Cath Lab Digest

Cites Insufficient Evidence of Improved Outcomes 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.