Genetic testing can provide physicians with information to help them estimate the best starting dose and titration regimen for treatment with the blood thinner warfarin, but in early May the Centers for Medicare & Medicaid Services (CMS) announced a decision to decline payment for warfarin genetic testing unless administered as part of a clinical trial comparing outcomes in tested and untested patients.
Although CMS’ decision has been characterized as a setback for personalized medicine, the abundance of variables other than genotype that can complicate warfarin dosing as well as the time it takes to receive test results can limit the utility and cost-effectiveness of warfarin genetic tests for initial dosing. The US Food and Drug Administration (FDA) estimates that 2 million people start taking warfarin in the United States every year to prevent blood clots, heart attacks, and stroke.
First approved in 1954, warfarin is a difficult drug to use because the optimal dose varies and depends on many risk factors, including a patient’s diet, age, and other medications they may use. Patients who take a dose larger than they can tolerate are at risk of life-threatening bleeding. Those who receive too low a dose are at risk of equally dangerous blood clots. Warfarin is second only to insulin as a cause of emergency room visits for adverse drug events.
Physicians and other healthcare professionals who prescribe warfarin check at regular intervals to see if the drug is working properly by ordering a test called the PT, or prothrombin time, that evaluates the blood’s ability to clot properly. The results are measured in seconds and compared with the expected value in healthy people, known as the international normalized ratio (INR). Dosing is particularly important at the beginning of therapy, when problems in adjusting the dose can lead to complications such as bleeding. According to the FDA, one third of patients receiving warfarin metabolize it differently than expected and experience a higher risk of bleeding.
Research has shown that some of the unexpected response to warfarin depends on variants of 2 genes, CYP2C9 and VKORC1. In April 2007, the first FDA-approved genetic test for warfarin sensitivity was cleared for marketing. Approval of the first genetic test for warfarin response was granted about a month after the FDA approved updated prescribing information for warfarin. The label change explained that a patient’s genetic makeup may influence response to the drug and that testing may help optimize the use of warfarin and lower the risk of bleeding complications. At a cost of about $500, CMS believes the available evidence does not demonstrate that paying for pharmacogenomic testing to predict warfarin responsiveness is reasonable and necessary. In a decision summary, the agency did express the belief that evidence supports coverage in the context of clinical trials, called Coverage with Evidence Development, is appropriate.
Lawrence J. Lesko, PhD, FCP, director, Office of Clinical Pharmacology at the FDA’s Center for Drug Evaluation and Research, said there is no contradiction between the FDA’s decision to recommend testing and CMS’ decision not to reimburse. “CMS and the FDA both have the duty to interpret scientific data under their respective statutory requirements,” Dr. Lesko said. “CMS has focused on reimbursement of genetic tests for warfarin, and the FDA has focused on improving the safety of warfarin. So 2 views will coexist and may, in some cases, be different.”
In comments submitted to CMS last fall, Howard Coleman, CEO of Genelex Corporation, a provider of DNA testing services, recommends that CMS seriously consider reimbursing genetic testing for CYP2C9 and VKORC1 gene variants in elderly patients before or shortly after starting warfarin. Mr. Coleman said that compared with age, body weight, and sex, genetic factors contribute 3 times more information about variability in stable dosage requirements—35% for CYP2C9 and VKORC1 versus 12% for age, sex, and body weight. Mr. Coleman told CMS that evidence suggests reimbursing for warfarin DNA testing could help reduce adverse events and costs as well as the number of failed treatments. “If CMS declines to reimburse for warfarin DNA testing it will be a major setback for pharmacogenetic-based personalized medicine and more importantly the millions of patients who will be denied the utility of this test and suffer accordingly as we have seen by published reports of the risks and bleeding complications in elderly patients treated with warfarin,” he added.
In an interview with Managed Care – First Report (MC-FR), Lewis H. Bender, CEO of Interleukin Genetics, said that paying for pharmacogenomic testing is easily justified when it provides information that can be used to determine whether or not to treat a patient with a particular drug. In the case of warfarin, the test is used only for dosing, and because multiple factors such as alcohol use and drug interactions influence the way patients react to treatment, the benefits are less certain. “When it comes to titrating a very sensitive drug beyond the very sophisticated algorithms that are already there, where the environmental factors are very complicated for the titration of that drug, you then run into the kind of issues that CMS came upon with regard to this particular genetic test,” Mr. Bender said. “But for indications where there is a clear benefit…then you can make a very easy and significant argument for the reimbursement of that product.”
Brian F. Gage, MD, MSc, associate professor of medicine, Washington University in St. Louis, told MC-FR that although there is little doubt that warfarin should be dosed more carefully in patients known to have certain genetic variants, the cost-effectiveness of routine testing is uncertain because small randomized trials have yielded inconsistent results. “As evidence from additional studies becomes available, Medicare should re-evaluate their coverage decision,” he added. Dr. Gage said that testing probably is cost-effective for certain people starting warfarin, such as high-risk patients who can get genetic results prior to their fourth warfarin dose and who require heparin or low-molecular-weight heparin until their warfarin dose is therapeutic. Dr. Gage and colleagues have developed a nonprofit Web site (www.WarfarinDosing.org) to help doctors and other clinicians estimate the therapeutic dose for patients new to warfarin. The site was designed to facilitate dosing that follows his recommended approach, but Dr. Gage said that most clinicians use the site without benefit of genotype.
Although he characterized his opinion as conjecture partially based on study data, Dr. Lesko told MC-FR that the cost of trial-and-error dosing far exceeds the cost of genetic testing. “The costs of trial-and-error dosing include a higher number of INRs, a larger number of dosing changes, physician time to monitor the patient, more patient time getting their tests done, and the cost of treating emergency department visits and hospitalizations due to warfarin-induced bleeding,” he said. “More importantly, the efficiency of anticoagulation has an impact on the quality of patient care and the adherence of patients to their warfarin regimen.” Dr. Lesko believes that for CMS to consider reimbursing for warfarin genetic testing, the agency is awaiting outcome data such as a reduction in bleeding events in a genetically dosed arm of a clinical study versus a clinical (no genetics) arm.
For those seeking to conduct trials in which testing is covered for participating Medicare beneficiaries, CMS provided information on the questions they must address. When comparing results in subjects whose warfarin therapy management does and does not include pharmacogenomic testing, trials need to measure the frequency and severity of the following outcomes: * Major hemorrhage * Minor hemorrhage * Thromboembolism related to the primary indication for anticoagulation * Other thromboembolic event * Mortality Mr. Bender said CMS is looking for clear evidence that based on genotype, patients can be assigned to one of 2 or 3 different dose-titration algorithms to more quickly achieve the proper INR levels of warfarin. “That’s a study that can be done, but you’re going to need to make sure that you have a real good understanding of the variability due to the genetics versus the variability due to the inherent nature of that drug,” he said. “And that’s going to require a significant amount of sample size and good covariate analysis when you do that study.”