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Clinical, genetic factors associated with race influence warfarin dosage
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The influence of certain clinical and genetic factors on warfarin dosage varies by race, according to study results.
Thus, race-stratified algorithms resulted in more accurate warfarin dosing compared with race-adjusted algorithms, results showed.
“As the outcomes of disease can vary by race, so can response to medication,” Nita A. Limdi, PharmD, PhD, MSPH, professor of neurology at the University of Alabama at Birmingham, said in a press release. “Therefore, warfarin dosing equations that combine race groups for analysis assume that effect of variables — such as age and genetics — are the same across race groups, which may compromise dose prediction among patients of both races.”
Warfarin is the most commonly used anticoagulant for stroke prevention and treatment of venous thromboembolism. However, clinicians experience difficulty determining the optimal dosage, and two recent clinical trials — the EU-PACT (Pirmohamed M, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1311386.) and COAG trials (Kimmel SE, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1310669.) — demonstrated conflicting results related to genotype-guided dosing, according to study background.
The researchers conducted a prospective cohort study to compare the predictive ability of race-combined models vs. race-stratified models. The analysis included data from 1,357 patients (mean age, 61 years; 43% black) treated with warfarin.
The researchers assessed the impact of clinical and genetic factors on warfarin dosing. Clinical factors included age, body surface area, additional prescribed medications, smoking status and co-therapy with amiodarone. Genetic factors included CYP2C9, a gene that helps break down warfarin; VKORC1, which activates clotting; rs12777823; and CYF4F2.
Using predictors included in the COAG trial, the researchers observed that CY2C9*2 variants resulted in significantly lower doses among European American patients only (20.7% vs. 4%; P < .001). The influence of factors — including age, body surface area, smoking status, amiodarone co-therapy and possession of CYP2C9*3 variants — did not differ by race.
When also evaluating potentially influential dosage variables not included in the COAG trial, CYP2C9*2 variants corresponded with dose changes in white patients only (20.6% vs. 3%; P ˂ .001), whereas rs12777823 variants resulted in dose changes among black patients only (12.3% vs. 2.3%; P = .006).
The possession of VKORC1 variants resulted in significant dosage decreases in white and black patients. However, white patients exhibited a significantly higher dose reduction per variant allele (28.9% vs. 19.9%; P = .003).
The researchers compared race-combined and race-stratified analyses using predictors from the COAG trial. Genetic factors accounted for greater dose variability compared with clinical factors in a race-combined analysis (22.1% vs. 16.1%; P < .001). However, these predictors produced a larger variability among white patients vs. black patients in a race-stratified analysis (R2 = 51.4% vs. 29.3%; P < .001), and white patients were more likely to experience dose variation based on genetic factors (R2 = 34.1% vs. 7%; P < .001).
When incorporating factors not considered by the COAG trial in a race-combined analysis, clinical and genetic figures explained a significant proportion of dosage variability (R2 = 48.3%), and genetic factors accounted for a higher proportion of dose variability than clinical factors (23.5% vs. 17.4%; P < .001).
However, a race-stratified analysis produced larger variability among white patients compared with black patients (R2 = 54% vs. 33.9%; P < .001). Genetic factors contributed to significantly greater dosage variability among white patients (R2 = 34.6% vs. 10%; P < .001), whereas clinical factors resulted in greater — although not statistically significant — variability among black patients (R2 = 22.8% vs. 16.4%).
The researchers acknowledged limitations to their study, including the exclusion of Asian and Hispanic patients, as well as the exclusion of other potentially influential clinical and genetic factors.
“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.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
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