Coverage Policy Manual
Policy #: 2007015
Category: Laboratory
Initiated: September 2007
Last Review: June 2022
  Genetic Test: Genotype-Guided Warfarin Dosing

Description:
Using information about an individual's genotype may help in guiding warfarin dosing and could reduce the time to dose stabilization and selection of an appropriate maintenance dose that might avoid the consequences of too much or too little anticoagulation.
 
Warfarin is administered for preventing and treating thromboembolic events in high-risk individuals; warfarin dosing is a challenging process, due to the narrow therapeutic window, variable response to dosing, and serious bleeding events in 5% or more of patients (depending on definition). Patients are typically initiated on a starting dose of 2-5 mg and monitored frequently with dose adjustments until a stable International Normalized Ratio (INR) value (a standardized indicator of clotting time) between 2 and 3 is achieved. During this adjustment period, a patient is at high risk for bleeding. Stable or maintenance warfarin dose varies among patients by more than an order of magnitude. Factors influencing stable dose include body mass index, age, interacting drugs, and indication for therapy.
 
Warfarin, which is primarily metabolized in the liver by the CYP2C9 enzyme, exerts an anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide variants, 2 in the CYP2C9 gene and 1 in the VKORC1 gene play key roles in determining the effect of warfarin therapy on coagulation (Wadelius, 2005; Wadelius, 2007; Wadelius, 2009; Gage, 2004; Hillman, 2004; Jonas, 2009; Rieder, 2005; Yuan, 2005; Geisen, 2005; D’Andrea, 2005). CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation. CYP2C9 and VKORC1 genetic variants account for approximately 55% of the variability in warfarin maintenance dose (Wadelius, 2005; Sconce, 2005). Genome-wide association studies have also identified that a single nucleotide variant in the CYP4F2 gene has been reported to account for a small proportion of the variability in stable dose (the CYP4F2 gene encodes a protein involved in vitamin K oxidation) (Takeuchi, 2009; Caldwell, 2008). Studies have predicted that CYP4F2 variants explain 2% to 7% of the variability in warfarin dose in models, including other genetic and nongenetic factors (Caldwell, 2008; Borgiani, 2009).
 
Using the results of CYP2C9 and VKORC1 genetic testing to predict a warfarin starting dose that approximates a likely maintenance dose may benefit patients by decreasing the risk of serious bleeding events and the time to stable INR. Algorithms have also been developed that corporate not only genetic variation but also other significant factors to predict the best starting dose (Wadelius, 2007; Zhu, 2007; Schelleman, 2008; Gage, 2008; Wu, 2008; Hatch, 2008; Lenzini, 2010; Wells, 2010). Studies have compared the ability of different algorithms to predict a stable warfarin dose accurately (Langley, 2009; Shaw, 2010; Lubitz, 2010; Roper, 2010; Zambon, 2011). Currently, there does not appear to be a consensus for a single algorithm (Roper, 2010).
 
Several studies have examined associations between CYP2C9 and VKORC1 variants and warfarin dosing requirements in children (Hamberg, 2014; Hawcutt, 2014; Vear, 2014).
 
There are different frequencies of variants related to warfarin pharmacokinetics across different races and ethnicities. Many of the original studies identifying associations between genes and prediction of warfarin dosing as well as studies developing algorithms were derived from cohorts composed largely of people of European descent. Evidence has suggested these algorithms do not perform as well in other ethnic groups (Schelleman, 2008; Gage, 2008; Wu, 2008; Cavallari, 2011).,For example, CYP2C9*2 and CYP2C9*3 are not as useful in predicting warfarin dosing in African Americans, but other important variants have been identified such as CYP2C9*5,*6,*8, and *11 (Kaye, 2017). Studies have also identified new genetic variants and/or evaluated clinical genetic algorithms for warfarin dose in African American, Puerto Rican, Thai, Egyptian, Chinese, Japanese, Arabic, Turkish, African, Russian, and Scandinavian populations (Perera, 2011; Perera, 2013; Ramirez, 2012; Valentin, 2012; Sangviroon, 2010; Shahin, 2011; Bazan, 2012; You, 2011; Ma, 2012; Xu, 2012; Aomori, 2011; Alzahrani, 2013; Ozer, 2013; Asiimwe, 2020; Panchenko, 2020; Skov, 2013).
 
Regulatory Status
Several tests to help assess warfarin sensitivity by determining presence or absence of the relevant CYP2C9, VKORC1, and CYP4F2 variants have been cleared by the U.S. Food and Drug Administration (FDA) for marketing. Similar tests may also be available as laboratory-developed tests in laboratories licensed under Clinical Laboratory Improvement Amendments (CLIA) for high complexity testing. The tests are not all the same in terms of the specific variants and number of variants detected. In general, such tests are not intended to be stand-alone tools to determine optimum drug dosage but should be used along with clinical evaluation and other tools, including the INR, to predict the initial dose that best approximates the maintenance dose for patients.
 
FDA-Cleared Warfarin Tests
  • eSensor® Warfarin Sensitivity Test (GenMark Dx) tests CYPC9*2 and *3 and VKORC1 1639G>A
  • Rapid Genotyping Assay (ParagonDx) tests CYPC9*2 and *3 and VKORC1 1173C>T
  • Verigene® Warfarin Metabolism Nucleic Acid Test (Nanosphere) tests CYPC9*2 and *3 and VKORC1 1173C>T
  • Infiniti® 2C9-VKORC1 Multiplex Assay for Warfarin (AutoGenomics) tests CYP2C9*2 and *3 and VKORC1 1639G>A
  • eQ-PCR™ LightCycler® Warfarin Genotyping Kit (TrimGen) tests CYP2C9*2 and *3 and VKORC1 1639G>A
 
The FDA (2007) approved updated labeling for Coumadin® to include information on testing for gene variants that may help "personalize" the starting dose for each patient and reduce the number of serious bleeding events. The label was updated again in 2010. With each update, manufacturers of warfarin (Coumadin) were directed to add similar information to their product labels. The 2010 update added information on guiding initial dose by genotyping results for CYP2C9 and VKORC1, providing a table of genotypes and suggested initial dose ranges for each. However, suggested starting doses are also provided when genotyping information is unavailable, indicating that genetic testing is not required. Furthermore, the FDA did not include information on genetic variation in the label's black box warning on bleeding risk.
 
Coding
 
Effective for 2012, there are CPT codes that are specific to this testing:
 
81227: CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6)
 
81355: VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (e.g., -1639/3673)
 
Prior to 2013, there were also specific CPT codes for array-based evaluation of multiple molecular markers:
 
88384: Array-based evaluation of multiple molecular probes: 11 through 50 probes
 
88385: 51 through 250 probes
 
88386: 251 through 500 probes
 
There was also a CPT genetic testing modifier that is specific to CYP2 genes:
 
-9B: CYP2 genes, commonly called cytochrome p 450 (drug metabolism)
 
In November 2009, the Centers for Medicare and Medicaid Services (CMS) issued a new HCPCS code that they made retroactive to August 3, 2009, to facilitate administration of their new national coverage decision on this testing. The code is:
 
G9143: Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)

Policy/
Coverage:
Effective June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing to determine warfarin response for patients receiving warfarin therapy who have a pattern of unstable dosing (those patients who require frequent testing and dose adjustments after the initiation of warfarin therapy) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered one time.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genotyping to determine cytochrome p450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms prior to or concurrent with the initial dosing of warfarin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genotyping to determine cytochrome p450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms prior to or concurrent with the initial dosing of warfarin is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to June 2018
 
Genetic testing to determine warfarin response meets primary coverage criteria for effectiveness and is covered one time for patients receiving warfarin therapy who have a pattern of unstable dosing (those patients who require frequent testing and dose adjustments after the initiation of warfarin therapy).
 
Genotyping to determine cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms prior to or concurrent with the initial dosing of warfarin is not covered because utility of this testing is presently under study in phase III trials and therefore this use of pharmacogenomic testing does not meet Primary Coverage Criteria.  For contracts without primary coverage criteria, this use of pharmacogenomic testing is considered investigational.  Investigational services are contract exclusions in the member benefit certificate of coverage.

Rationale:
Validation of genotyping to improve pharmacologic treatment outcomes is a multistep process. In general, important steps in the validation process address the following:
    • Analytic validity: measures technical performance, i.e., does the test accurately and reproducibly detect the gene markers of interest.
    • Clinical validity: measures the strength of the associations between the selected genetic markers and dose, therapeutic efficacy, and/or adverse events.
    • Clinical utility: determines whether the use of genotyping for specific genetic markers to guide prescribing and/or dosing improves patient outcomes such as therapeutic effect, time to effective dose, and/or adverse event rate compared to standard treatment without genotyping.
 
Warfarin is metabolized by the cytochrome P450 enzyme CYP2C9; genetic variants of CYP2C9 result in enzymes with decreased activity, increased serum warfarin concentration at standard doses, and a higher risk of serious bleeding. Information on cytochrome P450 pharmacogenetics is summarized in a TEC Assessment; application to warfarin dosing and the importance non-genetic influences is discussed in several publications.  VKORC1 genetic variants alter the degree of warfarin effect on its molecular target and are associated with differences in maintenance doses. CYP2C9 and VKORC1 genetic variation accounts for approximately 55% of the variability in warfarin maintenance dose; other factors influencing dose include body mass index, age, interacting drugs, and indication for therapy.
 
A recent systematic review, commissioned by the American College of Medical Genetics, evaluated CYP2C9 and VKORC1 genetic testing prior to warfarin dosing and concluded the following:
    • Analytic validity: Nearly all available data for analytic validity refer to two variants in the CYP2C9 gene; fewer data are available for the variants in the VKORC1 gene. Based on these data, analytic sensitivity and specificity are likely near 100%. Depending on methodology, 1% to 10% of samples may experience repeated assay failures resulting in inconclusive test results.
    • Clinical validity: CYP2C9 and VKORC1 genotypes contribute significant and independent information to the stable warfarin dose and compared to the most common combination, some individuals with other genotype combinations will need more than the usual dose, while others would require less. Time to steady state warfarin levels varies by CYP2C9 genotype (3 to 5 days vs. 5 to 8 vs. 12 to 15 for the three most common genotypes). CYP2C9 positive predictive value (PPV) for serious bleeding events is estimated to be 7%; the negative predictive value (NPV) is 96%. Similar information for VKORC1 was not available.
    • Clinical utility: The purpose of genetic testing in this clinical scenario is to predict an individual’s likely stable warfarin dose by incorporating demographic, clinical, and genotype data (CYP2C9 and VKORC1), and initiate warfarin at that predicted dose as a way to limit high INR values (over-anticoagulation) that are associated with an increased risk of serious bleeding events. No large study has yet shown this to be acceptable or effective. Several randomized trials are underway to determine the clinical utility. The number needed to treat to avoid one serious bleeding event is estimated to range from 48 to 385.
 
A pilot study indicates that a randomized, controlled trial in which patients in one study arm are dosed according to an algorithm that includes genotyping results and compared to a control arm administered a standard starting dose is feasible and acceptable to both patients and providers. Recent publications of warfarin dosing models provide the basis for some of the clinical trials in progress.
 
On August 16, 2007, the U.S. Food and Drug Administration (FDA) announced the approval of updated labeling for Coumadin®, to include information on genetic testing for gene variants that may help “personalize” the starting dose for each patient and reduce the number of serious bleeding events (15). Manufacturers of warfarin (generic for Coumadin®) are to add similar information to their products’ labels.
 
The FDA stated that “warfarin is the second most common drug—after insulin—implicated in emergency room visits for adverse drug events.” According to the FDA, 2 million patients are initiated on warfarin per year in the U.S.
 
Because of the current lack of outcomes (clinical utility) data, some experts do not believe that genetic testing for warfarin dosing is ready for routine clinical use. To accommodate uncertainty, the FDA did not include information on genetic variation in the label’s black box warning.
 
In a “Questions and Answers” document and during a call hosted by the FDA, several important points regarding the new labeling were made:
    • Healthcare professionals are not required to conduct CYP2C9 and VKORC1 testing before initiating warfarin therapy, nor should genetic testing delay the start of warfarin therapy.
    • Genetic testing is not appropriate for patients already on warfarin.
    • Genetic testing does not replace INR monitoring.
    • Based on available evidence, not all patients with one or more genetic variants in CYP2C9 or VKORC1 will have a serious bleeding event, nor will all patients without gene variants avoid a bleeding episode.
 
Genetic testing for CYP2C9 and VKORC1 is available at a limited number of laboratories; some companies have submitted testing kits to the FDA for approval and others are developing tests. Patients not near a testing lab may be subject to longer turnaround times (as long as 10 days, quoted in one newspaper article) to accommodate sample transport to distant laboratories; it is nor known how soon test results are needed during the warfarin initiation phase for full benefit (if projected benefits are realized in outcomes studies).
 
Since the impact of this testing on clinical outcomes (clinical utility) is not currently known, this testing is considered investigational.
 
Several randomized controlled trials are currently investigating the impact of pharmacogenomics on dosing accuracy, time to achieve and maintain target INR, incidence of bleeding or thromboembolic events, and monitoring requirements.  The Couma-Gen Investigator randomized 206 closely monitored inpatients beginning warfarin therapy to either clinical dosing or pharmacogenetic dosing based on CYP2C9 and VKORC1 SNPs. A rapid turnaround (1 hour) assay allowed determination of genotype and dose selection before the first dose. The pharmacogenetic-guided algorithm selected an initial dose much more closely predictive of the stable maintenance dose, led to significantly fewer and smaller average dose adjustments and a trend toward fewer INR measurements, but did not significantly increase the percentage of INR values in the therapeutic range, which was the primary endpoint.
 
2009 Update
The International Warfarin Pharmacogenetics Consortium published results of a retrospective study of over 5000 patients beginning warfarin treatment.  The dose of warfarin that resulted in the desired INR for each patient was identified.  Pharmacogenetic, clinical and fixed dosing algorithms were developed using clinical and genetic data from 4043 of these patients.  The dose predicted by the pharmacogenetic algorithm was closer to the empirical maintenance dose than both the clinical and fixed dosing algorithm.  Although this study does not lend scientific evidence of effectiveness for genetic testing for warfarin dosing, it does however provide a strong basis for a prospective trial to address the questions surrounding the efficacy of such testing.  
  
Langley and colleagues compared four algorithms for accuracy in predicting warfarin dose in a retrospective analysis of a local patient population on long-term stable warfarin therapy.  The predicted doses from two algorithms in particular showed the best correlation with actual warfarin doses (Langley, 2009).
 
 
In November 2008, the Agency for Healthcare Research and Quality published a Technology Assessment which included assessments of CYP2C9 and VKORC1 gene polymorphisms and their response to warfarin therapy.  Twenty-nine studies were reviewed testing the association of CYP2C9 and the response to warfarin.  The authors concluded that, “It is unclear whether dose-prediction algorithms using genetic information improve clinical outcomes over those of standard practice” (Raman et al, 2008).  Additionally, they reported that a genetic variation in CYP4F2 and its response to warfarin is currently being studied.  
 
Nineteen studies were reviewed which tested the association of VKORC1 and warfarin response. There were no published articles on the effect of genetic testing for  VKORC1 on clinical outcomes.  According to the authors, there was substantial information to conclude that three common variants of VKORC1 affect the average maintenance dose of warfarin.  “However, the clinical utility of the routine use of VKORC1 genotyping in anticoagulation clinics is uncertain” (Raman et al, 2008).
 
Cost-effectiveness studies emphasize the lack of information on clinical utility of genetic testing as a major source of uncertainty in results (Leey, 2009) (Patrick, 2009) (Eckman, 2009).
 
Several large clinical trials, including some randomized, comparative clinical trials, which address clinical utility, are currently in progress.
  
Further studies comparing the use of genetic testing versus not using genetic testing to determine warfarin response are necessary to determine the impact on health outcomes. Several trials are ongoing at this time.  Therefore, the policy statement remains unchanged.
 
2012 Update
A search of the MEDLINE database was conducted through August 2012. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key literature identified in the search.
 
Burmester et al. in association with the Agency for Healthcare Research and Quality and Third Wave Technologies conducted a prospective, randomized, blinded, 2-arm trial to determine whether initial warfarin dosing based on an algorithm using relevant genetic polymorphisms and clinical parameters (genetic and clinical arm) was superior to an algorithm using only usual clinical parameters (clinical only arm) in predicting stable therapeutic dose of warfarin and in anticoagulation outcomes (Burmester, 2011). A total of 230 primarily hospitalized patients were enrolled. The model including genotype predicted therapeutic dose better than the clinical-only model (p=0.0001); both models predicted dose better than the standard starting dose of 5 mg/day. However, the median percent time in INR range was the same at 28.6% in each arm. Observed times to stable therapeutic dose were also very similar in the 2 arms. During the trial, INR exceeded 4.0 in 35% of subjects in the clinical-only arm and in 38% of subjects in the genetic clinical arm. Thus, clinical outcomes were similar despite improved prediction with genetic information. Patients in this trial may have had frequent INR measurements and dose adjustments in a hospital setting; results may not reflect those likely to be obtained in an out-patient community setting.
 
Ferder et al. reported the predictive ability of CYP2C9 and VKORC1 genetic variants from PREVENT (Prevention of Recurrent Venous Thromboembolism) Trial subjects to gradually diminish over time from warfarin initiation starting with 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21 (Ferder, 2010). Moreau et al. (34) studied 187 elderly patients starting warfarin using a “geriatric dosing-algorithm.” Adding CYP2C9 and VKORC1 genotype variants to the initial dosing model increased the explained variance in the maintenance dose from less than 10% to 31%. By day 3 VKORC1 was no longer a significant predictor of maintenance dose, however, CYP2C9 genotype remained a significant predictor. By Day 6, neither CYP2C9 nor VKORC1 genotype variants were predictive of maintenance dose. These studies indicate that if genotyping results are clinically useful, it is likely only within the first week or less of beginning warfarin therapy.
 
Gong et al. conducted a prospective cohort study of patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism using a novel pharmacogenetic warfarin initiation protocol (Gong, 2011). Practical daily loading doses were prescribed for 2 days and were dependent on VKORC1 and CYP2C9 genotypes and, as it was found necessary, on weight. The maintenance dose was determined by combining key patient clinical parameters known to influence warfarin dose requirement along with genotypes in a regression model. Once VKORC1 and CYP2C9 genotypes were incorporated into warfarin initial dose determinations, they had no additional significant effect on time required to reach the first INR within therapeutic range, on risk of overcoagulation (INR4), or on time to stable anticoagulation.
 
Cavallari et al. tested the performance of published warfarin dosing algorithms derived from non-Hispanic cohorts in the Hispanic population. The combination of the VKORC1 and CYP2C9 genotypes and clinical factors explained 56% of patient variability in warfarin dose. The predicted dosage was within 1.0 mg/day of the therapeutic dose for 40-50% of the patients (Cavallari, 2011). Gan et al. studied Asian populations and found that Indians, compared to Chinese and Malay patients, required a dose of 4.9 versus 3.5 and 3.3mg/day, respectively. The higher warfarin doses correlated with particular VKORC1 genotypes more often found in the Indian population (Gan, 2011).
 
Perera et al. identified novel genetic markers in VKORC1 and CYP2C9 associated with higher warfarin dosing in African-Americans. A regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin maintenance dose (Perera, 2011).  Additional studies have identified new genetic variants and/or evaluated clinical-genetic algorithms for warfarin dose in Thai, (Sangviroon, 2010) Egyptian, (Shahin, 2011) Chinese, (You, 2011) and Japanese populations (Aomori, 2011). In general, genetic factors helped models explain 30-54% of the overall variance but were not always significant.
 
Burmester et al. in association with the Agency for Healthcare Research and Quality and Third Wave Technologies conducted a prospective, randomized, blinded, 2-arm trial to determine whether initial warfarin dosing based on an algorithm using relevant genetic polymorphisms and clinical parameters (genetic and clinical arm) was superior to an algorithm using only usual clinical parameters (clinical only arm) in predicting stable therapeutic dose of warfarin and in anticoagulation outcomes (Burmester, 2011). A total of 230 primarily hospitalized patients were enrolled. The model including genotype predicted therapeutic dose better than the clinical-only model (p=0.0001); both models predicted dose better than the standard starting dose of 5 mg/day. However, the median percent time in INR range was the same at 28.6% in each arm. Observed times to stable therapeutic dose were also very similar in the 2 arms. During the trial, INR exceeded 4.0 in 35% of subjects in the clinical-only arm and in 38% of subjects in the genetic clinical arm. Thus, clinical outcomes were similar despite improved prediction with genetic information. Patients in this trial may have had frequent INR measurements and dose adjustments in a hospital setting; results may not reflect those likely to be obtained in an out-patient community setting.
 
Practice Guidelines and Position Statements
The 2008 American College of Medical Genetics (ACMG) policy statement concluded: "There is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients" (Flockhart, 2008).
 
The 8th edition of the “American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy,” published in 2008 and reviewed in 2009, states, “At the present time, for patients beginning [vitamin K antagonist] therapy, without evidence from randomized trials, we suggest against the use of pharmacogenetic-based initial dosing to individualize warfarin dosing (Grade 2C )” (Hirsch, 2008).
 
The 3rd European Science Foundation–University of Barcelona (ESF–UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics published a summary on CYP2C9 and VKORCI genotyping for warfarin dosing. The report noted the FDA’s addition of genetic information to the warfarin label but stated that the European Medicines Agency (EMA) has not yet decided whether to include this information in European drug labels” (Becquemont, 2011).
 
Ongoing Clinical Trials
Several large clinical trials, including some randomized controlled trials are currently in progress. The following trials are currently ongoing:
 
    • Warfarin Adverse Event Reduction For Adults Receiving Genetic Testing at Therapy INITIATION (WARFARIN) Trial conducted by Iverson Genetic Diagnostics, Inc. (NCT01305148). The trial will determine if the use of genetic information can predict warfarin dosing that will result in fewer hospitalizations and deaths related to warfarin. Setting: 16 hospitals/research centers in 7 states. Targeted enrollment: 4,300 participants. Currently recruiting. Additional information online at: www.warfarinstudy.org.
    • Clarification of Optimal Anticoagulation Through Genetics (COAG) Trial conducted by the National Heart, Lung, and Blood Institute in collaboration with Bristol-Myers Squibb (NCT00839657). The trial will compare genotype-guided and clinical-guided dosing algorithms for warfarin dose. Setting: 12 hospital/university medical centers in 12 states. Targeted enrollment: 1,238 participants. Currently recruiting. The trial design was published by French, et al (French, 2010).  
    • European Pharmacogenetics of AntiCoagulant Therapy – Warfarin (EU-PACT) Trial conducted by the Utrecht Institute for Pharmaceutical Sciences (NCT01119300). The trial will determine whether a dosing algorithm containing genetic information increases the time within therapeutic INR range during anticoagulant therapy with warfarin (and other anticoagulant drugs) compared to a dosing regimen not using genetic information. Setting: university medical centers and hospitals. Target enrollment: 970 participants. Not yet recruiting. The trial design was published by van Schie, et al (van Schie, 2009).
    • Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (Coumagen-II) Trial conducted by Intermountain Healthcare, Inc. (NCT00927862). The trial will determine whether CYP2C9 and VKORC1 genotyping improves the efficiency of dosing and safety in patients being started on warfarin. Setting: hospitals and clinics owned by Intermountain Healthcare. Targeted enrollment: 1,000 participants. Not yet recruiting.
    • Clinical and Economic Implications of Genetic Testing for Warfarin Management trial conducted by the University of Chicago, in collaboration with AHRQ (NCT00964353). The trial will determine clinical outcomes and costs associated with the use of genotype-guided warfarin dose algorithms compared to current standards of care. Setting: University medical center. Targeted enrollment: 268 participants. Currently recruiting.
    • Genotype-Guided Warfarin Therapy Trial (WARFPGX) conducted by the University of North Carolina in collaboration with UNC Institute for Pharmacogenomics and Individualized Therapy (NCT00904293). The trial will determine the clinical utility of a warfarin-dosing algorithm that incorporates genetic information for adult patients initiating warfarin therapy. Setting: 2 anticoagulation clinics at UNC Hospitals. Targeted enrollment: 198 participants. Currently recruiting.
    • Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT Trial conducted by the Washington University School of Medicine, in collaboration with Intermountain Health Care, University of Utah, Hospital for Special Surgery, New York, and National Heart, Lung, and Blood Institute (NCT01006733). The trial will develop strategies to improve the safety and effectiveness of clot prevention by customizing anticoagulants to individual genetic and clinical profiles. Setting: 4 hospital/university medical centers. Targeted enrollment: 1,600 participants. Currently recruiting. The trial design was published by Lenzini, et al (Lenzini, 2010).
    • Pharmacogenetics of Warfarin in Puerto Rican Patients Using a Physiogenomics Approach Trial conducted by the University of Puerto Rico, in collaboration with National Heart, Lung, and Blood Institute, Hartford Hospital, and VA Caribbean Healthcare System (NCT01318057). The trial will determine the variants of CYP2C9 and VKORC1 alleles associated with warfarin treatment clinical responses in order to develop a better method of dose estimation in Puerto Ricans. Setting: hospital. Targeted enrollment: 350 participants. Currently recruiting.
 
2013 Update
A search of the MEDLINE database through August 2013 did not reveal any new literature that would prompt a change in the coverage statement. A number of publications addressing pharmacogenetic-driven dosing algorithms for warfarin therapy were identified. These publications and other key identified literature are discussed below.
 
A study by Horne and colleagues assessed if pharmacogenetic algorithms can contribute to dose refinements after INR response to warfarin is known (Horne, 2012). A population (n=1,684) drawn from 3 continents and 16 study sites was utilized to derive an algorithm explaining warfarin dose including a novel treatment response index comprised of prior warfarin dose and INR measurements. The pharmacogenetic warfarin dose-refinement algorithm explained more variability in dosing (R2=71.8%) compared to the clinical algorithm (R2=64.8%). In addition to these patients, a prospective external validation cohort (n=43) was recruited to determine the safety and accuracy of the clinical algorithm. The pooled pharmacogenetic algorithm explained 58% to 79% of the variation in therapeutic dose, and the time in therapeutic range during days 11-30 was 62%. The new pooled clinical algorithm was significantly more accurate than previously validated algorithms.
 
A prospective, single-arm study (n=344) by Perlstein et al. assessed the validity of 3 warfarin dosing algorithms to predict time in therapeutic range and time to first therapeutic INR in a predominantly Caucasian population (Perlstein, 2012). The dosing algorithms were developed sequentially to select both an initial warfarin dose and a titration scheme intended to maximize the likelihood of achieving and maintaining the target INR. Algorithm A determined the initial dosing with a decision tree including both clinical and genetic factors based on best practices in the hospital’s anticoagulation management service and the published literature. Algorithm B was generated from an analysis of warfarin dose, INR, genetic factors, demographic factors, and concomitant drug therapy from a group of 74 patients treated with Algorithm A. Algorithm C was an update to Algorithm B, with the chief difference being a revision of the half maximal inhibitory concentration for VKORC1 haplotypes. The authors found a significant (p=0.04) progressive improvement in mean percentage time in therapeutic range over the entire study period for Algorithm A (58.9), Algorithm B (59.7), and Algorithm C (65.8). The secondary endpoint of per-patient percentage of INRs outside of the therapeutic range had a similar statistically significant trend across algorithms (p=0.004) with Algorithm A reporting 21.6%, algorithm B 22.8%, and algorithm C 16.8%. Time to stable therapeutic anticoagulation decreased significantly across algorithms (p<0.001), but time to first therapeutic INR did not vary significantly among the 3 algorithm sub-groups. No differences in rates of adverse events were observed during this study.
 
Ramirez et al. developed a predictive algorithm for calculating dose variation in African-Americans including variants in CYP2C9*6 and CALU (Ramirez, 2012). The authors validated an expanded pharmacogenomic dosing algorithm and compared it to the previously established International Warfarin Pharmacogenomics Consortium (IWPC) algorithm with the algorithms explaining 41% and 29% of variation, respectively.
 
A retrospective cohort of Puerto Rican patients (n=97) were recruited to determine the influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose for this population (Valentin, 2012). Blood samples were collected during routine INR testing and underwent HILOmet PhyzioType assay to detect 5 single nucleotide polymorphisms (SNPs) in CYP2C9 and 7 SNPs in VKORC1 (Valentin, 2012). Median actual effective warfarin doses were compared between CYP2C9 and VKORC1 carrier status as (wild type/non-carriers, single, double, triple and quadruple carriers). Significant differences (p<0.001) in warfarin dose were observed between wild type (5.71 mg/day), single carrier (4.64 mg/day), double carrier (3.43 mg/day), triple carriers (2.36 mg/day) and quadruple carriers (1.86 mg/day). No significant difference in time to target INR was identified between groups (p=0.34). Predicted daily warfarin dose was assessed by comparing IWPC pharmacogenomic-guided algorithm, clinical algorithm, and fixed-dose approach. In the low-dose subgroup, the pharmacogenetic algorithm provided dose estimates that were more accurate, and closer to the actual doses required, than the estimates derived from fixed-dose or clinical algorithm (p<0.001 for both comparisons). No differences were detected among the intermediate-dose patients between algorithms, and in the high-dose subgroup, a marginal difference between pharmacogenetic algorithm and clinical algorithm was found (p<0.042). This study is the first time that the association between SNPs in CYP2C9 and VKORC1 genes and effective warfarin dose has been described in Puerto Rican patients.
 
A blinded, randomized clinical trial (CoumaGen-II) by Anderson et al. investigated if 2 pharmacogenetic-guided (PG) testing algorithms were better than standard empiric warfarin dosing (Anderson, 2012).  A parallel control group (n=1,866) included patients initiating warfarin treatment during the study period, and for these patients, warfarin dose was determined by physician/health-care provider. Same day genotyping of CYP2C9 and VKORC1 was provided to 504 patients randomized t257 in the 1-step arm (IWPC algorithm) and 247 in the 3-step arm (modified IWPC algorithm). The vast majority of patients (91.4% in the control group and 95.4% in the PG group) were of Caucasian ancestry. Primary endpoints were the percentage out-of-range of INRs and time in therapeutic range during the first month and through the third month of warfarin therapy. Both PG approaches were observed to be equivalent at 1 and 3 months for all outcomes with a stable maintenance dose determined in 444 patients. There was an inverse relation between the number of reduced function alleles and the ability to predict a stable maintenance dose (p<0.001). Pharmacogenomic guidance was more accurate in wild-type patients and those with multiple variants (p<0.001). Both PG arms were pooled and were observed to be superior to the standard dosing approach with significant (p<0.001) reductions in percent of time out of INR range and percentage of time in therapeutic range at 1 and 3 months after controlling for relevant variables. Adverse events (hemorrhagic events, thromboembolic events, or other serious adverse events) were greater in the control group (4.5%) compared to the PG group (9.4%), with an adjusted relative risk of .44 (95% CI: 0.28-0.70, p<0.001).
 
Ongoing Clinical Trials
The Coumagen-II trial (NCT00927862) mentioned in the 2012 Update has been completed and published (Anderson, 2012). The remaining clinical trials listed are ongoing as of this policy updated (clinicaltrials.org, 2013).
 
2015 Update
A literature search conducted using the MEDLINE database through August 2015 did not reveal any new information that would prompt a change in the coverage statement.   
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Systematic Reviews
Several published systematic reviews have assessed comparing genotype-guided warfarin dosing with clinical dosing. The systematic reviews include a total of 12 trials published before 2015, and most trials overlap in the reviews.
 
 The reviews all included similar eligibility criteria leading to a similar set of overlapping studies. In general, reviewers found that the percentage of time the international normalized ratio (INR) was in therapeutic range have been higher in patients treated with genotype-guided warfarin therapy; however, the heterogeneity between studies was high for this outcome. Reviewers also varied in their definitions for clinical outcomes, but none of the reviews found differences in rates of major bleeding, thromboembolic events, or death.
 
Given that the Belley-Cote et al review  included all 12 trials published up to the search date and used the GRADE approach to evaluate the quality of evidence, the following discussion focused on that systematic review (Belley-Cote, 2015). Reviewers identified 12 published RCTs (total N=3217 patients) and evidence that at least 3 trials were completed but not yet published. Only 1 study, Kimmel et al, was rated as low risk of bias for all domains (Kimmel, 2013). A summary of the risk of bias is as follows: (1) the trials inconsistently reported allocation concealment; (2) only 1 study blinded participants, clinicians, research personnel and outcome assessors; (3) patients who died during the trial period were excluded from analysis in 2 trials; (4) the 3 studies with highest loss to follow-up had losses of 12%, 16%, and 23%, respectively; and (5) 5 studies did not report the definitions used for bleeding events. Reviewers found that genotype-guided vitamin K antagonist dosing compared with standard dosing algorithms did not decrease a composite outcome of death, thromboembolism and major bleeding (n=2223, 87 events; RR=0.85; 0.54 to 1.34; p=0.48) but did result in an improved time of INR in the therapeutic range. The improvement in time in therapeutic range was reported in a pooled analysis of RCTs with fixed dosing algorithms, but not with clinical algorithms.
 
Randomized Controlled Trials
RCTs comparing genotype-guided warfarin dosing with clinical dosing were included with no limitations on the indication for warfarin use. Fourteen RCTs comparing genotype-guided with clinical dosing of warfarin were identified. Most RCTs were single-center studies including less than 250 patients. Four multicenter RCTs with more than 400 patients have been reported. The trials used varying algorithms in both the genotype-guided and the clinical dosing arms. Most studies included mixed indications for warfarin use. The trials primarily included patients of European descent; two trials were conducted in China. Twenty-seven percent of the participants in the COAG trial were African American (Kimmel, 2013).
 
 While a few of the RCTs reported differences in the percentage of time the INR was in therapeutic range or the proportion of patients with an INR greater than four, none reported statistically significant differences in major bleeding or thromboembolic events. However, it is important to note that the event rates were very low in the selected trials and the studies were not powered to show differences in rates of major bleeding or thromboembolic events.
 
Gage et al (2017) reported on results of the GIFT RCT, which evaluated genotype-guided warfarin dosing (n=831) and clinically guided dosing (n=819) in patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty; the trial was conducted at 6 U.S. medical centers (Gage, 2017). Patients were genotyped for VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M variants. The primary endpoint was the composite of major bleeding, INR of four or greater, venous thromboembolism, or death. The mean age of randomized patients was 72, 64% of participants were women, and 91% were white. Randomized participants who received 1 or more doses of warfarin were included in the analysis (808 in genotype-guided group vs 789 in clinically guided group). Eighty-seven (11%) patients in the genotype-guided group vs 116 (15%) patients in the clinically guided group met at least 1 of the components of the composite outcome (absolute difference, 3.9%; 95% CI, 0.7% to 7.2%; p=0.02). The difference in the composite outcome was primarily driven by the difference in percent of patients with INR of 4 or greater (56 vs 77; RR=0.71; 95% CI, 0.51 to 0.99). There were 2 vs 8 major bleeding events in the genotype vs clinical groups (RR=0.24; 95% CI, 0.05 to 1.15) and 33 vs 38 venous thromboembolism events (RR=0.85; 95% CI, 0.54 to 1.34). There were no deaths.
 
A risk of bias assessment for RCTs included in the Belley-Cote systematic review was summarized in the previous section (Belley-Cote, 2015). No major relevance, design or conduct gaps were identified for the Gage (2017) RCT, and it is a low risk of bias.
 
Genotype-Guided Warfarin Dosing Clinical Utility
Multiple randomized trials and meta-analyses of these trials have examined the use of pharmacogenomic algorithms to guide initial warfarin dosing
 
• Five of the 14 RCTs reported statistically significant differences favoring genotype-guided warfarin dosing for outcomes related to time in the therapeutic range for INR and/or the outcome related to events of INR greater than 4.
 
• None of the trials or pooled analyses of the trials showed a benefit for patient-important outcomes like major bleeding or venous thromboembolism.
 
• A 2015 systematic review including 12 trials (total N=3217 patients) did not report a decrease a composite outcome of death, thromboembolism and major bleeding (87 events, RR=0.85; 95% CI, 0.54 to 1.34) with genotype-guided dosing.
 
• A 2017 RCT (n=1650) demonstrated an improvement in the composite outcome of major bleeding, INR of 4 or greater, venous thromboembolism, or death (absolute difference, 3.9%; 95% CI, 0.7% to 7.2%) favoring genotype-guided dosing that was driven primarily by the difference in the INR component. There were no statistically significant differences in clinical events in genotype vs clinical groups: 2 vs 8 major bleeding events, 33 vs 38 venous thromboembolism events, and no deaths.
 
Very few trials have included a sufficient number of subgroups that were not white. In the COAG study, which included 27% African American participants, African Americans fared better in the clinically guided group than in the genotype-guided group. There are completed, registered studies that have not been published, so the possibility of publication bias cannot be excluded.
 
For individuals with conditions requiring warfarin treatment who receive genotype-guided warfarin dosing, the evidence includes multiple randomized controlled trials (RCTs) and systematic reviews of the RCTs.
Relevant outcomes are morbid events, medication use, treatment-related mortality and morbidity. Fourteen RCTs were identified. While 5 of the 14 RCTs reported statistically significant differences in outcomes related to the international normalized ratio, none of the trials or pooled meta-analyses of the trials have shown a benefit for outcomes of major bleeding or venous thromboembolism. In the pooled analysis including 2223 participants, 87 events of the composite outcome (mortality, major bleed, and thromboembolic events) occurred (relative risk, 0.85; 95% confidence interval , 0.54 to 1.34; p=0.48). In the GIFT trial, which included 1650 participants, conducted after the pooled analysis, 2 vs 8 major bleeding events occurred (relative risk=0.24; 95% confidence interval, 0.05 to 1.15), 33 vs 38 venous thromboembolism events occurred (relative risk= 0.85; 95% confidence interval, 0.54 to 1.34), and there were no deaths. Very few trials have enrolled sufficient numbers of subpopulations except White participants. In the COAG study, which included 27% African American participants, African Americans fared better in the clinically guided group than in the genotype-guided group. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
Clinical Pharmacogenetics Implementation Consortium
In 2017, the Clinical Pharmacogenetics Implementation Consortium updated guidelines for pharmacogenetics-guided warfarin dosing (Johnson, 2017). The guideline provides recommendations for genotype-guided warfarin dosing to achieve a target international normalized ratio of 2–3 for adult and pediatric patients specific to continental ancestry. The guideline also states that “Although there is substantial evidence associating CYP2C9 and VKORC1 variants with warfarin dosing, randomized clinical trials have demonstrated inconsistent results in terms of clinical outcomes.”
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Several systematic reviews and meta-analyses have assessed genotype-guided warfarin dosing compared with clinical dosing. The systematic reviews and meta-analyses included a total of 27 trials published between 2005 and 2020. The reviews used similar eligibility criteria leading to a similar set of overlapping studies. In the discussion below, we focus on the 5 most recent and comprehensive reviews, conducted by Belley-Cote et al (2015), Tse et al, the Washington State Health Technology Assessment Program, Yang et al, and Sridharan and Sivaramakrishnan (Belly-Cote, 2015; Tse, 2018; Washington State HCA, 2018; Yang, 2019; Sridharan, 2020).
 
All 5 reviews found that the percentage of time the international normalized ratio (INR) was in therapeutic range was higher in patients treated with genotype-guided warfarin therapy; however, the heterogeneity between studies was high for this outcome. In the Belley-Cote et al review, there was no difference between groups on the composite outcome of thromboembolic events (TEEs), major bleeding, or death. Similarly, Sridharan and Sivaramakrishnan evaluated these outcomes independently in a network meta-analysis and found no significant differences between clinically adjusted warfarin and genotype-guided dosing, except that bleeding risk was lower with CYP2C9-guided dosing compared with clinically adjusted warfarin. Meta-analyses in the 5 most recent systematic reviews were heavily weighted by the large Genetics Informatics Trial (GIFT), published in 2017. Authors of these reviews found no difference between genotype-guided dosing and clinical dosing for mortality or TEEs but genotype-guided dosing was associated with a lower risk of major bleeding. For example, the Washington HTA reviewers found a 57% reduction for risk of major bleeding in the pharmacogenetic testing group compared to controls (RR, 0.43; 95% CI, 0.22 to 0.84; p=.01) (Washington State HCA, 2018). The absolute number of major bleeding events was low, with an anticipated 8.6 fewer major bleeding events per 1000 people with pharmacogenetic testing (95% CI, 2.7 to 14.4 fewer major bleeding episodes per 1000 people). Subgroup analyses by comparator groups showed this difference was statistically significant only when pharmacogenetic testing was compared to using a clinical algorithm to guide initial dosing (RR, 0.39; 95% CI, 0.19 to 0.81), and not when compared to a fixed dose (RR, 0.70; 95% CI, 0.14 to 3.53). Washington HTA reviewers rated the overall quality of the evidence for major bleeding as moderate due to the imprecision of the estimate.
 
Belley-Cote et al used the GRADE approach to evaluate the quality of evidence (Belley-Cote, 2015). A summary of the risk of bias of individual studies is as follows: (1) the trials inconsistently reported allocation concealment; (2) only 1 study blinded participants, clinicians, research personnel, and outcome assessors; (3) patients who died during the trial period were excluded from analysis in 2 trials; (4) the 3 studies with highest loss to follow-up had losses of 12%, 16%, and 23%, respectively; and (5) 5 studies did not report the definitions used for bleeding events. Reviewers found that genotype-guided vitamin K antagonist dosing compared with standard dosing algorithms did not decrease a composite outcome of death, thromboembolism and major bleeding (n=2223, 87 events; RR=0.85; 0.54 to 1.34; p=.48) but did result in an improved time of INR in the therapeutic range. The improvement in time in therapeutic range was reported in a pooled analysis of RCTs with fixed dosing algorithms, but not with clinical algorithms. Of the 13 trials included in the Washington HTA systematic review, 3 were judged to be at low-risk of bias, 4 at moderate-risk of bias, and 6 at high-risk of bias. Study limitations included inadequate methods of randomization and allocation concealment and lack of blinding of outcomes (Washington State HCA, 2018).
 
Yang et al also completed a risk of bias assessment of included RCTs (Yang, 2019). All trials claimed to be randomized in nature; however, the random sequence generation was only explicitly described in 9 studies. Additionally, only 7 studies discussed allocation concealment; blinding was not implemented in most of the included RCTs as administration of an initial fixed warfarin dose would potentially imply to the participants and study personnel that the subject was randomized to the conventional dosing versus genotype-guided arm. Sridharan and Sivaramakrishnan assessed the quality of evidence as follows for the assessed outcomes and comparisons: time to first therapeutic INR with CYP2C9: low; time to first therapeutic INR with CYP2C9 and VKORC1: moderate; time to stable INR or warfarin dose with CYP2C9: very low; time to stable INR with CYP2C9 and VKORC1: very low; and percentage of time the INR was in therapeutic range with CYP2C9 and VKORC1: very low (Sridharan, 2020). The quality of evidence was often downgraded because of high risk of bias, potential for publication bias, and imprecision.
 
We identified 1 additional recent RCT not included in any of the systematic reviews and meta-analyses (Zhu, 2020). Zhu et al found that INR time in therapeutic range was improved with genotype-guided dosing based on CYP2C9 and VKORC1 compared with clinically-guided dosing in elderly Chinese patients with nonvalvular atrial fibrillation. Additionally, bleeding events did not differ between groups, but ischemic stroke occurred less frequently with genotype-guided dosing.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Wang et al was the only systematic review to find a significant reduction in TEEs with genotype-guided warfarin dosing (Wang, 2022). There was also a reduction in major bleeding events but not deaths, in the genotype-guided warfarin group compared to the control group.
 
Wang et al assessed risk of bias of their included studies (Wang, 2022). Three studies were identified as unclear on all of the bias assessments because they were conference abstracts with limited data. In the selection bias category, 3 studies were assigned high risk of bias. In the reporting bias category, 4 studies were identified as high risk of bias. For performance bias, 2 studies were assigned high risk. Overall, the majority of trials had a low risk of detection and attrition bias.
 
The updated American College of Chest Physicians' evidence-based clinical practice 2021 guidelines on antithrombotic therapy and prevention of thrombosis make no mention of genotype-guided warfarin dosing (Stevens, 2021).

CPT/HCPCS:
0030UDrug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823)
81227CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
81355VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variant(s) (eg, 1639G&gt;A, c.173+1000C&gt;T)
G9143Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)

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