Familial hypercholesterolemia
Routine screening for familial hypercholesterolemia (FH) is not as widely endorsed, but it does have backers, and evidence shows that the approach is cost effective. In part, that’s because both heterozygous and homozygous FH are substantially more common than had been believed until recently. Recent study results documented prevalence rates roughly threefold more common than previously calculated.
For example, a study published last year of more than 104,000 residents of the Netherlands documented a homozygous FH prevalence of 1 in 300,000 (Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu058]). Results from a 2012 study of more than 69,000 Danish residents demonstrated a prevalence of 1 in 137 for people with heterozygous FH (J. Clin. Endocrinol. Metab. 2012;97:3956-64).
“Genetic testing improves the care of individual patients with FH because with genetic testing you can catch patients with FH presymptomatically and you can then treat them and change their long-term prognosis,” Dr. Anne Tybjaerg-Hansen, professor of clinical biochemistry and chief physician at Copenhagen University Hospital, said in a talk at the AHA meeting last November. She cited a report last year from Australia on a model demonstrating the cost effectiveness of testing first-degree relatives of index patients diagnosed with FH, an approach known as cascade screening (J. Clin. Lipidology 2014;8:390-400).
Last year, a consensus panel of the European Atherosclerosis Society recommended that genetic testing “should be considered” for both the diagnostic work-up of index cases with suspected FH and for cascade screening of first-degree relatives of confirmed cases (Eur. Heart J. 2014;35:2146-57). The European panel noted that genetic testing was potentially useful not only to confirm a clinical diagnosis but also to better distinguish patients with heterozygous and homozygous FH. The panel’s report last year endorsed the updated understanding that heterozygous FH occurs in roughly 1 in every 200 people, while homozygous FH has a prevalence of 1 case in every 160,000-300,000 people.
Despite these relatively high prevalence rates, FH is woefully underdiagnosed. A 2013 report from the European Atherosclerosis Society cited recent data documenting that less than 1% of U.S. residents with FH are currently identified (Eur. Heart J. 2013;34:3478-90). The same report noted that less than half of all FH patients have been identified in every country worldwide with reported statistics – aside from the Netherlands, which topped the world with an estimated identification rate of 71% of patients with either form of FH.
Clopidogrel responsiveness
It’s now been several years since researchers determined that roughly 30% of people fail to adequately metabolize the antiplatelet drug clopidogrel into its active form, a finding that in 2010 led the Food and Drug Administration to mandate a boxed warning on clopidogrel’s labeling. The cytochrome P450 (CYP) 2C19 gene codes for the enzyme that activates clopidogrel, and the warning states that people in this significant minority carry alleles of the CYP2C19 gene that make them poor clopidogrel metabolizers and hence clinicians should consider using “alternative treatment strategies.” Usually this means treatment with prasugrel (Effient) or ticagrelor (Brilinta), two thienopyridines that match clopidogrel’s efficacy but do not require metabolic conversion and so are effective even in poor-metabolizing patients.
But years after this well documented and well publicized problem with blind clopidogrel dosing first became apparent, many clinicians remain uncertain how to deal with the issue and how to use genetic testing to clarify the risk faced by individual patients (Circulation 2012;122:445-8).
“The evidence for CYP2C19 is really strong, but because prospective, randomized clinical trials of genotype-directed antiplatelet testing have not been performed, there is a lot of resistance to adoption of genotype-directed treatment,” Dr. Alan R. Shuldiner said in a talk at the November AHA meeting. An editorial published in late 2011 called the boxed warning on clopidogrel “irrational exuberance” (JAMA 2011;306:2727-8). Dr. Shuldiner and others contend that overall evidence today supports a need to screen the CYP2C19 gene before starting clopidogrel, although he conceded that the optimal clinical algorithm for using testing has not yet been devised and that paying for screening remains problematic.
Despite these limitations, Dr. Shuldiner and several colleagues from around the United States issued recommendations in 2013 for the implementation of CYP2C19 genetic testing in patients (Clin. Pharmacol. Ther. 2013;94:317-23) on behalf of the Clinical Pharmacogenetics Implementation Consortium. And in February 2013, clinicians at the University of Maryland in Baltimore began to implement those recommendations as one of eight U.S. sites participating in the PGRN Translational Pharmacogenetics Program.
“It took us 18 months to figure out how to implement pharmacogenetics in the cath lab,” said Dr. Shuldiner, former director of the program for personalized and genomic medicine at the University of Maryland, and now vice president of translation genomics at Regeneron in Tarrytown, N.Y.