Personalized Antiplatelet Therapy Not Justified By Current Evidence

see A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

The rate of drug metabolism by the liver varies from person to person and can be influenced by a variety of factors, both genetic and environmental. Ideally, medication dosage should be calibrated for each patient, taking into account variation in metabolic rate caused by functional differences in enzymes responsible for these processes. Variants in the gene encoding cytochrome P450 (CYP) are well known to affect drug metabolism and have been the target of efforts to personalize medications in the context of several ailments. However, clinical outcomes of such personalization have often been difficult to document. Osnabrugge et al. reviewed several meta-analyses, and the primary literature cited therein, examining the association between loss-of-function variants in CYP and clinical efficacy of the popular antiplatelet drug clopidogrel, commonly used to treat acute coronary syndrome. All the meta-analyses within the scope of the review found substantial differences in the characteristics of study populations and primary outcome measures. However, they differed greatly in how they handled these heterogeneous study characteristics. Some ignored studies considered to introduce heterogeneity, a practice that Osnabrugge and colleagues believe is unjustified. The authors also uncovered evidence of bias in publication of small studies that showed relatively large effects. They therefore argue that the 2010 recommendation by the US Food and Drug Administration that CYP2C19 genotyping be considered for individualized antiplatelet management is currently not sufficiently evidence-based and should be abandoned. To support their case, they point to recent large clinical assessments, such as the ARCTIC trial, that showed no benefits of CYP2C19 genotyping. —Karyn Hede, News Editor

ACMG updates policy statement on release of secondary findings

see ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing

The results of a member survey conducted by the American College of Medical Genetics and Genomics (ACMG) revealed mixed opinions about what should be considered best practices for release of secondary findings (genetic variants that might be relevant for purposes of management but were not the primary targets of testing). However, contrary to ACMG recommendations released in 2013, most survey participants said they believe patients should be informed of the possibility of secondary findings during the consent process and be able to opt out of such analysis. In addition, members agreed that the ACMG should continue to maintain and update a list of medically actionable genes as a reference point for those offering clinical exome or genome sequencing. With this input from members in hand, the ACMG has published an update to its policy statement, which is available both in print and online (http://www.nature.com/gim/journal/v17/n1/full/gim2014151a.html). The update underlines the importance of obtaining written informed consent via a qualified genetics health-care professional detailing the nature of clinical genome-scale sequencing, addressing interpretive uncertainty, and explaining the inevitable generation of data not immediately medically relevant, among other issues. The guidelines suggest that patients be able to opt out of receiving the information but stress that they should be made aware of the ramifications of doing so. The ACMG is also recommending that, in the absence of clear consensus on how secondary findings should be handled when the patient is a child, parents be given the option to opt out of receiving secondary findings when such analysis is performed in their children. —Karyn Hede, News Editor