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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EPharmacogenetics, the study of the interaction between genes and drug therapy, has been proposed as a way to \u201cpersonalize\u201d medical therapy. It is a routine and expanding application in oncology. This article provides overview of progress to date for the use of pharmacogenetics in cardiovascular medicine and what is yet to be done.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EGenetically driven personalized pharmacotherapy was one of the subjects that were discussed during the International Congress on Genetics and Genomics, during this year\u0027s AHA Scientific Sessions. Pharmacogenetics, the study of the interaction between genes and drug therapy, has been proposed as a way to \u201cpersonalize\u201d medical therapy. It is a routine and expanding application in oncology. During this session, researchers provided an overview of progress to date for the use of pharmacogenetics in cardiovascular medicine and what is yet to be done.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003E\u201cWarfarin has been proposed as the first application for pharmacogenetics in cardiovascular medicine, primarily because of its high use, wide interindividual variation in dose requirement, narrow therapeutic range, and the frequent association of anticoagulants with adverse events and mortality,\u201d said Jeffrey L. Anderson, MD, Intermountain Medical Center, Murray, UT. The initiation of warfarin therapy is particularly challenging, and it has been suggested that the addition of genetic testing might reduce the number of strokes and serious bleeds and result in significant health care savings [\u003Ca href=\u0022http:\/\/www.aei-brookings.org\/publications\/abstract.php?pid=1127\u0022\u003Ehttp:\/\/www.aei-brookings.org\/publications\/abstract.php?pid=1127\u003C\/a\u003E].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EDr. Anderson discussed a few of the studies that have assessed warfarin pharmacogenetics. In one study that involved patients who were receiving warfarin and who had a stable INR (2 to 3) for \u0026gt;1 month, carriage of a single or double CYP2C9 variant reduced warfarin dose 18% to 72%; carriage of a q or 2 VKORC1 variant reduced it by 34% to 54%. At least one of these variants was shown to be present in 70% of the study population [Carlquist JF et al. \u003Cem\u003EJ Thromb Thrombolysis\u003C\/em\u003E 2006]. Results from another study (CoumaGen) that assessed pharmacogenetic-guided warfarin therapy and its impact on INR-based efficacy and safety showed that using pharmacogenetics to guide warfarin therapy did not reduce the percentage of out-of-range INR in the overall study population. However, it did improve the accuracy and efficiency of warfarin dose initiation, and results of a subset analysis indicated a reduction in the percentage of out-of-range INR for wild-type and multiple variant genotypes [Anderson JL et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2007]. A new study\u2014CoumaGen II\u2014with a larger patient population and a more refined algorithm has been initiated to follow up on these results. Several other studies that are evaluating the role of pharmacogenetic-guided warfarin therapy are ongoing or planned, including Clarify Optimal Anticoagulation Through Genetics (COAG; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00839657\u0026amp;atom=%2Fspmdc%2F9%2F5%2F10.atom\u0022\u003ENCT00839657\u003C\/a\u003E) and Genetics InFormation Trial of Warfarin Therapy (GIFT; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01006733\u0026amp;atom=%2Fspmdc%2F9%2F5%2F10.atom\u0022\u003ENCT01006733\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003E\u201cThe use of pharmacogenetics to guide warfarin dosing is feasible,\u201d said Dr. Anderson. \u201cIt better predicts the eventual maintenance dose, particularly in those with no or multiple variants, but we still don\u0027t know what the impact will be on patient outcomes, which will require additional clinical trials.\u201d\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003E\u201cEveryone who cares for patients with heart failure (HF) or hypertension is aware of the great deal of variability in response to \u03b2-blockers,\u201d said Amber Beitelshees, PharmD, University of Maryland School of Medicine, Baltimore, MD, \u201cas evidenced by the difference in response in systolic and diastolic blood pressure in hypertensive patients and ejection fraction, and left ventricular end-diastolic volume in HF patients, as well as the high number of nonresponders in both types of patients.\u201d Part of the reason for this variability is likely genetics, and it stems from a variety of areas in \u03b2-blocker pharmacology, such as the drug metabolism enzyme, the receptors themselves, the G-proteins to which the receptors couple, the G-protein receptor kinases, the enzymes that contribute to cyclic AMP formation, and the beta-arrestins. Key questions that concern \u03b2-blocker pharmacogenetics involve the portability of these associations across phenotypes and patient populations and whether they exhibit a class effect.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe ADRB1 gene is the most widely studied in \u03b2-blocker pharmacogenetics. Dr. Beitelshees reviewed a number of these studies, which show fairly consistent associations between ADRB1 Arg389Gly and both metoprolol and atenolol in antihypertensive response and with treatment outcomes with atenolol. In H F, ADRB1 is significantly associated with left ventricular function in response to metoprolol and carvedilol but not with treatment outcomes [Terra SG. \u003Cem\u003EClin Pharmacol Ther\u003C\/em\u003E 2005; Chen L. \u003Cem\u003EPharmacogenet Genom\u003C\/em\u003E 2007; Pancanowski MA et al. \u003Cem\u003EClin Pharmacol Ther\u003C\/em\u003E 2008]. Results from the BEST study indicate that ADRB1 is associated with improved survival in bucindolol-treated patients [Liggett SB et al. \u003Cem\u003EPNAS\u003C\/em\u003E 2006]. So far, study results are inconsistent concerning whether there is a class effect.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EDr. Beitelshees said that she believes that there is not yet sufficient evidence of a role for genotyping in the treatment of hypertension or H F. More robust studies are needed before genotyping can be applied practically in the clinic.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EAs with the anticoagulants and \u03b2-blockers, there is also a variable response to clopidogrel, with one study that shows that \u223c30% of patients are clopidogrel-resistant [Gurbel PA et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2003]. Marc Sabatine, MD, Brigham and Women\u0027s Hospital, Boston, MA, discussed how clopidogrel metabolism may contribute to this variability in response.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EClopidogrel is a prodrug that requires biotransformation by CYP450 enzymes into an active metabolite. About 85% of clopidogrel is degraded by esterases either in the intestinal lumen or the plasma. The remaining 15% undergoes two successive oxidative steps in the liver that are mediated by CYP450. Six genotypes are known to be associated with clopidogrel metabolism: CYP2C19, CYP2C, CYP2B6, CYP3A5, CYP3A4, and CYP1A2. Dr. Sabatine and colleagues have done extensive work that has examined the CY2C19 genotype. Approximately 30% of the population carries a reduced-function CYP2C19 allele. These individuals have been shown to have lower levels of the active metabolite of clopidogrel, less platelet inhibition, and higher rates of ischemic events and stent thrombosis (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Mega JL et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2009]. Although there are some data that indicate that higher doses of clopidogrel \u003Cem\u003Emay\u003C\/em\u003E improve platelet inhibition in carriers of reduced-function CYP2C19 alleles, an option for patients who carry this allele may be prasugrel, a third-generation ADP receptor blocker with a different metabolism that does not appear to be affected by common CYP450 genetic variation [Gladding P et al. \u003Cem\u003EJACC\u003C\/em\u003E 2008; Mega JL et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/9\/5\/10\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022CYP2C19 and Stent Thrombosis.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-363372158\u0022 data-figure-caption=\u0022CYP2C19 and Stent Thrombosis.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/9\/5\/10\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/9\/5\/10\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/9\/5\/10\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11416\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ECYP2C19 and Stent Thrombosis.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003ECopyright \u00a9 2009 Massachusetts Medical Society. All rights reserved.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003E\u201cWhat we are really trying to do with genetic testing is to discriminate who will have an outcome of one particular type versus another,\u201d said Robert M. Califf, MD, Duke Clinical Research Institute, Durham, NC, in the closing presentation. \u201cWhile there is no doubt that genes that alter the response to a drug can be found, it\u0027s rare that they provide a deterministic prediction of outcomes.\u201d As such, the use of pharmacogenetic testing is a comparative effectiveness issue, and the value of the information that is obtained can be determined the same way as with any other diagnostic or prognostic information.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003E\u201cWhile pharmacogenetic tests are promising and can provide information for medical decision-making, the clinical practice and reimbursement communities should be appropriately skeptical until the data are available. To avoid misinterpretation and misuse, randomized controlled trials are needed,\u201d said Dr. Califf.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EThe COAG research network, which was mentioned by several speakers, is conducting collaborative research to assess whether the use of genetic \u003Cem\u003Eand\u003C\/em\u003E clinical information for selecting the initial dose of warfarin will lead to improved anticoagulant stability compared with using clinical information only. The network includes 12 clinical sites, a clinical trial coordinating center, a central drug distribution center, and a central laboratory. Dr. Califf is the Chair, and Dr. Anderson is a member of the COAG Steering Committee. The study is currently recruiting. Additional information at \u003Ca href=\u0022http:\/\/coagstudy.org\u0022\u003Ehttp:\/\/coagstudy.org\u003C\/a\u003E.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2009 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/9\/5\/10.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmhn2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmhn2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}