Expert Review: Thrombosis

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background

Clinical management of warfarin therapy is difficult because of the narrow therapeutic index and marked inter-patient variability in drug pharmacokinetics and pharmacodynamics, which lead to unpredictable and variable (up to 10-fold or greater) dosing requirements. This often results in under- or over-therapeutic effects based on international normalized ratios (INRs) thus compromising anticoagulation efficacy and safety.

Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1, VKORC1, have been found to conjointly determine warfarin dose requirements. These observations suggest clinical applicability for CYP2C9 and VKORC1 genotyping regarding estimating dosing requirements for warfarin therapy.

Knowledge Gap

Although various pharmacogenetic (PG)-guided warfarin dosing algorithms have been developed, they have not been adequately tested for their impact on clinical outcomes in prospective controlled trials.

Aim of the Study

The present study sought to compare a simple (1-step), (PG-1) with a complex (3-steps), (PG-2) PG algorithm for warfarin dose initiation. Furthermore, the authors investigated the clinical effectiveness of PG guidance compared to standard dosing.

Methods

The study comprised two prospective clinical trial comparisons: (1) a blinded, randomized comparison of two refined PG-guided algorithms (n=504) and (2) a clinical effectiveness comparison of PG-guided therapy with use of either algorithm with parallel, non-randomized, standard dosing (n=1866). Study duration was three months or to the end of warfarin therapy if <3 months.

The primary end points of interest were percentage of out-of-range (% OOR) INRs and percentage of time in therapeutic range (% TTR) INRs during the first month and, secondarily, after up to three months of warfarin therapy.

Results

In the randomized comparison, PG-2 was non-inferior but not superior to PG-1 for % OOR  INRs at one and three months, and for %TTR INRs at three months. However, the combined PG cohort was superior to the parallel controls (%OOR INRs  31% versus 42% at 1 month; 30% versus 42% at 3 months; %TTR  INRs 69% versus 58%, 71% versus 59%, respectively, all p<0.001).

Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage INRs  ≥4 and ≤1.5 and serious adverse events at three months (4.5% versus 9.4% of patients, p<0.001) with PG guidance.

Conclusion

PG guidance was superior to standard dosing in achieving and maintaining therapeutic INRs and in reducing serious bleeding and thromboembolic events and death suggesting better clinical effectiveness and safety. Furthermore, the two PG algorithms were comparable with the more complex PG-2 algorithm failing to show superiority highlighting that a simpler PG approach may be preferable for clinical application.

Perspective-Clinical Impact

The present study showed that PG guidance using rapid genotyping assays in warfarin dosing may more accurately predict individual warfarin dose requirements, and that this approach may also decrease thromboembolic and bleeding events compared to blinded standard dosing. According to the authors the study is inherent to certain limitations.

Firstly, the study was underpowered to rigorously test for superiority of the PG-2 algorithm. Secondly, the control group was not randomized, and certain baseline characteristics differed between PG-guided and standard dosing group. Moreover, some demographic and treatment-related factors (e.g., dosing information) were not available for the parallel control group. Finally, the exact rate of compliance was also not determined.

Nevertheless, the findings in this clinical effectiveness study suggest that PG dosing may be worth consideration for broader application in clinical practice especially using simpler algorithms.

Corresponding author of original article:  Jeffrey L. Anderson, MD, Intermountain Medical Center, Cardiovascular Department, 5121 S Cottonwood St, Murray, UT 84107-5701. E-mail jeffrey.anderson@imail.org

Citation: Circulation. 2012 Apr 24;125(16):1997-2005. Epub 2012 Mar 19

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