Genotype-guided strategy may improve warfarin dosing in Asians
A genotype-guided approach to warfarin dosing may result in fewer dose adjustments in Asian patients, according to a study from Singapore.
“A growing body of evidence has emerged indicating that the cytochrome P450 2C9 [CYP2C9] and Vitamin K epoxide reductase complex subunit 1 [VKORC1] genotypes are associated with maintenance dose requirements,” said the researchers. [Trends Cardiovasc Med 2015;25:33-41]
“In this study … the number of dose titrations in the first 2 weeks, and also throughout the follow-up period, was lower in the genotype-guided group than in the traditional dosing group,” they said.
This open-label, noninferiority trial conducted at three South East Asian hospitals involved 322 patients (median age 60 years, 58.4 percent male, 61.2 percent Chinese) who were about to initiate anticoagulation treatment with warfarin and were randomized to either genotype-guided (n=159) or traditional dosing (n=163). Of these, 269 (n=133 and 136 from the genotype-guided and traditional groups, respectively) received warfarin for ≥14 days and formed the modified intention-to-treat group.
At randomization, all patients received low-molecular weight heparin and warfarin was initiated on day 3 following an estimated 2 days for receipt of genotype data. Patients assigned to genotype-guided dosing had their doses tailored for 3 consecutive days, while those assigned to traditional dosing received a standard loading dose of 5 mg on days 1 and 2 and 3 mg on day 3 (or 4 mg on day 2 for patients >75 years). International normalized ratio (INR) was measured three times during the first 14 days (day 6, 7–9, and 12–14). Patients in both groups were treated for a median 90 days.
Patients in the genotype-guided dosing group required fewer dose titrations of warfarin within the first 2 weeks of treatment compared with those in the traditional dosing group (1.77 vs 2.93; mean difference, -1.16, 90 percent confidence interval [CI], -1.48 to -0.84; p<0.001 for noninferiority and superiority). [BMC Med 2018;16:104]
This reduction in dose titration requirements persisted throughout the 3-month study period with fewer titrations among patients in the genotype-guided dosing group than in the traditional dosing group (4.51 vs 6.06, incidence rate ratio [IRR], 0.76, 95 percent CI, 0.67–0.86; p=0.001), though frequency of INR measurements was comparable between groups.
Genotype-guided dosing did not appear to affect median time to stable INR (36 days vs 37 in the traditional dosing group, 77.4 percent vs 79.4 percent of patients achieving stable INR, hazard ratio, 1.00; p=0.99) or time within therapeutic range (60.0 percent vs 57.1 percent, mean difference, 2.9 percent; p=0.29) over the 3-month study period.
Incidence of minor or major bleeding affected a similar proportion of patients in the genotype-guided and traditional dosing groups (RR, 1.02; p=0.96 and RR, 1.02; p=0.97, respectively), as did incidence of recurrent venous thromboembolism (RR, 2.05; p=0.55) and out-of-range INR (<1.9 [RR, 1.03; p=0.21] or >3.1 [RR, 1.01; p=0.97]).
The genotype-guided algorithm accurately predicted daily maintenance doses (mean percentage error, -7.4 percent, root mean squared error, 1.10 mg).
Study limitations included the lack of endpoint assessment according to ethnicity, the large proportion of patients from a single centre (86.7 percent), and the inability to test for differences in percentage of time in therapeutic range.
“Well-managed warfarin therapy is associated with a reduction in the risk of complications, yet the majority of patients do not achieve long-term stable INR within the therapeutic range, indicating the difficulty in identifying an optimal maintenance dose for individual patients,” said the researchers.
“On average, Asian patients homozygous for less-sensitive VKORC1 haplotypes [H7, H8, or H9] and wild-type for CYP2C9 will require more than 3.5 times the maintenance dosage needed by patients with the VKORC1 H1/H1 haplotype and a copy of the CYP2C9*3 allele [Clin Pharmacol Ther 2006;79:197-205], highlighting a potential pitfall of empirical dose initiation and titration,” they continued.
“[Findings of this study] imply that clinicians treating Asian patients may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages,” they said.