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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.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\u003EThe final results of the ILLUMINATE trial comparing the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib plus atorvastatin with atorvastatin alone in patients at high risk for cardiovascular disease showed that the rates of major cardiovascular events and all-cause mortality were higher with the addition of torcetrapib. The study had been prematurely terminated in December 2006 because of a significant excess of deaths and cardiovascular events in the group randomized to torcetrapib plus atorvastatin.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Elipid disorders clinical trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EThe final results of the ILLUMINATE trial comparing the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib plus atorvastatin with atorvastatin alone in patients at high risk for cardiovascular disease showed that the rates of major cardiovascular events and all-cause mortality were higher with the addition of torcetrapib. The study had been prematurely terminated in December 2006 because of a significant excess of deaths and cardiovascular events in the group randomized to torcetrapib plus atorvastatin.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EILLUMINATE included 15,067 patients at high risk for cardiovascular disease. The study was preceded by a run-in period of 4\u201310 weeks of treatment with atorvastatin and lifestyle interventions to achieve a low-density lipoprotein (LDL) level of \u0026lt;100 mg\/dL. Patients were then randomly assigned to either torcetrapib plus atorvastatin (7,533 patients) or matching placebo plus atorvastatin (7,534 patients).\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EPhilip J. Barter, MD, PhD, The Heart Research Institute, Sydney, Australia, explained that torcetrapib is a CETP inhibitor that has been shown to increase high-density lipoproteins (HDLs) in humans and to protect against atherosclerosis in rabbits. The study hypothesis was that torcetrapib would increase HDL and thus protect against cardiovascular disease.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EDr. Barter noted that the HDL and LDL levels in the study indicated that torcetrapib performed as predicted: compared with atorvastatin alone, at 12 months, torcetrapib and atorvastatin increased HDL by 72% (vs 1.8% for atorvastatin alone; p\u0026lt;0.001) and decreased LDL by 25% (vs an increase of 3.0% for atorvastatin alone; p\u0026lt;0.001). However, the drug was associated with a significantly higher number of major cardiovascular events (464 vs 373; p=0.001) and a significantly higher number of deaths (93 vs 59; p=0.006; \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigures 1A\u003C\/a\u003E and \u003Ca id=\u0022xref-fig-1-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003E1B\u003C\/a\u003E). Of note among the deaths, said Dr. Barter, were more deaths in the combination arm related to infection (9 vs 0), cancer (24 vs 14), and stroke (6 vs 0).\u003C\/p\u003E\n         \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\/7\/7\/14\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Kaplan-Meier Curves for Death from Any Cause and for the Primary Composite Outcome.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1368255377\u0022 data-figure-caption=\u0022Kaplan-Meier Curves for Death from Any Cause and for the Primary Composite Outcome.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figures 1A and 1B.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/7\/7\/14\/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\/7\/7\/14\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figures 1A and 1B.\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\/7\/7\/14\/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\/10850\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\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigures 1A and 1B.\u003C\/span\u003E \n               \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EKaplan-Meier Curves for Death from Any Cause and for the Primary Composite Outcome.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-7\u0022\u003ETorcetrapib was associated with several off-target pharmacologic effects unrelated to CETP inhibition, said Dr. Barter, such as significant increases in blood pressure, significant changes in serum electrolyte levels, and significant increases in the serum aldosterone level. The higher blood pressure associated with torcetrapib was thought to be related to the greater morbidity and mortality, but post hoc analysis indicated that this was unlikely to be the only explanation, as a greater increase in systolic blood pressure was associated with a lower rate of cardiovascular events. An increase in systolic pressure of more than 2.5 mm Hg was associated with a 5.9% rate of cardiovascular events, whereas an increase of 2.5 mm Hg or less was associated with a 6.3% increase.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EAnother interesting finding, said Dr. Barter was that in the torcetrapib group, the rate of cardiovascular events was lower in patients who had an increase in HDL-cholesterol (HDL-C) that was greater than the median. At 1 month, the rate of cardiovascular events was 5.9% among the patients who had an increase in HDL-C of more than 22 mg\/dL and was 6.4% among patients who had an increase of 22 mg\/dL or less. The hazard ratios for cardiovascular-related death or nonfatal myocardial infarction were lower for HDL-C levels that were greater than 60 mg\/dL than for a level less than 60 mg\/dL. The lowest hazard ratio (0.43; p\u0026lt;0.05) was associated with an HDL-C of more than 93 mg\/DL at 3 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EDr. Barter emphasized that these post hoc observations are only suggestive and do not rule out HDL dysfunctionality nor the possibility that other unknown effects of CETP inhibition may have contributed to a mechanism-related adverse outcome.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003E\u201cThis study neither validates nor invalidates the hypothesis that raising HDL-cholesterol by inhibiting CETP may be cardioprotective,\u201d said Dr. Barter. \u201cThe adverse clinical outcome associated with use of torcetrapib may have been the consequence of an off-target pharmacology but the possibility of an adverse effect of CETP inhibition cannot be excluded by the results of this randomized trial,\u201d he added.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe study findings have been published: [Barter et al. NEJM 2007;357:2109\u20132122].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2007 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\/7\/7\/14.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?nzm6re\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?nzm6re\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}