Editorial comment
Direct oral anticoagulants and surgical bioprosthetic valves: State of the art
DOACs e biopróteses cirúrgicas: estado da arte
Pedro Lamares Magro, Miguel Sousa-Uva
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Department of Cardio-thoracic Surgery, Hospital de Santa Cruz, Carnaxide, Portugal
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AO: aortic valve.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Arun Gopalakrishnan, Walse Rohit Sunil, Deepa Sasikumar, Harikrishnan K.N. Kurup, Kavassery Mahadevan Krishnamoorthy" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Arun" "apellidos" => "Gopalakrishnan" ] 1 => array:2 [ "nombre" => "Walse Rohit" "apellidos" => "Sunil" ] 2 => array:2 [ "nombre" => "Deepa" "apellidos" => "Sasikumar" ] 3 => array:2 [ "nombre" => "Harikrishnan K.N." "apellidos" => "Kurup" ] 4 => array:2 [ "nombre" => "Kavassery Mahadevan" "apellidos" => "Krishnamoorthy" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122004851?idApp=UINPBA00004E" "url" => "/08702551/0000004200000002/v1_202302081302/S0870255122004851/v1_202302081302/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "Direct oral anticoagulants and surgical bioprosthetic valves: State of the art" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "179" "paginaFinal" => "181" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Pedro Lamares Magro, Miguel Sousa-Uva" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Pedro Lamares" "apellidos" => "Magro" ] 1 => array:4 [ "nombre" => "Miguel" "apellidos" => "Sousa-Uva" "email" => array:1 [ 0 => "migueluva@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Cardio-thoracic Surgery, Hospital de Santa Cruz, Carnaxide, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "DOACs e biopróteses cirúrgicas: estado da arte" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">An estimated 300<span class="elsevierStyleHsp" style=""></span>000 prosthetic heart valves are implanted each year worldwide, a figure that is tending to grow as Western populations age.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> For the individual patient, implantation of a prosthetic valve is more than a simple surgical procedure, as it entails a lifelong added risk of bleeding (2–9% per year) and thromboembolic events (1–4% per year) compared with the general population.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Atrial fibrillation (AF) is a common comorbidity as well as a frequent complication in patients undergoing valvular surgery. The SWEDEHEART registry<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> showed that in a real-world population of more than 7000 patients undergoing surgical valve intervention with a biological prosthesis or valvuloplasty, 29% had a history of AF prior to surgery and 15% would go on to develop new-onset AF. Appropriate management of anticoagulation therapy is therefore a must in the follow-up of these patients. Direct oral anticoagulants (DOACs) were at least as effective as vitamin K antagonists in trials that included more than 70<span class="elsevierStyleHsp" style=""></span>000 patients with AF, and were associated with less serious bleeding, particularly less intracranial bleeding. In addition, DOACs have fewer drug interactions, and eliminating coagulation monitoring simplifies anticoagulation therapy. Warfarin is associated with many drug and food interactions and it is difficult to keep the international normalized ratio within therapeutic levels and to maintain constant adequate anticoagulation levels (time on target); in addition, warfarin is the top reason (33%) for emergency hospitalizations for drug events in older Americans.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">However, results from the phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN) trial showed a greater number of thromboembolic events in patients with mechanical valves treated with dabigatran compared with warfarin, leading to the premature termination of the trial. In light of these findings DOACs are contraindicated in patients with mechanical valves.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The ideal antithrombotic strategy in patients with bioprosthetic valves, however, remains the subject of debate. There has been a reversal in the proportions of mechanical and bioprosthetic valves implanted in the last 20 years, with the percentage of mechanical valves rapidly decreasing and increasing use of bioprosthetic valves, which currently account for more than 70% of valve implantations.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Adding further uncertainty to the already established gap in evidence in these patients is the multitude of possible clinical scenarios and variables contributing to thromboembolic risk, such as valve endothelization, valve position, and baseline indication for anticoagulation, including patients’ baseline rhythm. Further contributing to the difficulty in selecting the best antithrombotic strategy is the patient's background bleeding risk.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the recommendations of the recent American College of Cardiology/American Heart Association (ACC/AHA)<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> and European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS)<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> guidelines for patients with bioprosthetic valves according to the four most common clinical scenarios.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">After three months</span><p id="par0030" class="elsevierStylePara elsevierViewall">Neither the European nor the American guidelines specifically recommend oral anticoagulation three months after surgery in patients in sinus rhythm (SR).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Both guidelines recommend DOAC three months after index valvular surgery in patients with bioprosthetic valves in aortic or mitral position and AF. These recommendations are regardless of CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc score.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The recommendations in the guidelines are supported by cumulative evidence from post-hoc analysis of the ARISTOTLE<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> and ENGAGE AF-TIMI 48<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> trials, the small DAWA randomized controlled trial (RCT)<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a> and pooled analysis of these low-evidence studies in two metanalyses, by Malik et al.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> and Caldeira et al.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Pooled analysis showed no statistically significant difference in stroke or systemic embolization (Malik et al.: hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.13–2.69; p=0.49; I<span class="elsevierStyleSup">2</span>=24%; Caldeira et al.: HR 0.65; 95% CI 0.20–2.08; p=0.46; I<span class="elsevierStyleSup">2</span>=6%); major bleeding (Malik et al.: HR 0.67; 95% CI 0.27–1.63; p=0.38; I<span class="elsevierStyleSup">2</span>=0%; Caldeira et al.: HR 0.94; 95% CI 0.28–3.18; p=0.93; I<span class="elsevierStyleSup">2</span>=0%); or death (Malik et al.: HR 0.82; 95% CI 0.24–2.81; p=0.76; I<span class="elsevierStyleSup">2</span>=0%).<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10,11</span></a> This evidence, however, is based on a small group of patients and events and presents wide CIs suggestive of low statistical power.</p><p id="par0050" class="elsevierStylePara elsevierViewall">More recently, the RIVER trial,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> a multicenter, open-label, noninferiority trial, randomized 1005 patients with mitral bioprosthetic valves and AF (excluding post-operative transient AF) to receive either rivaroxaban (n=500) or warfarin (n=505). In this trial rivaroxaban achieved non-inferiority for the primary endpoint of mean time free from a composite of death, major cardiovascular events, or major bleeding at 12 months (rivaroxaban, 347.5 days; warfarin, 340.1 days; difference, 7.4 days; 95% CI −1.4 to 16.3; p<0.001 for noninferiority, p=0.10 for superiority). Additionally, stroke rates at 12 months were statistically different, favoring rivaroxaban (rivaroxaban, 0.6%; warfarin, 2.4%; HR 0.25; 95% CI 0.07–0.88). Other secondary endpoints were similar between the two groups including major bleeding, valve thrombosis and death.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">First three months</span><p id="par0055" class="elsevierStylePara elsevierViewall">Patients less than three to six months after the index valvular surgery present a particular challenge, as this is viewed as the most thrombogenic period.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The ACC/AHA guidelines recommend anticoagulation with a vitamin K antagonist (VKA) in the first three months after index valvular surgery, regardless of rhythm, valve type or position. This recommendation is based on observational studies, some of which have conflicting results.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">13–16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The ESC/EACTS guidelines also recommend VKAs in the first three months for valves in mitral position and for all patients in AF independently of valve position. In the ESC/EACTS guidelines the use of DOAC should be considered for patients with AF and bioprosthetic valves in mitral position (class of recommendation IIb). For patients with an aortic bioprosthetic valve in SR, the ESC/EACTS guidelines recommend either aspirin or a VKA with a IIa class recommendation. The latter recommendation is based on observational studies<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">16,17</span></a> and a small RCT.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Although still controversial, a growing body of evidence seems to indicate a potential role for DOAC use in the first three months after index surgery.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the above-mentioned RIVER trial,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> 18.8% of the randomized patients received either rivaroxaban or warfarin in the first three months after valve surgery. The authors found that the statistical difference between treatments (favoring rivaroxaban) regarding the primary endpoint was especially marked in this subgroup of patients (rivaroxaban, 6.4%; warfarin, 18.9%; HR 0.31; 95% CI 0.12–0.79). However, the authors did not report p-values for interaction in this subgroup (patients randomized in the first three months after surgery).</p><p id="par0080" class="elsevierStylePara elsevierViewall">ENAVLE<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a> was a non-inferiority RCT which randomized patients to receive either edoxaban (n=109) or warfarin (n=109) for the first three months after bioprosthesis implantation regardless of rhythm and valve position. Edoxaban was non-inferior to warfarin regarding the primary efficacy endpoint of a composite of death, clinical thromboembolic events or asymptomatic intracardiac thrombosis (edoxaban 0%, warfarin 3.7%; risk difference [RD], −0.0367; 95% CI −0.0720 to −0.0014; p<0.001 for noninferiority), as well as for major bleeding events (edoxaban 2.8%, warfarin 0.9%; RD 0.0183; 95% CI −0.0172 to 0.0539; p=0.013). ENAVLE was also a small RCT with a small number of events, and the results should be interpreted accordingly.</p><p id="par0085" class="elsevierStylePara elsevierViewall">One of the drawbacks of DOACs is the lack of rapidly available tests to measure their effect. Although general tests of coagulation such as activated partial thromboplastin time and prothrombin time can be useful to assess the effects of anticoagulation, the sensitivity of these tests is variable and a normal test does not exclude the presence of the drug. In cases of acute bleeding or need for emergent surgery, discontinuation of DOACs and general measures may be sufficient, due to their relatively short half-life, but DOAC-specific anti-Xa tests and ecarin chromogenic assays need to be readily available in order to identify patients who need reversal agents and to monitor reversal efficacy.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The authors of this editorial recently published a review of the best available evidence regarding DOAC use in the first three months following valve surgery.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a> The above-mentioned results of the RIVER and ENAVLE trials are exciting and hypothesis-generating. However, the low number of events reported overall and wide confidence intervals warrant caution when interpreting these results. Lower evidence data derived from retrospective analyses are consistent with the results of these trials. DOACs appear to be as safe and as effective as VKAs regarding thromboembolic prophylaxis and bleeding event rates in patients with surgical bioprosthetic valves and AF within three months of implantation. However, stronger confirmatory evidence is needed to extend current recommendations.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Nevertheless, current recommendations are mainly based on observational and largely outdated data.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">13–18</span></a> Although not without its flaws, the most recent data from the above-mentioned RCTs appear to indicate a promising future for the expansion of DOAC use to the immediate postoperative period in patients with mitral valve prostheses and patients with AF.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "After three months" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "First three months" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflicts of interest" ] 3 => array:2 [ "identificador" => "xack651083" "titulo" => "Acknowledgment" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => 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="spar0010" class="elsevierStyleSimplePara elsevierViewall">The class of recommendation and level of evidence are presented according to the corresponding guideline definitions.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">ACC/AHA: American College of Cardiology/American Heart Association; AF: atrial fibrillation; DOAC: direct oral anticoagulant; ESC/EACTS: European Society of Cardiology/European Association for Cardio-Thoracic Surgery; SR: sinus rhythm; VKA: vitamin K antagonist.</p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Clinical scenario \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2020 ACC/AHA</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2021 ESC/EACTS</th></tr><tr title="table-row"><th 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" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><3 months \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">>3 months \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><3 months \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">>3 months \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aortic in SR \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">VKA (2a B-NR) \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">Aspirin (2a B-NR) \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">Aspirin or VKA (IIa B) \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">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aortic in AF \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">VKA (2a B-NR) \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">DOAC (1 A) \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">VKA \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">DOAC (IIa B) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mitral in SR \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">VKA (2a B-NR) \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">Aspirin (2a B-NR) \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">VKA (IIa B) \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">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mitral in AF \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">VKA (2a B-NR) \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">DOAC (1 A) \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">VKA; may consider DOAC (IIb C) \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">DOAC (IIa B) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Summary of anticoagulation recommendations in patients with bioprosthetic valves according to the latest ACC/AHA and ESC/EACTS guidelines.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J.C. 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