Review article
Importance of dose selection in novel oral anticoagulants for atrial fibrillation
Importancia de seleccionar la dosis de los nuevos anticoagulantes orales para fibrilación auricular
Laura T. Grip, Robert P. Giugliano
Corresponding author
rgiugliano@partners.org
Corresponding author. 350 Longwood Avenue, 1st Floor Offices, Z.P. 02115, Boston, MA, USA. Tel.: +1 617 278 0145; fax: +1 617 734 7320.
Corresponding author. 350 Longwood Avenue, 1st Floor Offices, Z.P. 02115, Boston, MA, USA. Tel.: +1 617 278 0145; fax: +1 617 734 7320.
From the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
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Esquema de la capacidad del riñón para mantener la presión arterial constante ante cambios en la ingestion de sodio.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rafael González-Toledo, Martha Franco" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Rafael" "apellidos" => "González-Toledo" ] 1 => array:2 [ "nombre" => "Martha" "apellidos" => "Franco" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994012000377?idApp=UINPBA00004N" "url" => "/14059940/0000008200000004/v1_201305151541/S1405994012000377/v1_201305151541/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1405994012000365" "issn" => "14059940" "doi" => "10.1016/j.acmx.2012.09.006" "estado" => "S300" "fechaPublicacion" => "2012-10-01" "aid" => "18" "copyright" => "Instituto Nacional de Cardiología Ignacio Chávez" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Arch Cardiol Mex. 2012;82:303-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 29700 "formatos" => array:3 [ "EPUB" => 92 "HTML" => 27865 "PDF" => 1743 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Comunicación breve</span>" "titulo" => "Tratamiento endovascular exitoso del síndrome de cascanueces con stent autoexpandible" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "303" "paginaFinal" => "307" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Successful endovascular treatment of nutcracker's syndrome with self-expanding stent" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1587 "Ancho" => 1583 "Tamanyo" => 211501 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Proyección lateral, que muestra el resultado final del stent autoexpandible con adecuada apertura del mismo.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Marco Antonio Alcocer-Gamba, Jorge A. 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"apellidos" => "Torres-Quiroz" ] 8 => array:2 [ "nombre" => "Arturo" "apellidos" => "Velázquez-Verduzco" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994012000365?idApp=UINPBA00004N" "url" => "/14059940/0000008200000004/v1_201305151541/S1405994012000365/v1_201305151541/es/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Importance of dose selection in novel oral anticoagulants for atrial fibrillation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "308" "paginaFinal" => "311" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Laura T. Grip, Robert P. Giugliano" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Laura T." "apellidos" => "Grip" ] 1 => array:4 [ "nombre" => "Robert P." "apellidos" => "Giugliano" "email" => array:1 [ 0 => "rgiugliano@partners.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "From the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author. 350 Longwood Avenue, 1<span class="elsevierStyleSup">st</span> Floor Offices, Z.P. 02115, Boston, MA, USA. Tel.: +1 617 278 0145; fax: +1 617 734 7320." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Importancia de seleccionar la dosis de los nuevos anticoagulantes orales para fibrilación auricular" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">One of the biggest challenges with any novel oral anticoagulant is finding the therapeutic range for which the risk does not outweigh the benefit. With warfarin, the optimal INR range for most indications is 2.0-3.0. If the INR is <1.8 in patients with atrial fibrillation, the risk of ischemic stroke is increased, while INRs much above 3.0 are associated with an increased risk of intracranial bleeding.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">When developing a novel oral anticoagulant, there are several ideal properties that would be desirable. Once-daily vs twice-daily dosing is preferable to maximize compliance. Additionally, minimal food-drug and drug-drug interactions would simplify dosing. A drug with a predictable anticoagulant effect eliminates the need for coagulation monitoring. A drug with extra renal clearance enables patients with mild to moderate renal disease to take the anticoagulant safely. A rapid onset of action eliminates the need for bridging anticoagulant therapy (e.g., heparin), and a rapid offset in action simplifies management in case of bleeding or the need for an invasive procedure. It is also advantageous to have an antidote available to reverse the anticoagulation effect in case of emergencies. Clearly, selecting the right dose and regimen is a critical part of the development of an anticoagulant.</p><p id="par0015" class="elsevierStylePara elsevierViewall">There are currently 5 novel oral anticoagulants in late stage clinical development: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a> Each of these drugs is a Factor Xa inhibitor, except for dabigatran, which is a Factor IIa inhibitor. These drugs share some pharmacokinetic (PK) properties. They all have a rapid onset of action and most are substrates of the P-gp transporter. However, there are several PK differences between these drugs, most importantly related to dosing. The bioavailability of the drugs ranges from 7% (dabigatran) to 80% (rivaroxaban). Betrixaban has minimal renal clearance (< 5%), while dabigatran has 80% renal elimination. Lastly, there is variability in the half-lives ranging from 8-10<span class="elsevierStyleHsp" style=""></span>hours (edoxaban) to 19-20<span class="elsevierStyleHsp" style=""></span>hours (betrixaban).</p><p id="par0020" class="elsevierStylePara elsevierViewall">It is also important to consider PK data in specific subgroups of patients with AF. PK data in patients treated with dabigatran show that a reduction in creatinine clearance results in higher plasma concentration of dabigatran, which is associated with a prolongation of the aPTT.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> PK models used in clinical trial simulations with edoxaban showed a similar effect.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition, edoxaban levels are increased in patients treated concomitantly with strong P-gp inhibitors such as verapamil, quinidine and dronedarone, and in patients of low body weight (≤ 60 Kg). These differences in pharmacokinetic properties are important considerations when selecting the dose(s) of a novel oral anticoagulant.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Phase II dose-ranging studies have been conducted with dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban to evaluate safety and explore possible efficacy trends across various doses. The phase II studies helped guide the selection of dose(s) to be studied in phase III. Dedicated phase II trials with dabigatran and edoxaban were performed in patients with atrial fibrillation (as well as in other patient populations) while no similar phase II dose-ranging studies in AF have been published with rivaroxaban or apixaban. In the dabigatran AF phase II study,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> more frequent bleeding was observed in the highest dose studied (300<span class="elsevierStyleHsp" style=""></span>mg BID), while thromboembolic events were only observed in the lowest dose studied (50<span class="elsevierStyleHsp" style=""></span>mg BID). Based on these data, a decision was made to move forward with the intermediate doses of 150<span class="elsevierStyleHsp" style=""></span>mg BID and 110<span class="elsevierStyleHsp" style=""></span>mg BID in the phase III AF trial. In the edoxaban phase II AF trial,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> no significant differences in efficacy rates were shown in any of the treatment groups. Significantly higher rates of bleeding were observed in the 30<span class="elsevierStyleHsp" style=""></span>mg BID and 60<span class="elsevierStyleHsp" style=""></span>mg BID doses while similar rates of bleeding compared to warfarin were seen with the 30<span class="elsevierStyleHsp" style=""></span>mg QD and 60<span class="elsevierStyleHsp" style=""></span>mg QD doses; therefore these latter 2 doses were chosen to be studied in the phase III trial.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Large phase III studies in atrial fibrillation have been completed for 3 drugs (dabigatran, rivaroxaban, apixaban). Of these 3 studies, only the RE-LY trial<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> with dabigatran explored more than one dose of the novel anticoagulant. The higher dose (150<span class="elsevierStyleHsp" style=""></span>mg BID) of dabigatran was shown to reduce stroke and had a similar rate of bleeding as warfarin. The lower dose (110<span class="elsevierStyleHsp" style=""></span>mg BID) of dabigatran had a similar rate of stroke but reduced bleeding in comparison to warfarin. The ROCKET-AF trial<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> studied rivaroxaban 20<span class="elsevierStyleHsp" style=""></span>mg once-daily vs warfarin, with dose adjustment to 15<span class="elsevierStyleHsp" style=""></span>mg in patients with a creatinine clearance of 30 to 49<span class="elsevierStyleHsp" style=""></span>mL/min. The on-treatment analysis of rivaroxaban showed a reduction of stroke compared to warfarin and a similar rate of bleeding. The ARISTOTLE trial<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> studied 5<span class="elsevierStyleHsp" style=""></span>mg apixaban taken twice-daily. Only 5% of patients received a one-time dose reduction at randomization to 2.5<span class="elsevierStyleHsp" style=""></span>mg twice-daily because they met 2 or more of the following criteria: ≥ 80 years old, body weight < 60 Kg, or a serum creatinine level ≥1.5<span class="elsevierStyleHsp" style=""></span>mg/dl. Apixaban reduced hemorrhagic stroke compared to warfarin but did not affect ischemic stroke. Apixaban reduced all-cause mortality 3.5% vs 3.9% per year compared to warfarin (<span class="elsevierStyleItalic">p</span>=0.047). In addition, a lower rate of major bleeding was also observed with apixaban compared to warfarin. A substantial decrease (33%-70% relative) in intracranial hemorrhage was observed in all 3 drugs compared to warfarin.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Among the 5 novel oral anticoagulants, the development of edoxaban is unique in that a large phase IIb dose-ranging study<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> was conducted, and multiple doses are being evaluated in phase III.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In the phase IIb study,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> 4 doses of edoxaban (30<span class="elsevierStyleHsp" style=""></span>mg QD, 60<span class="elsevierStyleHsp" style=""></span>mg QD, 30<span class="elsevierStyleHsp" style=""></span>mg BID, 60<span class="elsevierStyleHsp" style=""></span>mg BID) were compared to warfarin. The expected pattern of dose-related bleeding with edoxaban was observed (i.e., the higher the dose, the greater the bleeding). Of note, less bleeding was observed in the 30<span class="elsevierStyleHsp" style=""></span>mg QD dose group compared to warfarin, while the 60<span class="elsevierStyleHsp" style=""></span>mg QD dose and warfarin had similar rates of bleeding. However, the most intriguing finding was that less bleeding occurred with once-daily dosing of 60<span class="elsevierStyleHsp" style=""></span>mg (7.3%) compared to 30<span class="elsevierStyleHsp" style=""></span>mg twice-daily dosing (12.7%), despite the fact that the <span class="elsevierStyleItalic">exact same</span> total daily dose (60<span class="elsevierStyleHsp" style=""></span>mg) was given. The two once-daily doses of 30<span class="elsevierStyleHsp" style=""></span>mg QD and 60<span class="elsevierStyleHsp" style=""></span>mg QD edoxaban are now being compared to warfarin in 21,105 patients enrolled in the double-blind, randomized phase III trial ENGAGE AF-TIMI 48.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In detailed pharmacokinetic analyses of edoxaban, <span class="elsevierStyleItalic">trough</span> levels corresponded best with the rate of bleeding.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Since once-daily dosing has lower <span class="elsevierStyleItalic">trough</span> values, this helps to explain the occurrence of less bleeding with the once-daily doses compared to twice-daily doses studied. This observation of less bleeding with once-daily regimens may seem counterintuitive, as the prevailing thought had been that <span class="elsevierStyleItalic">peak</span> levels of antithrombotic drugs might better predict bleeding. However, this finding regarding the superior safety profile of once-daily dosing of a factor Xa inhibitor (that achieve lower <span class="elsevierStyleItalic">trough</span> levels than twice-daily dosing) was further supported by the results of a dose-ranging phase II study with darexaban, known as RUBY-1.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Six dose regimens of darexaban were studied, including three once-daily doses (10<span class="elsevierStyleHsp" style=""></span>mg QD, 30<span class="elsevierStyleHsp" style=""></span>mg QD, 60<span class="elsevierStyleHsp" style=""></span>mg QD) and 3 comparable twice-daily doses (5<span class="elsevierStyleHsp" style=""></span>mg BID, 15<span class="elsevierStyleHsp" style=""></span>mg BID, 30<span class="elsevierStyleHsp" style=""></span>mg BID). In all 3 comparisons of once-daily vs twice-daily dosing of the same total daily dose, there was a similar pattern of a <span class="elsevierStyleItalic">lower</span> rate of bleeding with the <span class="elsevierStyleItalic">once-daily</span> dose.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Several factors are known to affect drug concentration such as decreased renal function, low body weight and concomitant medications that interfere with the metabolism of a drug. The ENGAGE AF-TIMI 48 study takes these factors into consideration and mandates a 50% edoxaban/placebo dose reduction if the creatinine clearance (CrCl) is below 50<span class="elsevierStyleHsp" style=""></span>mL/min, weight is below 60<span class="elsevierStyleHsp" style=""></span>kg, or there is concomitant use of a strong P-gp inhibitor (verapamil, quinidine, dronedarone).<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,7,12</span></a> Whereas the ROCKET-AF and ARISTOTLE trials only allowed a dose reduction at the time of randomization, ENGAGE AF-TIMI 48 also mandates dynamic dose adjustment (up or down) if any of these factors change <span class="elsevierStyleItalic">after</span> randomization. Of note, the RE-LY trial did not incorporate any dose reduction in their trial design.</p><p id="par0050" class="elsevierStylePara elsevierViewall">There are several other important differences in the way novel anticoagulants have been studied in each of the 4 large phase III trials (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The RE-LY trial was an open-label design while ROCKET-AF, ARISTOTLE and ENGAGE AF-TIMI 48 utilized a double-blind study design. In addition, whereas ROCKET-AF and ENGAGE AF-TIMI 48 studied once-daily doses, the RE-LY and ARISTOTLE trials studied twice-daily regimens. Two of the 4 trials, RE-LY and ENGAGE AF-TIMI 48, studied 2 different doses, however the dose differential in RE-LY was modest (110<span class="elsevierStyleHsp" style=""></span>mg vs 150<span class="elsevierStyleHsp" style=""></span>mg) compared to the 2-fold dose differential in ENGAGE AF-TIMI 48. Three of the 4 studies included a dose adjustment based on renal clearance, with ENGAGE AF-TIMI 48 being the only one of the 3 mandating dose adjustments post-randomization. Since the ENGAGE AF-TIMI 48 trial is randomizing to 2 dose levels of edoxaban, the additional reduced dose from 30<span class="elsevierStyleHsp" style=""></span>mg to 15<span class="elsevierStyleHsp" style=""></span>mg QD (in the case that a subject randomized to the low-dose regimen requires dose reduction due one of the factors described above) introduces a third dose group and creates a 4-fold differential from the lowest (15<span class="elsevierStyleHsp" style=""></span>mg) to the highest (60<span class="elsevierStyleHsp" style=""></span>mg) dose being evaluated.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">There are several excellent alternatives to warfarin on the horizon for atrial fibrillation. Results from the RE-LY, ROCKET-AF and ARISTOTLE trials, as well as pharmacokinetic data from the edoxaban studies, suggest that dose selection, based on pharmacokinetic and pharmacodynamic properties, is a critical component in the development of novel anticoagulants. Greater flexibility in dosing with edoxaban and the opportunity for dose adjustment throughout the ENGAGE AF-TIMI 48 trial may be advantageous in the competitive field of novel oral anticoagulants.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-02-13" "fechaAceptado" => "2012-04-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec163971" "palabras" => array:5 [ 0 => "Atrial fibrillation" 1 => "Oral anticoagulants" 2 => "Warfarin" 3 => "Intracranial bleeding" 4 => "USA" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec163972" "palabras" => array:5 [ 0 => "Fibrilación auricular" 1 => "Anticoagulantes orales" 2 => "Warfarina" 3 => "Sangrado intracraneal" 4 => "EUA" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are several excellent alternatives to warfarin on the horizon for atrial fibrillation. Results from the trials, as well as pharmacokinetic data from the edoxaban studies, suggest that dose selection, based on pharmacokinetic and pharmacodynamic properties, is a critical component in the development of novel anticoagulants. Greater flexibility in dosing with edoxaban and the opportunity for dose adjustment throughout the ENGAGE AF-TIMI 48 trial may be advantageous in the competitive field of novel oral anticoagulants.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Existen excelentes alternativas al tratamiento con warfarina en el campo de la fibrilación auricular. Los resultados de los ensayos con RE-LY, ROCKET-AF y ARISTOTLE, así como los datos fármaco cinéticos obtenidos en estudios con edoxaban, sugieren que la selección de la dosis, basada en propiedades fármaco cinéticas y fármaco dinámicas, es un componente crítico en el desarrollo de nuevos anticoagulantes. Una mayor flexibilidad en establecer la dosis de edoxaban y la oportunidad de ajustar la dosis mediante ENGAGE AF-TIMI 48, puede constituir una ventaja en el campo de los nuevos anticoagulantes orales.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">PROBE: prospective, randomized, open-label, blinded endpoint evaluation.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">RE-LY \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ROCKET-AF<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ARISTOTLE<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ENGAGEAF-TIMI 48<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dabigatran \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rivaroxaban \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apixaban \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Edoxaban \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Brand name (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pradaxa<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Xarelto<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eliquis<span class="elsevierStyleSup">®</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TBD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18,113 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14,264 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18,201 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21,105 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dose (mg)Frequency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150, 110BID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20QD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5BID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60, 30QD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Initial DoseAdjustment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20→15<span class="elsevierStyleHsp" style=""></span>mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5→2.5 mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60→30 mg30→15 mg \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DoseAdjustment afterrandomization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Design \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PROBE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab267942.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara">Dose adjusted in patients with ↓drug clearance.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Phase III AF Trials – Dose Comparisons.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => 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McMurray" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1107039" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2011" "volumen" => "365" "paginaInicial" => "981" "paginaFinal" => "992" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21870978" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P.G. Steg" 1 => "S.R. Mehta" 2 => "J.W. Jukema" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/eurheartj/ehr334" "Revista" => array:6 [ "tituloSerie" => "Eur Heart J" "fecha" => "2011" "volumen" => "32" "paginaInicial" => "2541" "paginaFinal" => "2554" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21878434" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "N. Chung" 1 => "H.K. Jeon" 2 => "L.M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 38 | 3 | 41 |
| 2024 September | 32 | 14 | 46 |
| 2024 August | 24 | 8 | 32 |
| 2024 July | 36 | 7 | 43 |
| 2024 June | 24 | 10 | 34 |
| 2024 May | 13 | 6 | 19 |
| 2024 April | 20 | 19 | 39 |
| 2024 March | 33 | 26 | 59 |
| 2024 February | 21 | 13 | 34 |
| 2024 January | 16 | 19 | 35 |
| 2023 December | 22 | 19 | 41 |
| 2023 November | 30 | 19 | 49 |
| 2023 October | 28 | 11 | 39 |
| 2023 September | 45 | 4 | 49 |
| 2023 August | 33 | 10 | 43 |
| 2023 July | 18 | 17 | 35 |
| 2023 June | 19 | 10 | 29 |
| 2023 May | 36 | 6 | 42 |
| 2023 April | 13 | 3 | 16 |
| 2023 March | 8 | 2 | 10 |
| 2023 February | 14 | 7 | 21 |
| 2023 January | 15 | 11 | 26 |
| 2022 December | 30 | 3 | 33 |
| 2022 November | 17 | 19 | 36 |
| 2022 October | 25 | 17 | 42 |
| 2022 September | 22 | 16 | 38 |
| 2022 August | 22 | 6 | 28 |
| 2022 July | 15 | 11 | 26 |
| 2022 June | 24 | 14 | 38 |
| 2022 May | 35 | 9 | 44 |
| 2022 April | 30 | 16 | 46 |
| 2022 March | 19 | 15 | 34 |
| 2022 February | 15 | 7 | 22 |
| 2022 January | 25 | 11 | 36 |
| 2021 December | 18 | 13 | 31 |
| 2021 November | 50 | 14 | 64 |
| 2021 October | 43 | 10 | 53 |
| 2021 September | 42 | 13 | 55 |
| 2021 August | 39 | 8 | 47 |
| 2021 July | 32 | 7 | 39 |
| 2021 June | 22 | 12 | 34 |
| 2021 May | 20 | 5 | 25 |
| 2021 April | 53 | 16 | 69 |
| 2021 March | 22 | 20 | 42 |
| 2021 February | 28 | 13 | 41 |
| 2021 January | 22 | 13 | 35 |
| 2020 December | 25 | 17 | 42 |
| 2020 November | 24 | 18 | 42 |
| 2020 October | 13 | 6 | 19 |
| 2020 September | 13 | 15 | 28 |
| 2020 August | 11 | 15 | 26 |
| 2020 July | 16 | 12 | 28 |
| 2020 June | 17 | 13 | 30 |
| 2020 May | 15 | 12 | 27 |
| 2020 April | 7 | 4 | 11 |
| 2020 March | 30 | 13 | 43 |
| 2020 February | 22 | 9 | 31 |
| 2020 January | 17 | 13 | 30 |
| 2019 December | 21 | 30 | 51 |
| 2019 November | 19 | 14 | 33 |
| 2019 October | 19 | 16 | 35 |
| 2019 September | 24 | 19 | 43 |
| 2019 August | 11 | 9 | 20 |
| 2019 July | 16 | 26 | 42 |
| 2019 June | 38 | 51 | 89 |
| 2019 May | 115 | 106 | 221 |
| 2019 April | 34 | 15 | 49 |
| 2019 March | 6 | 12 | 18 |
| 2019 February | 9 | 14 | 23 |
| 2019 January | 7 | 14 | 21 |
| 2018 December | 6 | 10 | 16 |
| 2018 November | 12 | 11 | 23 |
| 2018 October | 9 | 12 | 21 |
| 2018 September | 6 | 10 | 16 |
| 2018 August | 8 | 7 | 15 |
| 2018 July | 10 | 2 | 12 |
| 2018 June | 4 | 0 | 4 |
| 2018 May | 6 | 5 | 11 |
| 2018 April | 1 | 0 | 1 |
| 2018 March | 6 | 3 | 9 |
| 2018 February | 9 | 2 | 11 |
| 2018 January | 7 | 1 | 8 |
| 2017 December | 7 | 1 | 8 |
| 2017 November | 3 | 2 | 5 |
| 2017 October | 9 | 4 | 13 |
| 2017 September | 7 | 3 | 10 |
| 2017 August | 12 | 2 | 14 |
| 2017 July | 12 | 5 | 17 |
| 2017 June | 16 | 34 | 50 |
| 2017 May | 23 | 2 | 25 |
| 2017 April | 25 | 4 | 29 |
| 2017 March | 20 | 45 | 65 |
| 2017 February | 25 | 6 | 31 |
| 2017 January | 12 | 4 | 16 |
| 2016 December | 28 | 11 | 39 |
| 2016 November | 30 | 12 | 42 |
| 2016 October | 60 | 5 | 65 |
| 2016 September | 61 | 6 | 67 |
| 2016 August | 23 | 4 | 27 |
| 2016 July | 38 | 1 | 39 |
| 2016 June | 40 | 17 | 57 |
| 2016 May | 32 | 10 | 42 |
| 2016 April | 30 | 16 | 46 |
| 2016 March | 29 | 25 | 54 |
| 2016 February | 27 | 21 | 48 |
| 2016 January | 31 | 13 | 44 |
| 2015 December | 31 | 8 | 39 |
| 2015 November | 17 | 5 | 22 |
| 2015 October | 23 | 8 | 31 |
| 2015 September | 20 | 7 | 27 |
| 2015 August | 28 | 12 | 40 |
| 2015 July | 10 | 4 | 14 |
| 2015 June | 11 | 6 | 17 |
| 2015 May | 30 | 6 | 36 |
| 2015 April | 31 | 12 | 43 |
| 2015 March | 21 | 5 | 26 |
| 2015 February | 32 | 7 | 39 |
| 2015 January | 34 | 7 | 41 |
| 2014 December | 51 | 10 | 61 |
| 2014 November | 44 | 5 | 49 |
| 2014 October | 54 | 5 | 59 |
| 2014 September | 47 | 5 | 52 |
| 2014 August | 46 | 7 | 53 |
| 2014 July | 30 | 5 | 35 |
| 2014 June | 40 | 10 | 50 |
| 2014 May | 30 | 6 | 36 |
| 2014 April | 26 | 11 | 37 |
| 2014 March | 84 | 20 | 104 |
| 2014 February | 81 | 10 | 91 |
| 2014 January | 65 | 17 | 82 |
| 2013 December | 59 | 9 | 68 |
| 2013 November | 59 | 19 | 78 |
| 2013 October | 74 | 16 | 90 |
| 2013 September | 87 | 16 | 103 |
| 2013 August | 59 | 24 | 83 |
| 2013 July | 63 | 18 | 81 |
| 2013 June | 23 | 2 | 25 |
| 2013 May | 22 | 7 | 29 |
| 2013 April | 18 | 13 | 31 |
| 2013 March | 25 | 9 | 34 |
| 2013 February | 25 | 11 | 36 |
| 2013 January | 16 | 7 | 23 |
| 2012 December | 5 | 2 | 7 |
| 2012 September | 345 | 0 | 345 |
Show all