Responsabilidad subjetiva de los jueces - Responsabilidad judicial

Diseño del Consejo de la Judicatura y sus atribuciones disciplinarias

3.2 Responsabilidad judicial

3.2.2 Responsabilidad subjetiva de los jueces

• Warfarin (Coumadin®

) is a commonly prescribed anticoagulant with a narrow therapeutic range and a 20-fold inter-individual variation in dose

requirements.1 Incorrect dosage, especially during the initial dosing phase, is associated with either severe bleeding or failure to prevent thromboembolism.2 • Approximately 21% of patients who receive anticoagulant therapy will experience

a major or minor bleeding event.2 Environmental and genetic factors combined influence 55% of warfarin dose variability and include: age, height, body mass index (BMI), gender, diet, genetic variations in CYP2C9 and VKORC1, use of concomitant medications and indication for warfarin.3,5

• The activity of two genes [cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit-1 (VKORC1)] impact the rate of

warfarin metabolism and account for up to 40% of the inter-individual dose requirements for warfarin.5

• CYP2C9 is a p450 enzyme that influences warfarin pharmacokinetics by

impacting the rate of metabolism. Poor or intermediate metabolizing 2C9 variants are seen in between 2% to 20% of the population depending on ethnicity.2

Carriers of alleles *2 and *3 have decreased warfarin metabolism and may require lower warfarin doses.5

• Vitamin K activity is important to the blood’s ability to clot. VKORC1 influences the pharmacodynamics and sensitivity of warfarin on the vitamin K cycle.

Approximately 14% to 89% of the population display VKORC1 enzyme inhibition making them more sensitive to warfarin.2 Carriers of VKORC1 AA genotype (high warfarin sensitivity) require a significantly lower warfarin dose compared to

individuals with genotype GA or GG.5

• Testing these two genes predicts variability in warfarin dosage requirements. The presence of gene variants in CYP2C9 and VKORC1 indicate that more careful dosing and monitoring is required to achieve therapeutic anticoagulation and to decrease risk of bleeding or clotting during warfarin dose titration.

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Test Information

Guidelines and Evidence

• There has been a mixed response to genotyping from professional associations, payors, and other organizations, largely because data supporting the utility of genetic testing to improve clinical endpoints is still evolving.

• The Clinical Pharmacogenetics Implementation Consortium (CPIC, 2011) guidelines state "The recommendations for dosing based on genotype contained herein are rated as level A, or strong, and are derived from numerous observational studies and some prospective studies that suggest the ability to more accurately identify stable therapeutic warfarin dose requirements through use of both genetic and clinical information. However, there are limited

prospective data from randomized trials on the use of genetic information to guide warfarin dosing (summarized in Supplementary Note S4), and the impact on clinical outcomes is unknown, although several such studies are currently ongoing, the largest of which are described in Supplementary Note S5."9

• The American College of Medical Genetics (ACMG, 2008) and the American College of Chest Physicians (ACCP, 2008) both suggest against routine

genotyping to guide warfarin dosing until better evidence is available to support a policy decision, but the ACMG does say that testing might be useful to explain unexpected warfarin responses.4,6

• An FDA Advisory Committee convened in November of 2005 voted

unanimously that "sufficient mechanistic and clinical evidence exists to support the recommendation to use lower doses of warfarin for individuals with genetic variations in CYP2C9 and VKORC1 that lead to reduced activities." Furthermore, their report states "genotyping people in the induction phase of warfarin therapy would reduce adverse events and improve achievement" of a stable dose for anticoagulation.9

• Product labeling for Coumadin (warfarin) has been updated based on FDA recommendation to explain the impact of genetic variations and response to warfarin. Labeling also includes the range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes.5

Criteria

This test is considered investigational and/or experimental.

o Investigational and experimental (I&E) molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene

products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition.

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o In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.

References

1. Kangelaris KD, Bent S, Nussbaum RL.Genetic Testing Before Anticoagulation? A Systematic Review of Pharmacogenetic Dosing of Warfarin. J Gen Intern Med. 2009 May;24(5):656-64. 2. American Medical Association (AMA) Molecular medicine. Brochure: Personalized

Healthcare Report 2008: Warfarin and genetic testing.

3. Kamali F. Genetic influences on the response to warfarin. Curr Opin Hematol. 2006;13(5):357-361.

4. Flockhart DA, O'Kane D, Williams MS, et al; ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008 Feb;10(2):139-50.

5. U.S. Food and Drug Administration. Coumadin Labeling. Updated January 22, 2010. Available at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf. 6. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S.

7. Baudhuin L. Clinical Laboratory News: Warfarin Pharmacogenetics. February 2008;34(2). 8. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates:

results from the MM-WES (Medco-Mayo warfarin effectiveness study). J Am Coll Cardiol. 2010;55(25):2804-12.

9. Johnson A, Gong L, Whirl-Carrillo, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing. Clin

Pharmacol Ther. 2011;90(4):625-629.

10. Clinical Pharmacology Subcommittee Advisory Committee Meeting, November 14, 2005. Available at:http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4194T1.pdf.

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CYP2C19 Variant Analysis for

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