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array:23 [ "pii" => "S2341192919300228" "issn" => "23411929" "doi" => "10.1016/j.redare.2018.09.012" "estado" => "S300" "fechaPublicacion" => "2019-03-01" "aid" => "973" "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Revista Española de Anestesiología y Reanimación (English Version). 2019;66:149-56" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 1 "HTML" => 1 ] "Traduccion" => array:1 [ "es" => array:18 [ "pii" => "S0034935618301713" "issn" => "00349356" "doi" => "10.1016/j.redar.2018.09.004" "estado" => "S300" "fechaPublicacion" => "2019-03-01" "aid" => "973" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Esp Anestesiol Reanim. 2019;66:149-56" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 993 "formatos" => array:3 [ "EPUB" => 1 "HTML" => 506 "PDF" => 486 ] ] "es" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">ARTÍCULO ESPECIAL</span>" "titulo" => "Algoritmo de reversión para los pacientes anticoagulados con dabigatrán en cirugía urgente" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "149" "paginaFinal" => "156" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Reversion algorithm for patients anticoagulated with dabigatran in urgent surgery" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2176 "Ancho" => 1583 "Tamanyo" => 276524 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Protocolo propuesto para el manejo de los pacientes en tratamiento con dabigatrán que precisan ser sometidos a una cirugía o un procedimiento invasivo urgentes. RH: riesgo hemorrágico.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">*Si durante la cirugía se produce un sangrado excesivo o incontrolable, este se debe manejar con las medidas habituales de control de la hemorragia, incluyendo fluidoterapia, estabilización hemodinámica, administración de hemoderivados y hemostáticos. Se podría considerar la administración de una segunda dosis de 5<span class="elsevierStyleHsp" style=""></span>g de idarucizumab.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Ferrandis, M.J. Colomina, L. Durán, A. Gómez-Luque, F. Hidalgo, J.V. Llau" "autores" => array:6 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Ferrandis" ] 1 => array:2 [ "nombre" => "M.J." "apellidos" => "Colomina" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Durán" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Gómez-Luque" ] 4 => array:2 [ "nombre" => "F." "apellidos" => "Hidalgo" ] 5 => array:2 [ "nombre" => "J.V." "apellidos" => "Llau" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2341192919300228" "doi" => "10.1016/j.redare.2018.09.012" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341192919300228?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0034935618301713?idApp=UINPBA00004N" "url" => "/00349356/0000006600000003/v1_201902210632/S0034935618301713/v1_201902210632/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2341192919300241" "issn" => "23411929" "doi" => "10.1016/j.redare.2018.10.002" "estado" => "S300" "fechaPublicacion" => "2019-03-01" "aid" => "976" "copyright" => "Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Revista Española de Anestesiología y Reanimación (English Version). 2019;66:157-62" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "Combination of thoracic blocks as a main anasthetic technique in modified radical mastectomy for patients with severe respiratory disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "157" "paginaFinal" => "162" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Combinación de bloqueos torácicos como método anestésico principal en mastectomía radical modificada para pacientes con compromiso respiratorio severo" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1088 "Ancho" => 1583 "Tamanyo" => 176558 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Sequence for locating and infiltrating the serratus plane -SIPB: at the level of the external third of the clavicle, with the 2nd rib (C2) as a reference point and a single entry point, LA is injected between the anterior serratus muscle (MSA) and the external intercostal muscle (EIM). The pectoralis major (PM) and pectoralis minor (pm) muscles are superficial to the MSA.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.C. Galán Gutiérrez, B. Tobera Noval, F.J. Sáenz Abós, M. González Rodríguez, L.A. Fernández Meré, L.A. Sopena Zubiria" "autores" => array:6 [ 0 => array:2 [ "nombre" => "J.C." "apellidos" => "Galán Gutiérrez" ] 1 => array:2 [ "nombre" => "B." "apellidos" => "Tobera Noval" ] 2 => array:2 [ "nombre" => "F.J." "apellidos" => "Sáenz Abós" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "González Rodríguez" ] 4 => array:2 [ "nombre" => "L.A." "apellidos" => "Fernández Meré" ] 5 => array:2 [ "nombre" => "L.A." "apellidos" => "Sopena Zubiria" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0034935618301907" "doi" => "10.1016/j.redar.2018.10.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0034935618301907?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341192919300241?idApp=UINPBA00004N" "url" => "/23411929/0000006600000003/v1_201903070610/S2341192919300241/v1_201903070610/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2341192919300265" "issn" => "23411929" "doi" => "10.1016/j.redare.2018.10.004" "estado" => "S300" "fechaPublicacion" => "2019-03-01" "aid" => "982" "copyright" => "Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "crp" "cita" => "Revista Española de Anestesiología y Reanimación (English Version). 2019;66:144-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief Report</span>" "titulo" => "Locating the cricothyroid membrane in males: Influence of the morphological characteristics of the neck" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "144" "paginaFinal" => "148" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Localización de la membrana cricotiroidea en varones: influencia de las características morfológicas del cuello" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1954 "Ancho" => 2500 "Tamanyo" => 280636 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Photographic and ultrasound images from both models:</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Image A.1: Photograph of the neck of model 1 in the neutral position.</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Image A.2: Ultrasound image of the CTM (arrow) with posterior reverberations in model 1. Shown from superficial to deep: skin tissue, subcutaneous tissue and thyroid gland, then the CTM, which was located 5<span class="elsevierStyleHsp" style=""></span>mm from skin tissue.</p> <p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Image B.1: Photograph of the neck of model 2 in the neutral position.</p> <p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Image B.2: Ultrasound image of the CTM (arrow) in model 2. Shown from superficial to deep: skin tissue, subcutaneous tissue and thyroid gland, then the CTM, which was located 15<span class="elsevierStyleHsp" style=""></span>mm from skin tissue.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "V. Ruiz-Alcalá, X. Onrubia, C. García-Vitoria, J. Baldó, E. Martínez, J.M. Seller" "autores" => array:6 [ 0 => array:2 [ "nombre" => "V." "apellidos" => "Ruiz-Alcalá" ] 1 => array:2 [ "nombre" => "X." "apellidos" => "Onrubia" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "García-Vitoria" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Baldó" ] 4 => array:2 [ "nombre" => "E." "apellidos" => "Martínez" ] 5 => array:2 [ "nombre" => "J.M." "apellidos" => "Seller" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0034935618302093" "doi" => "10.1016/j.redar.2018.10.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0034935618302093?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341192919300265?idApp=UINPBA00004N" "url" => "/23411929/0000006600000003/v1_201903070610/S2341192919300265/v1_201903070610/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Reversion algorithm for patients anticoagulated with dabigatran in urgent surgery" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "149" "paginaFinal" => "156" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "R. Ferrandis, M.J. Colomina, L. Durán, A. Gómez-Luque, F. Hidalgo, J.V. Llau" "autores" => array:6 [ 0 => array:4 [ "nombre" => "R." "apellidos" => "Ferrandis" "email" => array:1 [ 0 => "raquelferrandis@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M.J." "apellidos" => "Colomina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "L." "apellidos" => "Durán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "A." "apellidos" => "Gómez-Luque" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "F." "apellidos" => "Hidalgo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "J.V." "apellidos" => "Llau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Hospital Universitari i Politècnic La Fe, València, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Hospital Clínico San Carlos, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Hospital Univesitario Virgen de la Victoria, Málaga, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Clínica Universidad de Navarra, Pamplona, Navarra, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Anestesiología y Reanimación, Hospital Universitari Doctor Peset, València, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Algoritmo de reversión para los pacientes anticoagulados con dabigatrán en cirugía urgente" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2176 "Ancho" => 1583 "Tamanyo" => 239627 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Proposed protocol for the management of patients receiving dabigatran who need to undergo an urgent surgery or invasive procedure. BR: bleeding risk.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">*If heavy or uncontrolled bleeding occurs during surgery, it must be treating using standard management strategies, including fluid replacement, haemodynamic stabilisation, administration of blood products and coagulants. Administration of a second dose of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab can be considered.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Direct acting oral anticoagulants (DOAC) are capable of inhibiting a specific factor in the coagulation cascade (factor IIA or Xa). In terms of their mechanism of action, they are divided into direct thrombin inhibitors (factor IIa): dabigatran etexilate; and direct factor Xa inhibitors: rivaroxaban, apixaban and edoxaban. The main clinical indications for their use are currently similar<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a>: primary prophylaxis of venous thromboembolism after total hip or knee arthroplasty, treatment and secondary prevention of deep vein thrombosis and pulmonary embolism, and prophylaxis for stroke and systemic embolism in nonvalvular atrial fibrillation.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Like other antithrombotic agents, haemorrhage is the most frequent adverse effect associated with the use of DOACs. Haemorrhage, in the context of DOAC therapy, can present spontaneously as a result of the therapy itself, but can also occur after injury or invasive procedures. In these circumstances, the lack of a standard analytical method to quantitatively and effectively assess the anticoagulant effect, coupled with the absence of specific neutralising antidotes, have raised some concerns about DOAC management. This has led to the development of agents that specifically reverse the effect of these drugs and facilitate the emergency treatment of these patients.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A specific antidote for dabigatran, idarucizumab, was recently approved for use in patients who require urgent anticoagulant reversal. Given the evident lack of clinical experience, in this document we have collected all the information available to date, and put forward a reversal protocol.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Pharmacological basis of direct oral anticoagulants</span><p id="par0020" class="elsevierStylePara elsevierViewall">All DOACs share a series of common characteristics that should be noted<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">2,3</span></a>: they are administered orally, they exert their action directly (they do not require antithrombin), they have a rapid onset of action, few drug interactions, and a predictable anticoagulant effect. Because of this, they can be administered at fixed doses (once or twice a day, depending on the drug and the indication) and routine monitoring of their anticoagulant action is unnecessary.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite their similarities, some of their pharmacokinetic characteristics differ considerably, and each drug needs to be analysed individually to ensure it is used correctly (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4–6</span></a> All DOACs, to a greater or lesser extent, are affected by impaired renal function (dabigatran<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>edoxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>rivaroxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>apixaban), by the presence of moderate to severe liver failure (rivaroxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>apixaban<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>edoxaban<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>dabigatran) and by concomitant medication. These characteristics justify the need for dose adjustment or limit the use of different drugs.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">One of the benefits of DOACs is their low potential for significant drug interactions. Most interactions occur with drugs that inhibit or induce CYP3A4 or P-gp, so concomitant treatment with these agents should be avoided. The most important are: antiarrhythmics (dronedarone, amiodarone, propafenone, verapamil, digoxin, etc.), antihypertensives (carvedilol, propranolol, labetalol, diltiazem, nifedipine, etc.), statins (atorvastatin, lovastatin), anti-infectives (clarithromycin, rifampicin, fluconazole, ketoconazole, etc.) or protease inhibitors (ritonavir).</p><p id="par0035" class="elsevierStylePara elsevierViewall">In addition, concomitant administration of DOACs with drugs that interfere with haemostasis (antiplatelet agents, fibrinolytics, etc.), should, logically, be avoided due to the high risk of bleeding. However, all DOACs can be used safely in patients with heparin-induced thrombocytopaenia, provided the clinical indication is adequate.</p><p id="par0040" class="elsevierStylePara elsevierViewall">There are no data on the use of DOACs in pregnant women; therefore, all of them are contraindicated during pregnancy.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Dabigatran monitoring</span><p id="par0045" class="elsevierStylePara elsevierViewall">Dabigatran, unlike antivitamin K, does not require routine monitoring. Because of this, most the laboratories in Spain do not have access to a relatively easy, inexpensive and reliable method to quantify their plasma concentration or their anticoagulant effect.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a> However, this determination may be necessary under some circumstances, such as bleeding, thrombosis, urgent invasive procedures, or when thrombolysis is required. It can also be useful to guide procedures or elective surgery (in specific populations or when DOAC elimination may be altered), in the event of overdose, or to ensure therapeutic levels in patients with multiple factors that may interfere with the pharmacokinetics of DOAC.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1,7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the absence of specific monitoring tests, traditional clotting tests have been used, although these have important limitations.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> Activated partial thromboplastin time (aPTT) or kaolin-cephalin clotting time, can provide a qualitative assessment of dabigatran activity, but sensitivity depends on the reagent and coagulometer used, and this complicates the interpretation of results.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">9</span></a> Most patients treated with dabigatran have prolonged aPTT (aPTT ratio<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">></span><span class="elsevierStyleHsp" style=""></span>1.2). Normal aPTT levels (aPTT ratio<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace"><</span><span class="elsevierStyleHsp" style=""></span>1.2) excludes dabigatran levels above the therapeutic range, but does not exclude the presence of lower levels.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">10</span></a> Conversely, a normal thrombin time (TT) has a high negative predictive value for excluding the presence of dabigatran.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> However, due to its high sensitivity, a prolonged TT could indicate the presence of either clinically relevant or negligible dabigatran levels, due to the fact that TT is prolonged in the presence of small plasma concentrations of dabigatran. Changes in ecarin clotting time (ECT) are both sensitive and specific for dabigatran; however, this test is not systematically recommended for monitoring due to the absence of specific and standardised kits for dabigatran.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Specific tests available include the diluted thrombin time test (dTT) (Hemoclot<span class="elsevierStyleSup">®</span> thrombin inhibitor assay), which determines dabigatran levels with a linear relationship and has good sensitivity in a concentration range of 50–500<span class="elsevierStyleHsp" style=""></span>ng/ml.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> Modified dTT tests that can determine low dabigatran concentrations are also available.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> There is also a chromogenic ecarin test that can accurately measure dabigatran concentrations both in the low range (<50<span class="elsevierStyleHsp" style=""></span>ng/ml) and the normal range (50–500<span class="elsevierStyleHsp" style=""></span>ng/ml).<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> In addition, ecarin tests are not sensitive to heparins, and can therefore be useful in cases of concomitant administration (bridging therapy from heparins to dabigatran and vice versa).<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> A chromogenic anti-IIa test has also been developed, but needs to be validated in clinical studies.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Characteristics of idarucizumab</span><p id="par0060" class="elsevierStylePara elsevierViewall">Idarucizumab is a specific reversal agent for dabigatran. Specifically, it is a humanised, monoclonal antibody fragment that binds dabigatran and its metabolites with an affinity that is 300 times stronger than its affinity for thrombin. The affinity for dabigatran and its metabolites is potent and specific, and therefore, immediately neutralises its anticoagulant effect.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17,18</span></a> The idarucizumab-dabigatran complex is characterised by a fast association constant and an extremely slow dissociation constant, resulting in a very stable complex.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> Because of this mechanism of action, reversal of dabigatran's anticoagulant action is practically instantaneous.<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18,19</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Idarucizumab does not only bind to free dabigatran, but also to thrombin-bound dabigatran and its active metabolites.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17–19</span></a> Once the bond and the corresponding complexes (idarucizumab-dabigatran) have been formed, the anticoagulant action of dabigatran is completely neutralised. These complexes are stable and irreversible, and only a minimal dissociation of dabigatran from the complex has been described, with no clinical repercussion.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The antidote is only specific for dabigatran. This means that idarucizumab has no effect on non-dabigatran-bound thrombin. This, therefore, rules out the risk of adverse effects involving the actions of thrombin on platelets or fibrinogen, and there is no interaction that alters the capacity of thrombin generation. This is why idarucizumab has no inherent or administration-derived procoagulant or anticoagulant effects, other than those that exclusively affect dabigatran.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17–21</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Pharmacokinetics</span><p id="par0075" class="elsevierStylePara elsevierViewall">The pharmacokinetics of idarucizumab were investigated in 224 healthy individuals in phase 1 trials<span class="elsevierStyleSmallCaps">,</span> of which data from a representative subgroup of 6 healthy individuals aged between 45 and 64 years who received 5<span class="elsevierStyleHsp" style=""></span>g intravenous infusion for pharmacokinetic analysis are presented.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5<span class="elsevierStyleHsp" style=""></span>g dose, the drug exhibited an initial half-life of 45<span class="elsevierStyleHsp" style=""></span>min.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19,22,23</span></a> Only about 4% of the drug was present at 4<span class="elsevierStyleHsp" style=""></span>h of administration; at 12<span class="elsevierStyleHsp" style=""></span>h of administration of idarucizumab, plasma concentration was minimal, and at 24<span class="elsevierStyleHsp" style=""></span>h it was practically undetectable.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19–23</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In some patients, plasma dabigatran concentrations at 12–24<span class="elsevierStyleHsp" style=""></span>h of idarucizumab administration showed slight rebound, along with a small increase in dTT and ECT clotting tests. This effect has been explained by the redistribution of existing dabigatran in the extravascular space (therefore, not initially neutralised after administration of idarucizumab) to the intravascular compartment. This increase in dabigatran does not reach therapeutic levels, and therefore does not imply, in itself, the need for administration of a further doses of the antidote.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">20,21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">After intravenous administration of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab, 32.1% of the dose was recovered in urine within a collection period of 6<span class="elsevierStyleHsp" style=""></span>h and less than 1% in the following 18<span class="elsevierStyleHsp" style=""></span>h. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19,20,23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Proteinuria has been observed after treatment with idarucizumab, a physiologic reaction to renal protein overflow that is reversed within 24<span class="elsevierStyleHsp" style=""></span>h of treatment. The transient proteinuria usually peaked about 4<span class="elsevierStyleHsp" style=""></span>h after idarucizumab administration, and normalised within 12–24<span class="elsevierStyleHsp" style=""></span>h. In isolated cases, the transient proteinuria persisted for more than 24<span class="elsevierStyleHsp" style=""></span>h.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17,19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Dosage, preparation and administration</span><p id="par0100" class="elsevierStylePara elsevierViewall">The recommended dose of idarucizumab is 5<span class="elsevierStyleHsp" style=""></span>g, which should be administered intravenously as 2 consecutive infusions of 2.5<span class="elsevierStyleHsp" style=""></span>g/50<span class="elsevierStyleHsp" style=""></span>ml over 5–10<span class="elsevierStyleHsp" style=""></span>min each or as a bolus injection not mixed with other drugs. It can be administered via a pre-existing intravenous line, provided it has been flushed with an injectable solution of sodium chloride (0.9%) before and after perfusion. No other infusion should be administered in parallel via the same intravenous access.</p><p id="par0105" class="elsevierStylePara elsevierViewall">As mentioned above, in some patients recurrence of plasma concentrations of unbound dabigatran and concomitant prolongation of clotting tests have occurred up to 24<span class="elsevierStyleHsp" style=""></span>h after administration of idarucizumab.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> A maximum daily dose has not yet been investigated,<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17,19</span></a> but from a clinical perspective, administration of a second dose of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab can be considered in the following situations:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0110" class="elsevierStylePara elsevierViewall">Recurrence of clinically relevant bleeding together with prolonged clotting times.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0115" class="elsevierStylePara elsevierViewall">If potential re-bleeding would be life-threatening and prolonged clotting times are observed.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0120" class="elsevierStylePara elsevierViewall">In patients requiring a second emergency surgery or urgent procedure and have prolonged clotting times that are considered likely to be related to the presence of dabigatran.</p></li></ul></p><p id="par0125" class="elsevierStylePara elsevierViewall">With regard to idarucizumab management in special populations,<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a> no dose adjustment is required in renally impaired patient, those with hepatic injury, or in patients aged over 65 years. The safety and efficacy of Praxbind in children below the age of 18 years have not yet been established. No data are available.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Evaluation of effectiveness</span><p id="par0130" class="elsevierStylePara elsevierViewall">The effectiveness of idarucizumab to reverse the anticoagulant effect of dabigatran is based on the results of the REVERSE-AD study,<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> which shows almost complete normalisation of dTT and ECT in the 2 groups of study patients (patients with uncontrolled bleeding and patients in whom reversal of dabigatran is considered necessary because they require urgent surgery) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The study also showed that haemostasis was achieved in patients with bleeding, and in slightly over 90% of those who received idarucizumab before urgent surgery.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In addition, since its approval by the FDA, several reports of idarucizumab use in patients, mainly to control critical bleeding have also shown its efficacy.<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25–30</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Safety profile</span><p id="par0140" class="elsevierStylePara elsevierViewall">Safety was evaluated in 224 healthy patient<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> and in the 503 patients of the REVERSE-AD study (phase 3)<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> with severe uncontrolled bleeding (301/503) or in need of an urgent invasive procedure (202/503); no adverse reactions directly attributable to the drug were observed. Of the 503 patients treated with idarucizumab included in the REVERSE-AD study, 35 died within the first 5 days after treatment (19 and 16, respectively, in group). Most of these deaths could be related to worsening of the underlying disease and existing comorbidities. Thrombotic events occurred in 24 (4.8%) and 34 (6.8%) patients at 30 and 90 days, respectively, and the 30-day rate was similar in both groups (5.0 and 4.6%). These rates are considered consistent with those reported after major surgical procedures or hospitalisation for uncontrolled bleeding. In the discussion section, the authors speculate that the low rate of reinitiation of anticoagulation that, especially in the group of patients with bleeding, could have contributed to the appearance of thrombotic events.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Mild symptoms associated with possible hypersensitivity (pyrexia, bronchospasm, hyperventilation, rash, or pruritus) were also reported. Other adverse effects occurring in 5% or more cases were hypokalaemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123; 6%) and pneumonia (7/123, 6%). In no case could a causal relationship with idarucizumab be established.</p><p id="par0150" class="elsevierStylePara elsevierViewall">However, idarucizumab binds specifically to dabigatran and its metabolites, reversing its anticoagulant effect, which exposes the patient to the thrombotic risk of their underlying disease. This is why it is essential to reinstate anticoagulant therapy 24<span class="elsevierStyleHsp" style=""></span>h after administration of idarucizumab, once clotting times have stabilised.<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22–24</span></a></p><span id="sec1040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect1040">Special precautions for use<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a></span><p id="par0160" class="elsevierStylePara elsevierViewall">Special precautions should be taken with idarucizumab administration in situations such as:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hereditary fructose intolerance</span></p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">The sorbitol content of the recommended dose of idarucizumab is 4<span class="elsevierStyleHsp" style=""></span>g. In patients with hereditary fructose intolerance, this amount of sorbitol has been associated with reports of hypoglycaemia, hypophosphataemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death. In these patients, risk of treatment must be weighed against the potential benefit. If idarucizumab is administered in these patients, intensified monitoring is needed for the first 24<span class="elsevierStyleHsp" style=""></span>h.<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thromboembolic complications</span></p></li></ul></p><p id="par0180" class="elsevierStylePara elsevierViewall">Patients being treated with dabigatran have underlying disease states that predispose them to thromboembolic events. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22–24</span></a><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Urinary protein testing</span></p></li></ul></p><p id="par0190" class="elsevierStylePara elsevierViewall">Idarucizumab causes transient proteinuria as a physiologic reaction to renal protein overflow after rapid intravenous administration of 5<span class="elsevierStyleHsp" style=""></span>g. The transient proteinuria is not indicative of renal damage, which should be taken into account for urine testing.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Sodium content</span></p></li></ul></p><p id="par0200" class="elsevierStylePara elsevierViewall">This medicinal product contains 2.2<span class="elsevierStyleHsp" style=""></span>mmol (or 50<span class="elsevierStyleHsp" style=""></span>mg) sodium per dose; this should be taken into consideration when treating patients on a controlled sodium diet.</p></span></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Therapeutic indications for idarucizumab</span><p id="par0205" class="elsevierStylePara elsevierViewall">It is important to note that most bleeding events in patients receiving treatment with DOACs, due to their short half-life, can be managed conservatively by temporarily suspending the drug and starting supportive measures; therefore, reversal agents are rarely used.</p><p id="par0210" class="elsevierStylePara elsevierViewall">Idarucizumab was approved under an Accelerated Approval Pathway by the U. S Food and Drug Administration and the European Medicines Agency for use in adult patients treated with dabigatran that require rapid reversal of its anticoagulant effect.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">31</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">It is indicated in:<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">•</span><p id="par0220" class="elsevierStylePara elsevierViewall">Severe acute bleeding, with haemodynamic instability, which does not respond to general measures and persists despite local haemostatic measures.</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">•</span><p id="par0225" class="elsevierStylePara elsevierViewall">Life-threatening bleeding or bleeding into an organ considered critical due to its sensitivity to bleeding, due to its persistence, or due to the risk of complications.</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">•</span><p id="par0230" class="elsevierStylePara elsevierViewall">Urgent surgical interventions associated with high risk of bleeding that cannot be delayed by 8<span class="elsevierStyleHsp" style=""></span>h or more.</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">•</span><p id="par0235" class="elsevierStylePara elsevierViewall">Urgent invasive diagnostic or therapeutic techniques associated with a high risk of bleeding.</p></li></ul></p><p id="par0240" class="elsevierStylePara elsevierViewall">The incidence of severe bleeding is difficult to estimate. In clinical practice, reports of major bleeding due to dabigatran vary greatly, ranging from 3.2%<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> to 9%,<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a> possibly due to the patient's comorbidities. Until now, management of dabigatran-induced severe bleeding events has been limited to supportive measures, administration of blood products, haemodialysis or administration of prohaemostatic agents (prothrombin complex concentrate). The use of prothrombin complex concentrate can reduce DOAC-induced bleeding by providing large volumes of factors II and X. This strategy is recommended when a specific antidote is not available.</p><p id="par0245" class="elsevierStylePara elsevierViewall">The introduction of idarucizumab calls for the creation of protocols, with their corresponding indications and method of administration, and the specific role of this reversal agent in the clinical management of acute dabigatran-induced bleeding must be defined.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Considerations for reversal with idarucizumab</span><p id="par0250" class="elsevierStylePara elsevierViewall">It is always important to bear in mind that bleeding complications in patients receiving dabigatran should be managed on a case-by-case basis, depending on the site and severity of the bleed, and the patient's coexisting medical conditions.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">35</span></a> When available, idarucizumab is the treatment of choice for the urgent reversal of the anticoagulant effect of dabigatran, following a protocol adapted to each institution.</p><p id="par0255" class="elsevierStylePara elsevierViewall">Certain factors must be considered before using idarucizumab:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">1.</span></span><p id="par0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Is reversal necessary?</span></p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0265" class="elsevierStylePara elsevierViewall">YES, in</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">•</span><p id="par0270" class="elsevierStylePara elsevierViewall">bleeding from a non-compressible site that is life-threatening or can lead to irreversible injury (central nervous system, intraspinal, intraocular, intrapulmonary, retroperitoneal bleeding or intramuscular bleeding with compartment syndrome),</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">•</span><p id="par0275" class="elsevierStylePara elsevierViewall">severe bleeding that does not respond to usual measures,</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">•</span><p id="par0280" class="elsevierStylePara elsevierViewall">urgent surgery or urgent invasive procedures that cannot be delayed by at least 8<span class="elsevierStyleHsp" style=""></span>h and that require adequate haemostasis due to a high risk of bleeding. Can include haemorrhage due to multiple trauma.</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0285" class="elsevierStylePara elsevierViewall">NO, if</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">•</span><p id="par0290" class="elsevierStylePara elsevierViewall">bleeding responds to usual support strategies, is not life threatening, or in patients in whom surgery or invasive procedure may be delayed by more than 8<span class="elsevierStyleHsp" style=""></span>h.</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">2.</span></span><p id="par0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Confirm the presence of dabigatran</span></p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">•</span><p id="par0300" class="elsevierStylePara elsevierViewall">Find out the patient's dabigatran dosage.</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">•</span><p id="par0305" class="elsevierStylePara elsevierViewall">Find out when the last dose was taken.</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">•</span><p id="par0310" class="elsevierStylePara elsevierViewall">Evaluate the possibility of an accidental or deliberate overdose.</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">•</span><p id="par0315" class="elsevierStylePara elsevierViewall">In each case, estimate the half-life of the drug, mainly on the basis of renal function.</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">3.</span></span><p id="par0320" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Evaluate coagulation</span></p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">•</span><p id="par0325" class="elsevierStylePara elsevierViewall">Run specific tests, whenever possible (ECT, dTT).</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">•</span><p id="par0330" class="elsevierStylePara elsevierViewall">aPTT ratio is the simplest, most useful tool, with the limitations already mentioned.</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">4.</span></span><p id="par0335" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Consider the immediate administration of idarucizumab</span></p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">•</span><p id="par0340" class="elsevierStylePara elsevierViewall">In the accepted indications, idarucizumab should be administered immediately without awaiting the results of laboratory tests.</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">5.</span><p id="par0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Maintain general support measures for bleeding management and the administration of</span> blood products and adjuvants, depending on the patient's evolution. Idarucizumab is not a substitute for these.</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">6.</span><p id="par0350" class="elsevierStylePara elsevierViewall">A <span class="elsevierStyleItalic">second dose</span> of 5<span class="elsevierStyleHsp" style=""></span>g idarucizumab could be considered if coagulation parameters remain altered, and only if the clinical need to rapidly reverse the anticoagulant effect persists.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a></p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">7.</span><p id="par0355" class="elsevierStylePara elsevierViewall">Evaluate the <span class="elsevierStyleItalic">resumption of anticoagulant therapy</span> on a case by case basis, weighing up the risk of bleeding against the risk of thrombosis. Because of the short half-life of idarucizumab, dabigatran can be restarted 24<span class="elsevierStyleHsp" style=""></span>h after administration, except in patients with renal failure, in whom the half-life can be prolonged.</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Future perspectives</span><p id="par0360" class="elsevierStylePara elsevierViewall">In the future, idarucizumab could be indicated in patients with moderate bleeding in whom usual bleeding management measures fail. More studies are needed, and the efficacy of a lower dose of idarucizumab must be analysed. It could potentially be indicated in cases in which patients with acute renal failure need urgent surgery.</p><p id="par0365" class="elsevierStylePara elsevierViewall">Although it has been used to reverse the effect of dabigatran prior to thrombolytic therapy in ischaemic stroke, there insufficient safety data to recommend this indication.</p><p id="par0370" class="elsevierStylePara elsevierViewall">Further understanding of idarucizumab will eventually clarify its role in other groups of patients.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protocol for the management of dabigatran in urgent surgery</span><p id="par0375" class="elsevierStylePara elsevierViewall">Following the development of indications for the use of idarucizumab, the dabigatran management protocol shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> is recommended in patients awaiting urgent surgery or an urgent invasive procedure. The protocol should only be implemented after completion of the initial steps recommended in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0380" class="elsevierStylePara elsevierViewall">The management of anticoagulated patients with bleeding or that require an urgent intervention with a moderate to high risk of bleeding is always controversial. Such a complicated situation is made even worse when the anticoagulant is a DOAC.</p><p id="par0385" class="elsevierStylePara elsevierViewall">The addition of idarucizumab, a specific dabigatran reverser, to the therapeutic arsenal will certainly facilitate the management of these patients. However, action protocols specific to each hospital must be developed and approved by a multidisciplinary committee.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0390" class="elsevierStylePara elsevierViewall">R. Ferrandis has taken part in conferences or educational projects sponsored by Octapharma, CSL Behring, Boehringer Ingelheim, Rovi, and has received honoraria to attend Octapharma congresses.</p><p id="par0395" class="elsevierStylePara elsevierViewall">M.J. Colomina has taken part in conferences and congresses sponsored by Baxter, and has received honoraria from Vifor for attending meetings.</p><p id="par0400" class="elsevierStylePara elsevierViewall">J.V<span class="elsevierStyleSmallCaps">.</span> Llau has provided scientific consultancy services, and has taken part in educational courses or conferences sponsored by Boehringer Ingelheim, Octapharma, Sanofi, Rovi, CSL Behring.</p><p id="par0405" class="elsevierStylePara elsevierViewall">The remaining authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Pharmacological basis of direct oral anticoagulants" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Dabigatran monitoring" ] 3 => array:3 [ "identificador" => "sec0020" "titulo" => "Characteristics of idarucizumab" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Pharmacokinetics" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Dosage, preparation and administration" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Evaluation of effectiveness" ] 3 => array:3 [ "identificador" => "sec0040" "titulo" => "Safety profile" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec1040" "titulo" => "Special precautions for use" ] ] ] ] ] 4 => array:3 [ "identificador" => "sec0045" "titulo" => "Therapeutic indications for idarucizumab" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Considerations for reversal with idarucizumab" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Future perspectives" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Protocol for the management of dabigatran in urgent surgery" ] ] ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusion" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-09-24" "fechaAceptado" => "2018-09-26" "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ferrandis R, Colomina MJ, Durán L, Gómez-Luque A, Hidalgo F, Llau JV. Algoritmo de reversión para los pacientes anticoagulados con dabigatrán en cirugía urgente. Rev Esp Anestesiol Reanim. 2019;66:149–156.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar1005">This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program. An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page: <a class="elsevierStyleInterRef" target="_blank" id="intr1005" href="https://www.elsevier.es/redar">https://www.elsevier.es/redar</a></p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2176 "Ancho" => 1583 "Tamanyo" => 239627 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Proposed protocol for the management of patients receiving dabigatran who need to undergo an urgent surgery or invasive procedure. BR: bleeding risk.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">*If heavy or uncontrolled bleeding occurs during surgery, it must be treating using standard management strategies, including fluid replacement, haemodynamic stabilisation, administration of blood products and coagulants. Administration of a second dose of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab can be considered.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cmax: peak plasma concentration; CYP34A: cytochrome P450 3A4; FIIa: activated factor <span class="elsevierStyleSmallCaps">ii</span>; FXa: activated factor <span class="elsevierStyleSmallCaps">x</span>; P-gp: permeability glycoprotein; T1/2: elimination half-life.</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"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Dabigatran \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Rivaroxaban \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Apixaban \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Edoxabán \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FIIa inhibitor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FXa inhibitor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FXa inhibitor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FXa inhibitor \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bioavailability, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3–7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66–80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cmax, h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3–4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T1/2, h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12–17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5–9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8–15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bound to proteins, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">55 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Volume of distribution, l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50–70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">107 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Renal excretion (active drug), % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25–27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepatic metabolism, % (interactions) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (P-gp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66 (CYP3A4, P-gp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75 (CYP3A4, P-gp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–30 (CYP3A4, P-gp) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1981139.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pharmacokinetics of direct acting oral anticoagulants.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">dTT: diluted thrombin time.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>: Pollack et al.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a></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"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A<br>Patients with bleeding \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B<br>Patients requiring surgery \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Primary end point</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Percentage reversal of the anticoagulant effect of dabigatran, based on determination of dTT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Secondary outcomes</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Restoration of haemostasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Haemostasis was restored in 100% of evaluable patients who presented severe bleeding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Haemostasis was normal in 93.4% of patients who needed an urgent procedure \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1981138.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Summary idarucizumab efficacy based on results obtained from the REVERSE-AD study.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">ECT: ecarin clotting time; aPTT: activated partial thromboplastin time; dTT: diluted thrombin time.</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Check that the patient is receiving dabigatran, verifying the dose administered and the time of the last intake \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Check renal function, preferably by calculating creatinine clearance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Request hemostasis tests, based on availability: aPTT, dTT, ECT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Classify the bleeding risk of the surgical procedure: high/moderate/low \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1981140.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Preliminary steps before implementation of the dabigatran reversal protocol.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0190" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Perioperative management of patients on direct oral anticoagulants" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. 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