Pharmacogenomic Testing for Warfarin Response

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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. Therefore, we have determined that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act. However, we do believe the available evidence supports that Coverage with Evidence Development (CED) under §1862(a)(1)(E) of the Social Security Act is appropriate. Thus, we are making the following decision: Pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness is 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 Coverage with Evidence Development (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 Mortality 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 Food and Drug Administration (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 three (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 Social Security Act (the Act), the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that the Centers for Medicare and Medicaid Services (CMS) determines meet the above-listed standards and address the above-listed research questions.

Decision Memo: To: Administrative File: 00400N From: Tamara Syrek Jensen, JD Acting Director, Coverage and Analysis Group Louis B. Jacques, MD Director, Division of Items and Devices Maria Ciccanti Lead Analyst Kim Long Analyst Lisa Eggleston Analyst Jeffrey Roche, MD, MPH Medical Officer Subject: Decision Memorandum for Pharmacogenomic Testing to Predict Warfarin Responsiveness Date: August 3, 2009 I. Decision 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. Therefore, we have determined that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness is not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act. However, we do believe the available evidence supports that Coverage with Evidence Development (CED) under §1862(a)(1)(E) of the Social Security Act is appropriate. Thus, we are making the following decision: Pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness is 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 Coverage with Evidence Development (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 Mortality 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 Food and Drug Administration (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 three (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 Social Security Act (the Act), the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that the Centers for Medicare and Medicaid Services (CMS) determines meet the above-listed standards and address the above-listed research questions. II. Background Warfarin sodium is an orally administered anticoagulant drug that is marketed most commonly as Coumadin®. Anticoagulant drugs are sometimes referred to as blood thinners by the lay public. According to a National Center for Health Statistics (NCHS) 2007 report about the most frequently prescribed classes of drugs prescribed during ambulatory care encounters for both men and women 65 years of age or greater, use of drugs which prevent blood clot formation (anticoagulants) or increase the rate of dissolution of blood clots (thrombolytics) increased as a class during the last decade. Other studies suggest that millions of persons in the United States are on warfarin therapy at any given time. Notes on Terminology Although some authors use the term warfarin sensitivity to describe the patient’s degree of response to warfarin administration, we have chosen to use the terms response or responsiveness in this decision memorandum unless citing the work of others. We believe that this will minimize the likelihood that a reader may interpret the term warfarin sensitivity to connote an allergic reaction or some other immune-mediated response to warfarin. Italicized abbreviations for gene names (e.g., the gene VKORC1 ) represent genes rather than their products (e.g., the enzyme VKORC1). The meanings of other non-italicized abbreviations (e.g., NCHS for the National Center for Health Statistics) will usually be clear in context. However, in quoted text from referenced sources, the use of italicization reflects usage in the original source document unless noted otherwise. Clotting factors are customarily named with Roman numerals and trailing small case letters, e.g. ‘Factor Xa’ refers to the activated form of plasma coagulation factor X. As suggested by NIH educational materials, we consider the term ‘allele’ to indicate one of the variant forms of a gene (http://ghr.nlm.nih.gov/glossary=allele). 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. Warfarin Action and Metabolism 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 (see below under "Evidence”). A few studies have investigated possible influences on warfarin metabolism due to other genetic variants (for example, those in CYP4F2 ). Scope of this Decision The new science of pharmacogenomic testing continues to evolve, and we are mindful that researchers may discover more associations between warfarin responsiveness and heritable factors and develop test strategies other than those for CYP2C9 and VKORC1 . We also consider that CYP2C9 and VKORC1 may in the future be found to be relevant to the human response to other intrinsic or extrinsic agents. Thus we are explicitly describing the scope of this decision without intending to establish a precedent for the scope of future decisions. This decision determines national coverage (as explained below) for pharmacogenomic testing by any method to identify CYP2C9 or VKORC1 alleles to predict warfarin responsiveness. It does not determine national coverage to identify CYP2C9 or VKORC1 alleles for other purposes, not does it determine national coverage to identify other alleles to predict warfarin responsiveness. Therapeutic Use of Warfarin Anticoagulation Retrospective studies of patients on warfarin indicate that the common indications for anticoagulation with warfarin include atrial fibrillation, venous thromboembolism, valvular heart disease, cerebrovascular disease and vascular prostheses including cardiac valve replacements (Oake 2008). The risk of thromboembolism due to atrial fibrillation increases with concomitant risk factors such as age over 65 years, diabetes, hypertension and congestive heart failure. The desired intensity or degree of anticoagulation will differ based on the specific indication and other factors. Patients at higher risk for forming thrombi, e.g. individuals with mechanical heart valves, may require a higher degree of anticoagulation. The duration of anticoagulation therapy varies with the underlying indication and with the patient’s response to therapy. Some acute conditions such as deep venous thrombosis generally require anticoagulation for only a period of a few months, while chronic conditions require long-term and possibly life-long anticoagulation. These chronic conditions, e.g. atrial fibrillation and stroke, are more common in the Medicare aged population than in younger populations. Older patients compared to younger patients generally have multiple comorbid conditions for which they take drugs of various classes known to interact with warfarin. Alternatives to warfarin anticoagulation use in specific clinical situations are described in published review articles. Brotman discusses anticoagulation for hospitalized patients with risk factors for venous thromboembolism, including the therapeutic choices of vitamin K antagonists such as warfarin, heparin and related agents, and newer anticoagulants such as fondaparinux, a pentasaccharide inhibitor of coagulation factor Xa (Brotman 2008). It is not unreasonable to anticipate that warfarin-based anticoagulation will eventually disappear from common use as newer agents with better safety profiles become available. Pharmacogenomic Testing 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. The recognized clinical goals of such testing fall generally into one of the following categories: To guide warfarin dosing in patients who are committed to anticoagulation therapy as treatment for an acute event; and To encourage physicians to initiate elective warfarin therapy in patients with certain chronic conditions, who are thought to be at higher risk of adverse events related to anticoagulation. Patients in the first category are anticoagulated urgently, often in response to a thromboembolic event such as a pulmonary embolus. Patients in the latter category are more likely to have a chronic cardiac dysrhythmia such as atrial fibrillation where anticoagulation is initiated with the hope of avoiding a stroke. Turnaround time for pharmacogenomic testing of CYP2C9 or VKORC1 alleles, i.e. the elapsed time from ordering the test to the receipt of the results by the physician, may vary due to a number of factors such as the patient’s location, the laboratory’s location, delivery of the specimen to the laboratory, the laboratory’s internal processes to prepare the specimen and perform the test, and the communication of the results to the treating physician. Advertised times to return results to the physician after receipt of the specimen range from 2 – 10 days. Titration of Warfarin During Initiation of Therapy/determinationprocess/downloads/ Warfarin has a narrow therapeutic window, meaning that there is a small difference in dosage (at times, less than one milligram of warfarin per day) between dosing that is too little, just right, or too much. Standard clinical practice for warfarin titration requires periodic testing of its anticoagulant effect. This is assessed with the prothrombin time (PT) and the International Normalized Ratio (INR). In the PT/INR test, the ratio of the patient's PT to the mean PT for a group of normal individuals is calculated, and that ratio is then raised to a power which adjusts for differences among different types of reagents used in the test procedure. Commonly, the PT/INR is assessed frequently during the first few weeks or months while warfarin therapy is begun, and after that, less frequently when the patient demonstrates a stable response. More frequent testing may be required if the patient exhibits signs of over- or under-treatment or if the patient begins (or stops) taking another drug that is recognized to affect warfarin action or metabolism. The Food and Drug Administration approved labeling for Coumadin® (warfarin sodium tablets) includes the following Black Box warning (FDA 2007). WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR > 4.0), age ≥ 65, highly variable PT/INR results, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS ) and long duration of warfarin therapy. Regular monitoring of PT/INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent PT/INR monitoring, careful dose adjustment to desired PT/INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS : Information for Patients ). As the FDA notes in the body of the prescribing information, PT/INR is a standard diagnostic test for coagulation activity and for assessing how the patient is reacting to the warfarin dose. Benefits and Adverse Effects of Warfarin Therapy The evidence of the benefit of warfarin therapy for certain indications is well-established. According to a published meta-analysis of anti-thrombotic therapy for stroke prevention, patients with non-valvular atrial fibrillation on adjusted-dose warfarin therapy were observed to have a reduced stroke risk of 64% in comparison to placebo (Hart 2007). This meta-analysis also showed that overall deaths in trial participants on warfarin compared to the control group were decreased by 26% (110 deaths in the warfarin-treated group compared to 143 deaths in the control group). A review of evidence about bleeding complications during various types of anticoagulant therapy summarized major determinants of bleeding in patients receiving warfarin (Levine 2004). Some of the relevant findings included: Multiple randomized trials in patients with atrial fibrillation showed that the annual risk of major bleeding averaged 1.3% in patients randomly assigned to warfarin therapy with a therapeutic target range for INR of 2 – 3, compared to 1% annual risk among placebo-treated controls; Patient age was found to be an independent risk factor for major bleeding. Major bleeding events occur at an annual rate of 5.1% among those greater than 75 years of age, as compared to a 1% annual rate among younger patients; and Bleeding was a more frequent complication in the first month following initiation of warfarin therapy. In clinical trials involving patients with deep vein thrombosis, atrial fibrillation, replacement of heart valves, or ischemic stroke, the frequency of major bleeding in patients randomly assigned to warfarin therapy targeted to reach an INR range of 2 – 3 was less than half of the frequency of bleeding in patients randomly assigned to a therapeutic range of INR > 3. Risk of intracranial hemorrhage was especially increased in patients with an INR > 4, with bleeding risk roughly doubling with each addition unit increase in INR above 3; An observational study followed a cohort of 472 patients with atrial fibrillation after warfarin initiation with at least one year of follow-up and compared outcomes and changes in therapy for two groups: an older group of 153 patients 80 years of age or older (mean age of 84 years, range from 80-97 years, 55% female) and a younger group of 319 patients less than 80 years of age (mean age 73 years, range from 65-79 years, 43% female) (Hylek 2007). The study found: The older group experienced a significantly higher rate of major hemorrhage (predominantly intracranial or gastrointestinal) at 13 per 100 person-years vs. 4.75 per 100 person-years in the younger group (p = 0.01). The study authors noted that about half (46%) of those with major hemorrhages were on low-dose (81 mg/day) aspirin therapy at the time of the major hemorrhage; but that the proportion of those with major hemorrhages was similar to the proportion (40%) of the overall cohort on aspirin during the study period; The risk of stroke was increased in three circumstances: during the first 90 days of warfarin therapy; in those at least 80 years of age; and in those with INR ≥ 4; and Warfarin therapy was stopped in 134 patients by the end of the first year. Among the older group, 81% of decisions to stop warfarin were due to safety concerns. Among the younger group, 37% of decisions to stop warfarin were due to safety concerns (p < 0.001). The study authors commented that the estimates of bleeding risk might be affected by the study’s focus on outpatient management of warfarin therapy; that is, outpatients might be more or less subject to bleeding risk than those of similar age who resided in a long-term care institution and were ineligible for this study. The study did not include any testing for genetic factors for response to warfarin therapy. Genetic and Other Factors Determining a Patient’s Response to Warfarin Administration The FDA approved label for Coumadin® notes many factors that can influence the anticoagulant effect of warfarin, including: dietary intake of green leafy vegetables and cranberry juice; alcohol consumption; age; Asian ethnicity; and liver function. Many other drugs affect warfarin metabolism, including analgesics, antibiotics, anticonvulsants, antineoplastics, beta adrenergic blockers, antifungals, hormone preparations and vitamins. The current label lists approximately 130 specific drugs reported to interact with coumadin. The label also notes several clinical trials that associate genomic factors with responsiveness to warfarin dose. The label includes the suggestion that pharmacogenomic testing may contribute to the identification of patients who may be more likely to over- or under-respond to warfarin. However, the label does not require or explicitly recommend pharmacogenomic testing prior to the initiation of warfarin therapy. Some studies have estimated that genetic factors, in combination, may account for 40-50% of inter-individual INR variability in response to oral warfarin (see comments from the American Association of Clinical Chemistry (AACC) below under Evidence Section VII(B)6). The label notes that initial response to warfarin therapy may be influenced by a multitude of factors (including diet and concomitant drug therapy) beyond genetic variation. The label also notes adjustments of warfarin dosage should be considered during initiation of therapy of elderly and/or debilitated patients, as noted in the final sentence (italics added) of the following excerpt: "Initial Dosage "The dosing of COUMADIN must be individualized according to patient’s sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. It is recommended that COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations. The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to COUMADIN (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).” III. History of Medicare Coverage There is currently no National Coverage Determination on pharmacogenomic testing to predict warfarin responsiveness. In addition, there are no local coverage determinations (LCDs) on pharmacogenomic testing to predict warfarin responsiveness. A. Current Request CMS internally generated the request for this National Coverage Analysis. B. Benefit Category Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage §1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. Pharmacogenomic testing to predict warfarin responsiveness may be considered a benefit under Social Security Act §1861(s)(3), "other diagnostic tests." This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. The Medicare regulations at 42 CFR § 410.32(a) state in part, "…diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary’s specific medical problem.” IV. Timeline of Recent Activities August 4, 2008 CMS opened an internally generated National Coverage Analysis to evaluate coverage of the diagnostic use of pharmacogenomic testing for warfarin response. The initial 30-day comment period began. September 3, 2008 The public comment period closed; 73 timely comments were received. May 4, 2009 CMS posted the proposed decision and opened a 30 day public comment period. June 3, 2009 The public comment period closed; 6 timely comments were received. V. FDA Status of Tests for VKORC1 and CYP2C9 Variants That Affect Warfarin Response Several laboratory test manufacturers offer FDA-cleared kits suitable for testing for VKORC1 and CYP2C9 variants associated with warfarin metabolism. These tests use oligonucleotide sequences, immobilized onto silicon or plastic film or attached to gold beads to detect multiple variants of both genes with or without polymerase chain reaction (PCR) methods for variant detection or amplification. A peripheral blood sample (or a buccal swab) is required for testing. The following table indicates several of the laboratory test manufacturers and the tests available. Instrument/Kit Name Approval or Clearance Status Manufacturer(s) Verigene Warfarin Metabolism Nucleic Acid Test 510(k) 09/07 Nanosphere INFINITI Warfarin (3 genetic variants) 510(k) 01/08 AutoGenomics Rapid Genotyping Assay – CYP2C9 & VKORC1 510(k) 04/08 ParagonDx eSensor Warfarin Sensitivity Test 510(k) 07/08 Osmetech eQ-PCR Warfarin Genotyping Kit 510(k) 02/09 TrimGen Pharmacogenomic testing for warfarin responsiveness is also available as ‘home-brew’ tests developed by individual clinical laboratories, using in-house methods of various types. In addition, certain laboratories provide direct-to-consumer pharmacogenomic testing for warfarin responsiveness and other genetically-associated personal health information. VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform the public of its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum. VII. Evidence A. Introduction Below is a summary of the evidence we considered during our review. CMS commissioned an external technology assessment (TA) from the Agency for Healthcare Research and Quality on pharmacogenomic testing in certain conditions. The agency also conducted its own independent search and review of applicable clinical studies, professional society and other group/organization statements, evidence-based practice guidelines, and other relevant sources detailed below. CMS did not hold a MEDCAC meeting to specifically address the evidentiary base for the use of pharmacogenetic testing as part of the workup of patients needing anticoagulation. However, we did hold a MEDCAC panel to address the appropriate evidentiary standards for diagnostic genetic tests in general. We discuss those results below. B. Discussion of Evidence Reviewed 1. Questions In Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin: a. Is the evidence sufficient to determine that pharmacogenomic testing to predict warfarin responsiveness improves patient oriented health outcomes related to the underlying indication for anticoagulation; and b. Is the evidence sufficient to determine that pharmacogenomic testing to predict warfarin responsiveness reduces the incidence or severity of adverse outcomes related to anticoagulation therapy? 2. External Technology Assessments CMS commissioned from the Agency for Healthcare Research and Quality (AHRQ) an external technology assessment (TA) on pharmacogenetic testing in selected conditions. Relevant portions of this TA (Raman 2008) are summarized in the following paragraphs. CMS is also aware of other systematic reviews on this topic; they are summarized below. Tufts-NEMC Review This technology assessment was based on research conducted by the Tufts-New England Medical Center Evidence-based Practice Center (EPC) under contract to AHRQ (Raman 2008). The findings and conclusions in this document are those of the authors, who are responsible for its contents. This study primarily examined two issues: Effect(s) of genetic variants of either CYP2C9 or of VKORC1 on warfarin pharmacokinetics (i.e., whether warfarin dosing’s effect on warfarin concentration or actions in the patient differ among patients with different genotypes of these genes in a consistent way); and Effect(s) of variants of either gene on benefit(s) or risk(s) of warfarin therapy at the patient level (i.e., whether warfarin’s preventive effect on thrombus formation or progression, or incidence of bleeding events in warfarin-treated patients, differ among patients with different genotypes in a consistent way). For CYP2C9 genetic variants *2 and *3 , the Tufts-NEMC EPC literature search identified 270 citations published between 1995 and 2007. Thirty-three of these, including two recent randomized controlled trials, were included in the systematic review. Studies chosen for this systematic review focused on the induction or maintenance phases of warfarin therapy. For VKORC1 variants (all of which were single nucleotide polymorphisms, or SNPs), the Tufts-NEMC EPC literature search identified 288 citations. Twenty-eight articles were retrieved and reviewed in full text, and 18 studies reported data on the correlation of common VKORC1 SNPs with outcomes of interest. Tufts-NEMC EPC addressed the following questions in its systematic review: Does a pharmacogenomic test diagnosis of being a variant genotype carrier compared to non-carriers among patients who will use warfarin correlate with therapeutic INR? Does a pharmacogenomic test diagnosis of being a variant genotype carrier compared to non-carriers among patients who will use warfarin correlate with adverse outcomes such as serious bleeding events or thrombotic events? What patient characteristics (e.g., age, race/ethnicity) and disease-related relevant factors (e.g., use of adjuvant medications) affect pharmacogenomic test results correlation with clinical or biochemical parameters, and other clinical outcomes among patients who will use warfarin? How does a pharmacogenomic test result impact the therapeutic choice among patients who will use warfarin (i.e., how often does planned warfarin induction therapy change after genetic testing is available to the treating physician)? What are the benefits and harms or adverse effects for patients from their subsequent therapeutic management after pharmacogenomic testing among patients on warfarin? Does pharmacogenomic testing among patients who are on warfarin and have supratherapeutic PT/INR findings result in better maintenance of therapeutic INR and fewer episodes of serious bleeding? Does pharmacogenomic testing among patients who are on warfarin and have subtherapeutic PT/INR findings result in better maintenance of therapeutic INR and fewer serious thromboembolic events, e.g., stroke, pulmonary embolus, etc., due to subtherapeutic INR? Findings of the Tufts-NEMC systematic review included: Carriers of the variant CYP2C9 alleles *2 or *3 receiving warfarin therapy were associated with lower mean maintenance warfarin dose requirements compared with the non-carriers. There was a lack of studies investigating the role of pharmacogenetic testing ( CYP2C9 or VKORC1 ) and warfarin dose requirements in the induction phase. Carriers of the three relatively common VKORC1 variants were more likely to need lower maintenance warfarin dose requirements, on average, compared with the non-carriers. Carriers of CYP2C9 variants *2 and *3 were associated with an increased rate of bleeding complications during warfarin induction phase, but the studies did not report if those patients had normal or supratherapeutic range of PT/INR. Risk of over-anticoagulation (INR results exceeded desired upper limits) was also noted among carriers of CYP2C9 variants *2 and *3 compared with non-carriers. Significant risk increases were noted in 5 of these 6 studies reviewed. The Tufts-NEMC researchers also summarize RCTs (see below) of warfarin dosing using pharmacogenomic test results, compared with standard warfarin dosing approaches. Some findings from these studies (among study group participants in comparison to control group participants) included fewer bleeding complication rates, shorter times to reach therapeutic INR range, longer times within therapeutic range, and fewer dosing changes required. One study noted a greater risk of over-anticoagulation among those who carried both CYP2C9 and VKORC1 variants. The researchers focused on RCTs in which warfarin induction dosage was algorithmically guided based on pharmacogenomic testing results, as compared to ‘standard’ dosing protocols. The Tufts NEMC TA identified three published RCTs on pharmacogenetic testing of CYP2C9 and/or VKORC1 and warfarin dosing. "Hillman (2005) evaluated the impact of pharmacogenetic based dosing compared with standard dosing on bleeding complications. The RCT reported lower bleeding complication rates among patients treated with pharmacogenetic based dosing compared to those treated with standard dosing (11% versus 25%). "Caraco (2008) randomized 191 adult patients to receive warfarin dosing in the induction phase either by six different CYP2C9 genotype-adjusted algorithms (study group) or by a validated algorithm (control group). The subjects were followed up for 2 years. The investigators were blinded to the genotype of study subjects until after completion of the induction phase period of 8 weeks. Baseline characteristics were similar for both groups except for the combined indication of warfarin (deep venous thrombosis and pulmonary embolism), and for the clinical characteristics of hyperlipidemia—these were significantly higher in the control group. The proportion of subjects with wild genotype ( CYP2C9 *1/*1 ) was higher in study group than in control group. The primary endpoints of the study were time to reach the first therapeutic INR range > 2 and time to reach stable anticoagulation. Compared with the control group, the time to reach first therapeutic INR > 2 and stable anticoagulation was statistically significantly earlier in the study group by 2.7 days and 18.1 days, respectively. Higher proportions of the study group patients were within therapeutic range INR for a longer time period and experienced less minor bleeding compared with the control group. This study did not evaluate the influence of VKORC1 in the variability of warfarin maintenance dose. "Anderson (2007) randomized 206 patients to pharmacogenetic-guided dosing compared with standard dosing. The pharmacogenetic guided dosing was derived from a regression equation based on 3 genetic variants ( CYP2C9 *2 and *3, and VKORC1 C1173T), age, sex, and weight. The subjects were followed up for 3 months. There were baseline differences in the patient characteristics. The study group included older subjects and higher proportion of subjects with hyper-tension, and the control group had a higher proportion of variant genotypes than the study group. The primary end point was per-patient percentage of out-of range INR (< 1.8 or > 3.2) in study group compared with control group. There were no differences between the groups for the primary outcome. However, the study group required statistically significantly fewer dosing changes and fewer INRs compared with control group. Patients who carried both CYP2C9 and VKORC1 variants had an increased risk for INR ≥ 4, and total number of adverse events defined as clinical events plus INR ≥ 4 were fewer in the pharmacogenetic dosing group compared with the standard dosing group.” Limitations and Scope : This TA noted that studies of CYP2C9 and VKORC1 had significant between-study heterogeneity. Few studies evaluated the questions related to patient- and disease-related factors and their relationship to the pharmacogenetic test results or their predicted response to therapy. No study reviewed in the external TA addressed the questions (their question 5) on therapeutic choice impact and benefits, harms or adverse effects for patients from their subsequent therapeutic management after pharmacogenetic testing for CYP2C9 and VKORC1 . The time-frame of included studies in this TA was from 1995 through September 2007. Sanderson 2005 This systematic review and meta-analysis of studies investigated the effects of CYP2C9 gene variants on warfarin dose requirements and on bleeding risks. The study used the HuGEnet™ database and other sources including PubMED and the Cochrane Library to include articles up to late January 2003 (Sanderson 2005). The review was based on 11 studies, including 3029 patients, of which nine studies, including 2775 patients, were used for the meta-analysis. This meta-analysis found that: Mean daily maintenance warfarin doses were reduced in those with the *2 (0.85 mg/d or 17%) and with the *3 (1.92 mg/d or 37%) variants; and Relative bleeding risk for variant *2 was 1.91, and for *3 was 1.77. This meta-analysis also found that: Variant alleles of CYP2C9 were present in twenty percent of participants: 12% were *2 , and 8% were *3 . The authors noted that these variants were rare among persons of Asian or African-American heritage; and In its discussion section, noting the changes in daily dose required and the higher risks of bleeding associated with certain genotypes, the review team suggested that testing for these variants could affect clinical management decisions in patients initiating warfarin therapy. However, the review acknowledged that additional evidence of clinical utility and cost-effectiveness would be needed before routine testing can be recommended. McClain 2008 This systematic review investigated the association of CYP2C9 and VKORC1 genotype information and the incidence of serious adverse events (McClain 2008). Its major findings included: Strength of evidence is low for an association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (CI 32-60%), clinical specificity 69% (CI 62-75%)). No evidence was found to demonstrate that VKORC1 testing and severe bleeding events are associated; and No evidence of clinical utility of such testing is available. McClain 2008 also noted: Analytic sensitivity and specificity of CYP2C9 genotyping are 98% or higher. Strength of evidence to establish the analytic sensitivity and specificity of VKORC1 genotyping is judged less than desirable; and Evidence gaps cited by this review included lack of information from external proficiency testing, lack of validated dosing algorithm including both clinical and genetic factors, and reliable economic analysis. Ongoing clinical studies: The Tufts-NEMC EPC TA noted nine ongoing clinical trials (registered with the national clinical trials database ( www.clinicaltrials.gov ) on pharmacogenomic testing of CYP2C9 and VKORC1. Additional information about clinical utility may be expected as these studies are completed and their results are published. 3. Internal technology assessment Articles from the medical literature were searched on February 27, 2009 for relevant abstracts, using the PubMED (National Library of Medicine, NIH) database and search engine. It was found that almost all of the relevant clinical articles retrieved are a subset of those reviewed by the Tufts-NEMC EPC, except for three clinical studies published since September 2007 (summarized below). Schwarz 2008 The authors assessed CYP2C9 genotypes ( CYP2C9 *1 , *2 , and *3 ), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the INR), and bleeding events in 297 patients starting warfarin therapy (Schwarz 2008). The median age of participants was 61, with an M:F ratio of 54:46. Indications for warfarin therapy in participants included joint replacement (41%), atrial fibrillation/flutter (36%), thrombosis or embolus (13%), and other or combined indications (10%). The study outcomes were: time to first PT/INR within the therapeutic range; time to first INR > 4; time above therapeutic INR range; PT/INR response over time; and warfarin dose requirement. As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first PT/INR within the therapeutic range (p = 0.02) and to the first PT/INR > 4 (p = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first PT/INR within the therapeutic range (p = 0.57) but was a significant predictor of the time to the first PT/INR > 4 (p = 0.03). Both CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy. Eight major and five minor bleeding events were noted, with 9/13 bleeding events occurring in the first 28 days after initiation of warfarin therapy. Patients with bleeding events tended to be older (median age of 71 years of age) than other participants, and were associated with INR values ranging from 1.7 to 12.3. The authors concluded that initial variability in the PT/INR response to warfarin was more strongly associated with genetic variability in the gene for the pharmacologic target of warfarin, VKORC1 , than with CYP2C9 . Wen 2008 The authors studied the effects on INR of genetically-guided warfarin dosing algorithms including information on CYP2C9 and VKORC1 variants in 108 Han Chinese patients in Taiwan without prior warfarin treatments (Wen 2008). The mean age of participants was 64 years. Fifty-eight percent of participants were males. There was no comparison group. Using genotype-based warfarin dosing, eighty-three percent of patients reached stable, therapeutic INR within 2 weeks of treatment initiation and none of the patients developed clinical bleeding or a thromboembolic event. The study noted that 11 patients developed INR > 4 without signs of clinical bleeding during the study period. At 12 weeks, sixty-nine percent of patients’ maintenance doses matched the dose predicted by the algorithm. Dosing algorithms incorporating genetic factors, age, and body surface area were developed, which could explain up to 62% of the total variation (R 2 of 0.62). The authors concluded that pharmacogenetics-based dosing could improve time to stable, therapeutic INR, reduce adverse events, and achieve high sensitivity. Wadelius 2008 This clinical study noted that harms (bleeding events) occurred more frequently among those with certain CYP2C9 genotypes, in particular *3/*3 homozygous persons. Among 1542 recruited participants, the mean age was 66 years, with about a 2:1 M:F proportion. Pharmacogenomic testing results were available (retrospectively) on 1496 participants. Warfarin dosing was initiated using various standard loading protocols. A serious bleeding event occurred in one of the eight persons in the *3/*3 subgroup in the first five weeks of therapy (12.5%); in contrast, the 1488 persons with other genotypes had only a 0.27% chance of such an event during the first five weeks. A graph of PT/INR response by week for all CYP2C9 genotypes (Figure 3b in that article) shows a large initial rise in PT/INR in the CYP2C9 *3/*3 homozygous groups. The study also noted no significant differences in the serious bleeding event rates among the VKORC1 genotypes studied during the first five weeks. A multiple regression model was developed for initial warfarin dosage based on CYP2C9 and VKORC1 genetic test results, age, gender, and drug interactions. The authors stated that this model accounted for 59% of the interindividual variation in the study population, and 53% of interindividual variation in a separate sample of 181 Swedish individuals. However, the authors recognized that the regression model was limited by lack of data on participants’ weight and height, and its consideration of only one ethnic group. Additional Evidence We reviewed evidence that has come to our attention after our earlier review. Articles from the medical literature were searched on 5/28/2009 for relevant abstracts, using the PubMED (National Library of Medicine, NIH) database and search engine. The additional evidence is summarized below. International Warfarin Pharmacogenetics Consortium 2009 The authors describe results from an international, multi-center study designed to derive and subsequently validate an algorithm in which genetic variables were added to clinical variables to derive initial warfarin dose. Clinical information was collected by 21 research groups from 9 countries; genotyping of VKORC1 and CYP2C9 was performed in a blinded manner by a single laboratory. The 5052 participants were grouped randomly into either into a ‘derivation’ cohort, from whose clinical and genetic variables a multiple regression model for initial warfarin dosage was calculated, and a ‘validation’ cohort used to assess the predictive ability of the model. Demographic and genetic features of these two cohorts were not statistically significant. Of the three models (fixed-dose, clinical algorithm, and pharmacogenetic (‘PG’) algorithm) the lowest mean absolute error in weekly warfarin dose was found in the PG (8.5 +/- 1.7 mg/week) with higher errors found in the clinical algorithm (9.9 +/- 1.9 mg/week) and the fixed-dose approach (13.0 +/- 2.3 mg/week). In particular, for the groups requiring low (21 mg/week or less) or high (49 mg/week or more) doses, the PG algorithm was a better predictor of dose than either other approach. Limitations of this study included insufficient data across the 21 research groups to include potentially important factors including smoking status, vitamin K intake, or alcohol consumption, and other genetic factors such as CYP4F2 status. Patient inclusion was limited to those whose therapeutic INR range targets were 2-3. In addition, missing data from some patients required imputing missing genotypes for some patients. Kangelaris 2009 This systematic review and meta-analysis included randomized trials comparing pharmacogenetic dosing of warfarin versus a ‘standard’ dose control algorithm in adult patients taking warfarin for the first time. Three studies met the inclusion criteria: Hillman 2005, Caraco 2007, and Anderson 2007 (summarized above in the Tufts-NEMC TA). In reviewing these three studies, the authors found "… little randomized trial data available to support the hypothesis that pharmacogenetic dosing at the onset of warfarin therapy reduces major bleeding events.” Specific challenges to trial validity were discussed for each of these three articles. The authors, citing a number of ongoing or planned clinical trials, suggest that additional evidence may be forthcoming to support the use of pharmacogenetic testing to guide warfarin therapy. Li 2009 The authors investigated the relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to predict warfarin responsiveness during the initiation of warfarin therapy in 214 subjects. The demographic characteristics of the subjects are described as 49% female, 92% self-reported European-American, and mean age 61 years (SD 14 years). Joint replacement, atrial fibrillation/atrial flutter, and venous thromboembolism accounted for 92% of the indications for anticoagulation. Results of pharmacogenomic testing along with the results of early (day 4-6) INR testing were entered into a regression model, adjusted for age, sex, ethnicity, use of amiodarone, target INR and cumulative warfarin dose. The authors conclude that pharmacogenomic testing adds little to no predictive value beyond early INR results. Lindh et al. 2009 In this publication, the authors present the results of a systematic review and meta-analysis focusing on the impact of CYP2C9 genotype on warfarin dose. 39 studies, including 7907 participants, were included in the meta-analysis. All 39 studies were published between 1999 and 2007, and were performed in Asia (12 studies), the Americas (13) and Europe (14). The mean age was 64 years (range 57-67 years); 59% of participants were males. Average maintenance warfarin dose (relative to that among patients with the CYP2C9 *1/*1 genotype) was lower by 20% (17-22%) for CYP2C9 *1/*2 patients (based on data from 31 studies), and lower by 78% (72-84%) among CYP2C9 *3/*3 patients (based on data from 7 studies). The authors noted that lack of VKORC1 haplotype data precluded the assessment of that gene’s effects on dose requirements. Millican et al. 2007 This study used retrospectively collected clinical d