect individual patients’ dose requirements, whether this translates to achieving and maintaining a safe level of anticoagulation was explored in two recent clinical studies with conflicting results.

In 2013, the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial reported that calculating a patient’s warfarin dose based on the presence of genetic factors (known as genotype-guided dosing) improved anticoagulation control. Meanwhile, the Clarification of Optimal Anticoagulation through Genetics (COAG) trial reported that a similar genotype-guided dosing strategy did not appear to make a difference among patients enrolled. Of note, the COAG trial included more African-Americans than did EU-PACT (27% of the study population vs. 0.9%, respectively), and the enrolled African-Americans fared worse after receiving genotype-guided therapy. According to a research group led by Nita Limdi, PhD, PharmD, MSPH, of the University of Alabama at Birmingham, the studies’ disparate findings may be attributed to differences in the racial diversity among participants.

“As the outcomes of disease can vary by race, so can response to medications,” Limdi said. “Therefore, warfarin dosing equations that combine race groups for analysis (race-adjusted analysis) assume that the effect of variables –– such as age and genetics –– are the same across racial groups, which may compromise dose prediction among patients of both races.”

To better understand how genetics and clinical factors influence warfarin dosing across racial groups, investigators analyzed 1,357 patients (762 European-Americans and 595 African-Americans) treated with warfarin, calculating and comparing their recommended doses according to both race-adjusted dosing models, such as COAG, and race-specific dosing models. Since 43% of the study population was African-American, the research team was able to assess the effect of clinical and genetic factors on warfarin dose by race.

The researchers made several significant observations. While genetic factors accounted for a larger proportion of the dose variability among European-American patients, clinical factors accounted for a greater dose variability among African-Americans. The investigators noted that gene variants may have a different effect on warfarin doses across racial groups. For example, European-Americans with a variant of CYP2C9 (CYP2C9*2) required less of the drug, according to race-specific dosing models, and yet African-Americans did not. While all participants, regardless of race, who carried VKORC1 required lower doses of warfarin, according to race-specific dosing models, the proportional dose reduction was greater among European-Americans.

The researchers concluded that the influence of genetic and clinical factors on warfarin dosing differs by race. They therefore recommended that race-specific equations, rather than race-adjusted equations, be used to guide warfarin dosing.

“Our findings highlight the need for adequate racial representation in warfarin dosing studies to improve our understanding of how the factors that influence warfarin dose differ according to race,” Limdi said. “This is the first step to developing race-specific algorithms to personalize therapy.”

Sources: EurekAlert; May 29, 2015; and Blood; May 29, 2015.

 

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