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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\u003EAn investigational, selective, orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) failed to significantly reduce the risk for cardiovascular death, myocardial infarction, or stroke in stable coronary heart disease patients on optimal medical therapy. The design and results of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial [STABILITY; The STABILITY Investigators. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014] are discussed in this article.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECoronary Artery Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECoronary Artery Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EAn investigational, selective, orally active inhibitor of lipoprotein-associated phospholipase A\u003Csub\u003E2\u003C\/sub\u003E (Lp-PLA\u003Csub\u003E2\u003C\/sub\u003E) failed to significantly reduce the risk for cardiovascular (CV) death, myocardial infarction (MI), or stroke in stable coronary heart disease (CHD) patients on optimal medical therapy.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe design and results of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial [STABILITY; The STABILITY Investigators. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014] were presented by Harvey D. White, DSc, Auckland City Hospital, Auckland, New Zealand.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EElevated plasma levels of Lp-PLA\u003Csub\u003E2\u003C\/sub\u003E are associated with an increased risk of coronary events. The enzyme is secreted by T cells and macrophages and circulates largely bound to low-density lipoproteins [Zalewski A, Macphee C. \u003Cem\u003EArterioscler Thromb Vasc Biol\u003C\/em\u003E 2005]. Within atheromatous plaque, it hydrolyzes oxidatively modified polyunsaturated fatty acids producing lysophosphatidylcholine and oxidized nonesterified fatty acids, explained Prof. White. \u201cUnstable\u201d plaques are characterized by a higher content of Lp-PLA\u003Csub\u003E2\u003C\/sub\u003E and other markers of inflammation [Corson MA et al. \u003Cem\u003EAm J Cardiol\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EDarapladib decreases Lp-PLA\u003Csub\u003E2\u003C\/sub\u003E levels by \u223c60% [Serruys PW et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2008]. In preclinical investigations, it reduced Lp-PLA\u003Csub\u003E2\u003C\/sub\u003E levels and necrotic core area within atherosclerotic plaque [Wilensky RL et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2008]. In humans, treatment with darapladib was shown to halt progression of coronary artery necrotic plaque core volume in patients with CHD, but not atheroma volume [Serruys PW et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ESTABILITY compared darapladib at a dosage of 160 mg\/day with placebo in a double-blind, randomized, global trial of 15,828 patients with chronic CHD receiving standard of care. The median patient age was 65 years, \u223c80% were white, and \u223c80% were male. Fifty-nine percent had a qualifying diagnosis of MI for more than 1 month prior to randomization and 75% had undergone prior coronary revascularization. Fifteen percent had multivessel CHD at baseline. Very high rates of evidence-based background therapies were used at baseline and throughout the duration of the study (\u0026gt;90% use of aspirin; \u0026gt;95% use of statins; \u223c80% use of \u03b2-blockers; and \u223c50% use of angiotensin-converting enzyme inhibitors).\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EAt a median follow-up of 3.7 years, the primary endpoint\u2014a composite of CV death, MI, and stroke\u2014occurred in 819 patients randomized to placebo (10.4%) compared with 769 patients randomized to darapladib (9.7%), corresponding to a hazard ratio of 0.94 (95% CI, 0.85 to 1.03) that did not achieve significance (p=0.20). Results for the components of the primary endpoint are shown in \u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E. There were no significant differences between darapladib and placebo on any of the individual components of the primary endpoint or all-cause mortality.\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15811\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15811\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15811\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\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003ECardiovascular and Mortality Endpoints\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-10\u0022\u003ECoronary-specific endpoints suggested benefit to darapladib. Darapladib was associated with a reduction in the rate of the prespecified secondary endpoints of major coronary events (10.3% vs 9.3%; HR, 0.90; p=0.045) and total coronary events (16.1% vs 14.6%; HR, 0.91; p=0.019; \u003Ca id=\u0022xref-table-wrap-1-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). These findings should be considered exploratory in light of the lack of effect on the primary endpoint, said Prof. White.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ESerious adverse events occurred at a similar frequency in the darapladib and placebo arms, 42.6% and 43.7%. Adverse events leading to study drug discontinuation occurred in 19.8% and 13.5% in the darapladib and placebo arms, respectively. Side effects that led to darapladib discontinuation included diarrhea, abnormal feces, abnormal skin odor, and abnormal urine odor.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EIn STABILITY, subgroup analyses based on biomarkers and genetics will further explore the potential utility of darapladib in specific high-risk patient subsets. The SOLID TIMI-52 trial [NCT010007277] which is testing darapladib in \u223c13,000 post-ACS patients is expected to report results in 2014.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\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\/14\/4\/14.2.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_openurl.js?nzpbhp\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_tables.js?nzpbhp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}