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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 Effective Anticoagulation With Factor Xa Next Generation in the Atrial Fibrillation\u2014TIMI 48 trial [ENGAGE AF-TIMI 48; Giugliano RP et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E. 2013] of 21?105 patients with atrial fibrillation and CHADS2 scores =?2 reported the noninferiority of the oral factor Xa inhibitor edoxaban 30 and 60 mg once daily versus warfarin and dose-related decreases in major bleeding. This article presents the results of a subanalysis showing that the protocol-driven dose adjustments in ENGAGE AF maintained the efficacy of edoxaban and reduced bleeding.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombotic Disorders\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\u003ECardiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombotic Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EArrhythmias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology Clinical Trials\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe Effective Anticoagulation With Factor Xa Next Generation in the Atrial Fibrillation\u2014TIMI 48 trial [ENGAGE AF-TIMI 48; Giugliano RP et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2013] of 21 105 patients with atrial fibrillation and CHADS\u003Csub\u003E2\u003C\/sub\u003E scores \u2265 2 reported the noninferiority of the oral factor Xa inhibitor edoxaban 30 and 60 mg once daily versus warfarin and dose-related decreases in major bleeding. Christian T. Ruff, MD, MPH, Brigham and Women\u0027s Hospital, Boston, Massachusetts, USA, presented the results of a subanalysis showing that the protocol-driven dose adjustments in ENGAGE AF maintained the efficacy of edoxaban and reduced bleeding.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EBy way of background, the novel oral anticoagulants (NOACs), such as edoxaban, unlike warfarin, seem to provide fixed dosing therapeutic anticoagulation without the need for routine monitoring. However, an emerging question is whether the drug concentration or anticoagulant activity should be measured to optimize the risk\/benefit ratio of a NOAC. Therefore, this subanalysis correlated the trough plasma concentrations of edoxaban in 6780 study patients and the anti\u2014factor Xa activity in 2865 of the 6780 patients, measured 1 month after randomization with the edoxaban dose. The efficacy and safety outcomes were compared in the no dose reduction (NDR) and dose reduction (DR) groups in the edoxaban arms against warfarin.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe primary efficacy outcome was stroke or systemic embolic events (SEEs), and the primary safety outcome was major bleeding defined by International Society on Thrombosis and Haemostasis criteria. At baseline, or if any factors developed during the trial, doses in both edoxaban arms were reduced by 50% for patients with reduced renal function (creatinine clearance 30\u201350 mL\/min), those with lower weight (\u2264 60 kg), and those coprescribed a potent P-glycoprotein inhibitor, which are indicators of increased bleeding risk or increased exposure to edoxaban.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe mean trough concentrations of edoxaban were 48.5 \u00b1 45.8 and 24.5 \u00b1 22.7 ng\/mL with the 60- and 30-mg doses in the NDR group and 34.6 \u00b1 30.9 and 16.0 \u00b1 14.5 ng\/mL in the DR groupo, respectively.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EMean trough anti\u2014factor Xa activity was 0.85 \u00b1 0.76 and 0.44 \u00b1 0.37 IU\/mL in the NDR group with the 60- and 30-mg doses and 0.64 \u00b1 0.54 and 0.35 \u00b1 0.28 IU\/mL in the DR group, respectively. There was a good correlation between the trough edoxaban concentration and trough anti\u2014factor Xa activity, irrespective of the edoxaban dose or DR (\u003Cem\u003Er\u003C\/em\u003E = 0.96, \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .0001).\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EFor the primary outcome, the efficacy of edoxaban (60 and 30 mg) versus warfarin was similar irrespective of a DR. Edoxaban 15 mg was associated with a nonsignificant increased risk versus warfarin and edoxaban 30 mg (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\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\/14\/27\/25\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Primary Outcome With Maintained or Lowered High- and Low-Dose Edoxaban\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-392051587\u0022 data-figure-caption=\u0022Primary Outcome With Maintained or Lowered High- and Low-Dose Edoxaban\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/27\/25\/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\/14\/27\/25\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\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\/14\/27\/25\/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\/14983\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 attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EPrimary Outcome With Maintained or Lowered High- and Low-Dose Edoxaban\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EEdox, edoxaban; FXa, factor Xa; HD, high-dose; LD, low-dose; NA, not applicable; SEE, systemic embolic event.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from C Ruff, MD, MPH.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EThe risk for major bleeding was lower with both doses of edoxaban versus warfarin. For both doses, there was a significantly lower risk for major bleeding in the DR group versus the NDR group (\u003Cem\u003EP\u003C\/em\u003E\n         \u003Csub\u003EInteraction\u003C\/sub\u003E = .02 for e doxaban 60 mg, \u003Cem\u003EP\u003C\/em\u003E\n         \u003Csub\u003EInteraction\u003C\/sub\u003E = .002 for edoxaban 30 mg; \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). A similar finding was evident for the annual risk for intracranial hemorrhage, with a significant reduction in the DR group versus the NDR group in the edoxaban 30 mg arm (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F2\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\/14\/27\/25\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Annual Risk for Major Bleeding\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-392051587\u0022 data-figure-caption=\u0022Annual Risk for Major Bleeding\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/27\/25\/F2.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\/14\/27\/25\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\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\/14\/27\/25\/F2.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\/14984\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 attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-10\u0022 class=\u0022first-child\u0022\u003EAnnual Risk for Major Bleeding\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EEdox, edoxaban; FXa, factor Xa; HD, high-dose; LD, low-dose; NA, not applicable; SEE, systemic embolic event.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced with permission from C Ruff, MD, MPH.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F3\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\/14\/27\/25\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Annual Risk for Intracranial Hemorrhage\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-392051587\u0022 data-figure-caption=\u0022Annual Risk for Intracranial Hemorrhage\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/27\/25\/F3.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\/14\/27\/25\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\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\/14\/27\/25\/F3.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\/14985\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 attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EAnnual Risk for Intracranial Hemorrhage\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EEdox, edoxaban; FXa, factor Xa; HD, high-dose; LD, low-dose; NA, not applicable; SEE, systemic embolic event.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-6\u0022\u003EReproduced with permission from C Ruff, MD, MPH.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EThe therapeutic window of edoxaban showed that the dose-response curve was steepest for major bleeding, shallower for stroke and SEEs, and nearly flat for intracranial hemorrhage.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EThe mean edoxaban exposure and anti\u2014factor Xa activity was reduced by 29% to 35% and 20% to 25%, respectively, in the DR and NDR groups. These data validate the strategy of tailoring the dose of NOACs on the basis of clinical factors alone to achieve the dual goal of preventing excess drug levels and optimizing an individual patient\u0027s risk for ischemic and bleeding events and demonstrate that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. Dose adjustment of edoxaban on the basis of clinical features obviates the need to measure drug levels or anticoagulant activity.\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\/25.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?nzoui1\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?nzoui1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}