Medical Policy

Policy Num:     11.003.067
Policy Name:    Genotype-Guided Warfarin Dosing
Policy ID:          [11.003.067]  [Ac / B / M- / P-]  [2.04.48]

Last Review:      July 08, 2024
Next Review:      July 20, 2025
 

Related Policies: None

Genotype-Guided Warfarin Dosing

Summary

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.

Summary of Evidence

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 RCTs. Relevant outcomes are morbid events, medication use, and treatment-related mortality and morbidity. Thirty RCTs and 6 recent systematic reviews were identified. Most RCTs were single-center studies including fewer than 250 patients. Systematic reviews found 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. No RCT reported statistically significant differences in major bleeding, and only 1 reported a significant reduction in thromboembolic events (TEEs) with genotype-guided dosing, but studies were not powered to show differences in these outcomes. Meta-analyses of RCTs found no difference between genotype-guided dosing and clinical dosing for mortality, and only 1 found reduction in TEEs, but genotype-guided dosing was associated with a lower risk of major bleeding. Very few trials enrolled sufficient numbers of subpopulations except White participants. In the COAG study, Black individuals (constituting 27% of trial participants) fared better in the clinically-guided group than in the genotype-guided group. One trial of elderly Chinese patients with atrial fibrillation experienced improved time with INR in the therapeutic range and a reduced risk of ischemic stroke but no difference in bleeding events. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether genotype-guided warfarin dosing improves the net health outcome (eg, to prevent or treat thromboembolic events [TEEs]) in individuals who require warfarin therapy.

POLICY statements

Genotyping to determine cytochrome P450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1) genetic variants is considered investigational for the purpose of managing the administration and dosing of warfarin, including use in guiding the initial warfarin dose to decrease time to stable international normalized ratio (INR) and to reduce the risk of serious bleeding.

POLICY GUIDELINES

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Warfarin

Warfarin is administered to prevent and treat thromboembolic events (TEEs) in high-risk patients; warfarin dosing is a challenging process, due to the narrow therapeutic window, variable response to dosing, numerous drug interactions, and serious bleeding events in 5% or more of patients (depending on definition).^1, Patients are typically given a starting dose of 2 mg to 5 mg and frequently monitored with dose adjustments until a stable international normalized ratio (INR) value (a standardized indicator of clotting time) between 2 and 3 is achieved (depending on indication). During this adjustment period, a patient is at high risk of 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.

Enzyme Variant Impact on Warfarin Metabolism

Warfarin, which is primarily metabolized in the liver by the cytochrome P450 2C9 (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.^{2,3,4,5,6,7,8,9,10,11,}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.^2,12, 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).^13,14,Studies have predicted that CYP4F2 variants explain 2% to 7% of the variability in warfarin dose in models, including other genetic and nongenetic factors.^14,15,

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 incorporated not only genetic variation but also other significant patient characteristics and clinical factors to predict the best starting dose.^{3,16,17,18,19,20,21,22,} Studies have compared the ability of different algorithms to predict a stable warfarin dose accurately.^{23,24,25,26,27,} Currently, there does not appear to be a consensus for a single algorithm.^26,

Several studies have examined associations between CYP2C9 and VKORC1 variants and warfarin dosing requirements in children.^28,29,30,

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.^17,18,19,31,For example, CYP2C9*2 and CYP2C9*3 are not as useful in predicting warfarin dosing in Black individuals, but other important variants have been identified such as CYP2C9*5,*6,*8, and *11.^32, Studies have also identified new genetic variants and/or evaluated clinical genetic algorithms for warfarin dose in Black,^33,34,35, Puerto Rican,^36, Thai,^37, Egyptian,^38,39, Chinese,^40,41,42, Japanese,^43, Arabic,^44, Turkish,^45, African,^46, Russian,^47, and Scandinavian^48, populations.

Regulatory Status

Several tests to help assess warfarin sensitivity by determining the 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 (Table 1). Similar tests also may be available as laboratory-developed services; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The tests are not identical regarding the specific variants and number of variants detected. Generally, such tests are not intended as stand-alone tools to determine optimum drug dosage but should be used with clinical evaluation and other tools, including the INR, to predict the initial dose that best approximates the maintenance dose for patients.

Table 1. FDA-Cleared Warfarin Tests

The FDA (2007) approved updated labeling for warfarin 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 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.

RATIONALE

This evidence review was created in September 2007 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 29, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of the condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Genotype-Guided Warfarin Dosing

Clinical Context and Therapy Purpose

The purpose of genotype-guided warfarin dosing is to guide an individual's initiation and maintenance dose of warfarin by incorporating demographic, clinical, and genotype data. In theory, this should lead to a predicted dose that will decrease the probability of over- or undercoagulation thereby avoiding the downstream consequences of thromboembolism or bleeding.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients being considered for treatment with warfarin.

Interventions

A number of commercial tests for individual genes or panel tests are available and listed in Table 1. Numerous algorithms have been developed to guide warfarin dosing based on the results of genetic tests and other demographic and clinical factors.

Comparators

The comparator of interest is standard clinical management without genetic testing.

Outcomes

Specific outcomes of interest are listed in Table 2. The interest is in whether genotype-guided warfarin dosing reduces adverse events during the dose adjustment period. Therefore, outcomes in the first 1 to 2 months are relevant.

Table 2. Outcomes of Interest for Individuals Undergoing Genotyping to Guide Warfarin Therapy

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
   
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
   
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
   
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews and Meta-Analyses

Several systematic reviews and meta-analyses have assessed genotype-guided warfarin dosing compared with clinical dosing. A comparison of the trials included in more recent systematic reviews and meta-analyses is shown in Table 3. The systematic reviews and meta-analyses included a total of 30 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 6 most recent and comprehensive reviews, conducted by Belley-Cote et al (2015)^50,, Tse et al (2018),^51, the Washington State Health Technology Assessment Program (Washington HTA; 2018),^52, Yang et al (2019),^53, Sridharan and Sivaramakrishnan (2020),^54,and Wang et al (2022).^55, Characteristics and results of these reviews are summarized in Tables 4 and 5.

Table 3. RCTs Included in Systematic Reviews of Genotype versus Clinical Dosing of Warfarin

Table 5. Results of Systematic Reviews of RCTs of Genotype versus Clinical Dosing of Warfarin

Belley-Cote et al (2015)^50, used the GRADE approach to evaluate the quality of evidence. 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; 95% CI, 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.^52, Yang et al (2019)^53, also completed a risk of bias assessment of included RCTs. 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 vitamin K epoxide reductase complex, subunit 1 (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.^54, The quality of evidence was often downgraded because of high risk of bias, potential for publication bias, and imprecision. Wang et al (2022)^55, assessed risk of bias of their included studies. 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 of detection and attrition bias.

Randomized Controlled Trials

A total of 30 RCTs comparing genotype-guided with clinical dosing of warfarin are included in this policy, all of which were included in at least 1 systematic review (Table 3). Characteristics and results of key RCTs included in these systematic reviews and meta-analyses are presented in Tables 6 and 7.

Most RCTs were single-center studies including fewer than 250 patients. The trials used varying algorithms in both the genotype-guided and clinical dosing arms. Most studies included mixed indications for warfarin use. The trials primarily included patients of European descent. Twenty-seven percent of the participants in the multicenter Clarification of Optimal Anticoagulation through Genetics (COAG) trial^67, were Black.

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 4, none reported statistically significant differences in major bleeding, and only 1 (Zhu et al [2020]) reported significant reduction in TEEs (ischemic stroke) with genotype-guided dosing.^83, 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 TEEs.

Three multicenter RCTs with more than 400 patients have been reported: COAG,^67, European Pharmacogenetics of Anticoagulant Therapy (EU-PACT), ^68, and GIFT.^5, These larger RCTs, along with the large single center trial by Zhu et al (2020),^83, are discussed in the following paragraphs and summarized in Tables 6 and 7. The systematic reviews discussed above included these large trials. The Belley-Cote systematic review was published prior to GIFT.

Table 6. Characteristics of Key RCTs of Genotype-guided Warfarin Dosing

Two larger RCTs of pharmacogenetic dosing algorithms were published by Kimmel et al (2013) and Pirmohamed et al (2013).^67,68, The larger of these, the COAG trial, was conducted in the U.S. by the National Heart, Lung, and Blood Institute,^67, and the smaller trial was conducted in Sweden and England by the EU-PACT consortium.^68, In both trials, the intervention period was the first 5 days of dosing; genotyping comprised the CYP2D6*2 and *3 and VKORC1 1639G>A alleles; the primary outcome was the mean percentage of time in the therapeutic INR range of 2.0 to 3.0. Neither trial reported an intention-to-treat analysis.

In the COAG trial, 1015 individuals, 6 to 70 years old, 51% male, and 27% Black were randomized to warfarin doses for the first 5 days of therapy based on their clinical and genetic characteristics or their clinical characteristics alone.^67, Patients were followed for 4 additional weeks during which time their drug doses were adjusted based on standard protocols. Ninety-four percent (n=955) of patients completed the 5-day intervention period and were included in efficacy analyses. Results showed that INR was within the desired range 45% (p=.91) of the time in both groups during the 28-day monitoring period, based on standardized blood clotting tests. The principal secondary outcome (a composite of INR ≥4, major bleeding [fatal hemorrhage, intracranial bleeding, or symptomatic bleeding requiring overnight hospitalization, transfusion, angiographic intervention, or surgery], or thromboembolism) was also similar in the 2 groups (20% vs. 21%, respectively; p=.93). A subgroup analysis of 255 Black patients showed that the clinically-guided group fared better than the genotype-guided group (INR was within the desired range 43.5% vs. 35.2%, respectively; p=.01).

In the EU-PACT trial, 455 individuals, 24 to 90 years old, 99% White, were randomized to warfarin doses for the first 3 days based on their clinical and genetic characteristics or their clinical characteristics alone.^68, Patients were followed for 12 additional weeks during which time their drug doses were adjusted based on standard protocols. Ninety-four percent of patients had 13 or more days of INR data and were included in efficacy analyses. Results showed that INR was within the desired range 67% of the time in the genotype-guided dosing group compared with 60% in the clinically-guided group (p<.001). There were no differences in secondary outcomes assessed (bleeding or TEEs). However, the percentage of patients with an INR >4 was lower in the genotype-guided group (27%) than in the clinically-guided group (37%). The time to achieving therapeutic INR was also shorter in the genotype-guided group (21 days) than in the clinically-guided group (29 days).

Gage et al (2017) reported on the 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.^84, 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 ≥4, 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 the genotype-guided group vs. 789 in the clinically-guided group). Eighty-seven (11%) patients in the genotype-guided group versus 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=.02). The difference in the composite outcome was primarily driven by the difference in the percent of patients with INR ≥4 (56 vs. 77; RR=0.71; 95% CI, 0.51 to 0.99). There were 2 versus 8 major bleeding events in the genotype versus clinical groups (RR=0.24; 95% CI, 0.05 to 1.15) and 33 versus 38 venous TEEs (RR=0.85; 95% CI, 0.54 to 1.34). There were no deaths.

Zhu et al (2020) randomized elderly Chinese patients, aged 60 years or greater, with nonvalvular atrial fibrillation to receive their warfarin dose based on an algorithm using genetic and clinical factors (genetic group, n=313) or an algorithm using clinical factors only (n=194).^83, Investigators found that INR time in therapeutic range was improved with genotype-guided dosing based on CYP2C9 and VKORC1 compared with clinically-guided dosing. Additionally, bleeding events did not differ between groups, but ischemic stroke occurred less frequently with genotype-guided dosing.

Risk of bias and quality of evidence assessments for the RCTs included in the Belley-Cote (2015),^50, Washington HTA (2018),^52, Yang (2019),^53, Sridharan and Sivaramakrishnan (2020),^54, and Wang (2022)^55, systematic reviews were summarized in the previous section.

Section Summary: Genotype-Guided Warfarin Dosing

Multiple randomized trials and meta-analyses of these trials have examined the use of pharmacogenomic algorithms to guide initial warfarin dosing. A total of 30 RCTs and 6 recent systematic reviews and meta-analyses of genotype-guided dosing of warfarin were identified.

Most RCTs were single-center studies including fewer than 250 patients. 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; 27% of the participants in the multicenter COAG trial^67, were Black. 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 >4, none reported statistically significant differences in major bleeding, and only 1 (Zhu et al [2020]) reported a significant reduction in TEE (ischemic stroke) with genotype-guided dosing. 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 TEEs.

Six systematic reviews found that the percentage of time the INR was in the therapeutic range was higher in patients treated with genotype-guided warfarin therapy; however, the heterogeneity between studies was high for this outcome. Recent systematic reviews including the large, multicenter GIFT trial found no difference between genotype-guided dosing and clinical dosing for mortality , but genotype-guided dosing was associated with a lower risk of major bleeding. 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 that 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).

Very few trials have included a sufficient number of subgroups that were not White. In the COAG study, Black individuals (constituting 27% of trial participants) fared better in the clinically-guided group than in the genotype-guided group. One trial of elderly Chinese patients with atrial fibrillation experienced improved time with INR in the therapeutic range and a reduced risk of ischemic stroke, but no difference in bleeding events. There are completed, registered studies that have not been published, so the possibility of publication bias cannot be excluded.

Summary of Evidence

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 RCTs. Relevant outcomes are morbid events, medication use, and treatment-related mortality and morbidity. Thirty RCTs and 6 recent systematic reviews were identified. Most RCTs were single-center studies including fewer than 250 patients. Systematic reviews found 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. No RCT reported statistically significant differences in major bleeding, and only 1 reported a significant reduction in thromboembolic events (TEEs) with genotype-guided dosing, but studies were not powered to show differences in these outcomes. Meta-analyses of RCTs found no difference between genotype-guided dosing and clinical dosing for mortality, and only 1 found reduction in TEEs, but genotype-guided dosing was associated with a lower risk of major bleeding. Very few trials enrolled sufficient numbers of subpopulations except White participants. In the COAG study, Black individuals (constituting 27% of trial participants) fared better in the clinically-guided group than in the genotype-guided group. One trial of elderly Chinese patients with atrial fibrillation experienced improved time with INR in the therapeutic range and a reduced risk of ischemic stroke but no difference in bleeding events. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Chest Physicians

In 2012, the ninth edition of the American College of Chest Physicians' evidence-based clinical practice guidelines on antithrombotic therapy and prevention of thrombosis stated: "For patients initiating VKA [vitamin K antagonist] therapy, we recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B)."^85, The updated 2021 guidelines make no mention of genotype-guided warfarin dosing.^86,

Clinical Pharmacogenetics Implementation Consortium

In 2017, the Clinical Pharmacogenetics Implementation Consortium updated guidelines for pharmacogenetics-guided warfarin dosing.^87, The guideline provides recommendations for genotype-guided warfarin dosing to achieve a target international normlized ratio (INR) of 2 to 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."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

The Centers for Medicare & Medicaid Services (2009) published a national coverage determination on pharmacogenomic testing for warfarin response.^88, The Centers for Medicare & Medicaid Services stated that "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries outside the context of CED [coverage with evidence development], and is therefore not reasonable and necessary…."

However, the Centers also "believes that the available evidence supports that coverage with evidence development (CED) … is appropriate for pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness by any method, and is therefore covered only when provided to Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin who:

1. Have not been previously tested for CYP2C9 or VKORC1 alleles; and

2. Have received fewer than 5 days of warfarin in the anticoagulation regimen for which the testing is ordered; and

3. Are enrolled in a prospective, randomized, controlled clinical study when that study meets [described] standards."

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

REFERENCES

1. Pengo V, Denas G. Optimizing quality care for the oral vitamin K antagonists (VKAs). Hematology Am Soc Hematol Educ Program. Nov 30 2018; 2018(1): 332-338. PMID 30504329
2. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005; 5(4): 262-70. PMID 15883587
3. Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. Mar 2007; 121(1): 23-34. PMID 17048007
4. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. Jan 22 2009; 113(4): 784-92. PMID 18574025
5. Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. Jan 2004; 91(1): 87-94. PMID 14691573
6. Hillman MA, Wilke RA, Caldwell MD, et al. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics. Aug 2004; 14(8): 539-47. PMID 15284536
7. Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci. Jul 2009; 30(7): 375-86. PMID 19540002
8. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. Jun 02 2005; 352(22): 2285-93. PMID 15930419
9. Yuan HY, Chen JJ, Lee MT, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. Jul 01 2005; 14(13): 1745-51. PMID 15888487
10. Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. Oct 2005; 94(4): 773-9. PMID 16270629
11. D'Andrea G, D'Ambrosio RL, Di Perna P, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. Jan 15 2005; 105(2): 645-9. PMID 15358623
12. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. Oct 01 2005; 106(7): 2329-33. PMID 15947090
13. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. Mar 2009; 5(3): e1000433. PMID 19300499
14. Caldwell MD, Awad T, Johnson JA, et al. CYP4F2 genetic variant alters required warfarin dose. Blood. Apr 15 2008; 111(8): 4106-12. PMID 18250228
15. Borgiani P, Ciccacci C, Forte V, et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. Feb 2009; 10(2): 261-6. PMID 19207028
16. Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G A) and CYP2C9 genotypes. Clin Chem. Jul 2007; 53(7): 1199-205. PMID 17510308
17. Schelleman H, Chen J, Chen Z, et al. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin Pharmacol Ther. Sep 2008; 84(3): 332-9. PMID 18596683
18. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. Sep 2008; 84(3): 326-31. PMID 18305455
19. Wu AH, Wang P, Smith A, et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics. Feb 2008; 9(2): 169-78. PMID 18370846
20. Hatch E, Wynne H, Avery P, et al. Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients. J Thromb Haemost. Jun 2008; 6(6): 1038-40. PMID 18419746
21. Lenzini P, Wadelius M, Kimmel S, et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. May 2010; 87(5): 572-8. PMID 20375999
22. Wells PS, Majeed H, Kassem S, et al. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism. Thromb Res. Jun 2010; 125(6): e259-64. PMID 20421126
23. Langley MR, Booker JK, Evans JP, et al. Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms. J Mol Diagn. May 2009; 11(3): 216-25. PMID 19324988
24. Shaw PB, Donovan JL, Tran MT, et al. Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic. J Thromb Thrombolysis. Aug 2010; 30(2): 220-5. PMID 20204461
25. Lubitz SA, Scott SA, Rothlauf EB, et al. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J Thromb Haemost. May 2010; 8(5): 1018-26. PMID 20128861
26. Roper N, Storer B, Bona R, et al. Validation and comparison of pharmacogenetics-based warfarin dosing algorithms for application of pharmacogenetic testing. J Mol Diagn. May 2010; 12(3): 283-91. PMID 20228265
27. Zambon CF, Pengo V, Padrini R, et al. VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study. Pharmacogenomics. Jan 2011; 12(1): 15-25. PMID 21174619
28. Hamberg AK, Wadelius M. Pharmacogenetics-based warfarin dosing in children. Pharmacogenomics. Feb 2014; 15(3): 361-74. PMID 24533715
29. Hawcutt DB, Ghani AA, Sutton L, et al. Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects. Pharmacogenomics J. Dec 2014; 14(6): 542-8. PMID 25001883
30. Vear SI, Ayers GD, Van Driest SL, et al. The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. Br J Haematol. Jun 2014; 165(6): 832-5. PMID 24601977
31. Cavallari LH, Momary KM, Patel SR, et al. Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells Mol Dis. Feb 15 2011; 46(2): 147-50. PMID 21185752
32. Kaye JB, Schultz LE, Steiner HE, et al. Warfarin Pharmacogenomics in Diverse Populations. Pharmacotherapy. Sep 2017; 37(9): 1150-1163. PMID 28672100
33. Perera MA, Gamazon E, Cavallari LH, et al. The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin Pharmacol Ther. Mar 2011; 89(3): 408-15. PMID 21270790
34. Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet. Aug 31 2013; 382(9894): 790-6. PMID 23755828
35. Ramirez AH, Shi Y, Schildcrout JS, et al. Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenomics. Mar 2012; 13(4): 407-18. PMID 22329724
36. Valentin II, Vazquez J, Rivera-Miranda G, et al. Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. Ann Pharmacother. Feb 2012; 46(2): 208-18. PMID 22274142
37. Sangviroon A, Panomvana D, Tassaneeyakul W, et al. Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. Drug Metab Pharmacokinet. 2010; 25(6): 531-8. PMID 20930419
38. Shahin MH, Khalifa SI, Gong Y, et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics. Mar 2011; 21(3): 130-5. PMID 21228733
39. Bazan NS, Sabry NA, Rizk A, et al. Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients. Int J Clin Pharm. Dec 2012; 34(6): 837-44. PMID 22851439
40. You JH, Wong RS, Waye MM, et al. Warfarin dosing algorithm using clinical, demographic and pharmacogenetic data from Chinese patients. J Thromb Thrombolysis. Jan 2011; 31(1): 113-8. PMID 20585834
41. Ma C, Zhang Y, Xu Q, et al. Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin. Int J Hematol. Dec 2012; 96(6): 719-28. PMID 23104259
42. Xu Q, Xu B, Zhang Y, et al. Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Thromb Haemost. Dec 2012; 108(6): 1132-40. PMID 23015069
43. Aomori T, Obayashi K, Fujita Y, et al. Influence of CYP2C9 and vitamin k oxide reductase complex (VKORC)1 polymorphisms on time to determine the warfarin maintenance dose. Pharmazie. Mar 2011; 66(3): 222-5. PMID 21553655
44. Alzahrani AM, Ragia G, Hanieh H, et al. Genotyping of CYP2C9 and VKORC1 in the Arabic population of Al-Ahsa, Saudi Arabia. Biomed Res Int. 2013; 2013: 315980. PMID 23586031
45. Özer M, Demirci Y, Hizel C, et al. Impact of genetic factors (CYP2C9, VKORC1 and CYP4F2) on warfarin dose requirement in the Turkish population. Basic Clin Pharmacol Toxicol. Mar 2013; 112(3): 209-14. PMID 23061746
46. Asiimwe IG, Zhang EJ, Osanlou R, et al. Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis. Clin Pharmacol Ther. Jun 2020; 107(6): 1420-1433. PMID 31869433
47. Panchenko E, Kropacheva E, Dobrovolsky A, et al. CYP2C9 and VKORC1 genotyping for the quality of long-standing warfarin treatment in Russian patients. Pharmacogenomics J. Oct 2020; 20(5): 687-694. PMID 32024944
48. Skov J, Bladbjerg EM, Leppin A, et al. The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment. Thromb Res. Feb 2013; 131(2): 125-9. PMID 23159229
49. Cavallari LH, Shin J, Perera MA. Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy. Dec 2011; 31(12): 1192-207. PMID 22122181
50. Belley-Cote EP, Hanif H, D'Aragon F, et al. Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation. A systematic review and meta-analysis. Thromb Haemost. Oct 2015; 114(4): 768-77. PMID 26158747
51. Tse G, Gong M, Li G, et al. Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol. Sep 2018; 84(9): 1868-1882. PMID 29704269
52. Washington State Health Care Authority. Pharmacogenetic Testing for Patients Being Treated with Oral Anticoagulants:Final Evidence Report. 2018. Available at: https://www.hca.wa.gov/assets/program/pharmacogenetics-anticoagulants-final-rpt-20180418.pdf. Accessed April 29, 2024.
53. Yang T, Zhou Y, Chen C, et al. Genotype-guided dosing versus conventional dosing of warfarin: A meta-analysis of 15 randomized controlled trials. J Clin Pharm Ther. Apr 2019; 44(2): 197-208. PMID 30593674
54. Sridharan K, Sivaramakrishnan G. A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional. J Clin Pharm Ther. Jun 2021; 46(3): 640-648. PMID 33346393
55. Wang X, Tang B, Zhou M, et al. Efficacy and safety of genotype-guided warfarin dosing versus non-genotype-guided warfarin dosing strategies: A systematic review and meta-analysis of 27 randomized controlled trials. Thromb Res. Feb 2022; 210: 42-52. PMID 34999431
56. Hillman MA, Wilke RA, Yale SH, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res. Aug 2005; 3(3): 137-45. PMID 16160068
57. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. Nov 27 2007; 116(22): 2563-70. PMID 17989110
58. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. Mar 2008; 83(3): 460-70. PMID 17851566
59. Huang SW, Chen HS, Wang XQ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics. Mar 2009; 19(3): 226-34. PMID 19177029
60. Burmester JK, Berg RL, Yale SH, et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med. Jun 2011; 13(6): 509-18. PMID 21423021
61. McMillin GA, Melis R, Wilson A, et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit. Jun 2010; 32(3): 338-45. PMID 20386359
62. Korneva E, Ratchina S, Miljagin V, Kozhuhova L, Romanov A, Eidelshtein M. Evaluation of pharmacogenetic-based warfarin therapy in patients with atrial fibrillation in Smolensk region of Russion: results. Basic Clin Pharmacol Toxicol. 109(2011):27-28. https://doi.org/10.1111/j.1742-7843.2011.00731.x.
63. Borgman MP, Pendleton RC, McMillin GA, et al. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb Haemost. Sep 2012; 108(3): 561-9. PMID 22836303
64. Wang M, Lang X, Cui S, et al. Clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial. Int J Med Sci. 2012; 9(6): 472-9. PMID 22927772
65. Radhakrishnan AV, D.; Tayur, S.; et al. Genotype Guided Therapeutic Dosing of Warfarin in Geriatric Patients. J Am Coll Cardiol. 2012;59:E1696. PMID
66. Jonas DE, Evans JP, McLeod HL, et al. Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics. Oct 2013; 14(13): 1593-603. PMID 24088130
67. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. Dec 12 2013; 369(24): 2283-93. PMID 24251361
68. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. Dec 12 2013; 369(24): 2294-303. PMID 24251363
69. Verhoef TI, Ragia G, de Boer A, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med. Dec 12 2013; 369(24): 2304-12. PMID 24251360
70. Li J, Liu S, Yang JH, et al. [A randomized controlled study of the VKORC1 and CYP2C9 genotypes in guiding warfarin therapy for pulmonary thromboembolism]. Zhonghua Jie He He Hu Xi Za Zhi. Dec 2013; 36(12): 950-3. PMID 24503429
71. Pengo V, Zambon CF, Fogar P, et al. A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation. PLoS One. 2015; 10(12): e0145318. PMID 26710337
72. Šupe S, Poljaković Z, Božina T, et al. Clinical Application of Genotype-guided Dosing of Warfarin in Patients with Acute Stroke. Arch Med Res. May 2015; 46(4): 265-73. PMID 25989350
73. Duan L, Zhang N, Liu C. A randomized controlled study of the VKORC1 and CYP2C9 genotypes in guiding warfarin initial dosing algorithm for pulmonary thromboembolism. Chest 2016;149: A519.
74. Jin H, Jiang F, Wei J, Yao Y, Yuan H, Yu M, et al. CYP2C9 and VKORC1 genotype-guided individualized warfarin therapy in Chinese patients with acute pulmonary thromboembolism: a randomized controlled clinical study. Int J Clin Exp Med 2017;10(3): 5595-602.
75. Wen MS, Chang KC, Lee TH, et al. Pharmacogenetic dosing of warfarin in the Han-Chinese population: a randomized trial. Pharmacogenomics. Feb 2017; 18(3): 245-253. PMID 28112575
76. Jiang NX, Ge JW, Xian YQ, et al. Clinical application of a new warfarin-dosing regimen based on the CYP2C9 and VKORC1 genotypes in atrial fibrillation patients. Biomed Rep. Apr 2016; 4(4): 453-458. PMID 27073631
77. Makar-Aušperger K, Krželj K, Lovrić Benčić M, et al. Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial. Ther Drug Monit. Jun 2018; 40(3): 362-368. PMID 29494423
78. Xu Z, Zhang SY, Huang M, et al. Genotype-Guided Warfarin Dosing in Patients With Mechanical Valves: A Randomized Controlled Trial. Ann Thorac Surg. Dec 2018; 106(6): 1774-1781. PMID 30205115
79. Syn NL, Wong AL, Lee SC, et al. Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. BMC Med. Jul 10 2018; 16(1): 104. PMID 29986700
80. Hao Y, Yang J, Zheng X, et al. Chinese Patients With Heart Valve Replacement Do Not Benefit From Warfarin Pharmacogenetic Testing on Anticoagulation Outcomes. Ther Drug Monit. Dec 2019; 41(6): 748-754. PMID 31259883
81. Guo C, Kuang Y, Zhou H, et al. Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial. Circ Genom Precis Med. Aug 2020; 13(4): e002602. PMID 32510984
82. Lee KE, Yee J, Lee GY, et al. Genotype-guided warfarin dosing may benefit patients with mechanical aortic valve replacements: randomized controlled study. Sci Rep. Apr 24 2020; 10(1): 6988. PMID 32332930
83. Zhu Y, Xu C, Liu J. Randomized controlled trial of genotype-guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation. J Clin Pharm Ther. Dec 2020; 45(6): 1466-1473. PMID 32710457
84. Gage BF, Bass AR, Lin H, et al. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA. Sep 26 2017; 318(12): 1115-1124. PMID 28973620
85. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012; 141(2 Suppl): 7S-47S. PMID 22315257
86. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. Dec 2021; 160(6): e545-e608. PMID 34352278
87. Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther. Sep 2017; 102(3): 397-404. PMID 28198005
88. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Pharmacogenomic Testing for Warfarin Response (90.1). 2009; https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=333. Accessed April 29, 2024.

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