Recommendations from the EGAPP Working Group: Routine testin... : Genetics in Medicine

Genetics in Medicine:
January 2011 - Volume 13 - Issue 1 - pp 67-76
doi: 10.1097/GIM.0b013e3181fbe46f
EGAPP Recommendation Statement
Recommendations from the EGAPP Working Group: Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group
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Author Information

*EGAPP Working Group: Chair: Alfred O. Berg, MD, MPH (Department of Family Medicine, University of Washington), Members: Jeffrey Botkin, MD, MPH (University of Utah); Ned Calonge, MD, MPH (Colorado Department of Public Health and Environment); Doug Campos-Outcalt, MD, MPA (Department of Family-Community Medicine, University of Arizona College of Medicine, Phoenix); James E. Haddow, MD (Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University); Maxine Hayes, MD, MPH (Washington State Department of Health); Celia Kaye, MD, PhD (Department of Pediatrics. University of Colorado School of Medicine); Roger D. Klein, MD, JD (BloodCenter of Wisconsin; Medical College of Wisconsin); Kenneth Offit, MD, MPH (Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center): Stephen G. Pauker, MD, MACP, FACC, ABMH (Division of Clinical Decision Making, Informatics and Telemedicine, Department of Medicine, Tufts Medical Center); Margaret Piper, PhD, MPH (Blue Cross/Blue Shield Association Technology Evaluation Center); Carolyn Sue Richards, PhD, FACMG (Oregon Health & Science University); Joan A. Scott, MS, CGC (Genetics and Public Policy Center, Johns Hopkins University); Ora L. Strickland, PhD, DSc (Hon.), RN, FAAN (Nell Hodgson Woodruff School of Nursing, Emory University); Steven Teutsch, MD, MPH (Los Angeles County Department of Public Health); David L. Veenstra, PharmD, PhD (Pharmaceutical Outcomes Research and Policy Program, and Institute for Public Health Genetics, University of Washington).

Disclaimer: This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services.

E-mail: egappinfo@egappreviews.org.

Disclosure: Steven Teutsch is a former employee, and an option holder in Merck & Co., Inc.

Submitted for publication May 28, 2010.

Accepted for publication September 9, 2010.

Published online ahead of print December 10, 2010.


Abstract

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms. The overall certainty of these findings was deemed “moderate.” The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. Based on the available evidence, the certainty of net health benefit was deemed “low.” The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE.

Rationale: In developing these recommendations the EGAPP Working Group considered evidence in the following three areas.

Analytic Validity: There is adequate evidence that testing accurately and reliably detects the R506Q (FVL) and 20210G>A (PT) variants in the Factor V and PT genes, respectively (a more complete definition of analytic validity, clinical validity, and clinical utility is contained under the “Clinical Considerations” section).

Clinical Validity: The presence of a heterozygous FVL variant seems to be a weak risk factor for recurrence of VTE (odds ratio [OR]: 1.56). Rare homozygous FVL mutations present somewhat greater risks of VTE recurrence (OR: 2.65). The evidence for this increased risk is convincing, but the magnitude of excess risk is not as great as previously thought. The evidence is insufficient to draw conclusions about excess VTE recurrence risk resulting from compound heterozygosity (FVL and PT), but it is likely to be at least as high as with FVL alone. The OR for compound heterozygosity is 6.69. The evidence is insufficient to draw conclusions about VTE recurrence risks associated with PT mutations alone. For family members of index VTE cases, there is convincing evidence that both heterozygosity and homozygosity for FVL are associated with higher risks for VTE occurrence (ORs 3.49 and 17.84, respectively) than for family members without FVL variants.

Clinical Utility: There is convincing evidence that longer term secondary prophylaxis after an initial idiopathic VTE event yields comparable benefits to those with and without a FVL or PT mutation. For asymptomatic family members of index cases, no prophylaxis trials have been reported. Hence, there is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high.

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Recommendations from the EGAPP Working Group: Routine testin... : Genetics in Medicine