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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\u003EAlthough the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction [BEAUTIFUL; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00143507\u0026amp;atom=%2Fspmdc%2F8%2F6%2F12.atom\u0022\u003ENCT00143507\u003C\/a\u003E] trial failed to meet its primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction (MI), and hospitalization for new-onset or worsening heart failure, it significantly reduced important secondary endpoints, such as hospitalization for fatal or non-fatal MI and coronary revascularization.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eheart failure\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ecoronary artery disease clinical trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EAlthough the BEAUTIFUL (morBidity-mortality EvAlUaTion of the \u003Cem\u003EI\u003C\/em\u003E\n            \u003Csub\u003Ef\u003C\/sub\u003E inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction) trial (\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00143507\u0026amp;atom=%2Fspmdc%2F8%2F6%2F12.atom\u0022\u003ENCT00143507\u003C\/a\u003E) failed to meet its primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction (MI), and hospitalization for new-onset or worsening heart failure (HF), it significantly reduced important secondary endpoints, such as hospitalization for fatal or non-fatal MI and coronary revascularization. In addition, BEAUTIFUL has provided valuable new mechanistic information in HF, indicating a threshold for the deleterious effect of heart rate (HR) in patients with stable coronary artery disease (CAD) and left ventricular dysfunction (LVD).\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EPrior studies have demonstrated that elevated resting HR is associated with an increased risk of all-cause mortality, cardiovascular mortality, and development of cardiovascular disease in the general population, as well as in individuals with preexisting CAD [Graham I et al. \u003Cem\u003EEur Heart J\u003C\/em\u003E 2007; Fox K et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2007; Palatini P and Julius S. \u003Cem\u003EClin Exp Hypertens\u003C\/em\u003E 2004].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EIvabradine, a selective HR-lowering agent, acts on the sinoatrial node, providing rate reduction without altering other cardiac functions. In a rat model of cardiac failure, it increased stroke volume and improved left ventricular function [Mulder P et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2004]. A preliminary study in patients with CAD and moderate LVD also has suggested that ivabradine has beneficial effects on left ventricle geometry [Jondeau G et al. \u003Cem\u003EEur Heart J 2004\u003C\/em\u003E].\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe BEAUTIFUL trial was designed to assess whether the addition of ivabradine to standard treatment would reduce cardiovascular death and morbidity in patients with HF and to evaluate the role of HR as a predictor of risk in patients with CAD and LVD [Fox K et al. \u003Cem\u003ELancet\u003C\/em\u003E 2008].\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EBEAUTIFUL was a randomized, double-blind, placebo-controlled trial that was conducted at 781 centers worldwide. Eligible patients included men and women aged 55 years or older (\u226518 years if diabetic) with documented CAD and a left ventricular ejection fraction (LVEF) \u0026lt;40%. Patients had to be in sinus rhythm with a resting HR \u226560 beats per minute (bpm). The trial also required that subjects were clinically stable for 3 months with regard to angina and HF symptoms and receiving conventional cardiovascular medication at constant doses for 1 month.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe primary study endpoint was a composite of cardiovascular mortality, hospital admission for acute MI, and hospitalization for new-onset or worsening HF. Secondary endpoints included all-cause mortality, cardiac death, cardiovascular death, hospital admission for new\/worsening HF, the composite of hospital admission for fatal and non-fatal acute MI or unstable angina, and coronary revascularization.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EThe study population included 10,917 subjects (mean age 65 years; 83% men). Subjects initially were assigned to receive ivabradine 5 mg (n=5479) or matching placebo (n=5438) twice daily. Follow-up visits were conducted at Week 2, at Months 1, 3, and 6, and every 6 months thereafter. At Week 2, the dose for subjects whose resting HR was \u226560 bpm was increased to 7.5 mg twice daily (or matching placebo).\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EPatients continued to receive their usual cardiovascular medical treatment throughout the study. Concomitant treatments included \u03b2-blockers (87%), angiotensin-converting enzyme inhibitors (90%), aspirin or antithrombotic agents (94%), statins (74%), antialdosterone agents (27%), and diuretics (59%). At baseline, the overall population had a mean resting HR of 71.6 bpm. Mean LVEF was 32.4%. Approximately 90% of all patients had a history of MI; 70% had hypertension and 40% were diabetics. Median duration of follow-up was 19 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003ESubjects who received ivabradine had a mean reduction in HR of 6 bpm at 12 months and 5 bpm at 24 months. This reduction did not translate to an improvement of the primary endpoint in the overall population (HR 1.00; 95% CI, 0.91 to 1.1; p=0.94). HR reductions in the subgroup of subjects whose HR was \u226570 bpm were 9 bpm at 6 months, 7.9 bpm at 12 months, and 6.9 bpm at 24 months. In this group, there was a significant reduction in the secondary outcomes of hospital admission for fatal and non-fatal MI (0.64; 95% CI, 0.49 to 0.84; p=0.001) and coronary revascularization (0.70; 95% CI, 0.52 to 0.93; p=0.016).\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe frequency of serious adverse events was not different between treatment groups (22.5% vs 22.8%; p=0.70); however, more patients in the ivabradine group discontinued treatment (28%) versus those who received placebo (16%). The most common reason for treatment discontinuation in the ivabradine group was bradycardia.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EIn commenting on the BEAUTIFUL study, Sidney C. Smith, MD, University of North Carolina, Chapel Hill, NC, noted that while the results of BEAUTIFUL do not change the guidelines for treatment of LVD, it does point to the need for prospective studies of ivabradine in subjects with CAD and HR \u226570 bpm.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EThe results of this study were presented by Kim Fox, MD, Imperial College, London, UK, Chairman of the BEAUTIFUL Executive Committee, and published simultaneously online in \u003Cem\u003EThe Lancet\u003C\/em\u003E [Fox K et al. \u003Cem\u003ELancet\u003C\/em\u003E 2008].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2008 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\/8\/6\/12.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?nzmcs3\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}