{"id":28836,"date":"2012-05-07T12:24:50","date_gmt":"2012-05-07T16:24:50","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=voices&p=28836"},"modified":"2012-05-07T12:24:50","modified_gmt":"2012-05-07T16:24:50","slug":"another-surrogate-endpoint-falls-short","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2012\/05\/07\/another-surrogate-endpoint-falls-short\/","title":{"rendered":"Another Surrogate Endpoint Falls Short"},"content":{"rendered":"

A recent paper in the Lancet <\/em>explores whether carotid intima\u2013media thickness (CIMT) is an adequate surrogate marker of risk for cardiovascular events. Matthias Lorenz and colleagues<\/a> combined data from 16 longitudinal observational studies of CIMT progression, involving about 37,000 patients. In their patient-level meta-analysis, less CIMT progression was not associated with a lower likelihood of subsequent cardiovascular events. An accompanying editorial by Vijay Nambi and colleagues<\/a> strikes the right chord, particularly with respect to heterogeneity in techniques for assessing CIMT and measurement errors (or noise) associated with its use.<\/p>\n

As a backdrop to this newly published information, current guidelines<\/a> make a class IIa recommendation for a single CIMT measurement to enhance risk-stratification in asymptomatic adults. Single CIMT \u201csnapshots\u201d may indeed be useful in certain clinical settings, but it\u2019s unclear what CIMT progression over time means for an individual patient\u2019s clinical outcomes, as the Lorenz study makes clear. Furthermore, that study is consistent with two recent meta-analyses<\/a> that used similar data from clinical trials on novel therapeutic agents; one was led by my colleague at the University of Michigan, Zach Goldberger<\/a>. Collectively, the three studies should discourage reliance on CIMT progression as a surrogate endpoint.<\/p>\n

Some have argued<\/a>, though, that CIMT avoids the substantial costs and lengthy follow-up required for trials that focus on \u201chard\u201d but uncommon outcomes such as death. Presumably, many of these folks will remain unconvinced by the accumulating data and point to the inherent limitations of meta-analyses<\/a>\u00a0while highlighting some strengths of CIMT.<\/p>\n

Overvaluing surrogate endpoints is nothing new, of course. Cardiologists have learned this lesson many times, beginning with the infamous CAST trial<\/a>,\u00a0which demonstrated that successful suppression of premature ventricular contractions by encainide and flecainide was not just ineffective at improving outcomes but also associated with higher rates of death.<\/p>\n

Nevertheless, unlike serum biomarkers, CIMT (along with IVUS) has achieved something of a unique status as a tool in clinical trials. That\u2019s because of its advantage in actually visualizing atherosclerosis directly in the vessel wall, making it appear to be less of a \u201csurrogate\u201d endpoint. However, oncologists would not be surprised that imaging does not correlate with hard outcomes<\/a>. They have long understood that tumors that initially melt away with chemotherapy can come back. Cardiologists, too, must be willing to admit that although our ability to view changes in atherosclerosis in the vessel wall over time is better than ever, we still don\u2019t know what those changes mean in terms of the outcomes that matter most to patients.<\/p>\n

Questions:<\/strong><\/p>\n

<\/strong>1. What do you think about the use of CIMT, IVUS, and other imaging modalities as surrogate endpoints in clinical trials?<\/p>\n

2. Can studies be better designed to identify surrogate endpoints that might be valuable early in a drug or device evaluation?<\/p>\n

3. How do we reconcile our need for tools to evaluate potentially useful therapies early in their development, given that it is impossible to imagine conducting large clinical trials with hard outcomes for every promising drug?<\/p>\n","protected":false},"excerpt":{"rendered":"

Brahmajee Nallamothu puts into context the most recent study on the value of measuring the progression of carotid intima-media thickness.<\/p>\n","protected":false},"author":253,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11],"tags":[968,1257,1258],"class_list":["post-28836","post","type-post","status-publish","format-standard","hentry","category-cardiac-imaging","tag-atherosclerosis","tag-carotid-intima-media-thickness","tag-surrogate-endpoints"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/28836","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\/253"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=28836"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/28836\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=28836"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=28836"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=28836"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}