Diagnostic Laboratory Tests
This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.
Warfarin sodium is an orally administered anticoagulant drug that is marketed most commonly as Coumadin®. (The Food and Drug Administration (FDA) approved labeling for Coumadin® includes a Black Box Warning dating back to 2007.) Anticoagulant drugs are sometimes referred to as blood thinners by the lay public. Warfarin affects the vitamin K-dependent clotting factors II, VII, IX, and X. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide. The elimination of warfarin is almost entirely by metabolic conversion to inactive metabolites by cytochrome P450 (CYP) enzymes in liver cells. CYP2C9 is the principal cytochrome P450 enzyme that modulates the anticoagulant activity of warfarin. From results of clinical studies, genetic variation in the CYP2C9 and/or VKORC1 genes can, in concert with clinical factors, predict how each individual responds to warfarin.
Pharmacogenomics denotes the study of how an individual's genetic makeup, or genotype, affects the body's response to drugs. Pharmacogenomics as a science examines associations among variations in genes with individual responses to a drug or medication. In application, pharmacogenomic results (i.e., information on the patient’s genetic variations) can contribute to predicting a patient’s response to a given drug: good, bad, or none at all. Pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict a patient’s response to warfarin occurs ideally prior to initiation of the drug. This would be an once-in-a-lifetime test, absent any reason to believe that the patient’s personal genetic characteristics would change over time. Although such pharmacogenomic testing would be used to attempt to better approximate the best starting dose of warfarin, it would not eliminate the need for periodic PT/INR testing, a standard diagnostic test for coagulation activity and for assessing how a patient is reacting to a warfarin dose.
Indications and Limitations of Coverage
Nationally Covered Indications
Effective August 3, 2009, the Centers for Medicare & Medicaid Services (CMS) believes that the available evidence supports that coverage with evidence development (CED) under §1862(a)(1)(E) of the Social Security Act (the Act) is appropriate for pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness by any method, and is therefore covered only when provided to Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin who:
- Have not been previously tested for CYP2C9 or VKORC1 alleles; and
- Have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and
- Are enrolled in a prospective, randomized, controlled clinical study when that study meets the following standards.
A clinical study seeking Medicare payment for pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness provided to the Medicare beneficiary who is a candidate for anticoagulation therapy with warfarin pursuant to CED must address one or more aspects of the following question:
Prospectively, in Medicare-aged subjects whose warfarin therapy management includes pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin response, what is the frequency and severity of the following outcomes, compared to subjects whose warfarin therapy management does not include pharmacogenomic testing?
- Major hemorrhage
- Minor hemorrhage
- Thromboembolism related to the primary indication for anticoagulation
- Other thromboembolic event
The study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
- The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.
- The research study is well-supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
- The research study does not unjustifiably duplicate existing studies.
- The research study design is appropriate to answer the research question being asked in the study.
- The research study is sponsored by an organization or individual capable of executing the proposed study successfully.
- The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the FDA, it also must be in compliance with 21 CFR Parts 50 and 56.
- All aspects of the research study are conducted according to the appropriate standards of scientific integrity.
- The research study has a written protocol that clearly addresses, or incorporates by reference, the Medicare standards.
- The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life-threatening as defined in 21 CFR § 312.81(a) and the patient has no other viable treatment options.
- The clinical research study is registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject.
- The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However, a full report of the outcomes must be made public no later than 3 years after the end of data collection.
- The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
- The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.
Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.
B. Nationally Non-Covered Indications
The CMS believes that the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries outside the context of CED, and is therefore not reasonable and necessary under §1862(a)(1)(A) of the Act.
This NCD does not determine coverage to identify CYP2C9 or VKORC1 alleles for other purposes, nor does it determine national coverage to identify other alleles to predict warfarin responsiveness.
(This NCD last reviewed August 2009.)
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