EUropean Pharmacogenetics of AntiCoagulant Therapy – Warfarin (2013)


Initiating anticoagulation with warfarin in patients with atrial fibrillation or venous thromboembolism

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Polymorphisms in two genes, CYP2C9 and VKORC1, account for a large portion of the inter-individual variability in warfarin dose requirements. To date, several pharmacogenetic guided dosing algorithms for warfarin have been developed. The aim of this trial was to compare the effect of genotypeguided dosing with that of standard dosing on anticoagulation control in patients requiring warfarin for AF or VTE

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Trial design

Randomized two-armed, single-blind, controlled trial using two different strategies to choose the initial warfarin dose for the first 5 days of anticoagulation
Active treatment: Patients assigned to the genotype-guided dosing group (n=227)received warfarin doses according to algorithms that included genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 in addition to clinical variables. For days 1 through 3, the warfarin doses were determined on the basis of a predefined loading-dose algorithm. For days 4 and 5 a dose-revision algorithm was used, that was based on the INR value on day 4
Control treatment: Patients in the standard-dosing group (n=228) received a 3-day loading-dose regimen. Patients ≤75 years of age received 10 mg of warfarin on day 1, 5 mg on day 2, and 5 mg on day 3, whereas patients >75 years received 5 mg per day on days 1 through 3. The doses on days 4 and 5 were determined according to usual local clinical practice After the 5-day initiation period, the treatment in both groups was managed according to routine clinical practice. All patients were followed for 3 months

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Primary outcome: percentage of time in therapeutic range (INR=2.0–3.0) during the first 12 weeks after the initiation of warfarin therapy
Secondary outcome: incidence of INR ≥4.0, percentage of time with an INR ≥4.0, percentage of time with an INR <2.0, time to reach a therapeutic INR, time to reach a stable warfarin dose, major and minor bleeding events, thromboembolic events, sensitivity to warfarin, resistance to warfarin, number of warfarin dose adjustments, clinical usefulness of the rapid point-of-care genotyping test

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Trial participants

455 patients ≥18 years (mean age 67.3 years) suffering from atrial fibrillation or venous thromboembolism and requiring anticoagulation with warfarin with a target INR of 2.0–3.0

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Primary outcome: Primary analysis was conducted only in the 427 patients who had at least 13 days of INR data (211 in the genotyped-guided group and 216 in the control group). The percentage of time with an INR of 2.0–3.0 was 67.4% in the genotype-guided group as compared with 60.3% in the control group (p<0.001). The difference in mean INR between the two groups was greatest near the start of the trial and became less pronounced during the 3-month follow-up period (54.6% vs. 45.7% in week 1–4, 73.9% vs. 63.5% in week 5–8, and 74.5% vs. 72.9% in week 9–12)
Secondary outcome: In the genotype-guided group, the incidence of excessive anticoagulation (INR ≥4.0) was significantly lower as in the standard dosing group (p<0.001). The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (p<0.001). 82.0% of the patients in the genotype-guided group reached a stable dose by 3 months, as compared with 70.4% in the control group. There were no significant differences in the other secondary outcomes (e.g. time spent <INR 2.0: 20% vs. 21.9%, bleeding events: 37.0% vs. 38.0%)

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Genotype-guided dosing of warfarin for days 1–5 was superior to standard dosing for achieving and maintaining therapeutic INR levels in patients with AF or VTE requiring anticoagulation. There was also a significant reduction in supratherapeutic INRs with genotype-based dosing

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Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlström B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294-2303

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Corresponding author

Munir Pirmohamed, PhD, Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Block A: Waterhouse Bldg., 1–5 Brownlow St., Liverpool L69 3GL, United Kingdom, e-mail:

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