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New Warfarin PGx Study Will Test New Dosing Algorithms, Aim to Avoid Criticisms of Past Trials

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Originally published April 12.

By Turna Ray

Brian Gage, an expert on pharmcogenomically-guided warfarin dosing, is leading a new study looking at how genetic testing can personalize the administration of the highly variable anticoagulant in orthopedic patients. This study will apply new PGx dosing algorithms in this patient subset and will hopefully avoid some of the design pitfalls of past clinical trials in this area.

The Washington University School of Medicine in St. Louis last week announced that a team led by Gage, an associate professor of medicine at the institution, has received $3.7 million from the National Heart, Lung, and Blood Institute for a five-year study, called the Genetics Informatics Trial of Warfarin, or GIFT, which will investigate the utility of genetic testing to dose the anticoagulant in 1,600 knee or hip replacement surgery patients at Barnes-Jewish Hospital and other institutions.

Warfarin, although widely used, causes one in five patients to be hospitalized within six months of starting the drug. For decades, doctors have monitored patients' international normalized ratio to dose the blood thinner. However, numerous studies have shown that polymorphisms in the VKORC1 gene account for 30 percent of dosing variability, and variations in the CYP2C9 gene explain 10 percent of dose differences between patients.

So far, several high-profile clinical trials have sought to determine whether genetic testing to dose warfarin is clinically useful and saves healthcare dollars, but these studies have yielded mixed answers. However, as researchers continue to hone in on which specific patient populations can benefit from PGx-guided warfarin dosing, the lukewarm reception of previously completed studies offer some insight as to the design of future trials.

Most recently, an observational trial conducted by pharmacy-benefit manager Medco and the Mayo Clinic reported that genetic testing to dose warfarin for heart patients reduced hospitalizations by 30 percent. While 75 percent of doctors contacted for the study agreed to genetically test their patients for warfarin sensitivity, critics have taken issue with the fact that the study was not a prospective, randomized-controlled trial.

Mandeep Mehra, chief of cardiology at the University of Maryland Medical Center, who reviewed the Medco/Mayo study at the American College of Cardiology's annual meeting in March, pointed out that since doctors knew which patients were getting genetically tested, they may have monitored those patients more closely, raising questions about whether the reduction in hospitalizations was due to genetic testing or due to the so-called Hawthorne effect — in which study subjects improve behavior simply in response to being studied and not as a result of the intervention (PGx Reporter 03/17/10).

Gage pointed out that in the Medco/Mayo study, the median time from warfarin initiation until the genotype was available to the prescribing physician was 32 days. "So I wonder whether the Hawthorne effect and/or patient selection contributed to the lower rate of hospitalizations."

Another study, published in Circulation in November 2007, called Couma-Gen, was a much anticipated randomized-controlled trial conducted by researchers at the University of Utah and LDS Hospital of Intermountain Healthcare. It compared outcomes when patients were initiated on warfarin by genetic risk factors versus clinical factors only. The study did not reach its primary endpoint of a reduction in bleeding outcomes, but researchers concluded that "an algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation."

Gage and Lawrence Lesko, director of FDA’s Office of Clinical Pharmacology, reviewed the Couma-Gen trial and concluded that although the trial didn't reach its primary endpoint, it has important implications for the design of future studies. The randomized-controlled trial was powered “to detect an ambitious difference in out-of-range [international normalized ratios] between pharmacogenetic (20 percent) and clinical arms (40 percent)," Gage and Lesko wrote in an article in Personalized Medicine in March 2008. They added that future trials should be powered to detect smaller differences (PGx Reporter 03-19-08).

In designing the GIFT study, Gage and colleagues have factored in many of the issues that hampered past trials, such as randomization, blinding, and delays in receiving test results. The researchers will be conducting a randomized, multi-centered, double-blinded trial comparing outcomes when hip and knee replacement surgery patients are initiated on warfarin using genetic testing results versus dosing using clinical factors. "In contrast to Couma-Gen, GIFT of warfarin is double-blinded and the primary outcome includes clinical adverse events," such as venous thromboembolism, hemorrhages, and death, Gage explained.

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Each group of patients will also be divided based on INR ranges, with half trying to reach a target INR of less than 2.0 and the other half aiming for an INR of 2.5. The researchers hypothesize that after the first two weeks of treatment, patients being dosed warfarin using the pharmacogenomic testing will have reached an appropriate warfarin dose with little adjustment needed thereafter.

Another difference of this new study is that it will use new PGx-guided dosing algorithms developed by Gage and colleagues in the Warfarin Dose Revision Collaboration, an international consortium of experts in warfarin pharmacogenetics. The new dosing algorithms were published last week in a paper in Clinical Pharmacology and Therapeutics.

In the paper, Gage and colleagues investigated the utility of genetic testing results after patients had been dosed on warfarin using INR results for four or five days. The researchers developed PGx algorithms that were refined after adjusting for INR values, clinical factors, and genotype and also created a separate algorithm based on just clinical factors.

"After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P

Lack of access to same-day testing results is a barrier to genetic testing for physicians starting patients on warfarin for certain acute conditions where they can't wait a week or longer for laboratories to analyze patient samples and return test results.

ParagonDx, Machaon Diagnostics, and AutoGenomics are a few firms that claim to offer same-day warfarin dosing results. Meanwhile, Kimball Genetics and Harvard Medical School’s testing services, which use Third Wave’s Invader assay, promise to return test results as early as one business day. Most other companies have turnaround times ranging from three to seven days (PGx Reporter 04/12/10).

"A logistical advantage of studying orthopedic patients is that they know in advance when they will be starting warfarin," Gage said. "Thus, we will be able to genotype all GIFT of warfarin participants prior to their first dose."

Gage is one of the creators of the online dosing calculator WarfarinDosing.org, which already includes the new algorithms published in the Clinical Pharmacology and Therapeutics paper.

In additional to looking at gene variants in CYP2C9 and VKORC1, the algorithms will also consider variants in CYP4F2.

Gage added that GIFT will look at the cost effectiveness of genetic testing in this study, but not as a primary outcome. A study published in the Annals of Internal Medicine in 2009 found that while genetic testing to dose warfarin may not be cost-effective in the "typical" atrial fibrillation patient, such testing could incur saving in patients at high risk of hemorrhage, if it is available within 24 hours, costs less than $200 and prevents 32 percent of bleeding events (PGx Reporter 01/21/09).

In addition to GIFT, there are several other ongoing studies looking at the clinical utility and cost effectiveness of PGx-guided warfarin dosing, including the Clarification of Optimal Anticoagulation through Genetics trial, the Clinical and Economic Implications of Genetic Testing for Warfarin Management trial, and the European Pharmacogenetics of Anticoagulant Therapy trial.

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