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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\u003EThis article presents the results of the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease Without Heart Failure [SIGNIFY; Fox K et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E. 2014]. The study found that treatment with ivabradine did not reduce the risk of cardiovascular (CV) death or nonfatal myocardial infarction (NFMI). However, in patients with Canadian Cardiovascular Society class II or greater angina at baseline, ivabradine increased the risk of CV death or myocardial infarction.\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\u003ECardiology\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\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EKim M. Fox, MD, Imperial College, London, United Kingdom, reported the results of the Study Assessing the Morbidity-Mortality Benefits of the \u003Cem\u003EI\u003C\/em\u003E\n         \u003Csub\u003Ef\u003C\/sub\u003E Inhibitor Ivabradine in Patients With Coronary Artery Disease Without Heart Failure [SIGNIFY; Fox K et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E. 2014]. The study found that treatment with ivabradine did not reduce the risk of cardiovascular (CV) death or nonfatal myocardial infarction (NFMI). However, in patients with Canadian Cardiovascular Society (CCS) class II or greater angina at baseline, ivabradine increased the risk of CV death or myocardial infarction (MI).\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe BEAUTIFUL study [Fox K et al. \u003Cem\u003ELancet\u003C\/em\u003E. 2008] also tested ivabradine in patients with stable coronary artery disease (CAD) and left ventricular systolic dysfunction. In the overall study population, the primary outcome of hospitalization for fatal and NFMI was not reduced with ivabradine versus placebo on top of standard therapy. However, ivabradine appeared to reduce the rate of the primary outcome in the patients with a heart rate \u2265 70 beats per minute (bpm). Ivabradine is currently approved in the European Union for use in patients with CAD and patients with heart failure and who are either intolerant of beta-blockers or are inadequately controlled despite treatment with beta-blockers.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ESIGNIFY\u2014a prospective, international, double-blind study\u2014enrolled patients aged \u2265 55 years with stable CAD and \u2265 1 other CV risk factor, including CCS class \u2265 II angina, a left ventricular ejection fraction (LVEF) \u0026gt; 40%, and a heart rate \u2265 70 bpm [Fox K et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2014], to further test the hypothesis that ivabradine improved outcomes in patients with elevated resting heart rate. A higher-dose regimen of ivabradine, a drug known to have a specific and direct effect on heart rate alone, was used to obtain maximum heart rate reduction in SIGNIFY. After a 14- to 30-day run-in, patients were randomized to ivabradine (7.5 mg, BID; n = 9550) or placebo (n = 9552), and the drug was uptitrated as tolerated to a maximum of 10 mg (BID) to obtain a target a heart rate of 55 to 60 bpm.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe study patients were mostly men (73%) aged 65 years with a LVEF (56%) and with a high frequency of prior MI (73%) and other risk factors. They were receiving optimal CV medical therapy [Gibbons RJ et al. \u003Cem\u003EJ Am Coll Cardiol.\u003C\/em\u003E 2003; Fox K et al. \u003Cem\u003EEur Heart J.\u003C\/em\u003E 2006]. The median follow-up was 27.8 months.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EThe baseline resting heart rate was 77 bpm in both groups. The mean reduction in heart rate was 9.7 bpm with ivabradine versus placebo. Prof Fox noted that the reduction in heart rate was less than what they had anticipated.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe incidence of the primary composite outcome of CV death or NFMI was similar with ivabradine (3.03% per year) and placebo (2.82%; \u003Cem\u003EP\u003C\/em\u003E = .20), as was the incidence of its components (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E).\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\/14975\/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\/14975\/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\/14975\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\u003EPrimary Outcome Results in SIGNIFY\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\u003EIn the overall study population, the incidence of adverse events was higher with ivabradine versus placebo (73% vs 66.9%; \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001). Symptomatic and asymptomatic bradycardia occurred in about 19% of patients in the ivabradine group versus about 2.5% in the placebo group. Atrial fibrillation occurred in 5.3% and 3.8% of the ivabradine and placebo groups, respectively. Importantly, the total incidence of life-threatening arrhythmias\u2014ventricular tachycardia, ventricular fibrillation, and Torsades de pointes\u2014was infrequent (\u2264 0.9%).\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EIn the prespecified analysis of patients with angina CCS class \u2265 II (n = 12 049), there was a significant increase of 18% in the composite of CV death and MI, and a similar nonsignificant trend was seen for the components of the primary outcome (\u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E). Prof Fox noted that this is the population in which the research group anticipated finding the maximum benefit with a lower heart rate. In the angina population, ivabradine improved symptoms, with a greater improvement in CCS class at 3 months (24.8% vs 19.4% with placebo; \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .01). The need for elective coronary revascularization was not significantly reduced with ivabradine versus placebo (HR, 0.82; \u003Cem\u003EP\u003C\/em\u003E = .06).\u003C\/p\u003E\u003Cdiv id=\u0022T2\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\/14976\/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\/14976\/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\/14976\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 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-12\u0022 class=\u0022first-child\u0022\u003EPrimary Outcomes in Patients With CCS Class \u2265 II Angina in SIGNIFY\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-14\u0022\u003EIn summary, in the absence of clinical heart failure in patients with stable CAD, lowering the heart rate with ivabradine did not prevent the progression of CAD, stated Prof Fox, and in patients with angina at baseline, there was an increase in CV death or NFMI. The results of this study has led a review by the European Medical Agency that is ongoing to determine what, if any, further action is needed.\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\/27\/13.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?nzotwd\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?nzotwd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}