Background

Warfarin is administered to prevent and treat TEEs in high-risk patients; 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 given a starting dose of 2 mg to 5 mg and frequently monitored with dose adjustments until a stable INR value (a standardized indicator of clotting time) between 2 and 3 is achieved. 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.

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.^{1,2,3,4,5,6,7,8,9,10,}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.^1,11, 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).^12,13,Studies have predicted that CYP4F2 variants explain 2% to 7% of the variability in warfarin dose in models, including other genetic and nongenetic factors.^13,14,

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.^{2,15,16,17,18,19,20,21,} Studies have compared the ability of different algorithms to predict stable warfarin dose accurately.^{22,23,24,25,26,} Currently, there does not appear to be a consensus for a single algorithm.^25,

Several studies have examined associations between CYP2C9 and VKORC1 variants and warfarin dosing requirements in children.^27,28,29,

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.^16,17,18,30,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.^31, Studies have also identified new genetic variants and/or evaluated clinical genetic algorithms for warfarin dose in African American,^32,33,34, Puerto Rican,^35, Thai,^36, Egyptian,^37,38, Chinese,^39,40,41, Japanese,^42, Arabic,^43, Turkish,^44,African,^45,Russian,^46, and Scandinavian^47, 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 (see 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

Test (Laboratories)	Alleles Tested	Estimated Time to Completion, h
eSensor® Warfarin Sensitivity Test (GenMark Dx)a	CYPC9*2 and *3, VKORC1 1639G>A	3-4
Rapid Genotyping Assay (ParagonDx)	CYPC9*2 and *3, VKORC1 1173 C>T	Not reportedb
Verigene® Warfarin Metabolism Nucleic Acid Test (Nanosphere)	CYPC9*2 and *3, VKORC1 1173C>T	≤2
Infiniti® 2C9-VKORC1 Multiplex Assay for Warfarin (AutoGenomics)c	CYP2C9*2 and *3, VKORC1 1639G>A	6-8
eQ-PCR™ LightCycler® Warfarin Genotyping Kit (TrimGen)	CYP2C9*2 and *3, VKORC1 1639G>A	≤2

Adapted from Cavallari et al (2011).^48,
FDA: Food and Drug Administration.

^a eSensor Warfarin Plus Test offers testing for CYP2C9*2, *3, *5, *6, *11, *14, *15, and *16, VKORC1 1639G>A, and CYP4F2.
^b Langley et al (2009) reported a turnaround time of 1.5 hours for the ParagonDx SmartCycler, which may be a precursor assay.^22,
c The expanded Infiniti CYP450 2C9 assay offers testing for CYP2C9*2, *3, *4, *5, *6, and *11, VKORC1 1639G>A, and 6 other VKORC variants.

Related Policies

• None

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medicare Coverage:
Per National Coverage Determination (NCD) 90.1 Pharmacogenomic Testing to Predict Warfarin Responsiveness, CMS has determined that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness is covered in the context of a Medicare-approved clinical study pursuant to Coverage with Evidence Development (CED) for candidates for anticoagulation therapy with warfarin who:

1. Have not been previously tested for CYP2C9 or VKORC1 alleles; and
2. Have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and
3. Are enrolled in a prospective, randomized, controlled clinical study that meets CMS standards as set forth in NCD 90.1.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2009 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through April 16, 2016.

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.

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. RCTs 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.

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 question addressed in this evidence review is: Does genotype-guided warfarin dosing improve health outcomes?

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

Patients

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.

Patients requiring treatment with warfarin are managed by multiple specialists, including but not limited to cardiologists, cardiovascular surgeons, pulmonologists, internists, critical care physicians, and neurologists based on the clinical indication. Warfarin is used in both inpatient and outpatient settings.

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

Outcomes	Details
Morbid events	Bleeding, thromboembolism
Medication use	Initial and maintenance dose selection
Treatment-related mortality	Death due to under- or overtreatment
Treatment-related morbidity	Time to achieve therapeutic INR, time in therapeutic INR, bleeding, thromboembolism

INR: international normalized ratio.

Review of Evidence
Systematic Reviews

Several systematic reviews have assessed genotype-guided warfarin dosing compared with clinical dosing. A comparison of the trials included in more recent systematic reviews is shown in Table 3. The systematic reviews included a total of 20 trials published between 2005 and 2017. The reviews used similar eligibility criteria leading to a similar set of overlapping studies. In the discussion below, we focus on the 4 most recent and comprehensive reviews, conducted by Belley-Cote et al (2015)^49,, Tse et al (2018),^50,the Washington State Health Technology Assessment Program (Washington HTA; 2018),^51,and Yang et al (2019)^52,. Characteristics and results of these reviews are summarized in Tables 4 and 5.

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

Trials	Systematic Reviews
	Belley-Cote et al (2015)49,	Tse (2018)50,	Washington HTA (2018)51,	Yang (2019)52,
Hillman et al (2005)53,	⚫	⚫	⚫	⚫
Anderson et al (2007)54,	⚫		⚫	⚫
Caraco et al (2008)55,	⚫	⚫	⚫
Huang et al (2009)56,	⚫	⚫	⚫	⚫
Burmester et al (2011)57,	⚫		⚫	⚫
Borgman et al (2012)58,	⚫		⚫	⚫
Wang et al (2012)59,	⚫		⚫	⚫
Radhakrishnan et al (2012)60,	⚫
Jonas et al (2013)61,	⚫		⚫	⚫
Kimmel et al (2013)62,	⚫		⚫	⚫
Pirmohamed et al (2013)63,	⚫	⚫	⚫	⚫
Verhoef et al (2013)64,	⚫
Li et al (2014)65,		⚫		⚫
Pengo et al (2015)66,		⚫	⚫	⚫
Supe et al (2015)67,		⚫
Duan (2016)68,		⚫
Gage (2017)4,		⚫	⚫	⚫
Jin (2017)69,		⚫		⚫
Wen (2017)70,		⚫	⚫	⚫
Jiang (2016)71,				⚫

RCT: randomized controlled trial.

Table 4. Summary of Systematic Reviews of RCTs of Genotype vs Clinical Dosing of Warfarin

Study	Dates	Participants	RCTs	N (Range)	Duration
Belley-Cote et al (2015)49,	To Feb 2014	Adults requiring initiation of anticoagulation for any indication	12	3217 (34-1015)	1-6 mo
Tse et al (2018)50,	2000-2015	Genotype-guided vs. conventional warfarin dosing (population not specified)	18	5230 (NR)	28-90 days
Washington HTA51,	To January 2018	Adults and children initiating or changing dosage of oral anticoagulant medications	13	4788 (34-1650)	30 days-6 months
Yang (2019)52,	To October 2017	Patients with any indication for warfarin therapy	15	4852 (26-1597)	28-90 days

NR: not reported; RCT: randomized controlled trial.

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

Study	TEEs	Major Bleeding, %	INR >4, %	% Time INR in Therapeutic Range	Deaths
Belley-Cote et al (2015)49,	TEEs, major bleeding, or death: 2223RR=0.85 (0.54 to 1.34); 0.4810% (0.35)
Total N			NR	2767	NR
Pooled effect (95% CI)				MD 4.3 (0.4 to 8.3); 0.03
I2(p)				79% (<0.001)
Tse et al (2018)50,
Total N	NR	NR	NR		NR
Pooled effect (95% CI)	RR 0.84 (0.56 to 1.26); 0.40	RR 0.82 (0.69 to 0.98); < 0.05	RR 0.87( 0.78 to 0.98); < 0.05	MD 3.1% standard error 1.2%;< 0.01	RR 1.16 (0.46 to 2.91); 0.76
I2 (p)	0%	31%	0%	80%	0%
Washington HTA (2018)51,
Total N	4241	4241	4056	4378	3540
Pooled effect (95% CI)	RR 0.85 (0.56 to 1.28); 0.44	RR 0.43 (0.22 to 0.84); 0.01	0.91 (0.80 to 1.04); 0.16	MD 3.11 (-0.28 to 6.50); 0.07	RR 1.17 (0.43 to 3.22); 0.76
I2 (p)	0%	0%	0%	78%; <0.00001	0%
Yang (2019)52,
Total N	NR	NR	NR	3831	NR
Pooled effect (95% CI)	RR 0.27 (0.03 to 2.38); 0.239 [vs. fixed-dose warfarin] RR 0.89 (0.58 to 1.35); 0.572 [vs. clinically adjusted warfarin]	RR 0.16 (0.01 to 3.96); 0.265 [vs. fixed-dose warfarin] RR 0.32 (0.13 to 0.74); 0.008 [vs. clinically adjusted warfarin]	RR 0.83 (0.67 to 1.03); 0.085 [vs. fixed-dose warfarin] RR 0.95 (0.78 to 1.15); 0.586 [vs. clinically adjusted warfarin]	WMD 3.36 (-2.12 to 8.84); 0.229 [vs. fixed-dose warfarin] WMD 0.88 (-2.26 to 4.02); 0.582 [vs. clinically adjusted warfarin]	RR 2.56 (0.50 to 13.05); 0.258 [vs. fixed-dose warfarin] RR 0.72 (0.20 to 2.62); 0.622 [vs. clinically adjusted warfarin]
I2 (p)	0%	0% [clinically adjusted]	0% [fixed dose]; 31.2% [clinically adjusted]	59.2% [fixed dose]; 63% [clinically adjusted]	0%

CI: confidence interval; INR: international normalized ratio; MD: mean difference; NR: not reported; RCT: randomized controlled trial; RR: relative risk; TEE: thromboembolic event; WMD: weighted mean difference.

All 4 reviews found that the percentage of time the 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 (2015) review, there was no difference between groups on the composite outcome of TEEs, major bleeding, or death. Meta-analyses in the 4 most recent systematic reviews were heavily weighted by the large Genetics Informatics Trial (GIFT), published in 2017.^4, 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=0.01).^51, 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 (2015)^49, 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; 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. 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.^51,Yang et al (2019)^52, 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.

Randomized Controlled Trials

A total of 22 RCTs comparing genotype-guided with clinical dosing of warfarin are included in this policy. Twenty of these RCTs were included in at least 1 systematic review (see Table 3). We identified 2 additional more recent RCTs not included in any of the systematic reviews.^72,73, Neither found a difference between groups in the percent of time in therapeutic range. One of the 2 trials reported major bleeding outcomes and found no significant difference between genotype-guided and traditional dosing.^72,

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. Twenty-seven percent of the participants in the multicenter Clarification of Optimal Anticoagulation through Genetics (COAG) trial^62, were African American.

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 or TEEs. 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,^62, European Pharmacogenetics of Anticoagulant Therapy (EU-PACT), ^63,and GIFT.^4,These larger RCTs are discussed in the following paragraphs and summarized in Tables 6 and 7. The 4 systematic reviews discussed above included the majority of these large trials. The Belley-Cote systematic review was published prior to GIFT.

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

Study; Trial	Countries	Sites	Dates	Participants	Interventions
Kimmel et al (2013) 62, COAG	US	18	2009-2013	Adults initiating warfarin therapy with expected duration ≥1 mo 27% black race	Algorithm including clinical variables only
Pirmohamed et al (2013)63, EU-PACT	UK, Sweden	2	2010-2013	Age >18 y; warfarin-naive; indications for anticoagulation with AF or VTE 99% white race	Clinical dosing algorithm including age, sex, height, weight, and amiodarone use
Gage (2017)74, GIFT	US	6	2011-2016	Patients aged ≥65 y initiating warfarin for elective hip or knee arthroplasty INR <1.35 91% white race	WarfarinDosing.org algorithm excluding genotype data

AF:atrial fibrillation; INR: international normalized ratio; RCT: randomized controlled trial; VTE: venous thromboembolism.

Table 7. Results of Key RCTs of Genotype-guided Warfarin Dosing

Study	Major Bleeding	TEEs	INR >4	% Time in Therapeutic Range	Deaths
Kimmel et al (2013) 62,COAG
N	1015	1015	955	955	1015
Genotype-guided dosing, n (%)	4 (1)	5 (1)	100 (19)	45%	2
Control, n (%)	10 (2)	4 (1)	92 (18)	45%	1
TE (95% CI); p	HR=0.41 (0.13 to 1.31); 0.13	HR=1.27 (0.34 to 4.73); 0.72	HR=1.08 (0.81 to 1.44); 0.59	p=0.91	HR=2.09 (0.19 to 23.22); 0.55
Pirmohamed et al (2013)63, EU-PACT
N	427	427	427	427	427
Genotype-guided dosing, n (%)	0	0	57 (27)	67.4%	5
Control, n (%)	0	1	79 (37)	60.3%	2
TE (95% CI); p			OR=0.63 (0.41 to 0.97); 0.03	MD=7.0 (3.3 to 10.6); <0.001
Gage (2017)74, GIFT
N	1597	1597	1597	1588	1597
Genotype-guided dosing, n (%)	2 (0.2)	33 (4.1)	56 (6.9)	55%	0
Control, n (%)	8 (1.0)	38 (4.8)	77 (9.8)	51%	0
TE (95% CI); p	RD=0.8 (-0.2 to 1.8); 0.06	RD=0.7 (-1.3 to 2.8); 0.48	RD=2.8 (0.1 to 5.6); 0.04	MD=3.4 (1.1 to 5.8); 0.004

CI: confidence interval; HR: hazard ratio; INR: international normalized ratio; MD: mean difference; OR: odds ratio; RCT: randomized controlled trial; RD: risk difference; TE: treatment effect; TEE: thromboembolic event.

^a Values are in person-months.

In the COAG trial, 1015 individuals, 6 to 70 years old, 51% male, and 27% African American were randomized to warfarin doses for the first 5 days of therapy based on their clinical and genetic characteristics or their clinical characteristics alone.^62, 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=0.91) 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=0.93). A subgroup analysis of 255 African American 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=0.01).

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.^63, 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<0.001). There were no differences in secondary outcomes assessed (bleeding or TEEs). However, the percentage of patients with 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.^74, 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 genotype-guided group vs 789 in the 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 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 vs 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.

Risk of bias assessments for the RCTs included in the Belley-Cote (2015),^49,Washington HTA (2018),^51, and Yang (2019)^52,systematic reviews were summarized in the previous section. An assessment of the limitations for the remaining RCTs is shown in Tables 8 and 9.

Table 8. Study Relevance Limitations of RCTs of Genotype vs Clinical Dosing of Warfarin

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of FUe
Makar-Aušperger et al (2017)72,				1. Major bleeding and TEEs not reported by treatment group 5. No discussion of clinically important differences
Syn et al (2018)73,				1. Major bleeding and TEEs not reported

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
FU: follow-up; RCT: randomized controlled trial; TEE: thromboembolic event.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Makar-Aušperger et al (2017)72,	1. Stated to be randomized but also stated that "those admitted to the Department of Cardiology, no pharmacogenetic assessment was performed prior to anticoagulation therapy start, while patients admitted to the Department of Internal Medicine were pharmacogenetically evaluated before being started on warfarin" 3. Allocation concealment not described		1. Registration not mentioned	1. Flow of participants not described, missing data unclear	1. No power calculations
Syn et al (2018)73,		1, 2, 3		3. High loss to follow-up and no ITT analysis

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Multiple randomized trials and meta-analyses of these trials have examined the use of pharmacogenomic algorithms to guide initial warfarin dosing. A total of 22 RCTs and 4 recent systematic reviews 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; Twenty-seven percent of the participants in the multicenter COAG trial^62, were African American. 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 or TEEs. 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.

Four systematic reviews found that the percentage of time the 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. Recent systematic reviews including the large, multicenter GIFT trial 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. 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, 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.

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 the RCTs. Relevant outcomes are morbid events, medication use, and treatment-related mortality and morbidity. Twenty-two RCTs and 4 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 or thromboembolic events (TEEs) 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 or 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 Clarification of Optimal Anticoagulation through Genetics 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.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American College of Medical Genetics

In 2008, the American College of Medical Genetics policy statement on pharmacogenetic testing concluded: "There is insufficient evidence, at this time, to recommend for or against routine CYP2C9 andVKORC1 testing in warfarin-naive patients."^75,

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)."^76,

Clinical Pharmacogenetics Implementation Consortium

In 2017, the Clinical Pharmacogenetics Implementation Consortium updated guidelines for pharmacogenetics-guided warfarin dosing.^77, The guideline provides recommendations for genotype-guided warfarin dosing to achieve a target INR 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."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00964353	The Hospital and Economics CERT: Project 1: The Clinical and Economic Implications of Genetic Testing for Warfarin Management	268	Dec 2018
NCT03479684	Genotype-guided Versus Standard for Warfarin Dosing	560	Dec 2019
NCT02592980	Evaluation of a Pharmacogenetic-based Warfarin Dosing Algorithm in Patients	300	Dec 2020
Unpublished
NCT01305148a	Warfarin Adverse Event Reduction For Adults Receiving Genetic Testing at Therapy INitiation (WARFARIN)	3800	Dec 2015 (suspended)
NCT02065388	Pharmacogenetic Dosing of Warfarin	300	Dec 2013 (completed)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genotype-Guided Warfarin Dosing
Genetic Testing for Warfarin Dose
Warfarin Dose, Genetic Testing for
VKORC1
CYP2C9
Nanosphere Test
Verigene System
CYP4F2

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