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Gene Data Can Help Fine-Tune Warfarin Dosing, International Group Finds

ARTICLE IN BRIEF

The International Warfarin Pharmacogenetics Consortium, comprising researchers from more than 20 teams in nine countries, pooled anonymous genetics data and treatment doses for 5,700 individuals taking warfarin, to determine an algorithm for determining ideal dosing regimens.

A large-scale international study, backed by the NIH, has concluded that pharmacogenetic data can help doctors find the best possible initial dose of the popular blood thinner warfarin.

The International Warfarin Pharmacogenetics Consortium, comprising researchers from more than 20 teams in nine countries, pooled anonymous genetics data and treatment doses for 5,700 individuals taking warfarin, one of the most widely prescribed drugs in the world for preventing blood clots that can lead to cardiovascular events.

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A total of 4,043 patients were used to create a dose algorithm based on clinical variables only and an algorithm in which genetic information was added; then the algorithm was tested in a validation cohort of 1,009 subjects.

Published in the Feb. 19 issue of the New England Journal of Medicine, the study will be followed by a major clinical trial to evaluate the effect of the technique on patient outcomes, also sponsored by NIH. Scheduled to begin recruiting patients in March, it will involve 1,200 patients from different backgrounds and ethnicities at twelve clinical sites, and is expected to be the largest prospective, multicenter, randomized clinical trial in the US.

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DR. MARK H. ECKMAN: “My guess is that it is still a little early — the efficacy data has not fully matured. If costs come down to around $200 per test, and the results can be made available immediately, it might be considered a reasonable expense.”

An estimated two million people are started on warfarin each year, but proper dosing is problematic because the ideal dose varies widely and is difficult to predict. One person may need 10 times more of the drug than another. Moreover, profuse bleeding can occur if a dose is too high, and clots may develop if the amount is too low.

In 2007, the FDA worked with the makers of warfarin products to modify the product label to indicate that a patient's genetic makeup may affect how he or she responds to the drug. Researchers know, for example, that variants in two genes, CYP2C9 and VKORC1, can influence warfarin's effectiveness. Both genes were included in the genetic tests.

THE PHARMACOGENETIC ALGORITHM

A pharmacogenetic algorithm produced levels in patients “significantly closer” to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were in the 46.2 percent of patients who required 21 mg or less of warfarin per week or 49 mg or more per week.

In the validation group, the pharmacogenetic algorithm accurately identified larger proportions of patients who would respond to the lower doses and those who required 49 mg or more per week to achieve the target international normalized ratio than the clinical-alone algorithm — 49.4 percent vs. 33.3 percent, p<0.001, in patients requiring less than or equal to 21 mg per week; and 24.8 percent vs. 7.2 percent, p<0.001, among those requiring more than or equal to 49 mg per week.

That the screening algorithm proved most effective in the lower- and higher-dose groups is encouraging, because almost half of the patients given warfarin are at either extreme, and they are also at the greatest risk for excessive bleeding or blood clots, noted Janet Woodcock, MD, and Lawrence Lesko, MD, of the Center for Drug Evaluation and Research at the FDA, in an accompanying editorial.

Although genetic tests are now available for doctors to use to help determine the initial dose of warfarin, a large, randomized clinical trial is needed to determine if the more precise, gene-based prescribing strategy is the best option, they wrote.

STILL TOO COSTLY?

Allen D. Roses, MD, the Jefferson-Pilot Professor of Neurobiology and Genetics, and director of the Deane Drug Discovery Institute at Duke University Medical Center in Durham, NC, is not convinced that such testing in necessary.

He told Neurology Today in an e-mail that he does not believe that genetic screening will add much to the way dosing is currently determined.

“In fact, it is easy to spot patients with high or low metabolism of warfarin in the first couple of days of anticoagulation and there could be clinical parameters established for this prediction of the patients who may require the testing.”

The cost of screening and the associated delays while awaiting results are both obstacles that also need to be considered, noted Mark H. Eckman, MD, director of the Division of General Internal Medicine and Center for Clinical Effectiveness at the University of Cincinnati Medical Center.

In a paper published in the Archives of Internal Medicine on Feb. 20, one day after the New England Journal of Medicine study, Dr. Eckman and his colleagues reported the results of the first meta-analysis of the cost effectiveness of screening for warfarin dosing.

While genotype-guided dosing offered better outcomes than unguided initial warfarin dosing, it did so at a relatively high cost that might be prohibitive for insurers, Dr. Eckman told Neurology Today in a telephone interview.

Measured in terms of adjusted quality of life years (QLY), the current cost of genetic-guided dosing exceeds $170,000.

Based on a “conservative” average cost of around $400 per test, he explained, it might be cost effective for just 10 percent of patients.

To achieve the $50,000 per QLY threshold used by many insurers and industry analysts in determining cost benefits, testing would have to be restricted to patients at high risk for hemorrhage or prevent more than 32 percent of major bleeding events, be available within 24 hours, and cost under $200, none of which is currently achievable in most clinical settings, according to Dr. Eckman.

“My guess is that it is still a little early — the efficacy data has not fully matured. If costs come down to around $200 per test, and the results can be made available immediately, it might be considered a reasonable expense,” he told Neurology Today.

“If testing moves in-house, we might be able to do it. It's not that far-fetched, but right now it takes three to five days, and test sites charge anywhere from $350 to $750. We're moving in that direction, we're just not there yet.”

FOR MORE INFORMATION ABOUT COAG

The new clinical trial, being sponsored by the National Heart Lung and Blood Institute — Clarification of Optimal Anticoagulation through Genetics (COAG) — will test two approaches to determine the initial dose of warfarin in patients who are expected to need therapy for three months or longer.

The trial will be conducted at 12 sites, with one site each in California, Florida, Maryland, Michigan, Minnesota, Missouri, New York, Pennsylvania, Tennessee, Texas, Utah, and Wisconsin. The COAG Coordinating Center is at the University of Pennsylvania School of Medicine.

Researchers will assess how long participants in each group maintain the desired level of blood thinning two and four weeks after starting therapy, as well as at three and six months. Researchers will also review bleeding problems and other complications, quality of life, and cost of therapy.

REFERENCES

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009;360:753–764.
    Eckman MH, Rosand J, Gage B, et al. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009;150:73–83.