European Pharmacogenetics of Anticoagulant Therapy–Warfarin - EU-PACT Warfarin

Nov 19, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
European Commission Seventh Framework Programme
Date Presented:
01/01/2013
Date Published:
01/01/2013
Date Updated:
11/19/2013
Original Posted Date:
11/19/2013
References

Description:

Although warfarin remains the most commonly used agent for treatment of atrial fibrillation (AF) and venous thromboembolism (VTE), it has a narrow therapeutic index, with wide variation among patients in the daily doses required. Although a number of factors are responsible, pharmacogenomic studies have identified that two genes, CYP2C9 (cytochrome p450 isoform) and VKORC1 (vitamin K epoxide reductase complex subunit 1), account for a large portion of this variability. The current trial sought to study the efficacy of genotype-guided dosing of warfarin compared with standard management in patients requiring warfarin for AF or VTE.

Hypothesis:

Genotype-guided dosing would be superior to standard dosing for achieving and maintaining therapeutic international normalized ratio (INR) levels in patients with AF or VTE requiring warfarin.

Study Design

  • Blinded
  • Parallel
  • Randomized
  • Placebo Controlled
  • Stratified

Patient Populations:

  • No prior treatment with warfarin
  • AF/VTE requiring anticoagulation with warfarin INR 2.0-3.0

    Number of enrollees: 455
    Duration of follow-up: 3 months
    Mean patient age: 67.3 years
    Percentage female: 39%

Primary Endpoints:

  • Time in therapeutic range (INR 2.0-3.0) during the 12 weeks after initiation of warfarin therapy

Secondary Endpoints:

  • INR values ≥4.0
  • Percentage of time with INR <2.0
  • Time to reach a stable warfarin dose
  • Major and minor bleeding events
  • Thromboembolic events
  • Sensitivity and resistance to warfarin
  • Number of dose adjustments in warfarin required
  • Clinical usefulness of point-of-care testing for genotyping

Drug/Procedures Used:

Patients were randomized in 1:1 fashion to either genotype-guided dosing or standard dosing. Genotyping for CYP2C9*2, CYP2C9*3, and VKOR1C (–1639G →A) alleles was performed using a point-of-care platform, which provided results within 2 hours. In the genotype-guided dosing arm, dosing between days 1 and 4 was determined based on a predefined algorithm. After day 5, it was determined based on local practice. In the control group, patients ≤75 years old received 10 mg warfarin on day 1, 5 mg on days 2 and 3, while patients >75 years old received 5 mg for days 1-3. After day 3, it was determined based on local practice.

Principal Findings:

A total of 455 patients were randomized, 227 to the genotype-guided group and to 228 to standard management. Primary analysis was conducted in 427 patients with at least 13 days of INR data. Baseline characteristics were fairly similar between the two arms. Nearly three-quarters of all patients were recruited for stroke prevention in patients with AF. Approximately 99% of enrolled patients were white. Wild-type VKORC1 genotype was noted in 42%, heterozygous in 41%, and homozygous for G-A mutation in 17% of patients. Wild-type CY2C9 genotype was noted in 66% of patients. The most common heterozygous form was *1/*2 in 21%.

The primary endpoint of target therapeutic range was significantly higher in the genotype-guided arm compared with the standard therapy arm (67.4% vs. 60.3%, p < 0.001). Differences in mean INR were most pronounced soon after initiation of anticoagulation, and then became less pronounced during the 3-month follow-up period. Time to reach therapeutic INR was lower in the genotype-guided arm (21 vs. 29 days, p < 0.001). Other outcomes such as INR ≥4.0 (27.0% vs. 36.6%, p = 0.03) and number of dosage adjustments (4.9 vs. 5.4, p = 0.02) were superior in the genotype-guided arm. Time spent below INR 2.0 was similar (20% vs. 21.9%, p = 0.20). Bleeding events were also similar (37.0% vs. 38.0%, p = 0.87); there were no major bleeding events.

Interpretation:

The results of the EU-PACT Warfarin trial indicate that genotype-based dosing for days 1-5 (for VKOR1C and CYP2C9) was superior to standard therapy in increasing the amount of time spent in target therapeutic range over 3 months in patients requiring warfarin for AF or VTE. There was also a significant reduction in supratherapeutic INRs with genotype-based dosing. This indicates both safety and efficacy with such a strategy.

Genotype-guided management is not endorsed by current guidelines due to largely negative results from other randomized controlled trials. The algorithm used in the current trial is different from other trials, and needs further validation in larger studies before this strategy can be broadly implemented. It is also important to note that nearly 99% of enrolled patients were white, which may limit generalizability to other ethnic groups.

References:

Pirmohamed M, Burnside G, Eriksson N, et al., on behalf of the EU-PACT Group. A Randomized Trial of Genotype-Guided Dosing of Warfarin. N Engl J Med 2013;369:2294-303.

Presented by Dr. Munir Pirmohamed at the American Heart Association Scientific Sessions, Dallas, TX, November 19, 2013.

Keywords: Cytochrome P-450 Enzyme System, Ethnic Groups, Stroke, Follow-Up Studies, Protein Isoforms, Homozygote, Warfarin, Vitamin K Epoxide Reductases, Venous Thromboembolism, Mutation, International Normalized Ratio, Blood Coagulation, Genotype, Pharmacogenetics, Hemorrhage


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