{"id":14982,"date":"2011-12-30T13:06:26","date_gmt":"2011-12-30T18:06:26","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=interventional&p=14982"},"modified":"2011-12-30T13:06:26","modified_gmt":"2011-12-30T18:06:26","slug":"cyp2c19-genotyping-down-for-the-count","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2011\/12\/30\/cyp2c19-genotyping-down-for-the-count\/","title":{"rendered":"CYP2C19 Genotyping: Down For The Count?"},"content":{"rendered":"

The controversy over the use of genetic testing to guide antiplatelet therapy\u00a0reminds us\u00a0of a WWF (Worldwide Wrestling Federation) tag team match.\u00a0 <\/strong><\/span><\/p>\n

What we agree upon (the match rules):
\n<\/strong><\/em>Clopidogrel is a prodrug activated by several enzymes, including CYP2C19, and common genetic variations alter CYP2C19 activity.<\/span><\/p>\n

Here\u2019s where the wrestling match begins:<\/strong>
\nAre the <\/em>CYP2C19 genetic variants associated with reduced enzyme function clinically important?
\nShould we be genotyping patients to identify those with reduced clopidogrel responsiveness?<\/em><\/span><\/p>\n

The heavyweights weigh in\u2026
\n<\/strong><\/em>The FDA<\/a><\/span>: <\/strong>\u201cPoor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. Tests are available to identify a patient\u2019s CYP2C19<\/em> genotype and can be used as an aid in determining therapeutic strategy.\u201d<\/span><\/p>\n

The ACC and AHA<\/a>:<\/span><\/strong>\u00a0\u201cThe evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.\u201d<\/span><\/p>\n

Now for the fun\u2026<\/strong><\/em><\/span><\/p>\n

Authors of the most recent meta-analysis<\/a><\/span> involving 42,016 patients in 32 studies conclude:<\/strong> \u201cThis study identified no clinically significant interaction of CYP2C19<\/em> genotype with the association of clopidogrel therapy and cardiovascular events.\u201d<\/span><\/p>\n

Steven Nissen (in an accompanying editorial) asserts:<\/a><\/span>\u00a0<\/strong>\u00a0\u201cIt now appears that the FDA warning reflected a case of \u201cirrational exuberance\u2026\u201d<\/span><\/p>\n

Topol and friends<\/a> <\/span>enter the ring, calling the meta-analysis\u00a0misleading: “<\/strong>A critical flaw of the analysis by Holmes and colleagues was the lack of testing for heterogeneity among patients who underwent stenting as compared with those treated medically\u2026.The analysis includes a large number of patients from trials that had nothing to do with coronary stenting (eg, atrial fibrillation or STEMI patients treated with thrombolytics) and assess outcomes where the benefit of clopidogrel itself is dubious (eg, target vessel revascularization).\u201d<\/span><\/p>\n

Lange on the \u201cslow-mo\u201d replay:<\/strong> Stratified by number of events per study, the meta-analysis by Holmes et al.\u00a0showed that\u00a0the association between CYP2C19<\/em> genetic variants linked to\u00a0reduced enzyme function and risk for stent thrombosis was as follows:<\/span><\/p>\n\n\n\n\n\n\n
\n

Number of events per study<\/strong><\/span><\/p>\n<\/td>\n

\n

Studies (No.)<\/strong><\/span><\/p>\n<\/td>\n

\n

Relative Risk of Stent Thrombosis<\/strong><\/span><\/p>\n<\/td>\n

\n

Confidence Intervals<\/strong><\/span><\/p>\n<\/td>\n<\/tr>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 < 100 events<\/span><\/td>\n\n

12<\/span><\/p>\n<\/td>\n

\n

2.01<\/span><\/p>\n<\/td>\n

\n

(1.60-2.53)<\/span><\/p>\n<\/td>\n<\/tr>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 100-199 events<\/span><\/td>\n\n

2<\/span><\/p>\n<\/td>\n

\n

1.54<\/span><\/p>\n<\/td>\n

\n

(1.26-1.88)<\/span><\/p>\n<\/td>\n<\/tr>\n

\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 All studies<\/span><\/td>\n\n

14<\/span><\/p>\n<\/td>\n

\n

1.75<\/span><\/p>\n<\/td>\n

\n

(1.50-2.03)<\/span><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

<\/strong>\u00a0<\/span><\/p>\n

How do we score the fight? It’s a draw!!\u00a0 <\/strong>The CYP2C19<\/em> genetic variants associated with reduced enzyme function are clinically important in patients who receive a drug-eluting stent (i.e., associated with increased risk for stent thrombosis), but<\/strong><\/em> we shouldn’t\u00a0be genotyping patients until we have an effective (and safe) alternative therapy.<\/span><\/p>\n

Do you feel comfortable jumping in the ring?<\/span><\/p>\n

Should we genotype patients who undergo stenting?<\/strong><\/span><\/p>\n

Why or why not? <\/strong><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

The controversy over the use of genetic testing to guide antiplatelet therapy\u00a0reminds us\u00a0of a WWF (Worldwide Wrestling Federation) tag team match.\u00a0 What we agree upon (the match rules): Clopidogrel is a prodrug activated by several enzymes, including CYP2C19, and common genetic variations alter CYP2C19 activity. Here\u2019s where the wrestling match begins: Are the CYP2C19 genetic […]<\/p>\n","protected":false},"author":214,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[9],"tags":[431,476,334,336,196,1046,332],"class_list":["post-14982","post","type-post","status-publish","format-standard","hentry","category-interventional-cardiology","tag-acc","tag-aha","tag-clopidogrel","tag-cyp2c19","tag-fda","tag-genetic-testing","tag-stent-thrombosis"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/14982","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/214"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=14982"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/14982\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=14982"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=14982"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=14982"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}