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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 discusses the results of the Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) Versus Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE-AF TIMI 48; Giugliano RP et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013] and new secondary analyses.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EArrhythmias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECerebrovascular Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology \u0026amp; Cardiovascular Medicine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EArrhythmias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECerebrovascular Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003ERobert P. Giugliano, MD, SM, Brigham and Women\u0027s Hospital, Boston, Massachusetts, USA, presented the results of the Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) Versus Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE-AF TIMI 48; Giugliano RP et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013] and new secondary analyses.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EIn ENGAGE-AF TIMI 48, the new oral anticoagulant (NOAC) edoxaban was studied in 21,105 patients who had atrial fibrillation (AF) and CHADS\u003Csub\u003E2\u003C\/sub\u003E scores \u22652. Patients were randomly assigned in a 1:1:1 double-blind, double-dummy fashion to warfarin (target international normalized ratio [INR] 2.0 to 3.0), high-dose edoxaban (60 mg\/day), or low-dose edoxaban (30 mg\/day). The objective of the study was to establish the noninferiority of once-daily edoxaban compared with warfarin.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe dose of edoxaban was reduced by half in about 25% of patients at randomization for creatinine clearance between 30 and 50 mL\/min, if the patient weighed \u226460 kg, or in the presence of a strong P-glycoprotein inhibitor, and it was adjusted (increased or decreased) in 8.3% after randomization. After a median follow-up period of 2.8 years, patients in the warfarin arm spent a median of 68.4% of the time in therapeutic range.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe primary end point of stroke or systemic embolic event (SEE) was lower with high-dose edoxaban compared with warfarin (HR, 0.79; p\u0026lt;0.0001 for noninferiority) but not for low-dose edoxaban (HR, 1.07; p=0.005 for non-inferiority) in the modified intention-to-treat analysis. In a superiority analysis in the intention-to-treat protocol, compared with warfarin, there was a favorable trend toward a reduction in the primary end point with high-dose edoxaban (HR, 0.87; p=0.08), and with low-dose edoxaban there was an unfavorable trend (HR, 1.13; p=0.10).\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EThe composite secondary endpoint of stroke, SEE, or cardiovascular death was lower with high-dose edoxaban (HR, 0.87; p=0.005) compared with warfarin, while it was similar between low-dose edoxaban (HR, 0.95; p=0.32) and warfarin.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe secondary end point of risk for hemorrhagic stroke was reduced by 46% with high-dose edoxaban and by 67% with low-dose edoxaban compared with warfarin (p\u0026lt;0.001 for both comparisons). For the secondary endpoint of ischemic stroke, compared with warfarin, the HR was 1.00 (p=0.97) with high-dose edoxaban and 1.41 with low-dose edoxaban (p\u0026lt;0.001), indicating that low-dose edoxaban did not protect from ischemic stroke as well as well-managed warfarin.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe primary safety endpoint of major bleeding, evaluated by the modified International Society on Thrombosis and Haemostasis criteria, compared with warfarin, occurred significantly less often with high-dose edoxaban (HR, 0.80; p\u0026lt;0.001) and was markedly reduced with low-dose edoxaban (HR, 0.47; p\u0026lt;0.001).\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EDr. Giugliano also presented several secondary findings, including a meta-analysis of recent trials, and 3 additional analyses from ENGAGE-AF TIMI 48 in patients by AF pattern, an in-depth analysis of cerebrovascular events, and explorations of the relationship between edoxaban dose, drug concentrations, anticoagulant activity, and outcomes.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EMETA-ANALYSIS OF 4 NOAC TRIALS\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EA meta-analysis of the 4 major trials of the NOACs showed a 19% overall reduction in the rate of stroke or SEE with these agents compared with warfarin ((p\u22650.0001) and a 10% reduction in all-cause mortality (p=0.0003) [Ruff CT et al. \u003Cem\u003ELancet\u003C\/em\u003E 2014].\u003C\/p\u003E\n         \u003Cdiv id=\u0022sec-2\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003ETransition to Open-Label Anticoagulation\u003C\/h3\u003E\n            \u003Cp id=\u0022p-11\u0022\u003EIn ENGAGE-AF TIMI 48, a detailed transition plan at the end of the trial permitted transition to any approved oral anticoagulant, and use of a transition kit, frequent INR monitoring, and an algorithm for those transitioning to vitamin K antagonists (VKAs). During a 30-day transition period to open-label warfarin, there were 7 strokes (1 hemorrhagic) in each treatment group, and the rates of major bleeding events through day 14 were similar (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). Of the patients randomly assigned to edoxaban, 85% and 99% had therapeutic INR values by Days 14 and 30, respectively. The transition from edoxaban to open-label anticoagulation at the end of the ENGAGE-AF TIMI 48 study was safe if open-label VKA was closely monitored, Dr. Giugliano said.\u003C\/p\u003E\n            \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\/14810\/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\/14810\/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\/14810\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-12\u0022 class=\u0022first-child\u0022\u003EOutcomes in ENGAGE-AF TIMI 48 During Transition From Edoxaban to Warfarin\u003C\/p\u003E\n               \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-3\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003EOutcomes by AF Pattern\u003C\/h3\u003E\n            \u003Cp id=\u0022p-14\u0022\u003EIn ENGAGE-AF TIMI 48, patients with paroxysmal AF had lower rates of stroke and death compared with those with persistent or permanent AF after multivariate adjustment. Major bleeding rates were similar across AF subtypes. Analyses comparing the multiple efficacy and safety outcomes of edoxaban with those of warfarin showed no significant interactions between the treatment group and the subtype of AF (paroxysmal, persistent, or permanent). Thus, the efficacy and safety profile of edoxaban was consistent regardless of the subtype of AF.\u003C\/p\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003ECorrelations of Dose, Concentration, Factor Xa Activity, and Outcomes\u003C\/h3\u003E\n            \u003Cp id=\u0022p-15\u0022\u003EThe 4-fold dose range of edoxaban studied translated into a 3-fold range of edoxaban concentration and level of factor Xa activity. Dose reduction resulted in improved safety and similar efficacy as was observed for those who did not require dose reduction. However, patients who were reduced from 30 to 15 mg had a significantly greater risk for stroke or SEE compared with those taking warfarin (p=0.02).\u003C\/p\u003E\n         \u003C\/div\u003E\n      \u003C\/div\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\/21\/15.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?nzp0dq\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?nzp0dq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}