Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants

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Do not administer LMWH or UFH after the discontinuation of DOAC in the preoperative period." ] ] ] "textoCompleto" => "IntroductionThe incorporation of direct oral anticoagulants (DOACs) as anticoagulant drugs has considerably increased the therapeutic arsenal for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), as well as for the prevention and treatment of venous thromboembolic disease (VTD). Unlike vitamin K antagonists (VKA), DOACs can be administered at fixed doses, have few pharmacological interactions, and do not require systematic monitoring. Fundamental studies have shown that they are at least as effective as warfarin in preventing thromboembolic events by decreasing the risk of severe bleeding and intracranial haemorrhage.<a class="elsevierStyleCrossRefs" href="#bib0205">1–8</a> For some years now, DOACs have been available in our country and the anticoagulant treatment units (ATUs) and the primary care centres (PCCs) use these drugs in their clinical practice. Although there are several national and international documents on their management, there are no clear guidelines on how to perform follow-up, health education and coordinated and interdisciplinary management between ATUs and PCCs in special clinical situations presented by patients while on DOAC therapy. Hence the need to have clear recommendations so that those responsible for antithrombotic therapy can know the results of the different clinical studies.ObjectiveThe Catalan Group of Thrombosis and Haemostasis (TROMBOC@T), part of the Catalan Society of Haematology and Hemotherapy (SCHH), met for the first time in 2015 to create a consensus document with practical recommendations with the aim of standardizing the management of patients anticoagulated with DOAC. The availability of the results of large cohorts of patients obtained from routine clinical practice and the occurrence of reverting agents in 2016 led to an update of the document in which, among others, the current role of reverting agents was revised and a post-authorization study was launched: «Effectiveness and safety in the use of new generation oral anticoagulants in routine clinical practice: “The Real Life Cohort”; Protocol code: ASO-DAB-2014-01; this project aims to obtain real-life results from our environment.These guidelines are a summary of the latest update of the TROMBOC@T group consensus document and aims to establish, in a standard way, recommendations that incorporate the findings of scientific research into clinical practice, hence, improving the quality of care in the field of anticoagulation.MethodologyTo obtain a consensus document with the most up-to-date information, we reviewed the studies published in the MEDLINE and EMBASE databases and the abstracts presented at the annual conference of the American Society of Haematology (2016). The key words used in the literature search were: direct oral anticoagulants, atrial fibrillation, venous thromboembolism and treatment. It was limited to studies carried out on humans between 2007 and 2016 (December). The literature searches focused on randomized controlled trials, but also include registries, non-randomized comparative and descriptive studies, case series, cohort studies, and systematic reviews. The literature references were classified according to the level of evidence (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), following the criteria established by the US Agency for Health Research and Quality.<a class="elsevierStyleCrossRef" href="#bib0245">9</a> A group of experts from the Societat Catalana d’Hematologia i Hemoteràpia and the Catalan Group of Thrombosis and Haemostasis (TROMBOC@T) evaluated all the information collected and established a series of recommendations and therapeutic algorithms based on proven clinical evidence. The recommendations were classified according to the US National Comprehensive Cancer Network criteria (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0250">10</a> In those areas where no scientific evidence was found, the group of experts established consensus recommendations based on their clinical experiences.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Characteristics of direct oral anticoagulantsDabigatranDabigatran etexilate (Pradaxa®), a direct thrombin inhibitor, is a prodrug with an oral bioavailability of 6–7%. Peak levels (Cmax) are reached 1–2h after oral administration. Its half-life is from 14 to 17h and about 80% of the drug is excreted though the kidneys.<a class="elsevierStyleCrossRef" href="#bib0255">11</a> Dabigatran is not metabolized by cytochrome P-450, however, drug interactions can occur because it is a substrate of the P-glycoprotein (P-gp). Dabigatran can cause dyspepsia; taking it with food can alleviate this problem.<a class="elsevierStyleCrossRef" href="#bib0260">12</a>RivaroxabanRivaroxaban (Xarelto®) is a direct inhibitor of activated factor X (FXa), with a bioavailability of 66% if taken without food and 100% if taken with food. It reaches Cmax between 2 and 3h after its administration. Its half-life is from 7 to 11h, and a third is eliminated by the kidneys. It is metabolized by CYP3A4 cytochrome, CYP2J2 and CYP independent mechanisms. It is a substrate of the transport proteins P-gp and Bcrp (protein of resistance to breast cancer).<a class="elsevierStyleCrossRef" href="#bib0265">13</a>ApixabanApixaban (Eliquis)®) is another direct FXa inhibitor and has a bioavailability of around 50%. It reaches Cmax between 3 and 4h after its administration. It has a half-life of 8–14h and his metabolism is hepatic through CYP3A4/5. About 25% of the drug is eliminated by the kidneys and the rest is excreted in the stool.<a class="elsevierStyleCrossRef" href="#bib0270">14</a>EdoxabanEdoxaban tosylate (Lixiana®) is an FXa inhibitor, with a bioavailability of 62% and a biphasic clearance (35–40% renal and 60% through stools).<a class="elsevierStyleCrossRef" href="#bib0275">15</a> It reaches Cmax between 1 and 2h after its administration and has a half-life of between 9 and 11h. Edoxaban is a substrate of P-gp and is partially metabolized by CYP3A4.<a class="elsevierStyleCrossRef" href="#bib0280">16</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the most relevant characteristics of DOAC.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In patients with non-valvular atrial fibrillationDOACs are indicated for the prevention of stroke and systemic embolism in adults with one or more of the following risk factors (level of evidence Ib)<a class="elsevierStyleCrossRefs" href="#bib0205">1–4</a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Age >65 years</li><li class="elsevierStyleListItem" id="lsti0010">•Hypertension, diabetes</li><li class="elsevierStyleListItem" id="lsti0015">•Stroke, transient ischaemic attack</li><li class="elsevierStyleListItem" id="lsti0020">•Heart failure (≥functional class II of the NYHA scale)</li></ul>NVAF is considered when it occurs in the absence of mechanical prosthetic heart valves and of moderate or severe mitral stenosis (usually of rheumatic origin) since these patients were excluded from clinical trials<a class="elsevierStyleCrossRef" href="#bib0285">17</a> (see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DabigatranThe recommended dose is 150mg every 12h and should be reduced to 110mg every 12h in the following situations:Patients older than 80 years, creatinine clearance (CrCl) 30–50mL/min, high bleeding risk, especially risk of gastrointestinal bleeding and concomitant treatment with verapamil.Factors to consider when starting therapy with dabigatran:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">•Renal function should be evaluated in all patients before starting treatment, using the Cockcroft–Gault formula for the calculation of glomerular filtration rate (GFR).</li><li class="elsevierStyleListItem" id="lsti0030">•It needs a strict monitoring of renal function, especially when CrCl is 30–40mL/min. It is contraindicated in patients with severe renal failure (CrCl <30mL/min).</li><li class="elsevierStyleListItem" id="lsti0035">•Dabigatran is dialyzable given its poor binding to plasma proteins.</li><li class="elsevierStyleListItem" id="lsti0040">•It should be avoided if the risk of gastrointestinal bleeding is very high.<a class="elsevierStyleCrossRef" href="#bib0290">18</a></li><li class="elsevierStyleListItem" id="lsti0045">•Activated partial thromboplastin time (aPTT) and thrombin time (TT) are qualitative markers of drug activity.<a class="elsevierStyleCrossRef" href="#bib0205">1</a></li><li class="elsevierStyleListItem" id="lsti0050">•Keep the capsules in their original packaging and avoid the use of pill organizers.</li><li class="elsevierStyleListItem" id="lsti0055">•Capsules should not be opened to take their contents.</li></ul>RivaroxabanThe recommended dose is 20mg once a day. The reduction to 15mg per day is indicated in the following situations:CrCl between 30 and 50mL/min. Although clinical data in patients with severe renal failure are scarce, there is no contraindication to use it in patients with CrCl between 15 and 29mL/min, provided that renal function and bleeding risk are monitored.Factors to consider when starting therapy with rivaroxaban:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060">•It must be administered with food, otherwise its absorption decreases.</li><li class="elsevierStyleListItem" id="lsti0065">•Needs strict renal function monitoring, especially when CrCl is 15–30mL/min. It is not recommended if CrCl <15mL/min.</li><li class="elsevierStyleListItem" id="lsti0070">•Prothrombin time (PT) may be a qualitative marker that indicates the presence of the drug but does not measure the intensity of anticoagulation.</li><li class="elsevierStyleListItem" id="lsti0075">•It may increase the risk of gastrointestinal bleeding compared to warfarin.<a class="elsevierStyleCrossRef" href="#bib0210">2</a></li><li class="elsevierStyleListItem" id="lsti0080">•It is contraindicated in patients with liver disease associated with coagulopathy and in cirrhotic Child Pugh B and C patients. It can be used with caution in patients with Child Pugh A mild hepatic impairment.<a class="elsevierStyleCrossRef" href="#bib0265">13</a></li><li class="elsevierStyleListItem" id="lsti0085">•It is not dialyzable due to its high binding to plasma proteins.</li></ul>ApixabanThe recommended dose is 5mg orally every 12h. Dosage reduction to 2.5mg every 12h is indicated in the following situations:Patients with at least two of the following characteristics: age ≥80 years, body weight ≤60kg, serum creatinine ≥1.5mg/dL.Factors to keep in mind when starting therapy with apixaban:<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0090">•It presents a good safety profile in pivotal and real-life studies in patients with a high risk of digestive haemorrhage.</li><li class="elsevierStyleListItem" id="lsti0095">•PT and aPTT are not useful tests.<a class="elsevierStyleCrossRefs" href="#bib0295">19–23</a></li><li class="elsevierStyleListItem" id="lsti0100">•It requires strict monitoring of renal function, especially when CrCl is 15–30mL/min. Not recommended in the case of CrCl <15mL/min.</li><li class="elsevierStyleListItem" id="lsti0105">•It can be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B).<a class="elsevierStyleCrossRef" href="#bib0270">14</a></li><li class="elsevierStyleListItem" id="lsti0110">•It is not dialyzable.</li></ul>EdoxabanThe recommended dose is 60mg once a day. The dose reduction to 30mg every 24h is indicated in the following situations: moderate or severe renal failure (CrCl 15–50mL/min), body weight ≤60kg or concomitant use of P-gp inhibitors such as cyclosporine, dronedarone, erythromycin or ketoconazole.<a class="elsevierStyleCrossRef" href="#bib0320">24</a>Factors to consider when starting therapy with edoxaban:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0115">•It prolongs PT and aPTT, but they are not quantitative tests.<a class="elsevierStyleCrossRef" href="#bib0275">15</a></li><li class="elsevierStyleListItem" id="lsti0120">•It requires strict monitoring of renal function, especially when CrCl is 15–30mL/min. Not recommended in the case of CrCl <15mL/min.</li><li class="elsevierStyleListItem" id="lsti0125">•Not recommended in patients with CrCl >95mL/min (increased risk of stroke compared to warfarin for a 60mg dose).<a class="elsevierStyleCrossRef" href="#bib0220">4</a></li><li class="elsevierStyleListItem" id="lsti0130">•It is mainly absorbed in the upper gastrointestinal tract, so it is possible that drugs or diseases that increase gastric emptying and intestinal motility can also reduce its absorption.<a class="elsevierStyleCrossRef" href="#bib0275">15</a></li><li class="elsevierStyleListItem" id="lsti0135">•It is contraindicated in patients with liver disease associated with coagulopathy and with a risk of clinically relevant bleeding.</li><li class="elsevierStyleListItem" id="lsti0140">•It is not dialyzable.</li></ul>Although there are no comparative studies between the different DOACs, <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> summarizes the current clinical evidence to be considered when starting therapy with a DOAC in patients with NVAF according to their clinical characteristics.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>In patients with venous thromboembolic diseaseDOACs show an efficacy comparable to standard treatment (parenteral therapy with low molecular weight heparin [LMWH] followed by VKA) with a significant decrease in the risk of bleeding (level of evidence Ib).<a class="elsevierStyleCrossRefs" href="#bib0225">5–8</a> Therefore, the latest recommendations of the American College of Chest Physicians guidelines position DOACs as first-line treatment for patients with VTD without cancer and an option to consider in patients with VTD and cancer.<a class="elsevierStyleCrossRef" href="#bib0325">25</a><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> summarizes the most important considerations to be considered for the initiation of treatment with DOAC in patients with VTD.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Follow-up and health educationAs experts in the management of anticoagulant therapy, we believe that ATUs have an important role to ensure the correct use of these drugs and their follow-up. Considering the recommendations of the European Heart Rhythm Association (level of evidence IV),<a class="elsevierStyleCrossRef" href="#bib0285">17</a> we suggest the following visit schedule:First visitWe recommend making the first visit to the ATU, during which the following data should be recorded (grade 2B recommendation):<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0145">•Indication of anticoagulant therapy.</li><li class="elsevierStyleListItem" id="lsti0150">•Relevant pathological, thrombotic and haemorrhagic history.</li><li class="elsevierStyleListItem" id="lsti0155">•Concomitant medication.</li><li class="elsevierStyleListItem" id="lsti0160">•Actual weight.</li><li class="elsevierStyleListItem" id="lsti0165">•Determination of thrombotic and bleeding risk (CHA)2DS2-VASc and HAS-BLED.</li><li class="elsevierStyleListItem" id="lsti0170">•In the case of patients with atrial fibrillation and mitral valve disease, we recommend carrying out an echocardiogram (valid for at least one year).</li><li class="elsevierStyleListItem" id="lsti0175">•Recent analysis (last 3 months) with renal function (CrCl calculation according to the Cockcroft–Gault formula), liver function, basic coagulation tests and blood count.</li><li class="elsevierStyleListItem" id="lsti0180">•Individualize DOAC according to the clinical characteristics of each patient.</li><li class="elsevierStyleListItem" id="lsti0185">•Record the start date and all the demographic data of the patient in the specific oral anticoagulant treatment control software of each centre.</li><li class="elsevierStyleListItem" id="lsti0190">•Health education will be essential at the beginning of treatment, where the following actions will be carried out.</li><li class="elsevierStyleListItem" id="lsti0195">•Explain the mechanism of action, most common adverse events, possible interactions (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), perioperative environment and posology.<elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0200">•Provide the anticoagulation card with DOAC.<a class="elsevierStyleCrossRef" href="#bib0285">17</a></li><li class="elsevierStyleListItem" id="lsti0205">•Provide any teaching material available.</li><li class="elsevierStyleListItem" id="lsti0210">•Emphasize the importance of adherence to treatment.</li><li class="elsevierStyleListItem" id="lsti0215">•Provide the contact telephone number of the ATU or PCC to clarify doubts, report possible adverse events.</li></ul>Follow-up visitsFollow-up visits are recommended every 3 months during the first year (grade 2B recommendation), considering the following:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0220">•Adherence, quality of life and satisfaction with treatment.</li><li class="elsevierStyleListItem" id="lsti0225">•In the case of adverse events, these should be recorded in the clinical history and reported through the yellow pharmacovigilance card.</li><li class="elsevierStyleListItem" id="lsti0230">•In the case of haemorrhagic event, record the start date, classify the bleeding intensity (WHO, ISTH, GUSTO or TIMI scores), need for hospitalization and therapeutic measures.</li><li class="elsevierStyleListItem" id="lsti0235">•In the case of thromboembolic event, record the date, anticoagulant therapy, complications and hospitalization.</li><li class="elsevierStyleListItem" id="lsti0240">•Concomitant medication review.</li><li class="elsevierStyleListItem" id="lsti0245">•Record the current weight.</li><li class="elsevierStyleListItem" id="lsti0250">•Lab results data to be considered: renal function (CrCl), liver function tests, haemoglobin and platelet count.</li><li class="elsevierStyleListItem" id="lsti0255">•Record the discontinuation or change of dosage, indicating date and reason.</li><li class="elsevierStyleListItem" id="lsti0260">•Reassess the indication of DOAC.</li><li class="elsevierStyleListItem" id="lsti0265">•All these data will be recorded in the patient's medical history.</li></ul>Recommendations for follow-up in the Anticoagulant Treatment UnitThe follow-up will be carried out in the ATU when the patients meet the following characteristics (grade 2B recommendation):<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0270">•NVAF patients with a very high thromboembolic risk: CHA2DS2-VASc ≥5,</li><li class="elsevierStyleListItem" id="lsti0275">•Mitral valve disease or stroke recurrence.</li><li class="elsevierStyleListItem" id="lsti0280">•Patients with NVAF of very high bleeding risk (HAS-BLED >5).</li><li class="elsevierStyleListItem" id="lsti0285">•Patients with VTD or special conditions.</li><li class="elsevierStyleListItem" id="lsti0290">•Patients with CrCl <30mL/min.</li></ul>Recommendations for primary care centre follow-upAfter the first year of treatment, patients may be referred for a follow-up in the PCC when they meet the following criteria (grade 2B recommendation):<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0295">•Patients who do not meet ATU's control criteria.</li><li class="elsevierStyleListItem" id="lsti0300">•Patients who have made at least 2 visits to an ATU during the first year.</li><li class="elsevierStyleListItem" id="lsti0305">•Annual controls are recommended for patients with CrCl >50mL/min and renal function stability during the first year.</li><li class="elsevierStyleListItem" id="lsti0310">•For patients with CrCl between 30 and 60mL/min and stability of renal function during the first year, controls are recommended every 4–6 months.</li><li class="elsevierStyleListItem" id="lsti0315">•In the following situations, referring the patient to an ATU is recommended.</li><li class="elsevierStyleListItem" id="lsti0320">•Impaired renal function (a decrease in CrCl of 10mL/min in the last 4–6 months) that requires an evaluation regarding dose change and/or change of anticoagulant treatment.</li><li class="elsevierStyleListItem" id="lsti0325">•Presence of adverse events or unexpected laboratory abnormalities.</li><li class="elsevierStyleListItem" id="lsti0330">•Prognosis of surgery or moderate and high-risk procedures for perioperative recommendations.</li></ul>Special conditionsPerioperative managementDOAC discontinuation will be necessary prior to any invasive procedure that entails a bleeding risk. In order to establish the haemostatic safety threshold of these drugs, it is necessary to consider their pharmacokinetics and pharmacodynamics. <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> summarizes the perioperative approach in patients anticoagulated with DOAC.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Considerations<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0335">•Bridge therapy, common in patients anticoagulated with VKA, is not applicable in DOAC. The use of heparin in the perioperative setting of anticoagulated patients with DOAC is controversial. The Dresden prospective registry does not contemplate the use of heparin after DOAC discontinuation during the preoperative period due to a significant increase in the bleeding rate (level of evidence III).<a class="elsevierStyleCrossRef" href="#bib0330">26</a> However, patients at high thromboembolic risk could benefit from the use of LMWH at prophylactic or intermediate doses during the postoperative period until they can safely restart DOAC or when the patient does not tolerate the oral route. GIHP (Le Groupe d’Intérêt in Hémostase Périopératoire), on the contrary, suggests discontinuing DOAC 5 days before any surgery of moderate or high bleeding risk to ensure the complete clearance of the drug and recommend assessing the use of LMWH or unfractionated heparin (UFH) in the preoperative period when the patient has an elevated thromboembolic risk (level of evidence IV).<a class="elsevierStyleCrossRef" href="#bib0335">27</a></li><li class="elsevierStyleListItem" id="lsti0340">•Renal function, CrCl should be estimated by the Cockcroft–Gault formula, because overestimation of renal function by other methods could induce a wrong prescription and increase the risk of bleeding during the perioperative period (level of evidence IIb).<a class="elsevierStyleCrossRef" href="#bib0340">28</a>.<a class="elsevierStyleCrossRef" href="#bib0345">29</a></li><li class="elsevierStyleListItem" id="lsti0345">•The patient's bleeding risk, for which the HAS-BLED and RIETE scores for NVAF and VTD (level of evidence I-II) could be used, respectively.<a class="elsevierStyleCrossRefs" href="#bib0350">30,31</a></li><li class="elsevierStyleListItem" id="lsti0350">•The bleeding risk of surgery and the possible consequences of bleeding on the outcome of surgery and patient safety (level of evidence IIb).<a class="elsevierStyleCrossRef" href="#bib0360">32</a></li><li class="elsevierStyleListItem" id="lsti0355">•Coagulation tests. Routine tests only assess the anticoagulant effect qualitatively and should not be used in this clinical scenario. The anti-factor Xa determination with calibrated techniques (rivaroxaban, apixaban and edoxaban) and diluted TT or ecarin time (dabigatran) could be useful to quantify the plasma levels of these drugs.</li></ul>Recommendations<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0360">•Do not systematically use LMWH or UFH in the preoperative period after the discontinuation of DOAC (grade 2A recommendation).</li><li class="elsevierStyleListItem" id="lsti0365">•During the postoperative period of patients with NVAF, use prophylactic doses of LMWH or UFH, until haemostasis is considered safe and DOAC can be restarted (grade 2B recommendation).</li><li class="elsevierStyleListItem" id="lsti0370">•During the postoperative period of patients with VTD, use LMWH or UFH at increasing doses. It should be started within 24h postoperatively until haemostasis is considered safe and DOAC can be restarted (grade 2B recommendation).</li><li class="elsevierStyleListItem" id="lsti0375">•In relation to the laboratory tests, according to each DOAC:</li></ul><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0380">-Dabigatran: Normal TT indicates the absence of the anticoagulant effect of dabigatran and, due to its extreme sensitivity, it may not be useful in emergency situations because it could unnecessarily delay the decision to perform the surgery. A normal aPTT indicates with relative reliability that dabigatran levels allow safe haemostasis (grade 2A recommendation).<a class="elsevierStyleCrossRef" href="#bib0295">19</a></li><li class="elsevierStyleListItem" id="lsti0385">-Rivaroxaban: can lengthen the PT, but its normal values do not imply absence of anticoagulant effect (grade 2A recommendation).<a class="elsevierStyleCrossRef" href="#bib0315">23</a></li><li class="elsevierStyleListItem" id="lsti0390">-Apixaban: PT is not a sensitive test, so it should not be considered a qualitative test (grade 2A recommendation).<a class="elsevierStyleCrossRefs" href="#bib0295">19–23</a></li><li class="elsevierStyleListItem" id="lsti0395">-Edoxaban: PT and aPTT may be prolonged, but they are not quantitative tests (grade 2A recommendation).<a class="elsevierStyleCrossRef" href="#bib0280">16</a></li></ul>Advanced ageThe possibility of presenting an episode of atrial fibrillation or VTD increases with age. The risk of ischaemic stroke increases 1.5 times for every 10 years of age. Those over 85 years of age are the most exposed given the higher prevalence of atrial fibrillation in this age group. Similarly, the incidence of VTD increases with age and is up to 6 times higher in patients over 80 years of age. On the other hand, the bleeding risk related to anticoagulation increases by 40% for every 10 years of age; for this reason, only 50–60% of patients with atrial fibrillation are anticoagulated, and only 35% of those over 85 years of age.<a class="elsevierStyleCrossRef" href="#bib0365">33</a>DOACs have shown a reduction in stroke compared to warfarin in the subgroup of patients over 75 years of age (level of evidence Ib).<a class="elsevierStyleCrossRefs" href="#bib0205">1–4</a> In the analyses by subgroups, for those over 75 years of age, dabigatran and apixaban at high doses showed a reduction in stroke compared to warfarin, with similar results in the case of rivaroxaban and dabigatran at low doses.In addition, dabigatran 110mg and apixaban 5mg were shown to significantly reduce the risk of fatal bleeding (level of evidence Ib).<a class="elsevierStyleCrossRefs" href="#bib0205">1,3</a> Edoxaban has been shown to be safe in patients at risk of falls (level of evidence Ib).<a class="elsevierStyleCrossRef" href="#bib0220">4</a> DOACs are an alternative to consider in this population, because they do not require monitoring, avoid frequent point-of-care visits, and have a lower number of drug interactions, an important aspect given the common polypharmacy of elderly patients.Considerations<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0400">-When an elderly patient is anticoagulated, the risk of falls should always be assessed.</li><li class="elsevierStyleListItem" id="lsti0405">-There is a higher prevalence of renal failure and comorbidities in this group of patients.</li></ul>Recommendations<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0410">•In patients ≥80 years of age with a history of frequent falls or high bleeding risk, we recommend considering apixaban 2.5mg/12h, dabigatran 110mg/12h, edoxaban 30mg/24h rivaroxaban 15mg per day (grade 2A recommendation).</li><li class="elsevierStyleListItem" id="lsti0415">•The use of apixaban, rivaroxaban, dabigatran or edoxaban is recommended over VKAs in patients ≥80 years of age candidates for anticoagulant treatment with a history of intracranial haemorrhage (grade 1 recommendation).</li><li class="elsevierStyleListItem" id="lsti0420">•In those patients in whom a simple posology guarantees a better adherence, evaluate rivaroxaban or edoxaban by adjusting dose to renal function (grade 2B recommendation).</li><li class="elsevierStyleListItem" id="lsti0425">•In patients ≥80 years of age with gastrointestinal symptomatology (hiatal hernia, gastro-oesophageal reflux, gastritis, oesophagitis) we recommend the use of apixaban, rivaroxaban or edoxaban (grade 2A recommendation).</li></ul>Cancer patientOncology patients have a higher risk of venous thromboembolic events and arrhythmias, as well as a considerable risk of bleeding, taking into account the invasive procedures they sometimes undergo and drug-induced thrombocytopaenia; so, the use of anticoagulants in these patients is usually a challenge.The number of patients with cancer in the main studies for both NVAF and VTD does not reach 5%. However, the analyses by subgroups do not show differences in efficacy and safety (level of evidence Ib).<a class="elsevierStyleCrossRefs" href="#bib0205">1–8</a>DOACs have not been compared to the recommended treatment (LMWH) in cancer patients with VTD. The safety profile of these antithrombotic agents could favour their use, since they demonstrated a significant reduction in the risk of recurrent VTD or major bleeding, compared to VKA (level of evidence IIb).<a class="elsevierStyleCrossRef" href="#bib0370">34</a>There is no evidence of the use of DOAC in patients with NVAF and active cancer, since many of them were excluded from the main studies because they present a high risk of haemorrhage or a short life expectancy.<a class="elsevierStyleCrossRefs" href="#bib0205">1–4</a>ConsiderationsA DOAC can always be considered under the ATU's monitoring and taking into account:<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0430">•Pharmacological interactions with antineoplastic, antifungals and drugs that induce or inhibit CYP3A4 or P-gp (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</li><li class="elsevierStyleListItem" id="lsti0435">•A correct oral tolerance.</li><li class="elsevierStyleListItem" id="lsti0440">•Possibility of thrombocytopaenia secondary to toxicity due to antineoplastic treatment.</li><li class="elsevierStyleListItem" id="lsti0445">•Possibility of nephrotoxicity by some antineoplastics such as platinum-based agents.</li></ul>RecommendationsThe current indication in the patient with active cancer is LMWH, although the use of DOAC in selected situations and in specific cancer patients can be assessed, which requires a multidisciplinary assessment, given the lack of clinical evidence. Some of these situations are the following:<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0450">•In patients with NVAF and active cancer, it is recommended to assess the use of DOAC taking into account the considerations previously discussed (grade 2B recommendation).</li><li class="elsevierStyleListItem" id="lsti0455">•The use of DOAC in cancer-related VTD should be considered during the extended treatment after the initial 6-month therapy (grade 2B recommendation).</li><li class="elsevierStyleListItem" id="lsti0460">•In patients with active antineoplastic treatment and DOAC, the platelet count (making sure it does not decrease below 501×09/L) and renal function (grade 2B recommendation; consensus recommendation based on the clinical experience observed after the use of LMWH in cancer patients under active treatment) should be monitored.</li></ul>Renal failureThe coexistence of chronic renal failure (CRF) in patients with atrial fibrillation is common, since both entities frequently develop with age. CRF is a known risk factor for the development of VTD and severe bleeding with or without anticoagulant therapy.<a class="elsevierStyleCrossRef" href="#bib0375">35</a> DOACs have different degrees of renal clearance and, although patients with severe renal failure were excluded from the trials, the indirect comparison between DOACs shows certain differences depending on CrCl.Patients with mild renal failure treated with DOAC had a lower rate of stroke and systemic embolism, with a reduction of major or clinically relevant bleeding compared to VKA, and similar rates of bleeding compared to LMWH. In the case of moderate renal failure, a significant reduction in thrombotic risk was also demonstrated, without bleeding differences compared to VKA, LMWH or anti-platelet agents (level of evidence Ia).<a class="elsevierStyleCrossRef" href="#bib0380">36</a>Considerations<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0465">•DOACs have different degrees of renal clearance (dabigatran 80%, edoxaban 50%, rivaroxaban 33% and apixaban 27%) and the indirect comparison between them shows certain differences in the case of renal failure (level of evidence Ia).<a class="elsevierStyleCrossRefs" href="#bib0380">36,37</a></li><li class="elsevierStyleListItem" id="lsti0470">•In mild renal failure (GF 50–79mL/min), apixaban and dabigatran 110mg were associated with lower rates of major bleeding (level of evidence Ia).<a class="elsevierStyleCrossRef" href="#bib0390">38</a></li><li class="elsevierStyleListItem" id="lsti0475">•In moderate renal failure (GF 25–49mL/min), apixaban presented a better safety profile (but not efficacy) compared to dabigatran 110mg and rivaroxaban (level of evidence Ia).<a class="elsevierStyleCrossRef" href="#bib0390">38</a></li><li class="elsevierStyleListItem" id="lsti0480">•In patients with NVAF who presented a continuous worsening of renal function (decrease in CrCl >20% in patients with GF >30mL/min), rivaroxaban was associated with lower rates of stroke and systemic embolism compared to patients on warfarin, without showing a higher risk of bleeding.<a class="elsevierStyleCrossRef" href="#bib0385">37</a></li><li class="elsevierStyleListItem" id="lsti0485">•In patients with GFR between 30 and 50mL/min, edoxaban was not lower than warfarin in stroke prevention and showed a significant reduction in bleeding (level of evidence IIa).<a class="elsevierStyleCrossRef" href="#bib0395">39</a></li></ul>Recommendations<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0490">•If CrCl >50mL/min: DOAC should be prescribed according to comorbidities and concomitant medication (grade 2A recommendation).</li><li class="elsevierStyleListItem" id="lsti0495">•If CrCl 31–49mL/min: apixaban 5mg/12h (if creatinine ≥1.5mg/dL and, besides, associates ≥80 years of age or weight ≤60kg, reduce dose to 2.5mg/12h), rivaroxaban 15mg/24h, or edoxaban 30mg/24h. As for dabigatran, a dose of 110mg/12h is recommended (grade 1 recommendation).</li><li class="elsevierStyleListItem" id="lsti0500">•If CrCl 15–30mL/min, it can be used with caution: apixaban 2.5mg/12h, rivaroxaban 15mg/24h edoxaban 30mg/24h. Dabigatran is contraindicated (grade 2A recommendation).</li><li class="elsevierStyleListItem" id="lsti0505">•If CrCl <15mL/min: contraindication for any DOAC (grade 1 recommendation).</li><li class="elsevierStyleListItem" id="lsti0510">•Haemodialysis: there are no efficacy and safety data.</li></ul>Practical management during bleedingIf any bleeding occurs in the context of anticoagulation with a DOAC, the measures to be considered are the withdrawal of the drug and quantifying the time elapsed since the last dose of anticoagulant. The management of bleeding according to its severity includes the usual support measures. The renal function and the basic haemostasis study should be determined to assess the possible anticoagulant effect in cases where it may be useful.<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a> outlines the recommended management from the TROMBOC@T group in case of bleeding and depending on its severity.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Reversing agentsThe monoclonal antibody, idarucizumab, is the specific antidote for dabigatran. It achieves a dose-dependent, irreversible inhibition of both free and thrombin-bound dabigatran. It has a biphasic renal clearance, with a half-life of approximately 45min (level of evidence IIa).<a class="elsevierStyleCrossRef" href="#bib0400">40</a>After the results of the RE-VERSE AD study,<a class="elsevierStyleCrossRef" href="#bib0400">40</a> it has been approved for hospital use, both by the FDA and by the EMA. It is available in Spain since December 2015.In case of severe bleeding or emergency surgery, requiring the immediate reversion of the anticoagulant effect of dabigatran, the use of idarucizumab will be assessed taking into account the time elapsed since the last administration of DOAC, CrCl according to the Cockcroft–Gault formula and the extension of the aPTT and TT (grade 2A recommendation). See <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a> on the protocol of use.<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Andexanet alfa (PRT064445), an anti-Xa anticoagulant reversal agent, including heparins and fondaparinux, is currently in the clinical trial phase, like ciraparantag, which seems effective in the reversal of all DOACs, fondaparinux and heparins.ConclusionsThe progressive increase in the use of DOACs requires the establishment and standardization of clinical practice guidelines for the benefit of patients anticoagulated with these antithrombotic agents in both ATU and PCC. The present work corresponds to the consensus guidelines of the TROMBOC@T working group on the management and follow-up of patients receiving DOAC. To this end, the available medical literature has been thoroughly reviewed and a series of meetings have been held with experts in the field of anticoagulation to identify the areas where data with a high degree of evidence exist and those where consensus is required based on clinical experience. The work includes novel aspects, not mentioned in other guidelines, to carry out an interdisciplinary and bidirectional management between ATUs and PCCs. A set of practical recommendations has been established as a result of the project, which will facilitate the management and follow-up of patients on DOAC therapy.Conflict of interestsThe authors declare no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres1090449" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1033726" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1090450" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1033725" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Objective" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Methodology" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Characteristics of direct oral anticoagulants" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Dabigatran" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Rivaroxaban" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Apixaban" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Edoxaban" ] ] ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "In patients with non-valvular atrial fibrillation" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Dabigatran" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Rivaroxaban" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Apixaban" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Edoxaban" ] ] ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "In patients with venous thromboembolic disease" ] 10 => array:3 [ "identificador" => "sec0075" "titulo" => "Follow-up and health education" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "First visit" ] 1 => array:3 [ "identificador" => "sec0085" "titulo" => "Follow-up visits" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Recommendations for follow-up in the Anticoagulant Treatment Unit" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Recommendations for primary care centre follow-up" ] ] ] ] ] 11 => array:3 [ "identificador" => "sec0100" "titulo" => "Special conditions" "secciones" => array:9 [ 0 => array:3 [ "identificador" => "sec0105" "titulo" => "Perioperative management" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0110" "titulo" => "Considerations" ] 1 => array:2 [ "identificador" => "sec0115" "titulo" => "Recommendations" ] ] ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Advanced age" ] 2 => array:3 [ "identificador" => "sec0125" "titulo" => "Considerations" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0130" "titulo" => "Recommendations" ] ] ] 3 => array:2 [ "identificador" => "sec0135" "titulo" => "Cancer patient" ] 4 => array:3 [ "identificador" => "sec0140" "titulo" => "Considerations" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0145" "titulo" => "Recommendations" ] ] ] 5 => array:2 [ "identificador" => "sec0150" "titulo" => "Renal failure" ] 6 => array:3 [ "identificador" => "sec0155" "titulo" => "Considerations" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0160" "titulo" => "Recommendations" ] ] ] 7 => array:2 [ "identificador" => "sec0165" "titulo" => "Practical management during bleeding" ] 8 => array:2 [ "identificador" => "sec0170" "titulo" => "Reversing agents" ] ] ] 12 => array:2 [ "identificador" => "sec0175" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0180" "titulo" => "Conflict of interests" ] 14 => array:2 [ "identificador" => "xack370419" "titulo" => "Acknowledgement" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-08-07" "fechaAceptado" => "2018-01-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1033726" "palabras" => array:5 [ 0 => "Direct" 1 => "Atrial fibrillation" 2 => "Venous thromboembolism" 3 => "Recommendations" 4 => "Reversal" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1033725" "palabras" => array:5 [ 0 => "Anticoagulantes orales directos" 1 => "Fibrilación auricular" 2 => "Tromboembolismo venoso" 3 => "Recomendaciones" 4 => "Reversión" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectivesIn recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for the prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the anticoagulant treatment units (ATUs) and primary care centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation. Material and methodsA group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence. ResultsAs a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs. ConclusionsProgressive increase in the use of DOACs calls for measures to establish and homogenize clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivosEn los últimos años los anticoagulantes orales directos (ACOD) se han convertido en una alternativa a los antagonistas de la vitamina K (AVK) para la prevención del ictus y embolia sistémica en pacientes con fibrilación auricular no valvular (FANV), así como para la prevención y tratamiento de la trombosis venosa profunda. Los ensayos clínicos han demostrado la no inferioridad y la potencial superioridad en comparación con la warfarina, lo cual permite ampliar las opciones de anticoagulación. En nuestro medio, las Unidades de Tratamiento Anticoagulante (UTA) y los Centros de Atención Primaria (CAP) son los encargados de la educación, seguimiento, control de adherencia y del manejo en situaciones especiales de los pacientes anticoagulados. Estas consideraciones han motivado la preparación del presente documento de consenso, que tiene como objetivo establecer recomendaciones que incorporen los hallazgos de la investigación científica a la práctica clínica para mejorar la calidad asistencial en el ámbito de la anticoagulación. Material y métodosUn grupo de expertos del Grupo Catalán de Trombosis (TROMBOC@T) ha revisado la bibliografía publicada entre 2007 y 2016 para poder establecer recomendaciones basadas en la evidencia clínica. ResultadosComo resultado del proyecto se han establecido un conjunto de recomendaciones de carácter práctico que facilitarán el tratamiento, educación, seguimiento y manejo en situaciones especiales de los pacientes anticoagulados con ACOD. ConclusionesEl aumento progresivo del uso de los ACOD requiere establecer y homogeneizar las directrices de actuación clínica en el paciente anticoagulado con estos antitrombóticos tanto en las UTA como en los CAP." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Olivera P, Gabilondo M, Constans M, Tàssies D, Plensa E, Pons V, et al. Recomendaciones del Grupo Catalán de Trombosis (Tromboc@t Working Group) para el tratamiento de los pacientes que reciben anticoagulantes orales directos. Med Clin. 2018;151:210." ] ] "multimedia" => array:12 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1184 "Ancho" => 2331 "Tamanyo" => 157831 ] ] "descripcion" => array:1 [ "en" => "Considerations for the start of treatment with DOAC in VTD." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3130 "Ancho" => 2827 "Tamanyo" => 736378 ] ] "descripcion" => array:1 [ "en" => "Main pharmacological interactions of DOAC. <elsevierMultimedia ident="201810040626358081"></elsevierMultimedia>: contraindicated; <elsevierMultimedia ident="201810040626358082"></elsevierMultimedia>: use with caution; <elsevierMultimedia ident="201810040626358083"></elsevierMultimedia>: no interaction. Positive (+): enhances the effect; negative (−): decreases the effect; NK: not known. *Decrease from 12% to 30%, without reducing efficacy in clinical trials." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3099 "Ancho" => 2383 "Tamanyo" => 725352 ] ] "descripcion" => array:1 [ "en" => "Perioperative approach for patients anticoagulated with DOAC.*Assess DOAC withdrawal one more day, depending on the risk of bleeding. **Assess delaying the restart of DOAC one more day, depending on haemostatic safety. Do not administer LMWH or UFH after the discontinuation of DOAC in the preoperative period." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3979 "Ancho" => 2917 "Tamanyo" => 814228 ] ] "descripcion" => array:1 [ "en" => "Algorithm for the management of bleeding in patients anticoagulated with DOAC. *Classification of bleeding according to ISTH and GUSTO scores." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 4105 "Ancho" => 2917 "Tamanyo" => 464119 ] ] "descripcion" => array:1 [ "en" => "Protocol for the use of idarucizumab. *Classification of bleeding according to the ISTH." ] ] 5 => 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:1 [ "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" title="table-entry " colspan="2" align="left" valign="top">Levels of evidence</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Level Ia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Meta-analysis of controlled, randomized, well-designed trials \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">Level Ib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At least one randomized controlled trial \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">Level IIa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At least, a well-designed controlled study without randomizing \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">Level IIb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At least, a study not completely experimental, well designed, like the cohort studies \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">Level III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-experimental, well-designed descriptive studies such as comparative studies, correlation studies or case-control studies \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">Level IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Documents or opinions of expert committees or clinical experiences of prestigious authorities or case series studies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Degrees of recommendation</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Category 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The available evidence is of high quality and there is consensus among the experts \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">Category 2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The available evidence is of moderate quality and there is unanimous consensus among experts \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">Category 2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The available evidence is of moderate quality and there is no unanimous consensus among experts \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">Category 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The available evidence may have any grade, but there is no consensus among experts \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1864487.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Levels of evidence and degrees of recommendation." ] ] 6 => 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 [ "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">Characteristics \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">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" style="border-bottom: 2px solid black">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" style="border-bottom: 2px solid black">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" style="border-bottom: 2px solid black">Edoxaban \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">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FIIa inhibitor (thrombin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Direct FXa inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Direct FXa inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Direct FXa inhibitor \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">Dosage (mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">150 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15.30<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">110 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \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">Frequency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every 24h \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">Bioavailability% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.5 (pH-dependent) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80 (100% with food) \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">Renal clearance % \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">33 (active metabolite) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35–50 \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">Metabolic pathway \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P-gP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CYP 3A4/2J2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CYP3A4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CYP3A4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P-gP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P-gP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">P-gP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Half-life (hours)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CrCl>80mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \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">CrCl 50–80mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \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">CrCl 30–49mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15–17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–15 \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><td class="td" title="table-entry " align="left" valign="top">10–11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hours to reach Cmax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–3 \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">Absorption with Ibp \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No effect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No effect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No effect \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top">Practical points</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Interactions with food or alcohol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \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">Dyspepsia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5–10% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \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">Dialyzable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Possible \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">Antidote \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Idarucizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Andexanet alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Andexanet alfa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Andexanet alfa \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1864488.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Primary prevention for VTD." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Treatment for NVAF/DVT and PTE; Andexanet alfa still in clinical trial phase." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Decrease from 12% to 30%, without reducing efficacy in clinical trials." ] ] ] "descripcion" => array:1 [ "en" => "Most relevant DOAC characteristics." ] ] 7 => 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 [ "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">Moderate or severe mitral stenosis (usually of rheumatic aetiology) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Contraindicated \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">Mechanical prosthetic valves in any position \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Contraindicated \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">Severe aortic stenosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Indicated \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">Mild or moderate disease of another native valve \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Indicated \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">Valvular bioprosthesis<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From the third postoperative month \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">Mitral valve repair<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From the third postoperative month \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">Percutaneous Transluminal Aortic Valvuloplasty and Transcatheter Aortic Valve Stent Implantation (TAVI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To be assessed, considering the bleeding risk, because they can associate simple or double antiplatelet therapy (no prospective data available) \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">Hypertrophic cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">To be assessed, given that there is no prospective data \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1864490.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "The American guidelines do not recommend the use of DOAC in patients with valvular repair or after valve replacement with biological prostheses." ] ] ] "descripcion" => array:1 [ "en" => "Indications and contraindications in patients with NVAF." ] ] 8 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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">Patient characteristics \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">Recommended dose \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">Comments \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 " rowspan="4" align="left" valign="top">Patients with NVAF at high risk of thrombosis: CHA2DS2-VASc ≥3 or previous stroke</td><td class="td" title="table-entry " align="left" valign="top">Dabigatran 150mg orally every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">This dose of dabigatran associated a greater reduction in the risk of stroke compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0205">1</a> \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">Rivaroxaban 20mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The pivotal study with rivaroxaban had a higher number of patients with previous stroke. Compared to warfarin, patients with a previous myocardial infarction assigned to rivaroxaban had a nonsignificant 14% reduction in the risk of ischaemic heart events<a class="elsevierStyleCrossRef" href="#bib0210">2</a> \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">Apixaban 5mg orally every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">This dose associated a greater reduction in the risk of stroke compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0215">3</a> \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">Edoxaban 60/30mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In patients with NVAF, both doses were not inferior to warfarin in the prevention of stroke and systemic embolism<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Patients with NVAF at high risk of bleeding (HAS-BLED >3)</td><td class="td" title="table-entry " align="left" valign="top">Apixaban 5mg orally every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">This dose of apixaban associated a decrease in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0215">3</a> \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">Dabigatran 110mg orally every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">This dose of dabigatran associated a decrease in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0205">1</a> \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">Rivaroxaban 20mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No significant difference was found in the risk of major bleeding compared to warfarin (p=0.44), however, intracranial and fatal bleeding occurred less frequently in the rivaroxaban group<a class="elsevierStyleCrossRef" href="#bib0210">2</a> \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">Edoxaban 60/30mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Both doses were significantly associated with a lower rate of bleeding. The dose of 30mg was significantly associated with a lower mortality rate from all causes<a class="elsevierStyleCrossRef" href="#bib0220">4</a> \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">Patients with dyspepsia or other gastrointestinal complications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rivaroxaban, apixaban and edoxaban \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">These drugs have been associated with less dyspepsia than dabigatran \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Patients with NVAF and in whom difficulties of treatment adherence are expected</td><td class="td" title="table-entry " align="left" valign="top">Rivaroxaban and edoxaban \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dosing once a day could allow a better medication compliance in the long term \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">Dabigatran or apixaban \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Real-life data support DOACs adherence when these have a posology of every 12h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Elderly patients >80 years of age, frail, with severe deterioration of renal function (e.g. CrCl <30mL/min)</td><td class="td" title="table-entry " align="left" valign="top">Apixaban 2.5mg every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Apixaban was associated with a decrease in bleeding in patients with impaired renal function<a class="elsevierStyleCrossRef" href="#bib0215">3</a> \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">Rivaroxaban 15mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No significant difference was found in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0210">2</a> \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">Edoxaban 30mg orally every 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Only a small amount of edoxaban is metabolized through carboxylesterase1 and CYP3A4, being less susceptible to drug interactions, so polypharmacy patients show an adequate profile \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1864489.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Considerations for the initiation of DOAC according to the clinical characteristics of the patient." ] ] 9 => array:5 [ "identificador" => "201810040626358081" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 34 "Ancho" => 33 "Tamanyo" => 676 ] ] ] 10 => array:5 [ "identificador" => "201810040626358082" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx2.jpeg" "Alto" => 34 "Ancho" => 33 "Tamanyo" => 693 ] ] ] 11 => array:5 [ "identificador" => "201810040626358083" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx3.jpeg" "Alto" => 34 "Ancho" => 35 "Tamanyo" => 754 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dabigatran versus warfarin in patients with atrial fibrillation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.J. 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Consensus statement

Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants

Recomendaciones del Grupo Catalán de Trombosis (Tromboc@t Working Group) para el tratamiento de los pacientes que reciben anticoagulantes orales directos

Pável Oliveraa, Miren Gabilondob, Mireia Constansa, Dolors Tàssiesc, Esther Plensad, Verónica Ponsa, Germán Las Herase, Carmen Jiménezf, Desirée Campoyg, Anna Bustinsh, Artur Oliveri, Cristina Marzoj, Tania Canalsa, Anna Varelaa, Marc Soriguek, Eva Sáncheza, Gabriela Enel, Granada Peream, Laura Vicenten, Meritxell Lópezo..., María Cerdáa, Erik Johanssona, M. Reyes Aguinacop, Nazly Santosj, José Mateoq, Joan Carles Reverterd, Ángel Moyar, Amparo Santamaríaa,

Corresponding author

asantamaria@vhebron.net

Corresponding author.

a Unidad de Trombosis y Hemostasia, Departamento de Hematología, Hospital Universitari Vall d’ Hebron, Barcelona, Spain

b Departamento de Hematología, Hospital Universitario Araba Txagorritxu, Vitoria, Spain

c Unidad de Hemostasia y Trombosis, Departamento de Hemoterapia y Hemostasia (ICMHO), Hospital Clínic, Barcelona, Spain

d Departamento de Hematología, Consorci Sanitari del Maresme, Mataró, Spain

e Departamento de Hematología, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain

f Departamento de Hematología, Hospital del Mar, Barcelona, Spain

g Departamento de Hematología, Hospital Universitari Sagrat Cor, Barcelona, Spain

h Departamento de Hematología, Hospital Universitari Doctor Josep Trueta, Girona, Spain

i Departamento de Hematología, Fundació Puigvert, Barcelona, Spain

j Departamento de Hematología, Hospital Universitari Arnau de Vilanova, Lleida, Spain

k Unidad de Trombosis y Hemostasia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

l Departamento de Hematología, Hospital Sant Joan de Déu de Martorell, Spain

m Departemento de Hematología, Corporació Sanitaria Parc Taulí, Sabadell, Spain

n Departamento de Hematología, Consorci Sanitari de Terrasa - Hospital de Terrasa, Spain

o Departamento de Hematología, Hospital Universitario Mútua Terrassa, Spain

p Departamento de Hematología, Hospital Universitari Joan XXIII, Tarragona, Spain

q Unidad de Trombosis y Hemostasia, Departamento de Hematología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

r Unidad de Arritmias, Departamento de Cardiología, Hospital Universitari Vall d’ Hebron, Barcelona, Spain

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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Perioperative approach for patients anticoagulated with DOAC&#46;<span class="elsevierStyleSup">&#42;</span>Assess DOAC withdrawal one more day&#44; depending on the risk of bleeding&#46; &#42;&#42;Assess delaying the restart of DOAC one more day&#44; depending on haemostatic safety&#46; Do not administer LMWH or UFH after the discontinuation of DOAC in the preoperative period&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The incorporation of direct oral anticoagulants &#40;DOACs&#41; as anticoagulant drugs has considerably increased the therapeutic arsenal for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation &#40;NVAF&#41;&#44; as well as for the prevention and treatment of venous thromboembolic disease &#40;VTD&#41;&#46; Unlike vitamin K antagonists &#40;VKA&#41;&#44; DOACs can be administered at fixed doses&#44; have few pharmacological interactions&#44; and do not require systematic monitoring&#46; Fundamental studies have shown that they are at least as effective as warfarin in preventing thromboembolic events by decreasing the risk of severe bleeding and intracranial haemorrhage&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#8211;8</span></a> For some years now&#44; DOACs have been available in our country and the anticoagulant treatment units &#40;ATUs&#41; and the primary care centres &#40;PCCs&#41; use these drugs in their clinical practice&#46; Although there are several national and international documents on their management&#44; there are no clear guidelines on how to perform follow-up&#44; health education and coordinated and interdisciplinary management between ATUs and PCCs in special clinical situations presented by patients while on DOAC therapy&#46; Hence the need to have clear recommendations so that those responsible for antithrombotic therapy can know the results of the different clinical studies&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objective</span><p id="par0010" class="elsevierStylePara elsevierViewall">The Catalan Group of Thrombosis and Haemostasis &#40;TROMBOC&#64;T&#41;&#44; part of the <span class="elsevierStyleItalic">Catalan Society of Haematology and Hemotherapy</span> &#40;SCHH&#41;&#44; met for the first time in 2015 to create a consensus document with practical recommendations with the aim of standardizing the management of patients anticoagulated with DOAC&#46; The availability of the results of large cohorts of patients obtained from routine clinical practice and the occurrence of reverting agents in 2016 led to an update of the document in which&#44; among others&#44; the current role of reverting agents was revised and a post-authorization study was launched&#58; &#171;Effectiveness and safety in the use of new generation oral anticoagulants in routine clinical practice&#58; &#8220;The Real Life Cohort&#8221;&#59; Protocol code&#58; ASO-DAB-2014-01&#59; this project aims to obtain real-life results from our environment&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">These guidelines are a summary of the latest update of the TROMBOC&#64;T group consensus document and aims to establish&#44; in a standard way&#44; recommendations that incorporate the findings of scientific research into clinical practice&#44; hence&#44; improving the quality of care in the field of anticoagulation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methodology</span><p id="par0020" class="elsevierStylePara elsevierViewall">To obtain a consensus document with the most up-to-date information&#44; we reviewed the studies published in the MEDLINE and EMBASE databases and the abstracts presented at the annual conference of the <span class="elsevierStyleItalic">American Society of Haematology</span> &#40;2016&#41;&#46; The key words used in the literature search were&#58; <span class="elsevierStyleItalic">direct oral anticoagulants</span>&#44; <span class="elsevierStyleItalic">atrial fibrillation</span>&#44; <span class="elsevierStyleItalic">venous thromboembolism</span> and <span class="elsevierStyleItalic">treatment</span>&#46; It was limited to studies carried out on humans between 2007 and 2016 &#40;December&#41;&#46; The literature searches focused on randomized controlled trials&#44; but also include registries&#44; non-randomized comparative and descriptive studies&#44; case series&#44; cohort studies&#44; and systematic reviews&#46; The literature references were classified according to the level of evidence &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; following the criteria established by the <span class="elsevierStyleItalic">US Agency for Health Research and Quality&#46;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> A group of experts from the <span class="elsevierStyleItalic">Societat Catalana d&#8217;Hematologia i Hemoter&#224;pia</span> and the Catalan Group of Thrombosis and Haemostasis &#40;TROMBOC&#64;T&#41; evaluated all the information collected and established a series of recommendations and therapeutic algorithms based on proven clinical evidence&#46; The recommendations were classified according to the <span class="elsevierStyleItalic">US National Comprehensive Cancer Network</span> criteria &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> In those areas where no scientific evidence was found&#44; the group of experts established consensus recommendations based on their clinical experiences&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Characteristics of direct oral anticoagulants</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Dabigatran</span><p id="par0025" class="elsevierStylePara elsevierViewall">Dabigatran etexilate &#40;Pradaxa<span class="elsevierStyleSup">&#174;</span>&#41;&#44; a direct thrombin inhibitor&#44; is a prodrug with an oral bioavailability of 6&#8211;7&#37;&#46; Peak levels &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#41; are reached 1&#8211;2<span class="elsevierStyleHsp" style=""></span>h after oral administration&#46; Its half-life is from 14 to 17<span class="elsevierStyleHsp" style=""></span>h and about 80&#37; of the drug is excreted though the kidneys&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> Dabigatran is not metabolized by cytochrome P-450&#44; however&#44; drug interactions can occur because it is a substrate of the P-glycoprotein &#40;P-gp&#41;&#46; Dabigatran can cause dyspepsia&#59; taking it with food can alleviate this problem&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Rivaroxaban</span><p id="par0030" class="elsevierStylePara elsevierViewall">Rivaroxaban &#40;Xarelto<span class="elsevierStyleSup">&#174;</span>&#41; is a direct inhibitor of activated factor X &#40;FXa&#41;&#44; with a bioavailability of 66&#37; if taken without food and 100&#37; if taken with food&#46; It reaches <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> between 2 and 3<span class="elsevierStyleHsp" style=""></span>h after its administration&#46; Its half-life is from 7 to 11<span class="elsevierStyleHsp" style=""></span>h&#44; and a third is eliminated by the kidneys&#46; It is metabolized by CYP3A4 cytochrome&#44; CYP2J2 and CYP independent mechanisms&#46; It is a substrate of the transport proteins P-gp and Bcrp &#40;protein of resistance to breast cancer&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Apixaban</span><p id="par0035" class="elsevierStylePara elsevierViewall">Apixaban &#40;Eliquis&#41;<span class="elsevierStyleSup">&#174;</span>&#41; is another direct FXa inhibitor and has a bioavailability of around 50&#37;&#46; It reaches <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> between 3 and 4<span class="elsevierStyleHsp" style=""></span>h after its administration&#46; It has a half-life of 8&#8211;14<span class="elsevierStyleHsp" style=""></span>h and his metabolism is hepatic through CYP3A4&#47;5&#46; About 25&#37; of the drug is eliminated by the kidneys and the rest is excreted in the stool&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Edoxaban</span><p id="par0040" class="elsevierStylePara elsevierViewall">Edoxaban tosylate &#40;Lixiana<span class="elsevierStyleSup">&#174;</span>&#41; is an FXa inhibitor&#44; with a bioavailability of 62&#37; and a biphasic clearance &#40;35&#8211;40&#37; renal and 60&#37; through stools&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a> It reaches <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> between 1 and 2<span class="elsevierStyleHsp" style=""></span>h after its administration and has a half-life of between 9 and 11<span class="elsevierStyleHsp" style=""></span>h&#46; Edoxaban is a substrate of P-gp and is partially metabolized by CYP3A4&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the most relevant characteristics of DOAC&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">In patients with non-valvular atrial fibrillation</span><p id="par0050" class="elsevierStylePara elsevierViewall">DOACs are indicated for the prevention of stroke and systemic embolism in adults with one or more of the following risk factors &#40;level of evidence Ib&#41;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#8211;4</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Age &#62;65 years</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Hypertension&#44; diabetes</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Stroke&#44; transient ischaemic attack</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Heart failure &#40;&#8805;functional class II of the NYHA scale&#41;</p></li></ul></p><p id="par0075" class="elsevierStylePara elsevierViewall">NVAF is considered when it occurs in the absence of mechanical prosthetic heart valves and of moderate or severe mitral stenosis &#40;usually of rheumatic origin&#41; since these patients were excluded from clinical trials<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Dabigatran</span><p id="par0080" class="elsevierStylePara elsevierViewall">The recommended dose is 150<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h and should be reduced to 110<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h in the following situations&#58;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Patients older than 80 years&#44; creatinine clearance &#40;CrCl&#41; 30&#8211;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; high bleeding risk&#44; especially risk of gastrointestinal bleeding and concomitant treatment with verapamil&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Factors to consider when starting therapy with dabigatran&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Renal function should be evaluated in all patients before starting treatment&#44; using the Cockcroft&#8211;Gault formula for the calculation of glomerular filtration rate &#40;GFR&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">It needs a strict monitoring of renal function&#44; especially when CrCl is 30&#8211;40<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; It is contraindicated in patients with severe renal failure &#40;CrCl &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Dabigatran is dialyzable given its poor binding to plasma proteins&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">It should be avoided if the risk of gastrointestinal bleeding is very high&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a></p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Activated partial thromboplastin time &#40;aPTT&#41; and thrombin time &#40;TT&#41; are qualitative markers of drug activity&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a></p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Keep the capsules in their original packaging and avoid the use of pill organizers&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0125" class="elsevierStylePara elsevierViewall">Capsules should not be opened to take their contents&#46;</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Rivaroxaban</span><p id="par0130" class="elsevierStylePara elsevierViewall">The recommended dose is 20<span class="elsevierStyleHsp" style=""></span>mg once a day&#46; The reduction to 15<span class="elsevierStyleHsp" style=""></span>mg per day is indicated in the following situations&#58;</p><p id="par0135" class="elsevierStylePara elsevierViewall">CrCl between 30 and 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Although clinical data in patients with severe renal failure are scarce&#44; there is no contraindication to use it in patients with CrCl between 15 and 29<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; provided that renal function and bleeding risk are monitored&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Factors to consider when starting therapy with rivaroxaban&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">It must be administered with food&#44; otherwise its absorption decreases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Needs strict renal function monitoring&#44; especially when CrCl is 15&#8211;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; It is not recommended if CrCl &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Prothrombin time &#40;PT&#41; may be a qualitative marker that indicates the presence of the drug but does not measure the intensity of anticoagulation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0160" class="elsevierStylePara elsevierViewall">It may increase the risk of gastrointestinal bleeding compared to warfarin&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a></p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0165" class="elsevierStylePara elsevierViewall">It is contraindicated in patients with liver disease associated with coagulopathy and in cirrhotic Child Pugh B and C patients&#46; It can be used with caution in patients with Child Pugh A mild hepatic impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a></p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">It is not dialyzable due to its high binding to plasma proteins&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Apixaban</span><p id="par0175" class="elsevierStylePara elsevierViewall">The recommended dose is 5<span class="elsevierStyleHsp" style=""></span>mg orally every 12<span class="elsevierStyleHsp" style=""></span>h&#46; Dosage reduction to 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h is indicated in the following situations&#58;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Patients with at least two of the following characteristics&#58; age &#8805;80 years&#44; body weight &#8804;60<span class="elsevierStyleHsp" style=""></span>kg&#44; serum creatinine &#8805;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Factors to keep in mind when starting therapy with apixaban&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">It presents a good safety profile in pivotal and real-life studies in patients with a high risk of digestive haemorrhage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">PT and aPTT are not useful tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">19&#8211;23</span></a></p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">It requires strict monitoring of renal function&#44; especially when CrCl is 15&#8211;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Not recommended in the case of CrCl &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0205" class="elsevierStylePara elsevierViewall">It can be used with caution in patients with mild or moderate hepatic impairment &#40;Child Pugh A or B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a></p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0210" class="elsevierStylePara elsevierViewall">It is not dialyzable&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Edoxaban</span><p id="par0215" class="elsevierStylePara elsevierViewall">The recommended dose is 60<span class="elsevierStyleHsp" style=""></span>mg once a day&#46; The dose reduction to 30<span class="elsevierStyleHsp" style=""></span>mg every 24<span class="elsevierStyleHsp" style=""></span>h is indicated in the following situations&#58; moderate or severe renal failure &#40;CrCl 15&#8211;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;&#44; body weight &#8804;60<span class="elsevierStyleHsp" style=""></span>kg or concomitant use of P-gp inhibitors such as cyclosporine&#44; dronedarone&#44; erythromycin or ketoconazole&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Factors to consider when starting therapy with edoxaban&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0225" class="elsevierStylePara elsevierViewall">It prolongs PT and aPTT&#44; but they are not quantitative tests&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a></p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">It requires strict monitoring of renal function&#44; especially when CrCl is 15&#8211;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46; Not recommended in the case of CrCl &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Not recommended in patients with CrCl &#62;95<span class="elsevierStyleHsp" style=""></span>mL&#47;min &#40;increased risk of stroke compared to warfarin for a 60<span class="elsevierStyleHsp" style=""></span>mg dose&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a></p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">It is mainly absorbed in the upper gastrointestinal tract&#44; so it is possible that drugs or diseases that increase gastric emptying and intestinal motility can also reduce its absorption&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a></p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">It is contraindicated in patients with liver disease associated with coagulopathy and with a risk of clinically relevant bleeding&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">It is not dialyzable&#46;</p></li></ul></p><p id="par0255" class="elsevierStylePara elsevierViewall">Although there are no comparative studies between the different DOACs&#44; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a> summarizes the current clinical evidence to be considered when starting therapy with a DOAC in patients with NVAF according to their clinical characteristics&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">In patients with venous thromboembolic disease</span><p id="par0260" class="elsevierStylePara elsevierViewall">DOACs show an efficacy comparable to standard treatment &#40;parenteral therapy with low molecular weight heparin &#91;LMWH&#93; followed by VKA&#41; with a significant decrease in the risk of bleeding &#40;level of evidence Ib&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">5&#8211;8</span></a> Therefore&#44; the latest recommendations of the <span class="elsevierStyleItalic">American College of Chest Physicians</span> guidelines position DOACs as first-line treatment for patients with VTD without cancer and an option to consider in patients with VTD and cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> summarizes the most important considerations to be considered for the initiation of treatment with DOAC in patients with VTD&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Follow-up and health education</span><p id="par0270" class="elsevierStylePara elsevierViewall">As experts in the management of anticoagulant therapy&#44; we believe that ATUs have an important role to ensure the correct use of these drugs and their follow-up&#46; Considering the recommendations of the <span class="elsevierStyleItalic">European Heart Rhythm Association</span> &#40;level of evidence IV&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a> we suggest the following visit schedule&#58;</p><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">First visit</span><p id="par0275" class="elsevierStylePara elsevierViewall">We recommend making the first visit to the ATU&#44; during which the following data should be recorded &#40;grade 2B recommendation&#41;&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8226;</span><p id="par0280" class="elsevierStylePara elsevierViewall">Indication of anticoagulant therapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#8226;</span><p id="par0285" class="elsevierStylePara elsevierViewall">Relevant pathological&#44; thrombotic and haemorrhagic history&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#8226;</span><p id="par0290" class="elsevierStylePara elsevierViewall">Concomitant medication&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#8226;</span><p id="par0295" class="elsevierStylePara elsevierViewall">Actual weight&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">&#8226;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Determination of thrombotic and bleeding risk &#40;CHA&#41;<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc and HAS-BLED&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">&#8226;</span><p id="par0305" class="elsevierStylePara elsevierViewall">In the case of patients with atrial fibrillation and mitral valve disease&#44; we recommend carrying out an echocardiogram &#40;valid for at least one year&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">&#8226;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Recent analysis &#40;last 3 months&#41; with renal function &#40;CrCl calculation according to the Cockcroft&#8211;Gault formula&#41;&#44; liver function&#44; basic coagulation tests and blood count&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">&#8226;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Individualize DOAC according to the clinical characteristics of each patient&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">&#8226;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Record the start date and all the demographic data of the patient in the specific oral anticoagulant treatment control software of each centre&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">&#8226;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Health education will be essential at the beginning of treatment&#44; where the following actions will be carried out&#46;</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">&#8226;</span><p id="par0330" class="elsevierStylePara elsevierViewall">Explain the mechanism of action&#44; most common adverse events&#44; possible interactions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; perioperative environment and posology&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">&#8226;</span><p id="par0335" class="elsevierStylePara elsevierViewall">Provide the anticoagulation card with DOAC&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a></p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">&#8226;</span><p id="par0340" class="elsevierStylePara elsevierViewall">Provide any teaching material available&#46;</p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">&#8226;</span><p id="par0345" class="elsevierStylePara elsevierViewall">Emphasize the importance of adherence to treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">&#8226;</span><p id="par0350" class="elsevierStylePara elsevierViewall">Provide the contact telephone number of the ATU or PCC to clarify doubts&#44; report possible adverse events&#46;</p></li></ul></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Follow-up visits</span><p id="par0355" class="elsevierStylePara elsevierViewall">Follow-up visits are recommended every 3 months during the first year &#40;grade 2B recommendation&#41;&#44; considering the following&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">&#8226;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Adherence&#44; quality of life and satisfaction with treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">&#8226;</span><p id="par0365" class="elsevierStylePara elsevierViewall">In the case of adverse events&#44; these should be recorded in the clinical history and reported through the yellow pharmacovigilance card&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">&#8226;</span><p id="par0370" class="elsevierStylePara elsevierViewall">In the case of haemorrhagic event&#44; record the start date&#44; classify the bleeding intensity &#40;WHO&#44; ISTH&#44; GUSTO or TIMI scores&#41;&#44; need for hospitalization and therapeutic measures&#46;</p></li><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">&#8226;</span><p id="par0375" class="elsevierStylePara elsevierViewall">In the case of thromboembolic event&#44; record the date&#44; anticoagulant therapy&#44; complications and hospitalization&#46;</p></li><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">&#8226;</span><p id="par0380" class="elsevierStylePara elsevierViewall">Concomitant medication review&#46;</p></li><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">&#8226;</span><p id="par0385" class="elsevierStylePara elsevierViewall">Record the current weight&#46;</p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">&#8226;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Lab results data to be considered&#58; renal function &#40;CrCl&#41;&#44; liver function tests&#44; haemoglobin and platelet count&#46;</p></li><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">&#8226;</span><p id="par0395" class="elsevierStylePara elsevierViewall">Record the discontinuation or change of dosage&#44; indicating date and reason&#46;</p></li><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel">&#8226;</span><p id="par0400" class="elsevierStylePara elsevierViewall">Reassess the indication of DOAC&#46;</p></li><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel">&#8226;</span><p id="par0405" class="elsevierStylePara elsevierViewall">All these data will be recorded in the patient&#39;s medical history&#46;</p></li></ul></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Recommendations for follow-up in the Anticoagulant Treatment Unit</span><p id="par0410" class="elsevierStylePara elsevierViewall">The follow-up will be carried out in the ATU when the patients meet the following characteristics &#40;grade 2B recommendation&#41;&#58;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel">&#8226;</span><p id="par0415" class="elsevierStylePara elsevierViewall">NVAF patients with a very high thromboembolic risk&#58; CHA<span class="elsevierStyleInf">2</span>DS<span class="elsevierStyleInf">2</span>-VASc &#8805;5&#44;</p></li><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel">&#8226;</span><p id="par0420" class="elsevierStylePara elsevierViewall">Mitral valve disease or stroke recurrence&#46;</p></li><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel">&#8226;</span><p id="par0425" class="elsevierStylePara elsevierViewall">Patients with NVAF of very high bleeding risk &#40;HAS-BLED &#62;5&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0285"><span class="elsevierStyleLabel">&#8226;</span><p id="par0430" class="elsevierStylePara elsevierViewall">Patients with VTD or special conditions&#46;</p></li><li class="elsevierStyleListItem" id="lsti0290"><span class="elsevierStyleLabel">&#8226;</span><p id="par0435" class="elsevierStylePara elsevierViewall">Patients with CrCl &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#46;</p></li></ul></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Recommendations for primary care centre follow-up</span><p id="par0440" class="elsevierStylePara elsevierViewall">After the first year of treatment&#44; patients may be referred for a follow-up in the PCC when they meet the following criteria &#40;grade 2B recommendation&#41;&#58;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0295"><span class="elsevierStyleLabel">&#8226;</span><p id="par0445" class="elsevierStylePara elsevierViewall">Patients who do not meet ATU&#39;s control criteria&#46;</p></li><li class="elsevierStyleListItem" id="lsti0300"><span class="elsevierStyleLabel">&#8226;</span><p id="par0450" class="elsevierStylePara elsevierViewall">Patients who have made at least 2 visits to an ATU during the first year&#46;</p></li><li class="elsevierStyleListItem" id="lsti0305"><span class="elsevierStyleLabel">&#8226;</span><p id="par0455" class="elsevierStylePara elsevierViewall">Annual controls are recommended for patients with CrCl &#62;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min and renal function stability during the first year&#46;</p></li><li class="elsevierStyleListItem" id="lsti0310"><span class="elsevierStyleLabel">&#8226;</span><p id="par0460" class="elsevierStylePara elsevierViewall">For patients with CrCl between 30 and 60<span class="elsevierStyleHsp" style=""></span>mL&#47;min and stability of renal function during the first year&#44; controls are recommended every 4&#8211;6 months&#46;</p></li><li class="elsevierStyleListItem" id="lsti0315"><span class="elsevierStyleLabel">&#8226;</span><p id="par0465" class="elsevierStylePara elsevierViewall">In the following situations&#44; referring the patient to an ATU is recommended&#46;</p></li><li class="elsevierStyleListItem" id="lsti0320"><span class="elsevierStyleLabel">&#8226;</span><p id="par0470" class="elsevierStylePara elsevierViewall">Impaired renal function &#40;a decrease in CrCl of 10<span class="elsevierStyleHsp" style=""></span>mL&#47;min in the last 4&#8211;6 months&#41; that requires an evaluation regarding dose change and&#47;or change of anticoagulant treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0325"><span class="elsevierStyleLabel">&#8226;</span><p id="par0475" class="elsevierStylePara elsevierViewall">Presence of adverse events or unexpected laboratory abnormalities&#46;</p></li><li class="elsevierStyleListItem" id="lsti0330"><span class="elsevierStyleLabel">&#8226;</span><p id="par0480" class="elsevierStylePara elsevierViewall">Prognosis of surgery or moderate and high-risk procedures for perioperative recommendations&#46;</p></li></ul></p></span></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Special conditions</span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Perioperative management</span><p id="par0485" class="elsevierStylePara elsevierViewall">DOAC discontinuation will be necessary prior to any invasive procedure that entails a bleeding risk&#46; In order to establish the haemostatic safety threshold of these drugs&#44; it is necessary to consider their pharmacokinetics and pharmacodynamics&#46; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> summarizes the perioperative approach in patients anticoagulated with DOAC&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Considerations</span><p id="par0490" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0335"><span class="elsevierStyleLabel">&#8226;</span><p id="par0495" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Bridge therapy</span>&#44; common in patients anticoagulated with VKA&#44; is not applicable in DOAC&#46; The use of heparin in the perioperative setting of anticoagulated patients with DOAC is controversial&#46; The Dresden prospective registry does not contemplate the use of heparin after DOAC discontinuation during the preoperative period due to a significant increase in the bleeding rate &#40;level of evidence III&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a> However&#44; patients at high thromboembolic risk could benefit from the use of LMWH at prophylactic or intermediate doses during the postoperative period until they can safely restart DOAC or when the patient does not tolerate the oral route&#46; GIHP <span class="elsevierStyleItalic">&#40;Le Groupe d&#8217;Int&#233;r&#234;t in H&#233;mostase P&#233;riop&#233;ratoire&#41;</span>&#44; on the contrary&#44; suggests discontinuing DOAC 5 days before any surgery of moderate or high bleeding risk to ensure the complete clearance of the drug and recommend assessing the use of LMWH or unfractionated heparin &#40;UFH&#41; in the preoperative period when the patient has an elevated thromboembolic risk &#40;level of evidence IV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p></li><li class="elsevierStyleListItem" id="lsti0340"><span class="elsevierStyleLabel">&#8226;</span><p id="par0500" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Renal function</span>&#44; CrCl should be estimated by the Cockcroft&#8211;Gault formula&#44; because overestimation of renal function by other methods could induce a wrong prescription and increase the risk of bleeding during the perioperative period &#40;level of evidence IIb&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a></p></li><li class="elsevierStyleListItem" id="lsti0345"><span class="elsevierStyleLabel">&#8226;</span><p id="par0505" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">patient&#39;s bleeding risk</span>&#44; for which the HAS-BLED and RIETE scores for NVAF and VTD &#40;level of evidence I-II&#41; could be used&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">30&#44;31</span></a></p></li><li class="elsevierStyleListItem" id="lsti0350"><span class="elsevierStyleLabel">&#8226;</span><p id="par0510" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">bleeding risk of surgery</span> and the possible consequences of bleeding on the outcome of surgery and patient safety &#40;level of evidence IIb&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a></p></li><li class="elsevierStyleListItem" id="lsti0355"><span class="elsevierStyleLabel">&#8226;</span><p id="par0515" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Coagulation tests&#46;</span> Routine tests only assess the anticoagulant effect qualitatively and should not be used in this clinical scenario&#46; The anti-factor Xa determination with calibrated techniques &#40;rivaroxaban&#44; apixaban and edoxaban&#41; and diluted TT or ecarin time &#40;dabigatran&#41; could be useful to quantify the plasma levels of these drugs&#46;</p></li></ul></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Recommendations</span><p id="par0520" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0360"><span class="elsevierStyleLabel">&#8226;</span><p id="par0525" class="elsevierStylePara elsevierViewall">Do not systematically use LMWH or UFH in the preoperative period after the discontinuation of DOAC &#40;grade 2A recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0365"><span class="elsevierStyleLabel">&#8226;</span><p id="par0530" class="elsevierStylePara elsevierViewall">During the postoperative period of patients with NVAF&#44; use prophylactic doses of LMWH or UFH&#44; until haemostasis is considered safe and DOAC can be restarted &#40;grade 2B recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0370"><span class="elsevierStyleLabel">&#8226;</span><p id="par0535" class="elsevierStylePara elsevierViewall">During the postoperative period of patients with VTD&#44; use LMWH or UFH at increasing doses&#46; It should be started within 24<span class="elsevierStyleHsp" style=""></span>h postoperatively until haemostasis is considered safe and DOAC can be restarted &#40;grade 2B recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0375"><span class="elsevierStyleLabel">&#8226;</span><p id="par0540" class="elsevierStylePara elsevierViewall">In relation to the laboratory tests&#44; according to each DOAC&#58;</p></li></ul><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0380"><span class="elsevierStyleLabel">-</span><p id="par0545" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Dabigatran</span>&#58; Normal TT indicates the absence of the anticoagulant effect of dabigatran and&#44; due to its extreme sensitivity&#44; it may not be useful in emergency situations because it could unnecessarily delay the decision to perform the surgery&#46; A normal aPTT indicates with relative reliability that dabigatran levels allow safe haemostasis &#40;grade 2A recommendation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">19</span></a></p></li><li class="elsevierStyleListItem" id="lsti0385"><span class="elsevierStyleLabel">-</span><p id="par0550" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Rivaroxaban</span>&#58; can lengthen the PT&#44; but its normal values do not imply absence of anticoagulant effect &#40;grade 2A recommendation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a></p></li><li class="elsevierStyleListItem" id="lsti0390"><span class="elsevierStyleLabel">-</span><p id="par0555" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Apixaban</span>&#58; PT is not a sensitive test&#44; so it should not be considered a qualitative test &#40;grade 2A recommendation&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">19&#8211;23</span></a></p></li><li class="elsevierStyleListItem" id="lsti0395"><span class="elsevierStyleLabel">-</span><p id="par0560" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Edoxaban</span>&#58; PT and aPTT may be prolonged&#44; but they are not quantitative tests &#40;grade 2A recommendation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a></p></li></ul></p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Advanced age</span><p id="par0565" class="elsevierStylePara elsevierViewall">The possibility of presenting an episode of atrial fibrillation or VTD increases with age&#46; The risk of ischaemic stroke increases 1&#46;5 times for every 10 years of age&#46; Those over 85 years of age are the most exposed given the higher prevalence of atrial fibrillation in this age group&#46; Similarly&#44; the incidence of VTD increases with age and is up to 6 times higher in patients over 80 years of age<span class="elsevierStyleInf">&#46;</span> On the other hand&#44; the bleeding risk related to anticoagulation increases by 40&#37; for every 10 years of age&#59; for this reason&#44; only 50&#8211;60&#37; of patients with atrial fibrillation are anticoagulated&#44; and only 35&#37; of those over 85 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a></p><p id="par0570" class="elsevierStylePara elsevierViewall">DOACs have shown a reduction in stroke compared to warfarin in the subgroup of patients over 75 years of age &#40;level of evidence Ib&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#8211;4</span></a> In the analyses by subgroups&#44; for those over 75 years of age&#44; dabigatran and apixaban at high doses showed a reduction in stroke compared to warfarin&#44; with similar results in the case of rivaroxaban and dabigatran at low doses&#46;</p><p id="par0575" class="elsevierStylePara elsevierViewall">In addition&#44; dabigatran 110<span class="elsevierStyleHsp" style=""></span>mg and apixaban 5<span class="elsevierStyleHsp" style=""></span>mg were shown to significantly reduce the risk of fatal bleeding &#40;level of evidence Ib&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;3</span></a> Edoxaban has been shown to be safe in patients at risk of falls &#40;level of evidence Ib&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a> DOACs are an alternative to consider in this population&#44; because they do not require monitoring&#44; avoid frequent point-of-care visits&#44; and have a lower number of drug interactions&#44; an important aspect given the common polypharmacy of elderly patients&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Considerations</span><p id="par0580" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0400"><span class="elsevierStyleLabel">-</span><p id="par0585" class="elsevierStylePara elsevierViewall">When an elderly patient is anticoagulated&#44; the risk of falls should always be assessed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0405"><span class="elsevierStyleLabel">-</span><p id="par0590" class="elsevierStylePara elsevierViewall">There is a higher prevalence of renal failure and comorbidities in this group of patients&#46;</p></li></ul></p><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Recommendations</span><p id="par0595" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0410"><span class="elsevierStyleLabel">&#8226;</span><p id="par0600" class="elsevierStylePara elsevierViewall">In patients &#8805;80 years of age with a history of frequent falls or high bleeding risk&#44; we recommend considering apixaban 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; dabigatran 110<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; edoxaban 30<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h rivaroxaban 15<span class="elsevierStyleHsp" style=""></span>mg per day &#40;grade 2A recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0415"><span class="elsevierStyleLabel">&#8226;</span><p id="par0605" class="elsevierStylePara elsevierViewall">The use of apixaban&#44; rivaroxaban&#44; dabigatran or edoxaban is recommended over VKAs in patients &#8805;80 years of age candidates for anticoagulant treatment with a history of intracranial haemorrhage &#40;grade 1 recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0420"><span class="elsevierStyleLabel">&#8226;</span><p id="par0610" class="elsevierStylePara elsevierViewall">In those patients in whom a simple posology guarantees a better adherence&#44; evaluate rivaroxaban or edoxaban by adjusting dose to renal function &#40;grade 2B recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0425"><span class="elsevierStyleLabel">&#8226;</span><p id="par0615" class="elsevierStylePara elsevierViewall">In patients &#8805;80 years of age with gastrointestinal symptomatology &#40;hiatal hernia&#44; gastro-oesophageal reflux&#44; gastritis&#44; oesophagitis&#41; we recommend the use of apixaban&#44; rivaroxaban or edoxaban &#40;grade 2A recommendation&#41;&#46;</p></li></ul></p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Cancer patient</span><p id="par0620" class="elsevierStylePara elsevierViewall">Oncology patients have a higher risk of venous thromboembolic events and arrhythmias&#44; as well as a considerable risk of bleeding&#44; taking into account the invasive procedures they sometimes undergo and drug-induced thrombocytopaenia&#59; so&#44; the use of anticoagulants in these patients is usually a challenge&#46;</p><p id="par0625" class="elsevierStylePara elsevierViewall">The number of patients with cancer in the main studies for both NVAF and VTD does not reach 5&#37;&#46; However&#44; the analyses by subgroups do not show differences in efficacy and safety &#40;level of evidence Ib&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#8211;8</span></a></p><p id="par0630" class="elsevierStylePara elsevierViewall">DOACs have not been compared to the recommended treatment &#40;LMWH&#41; in cancer patients with VTD&#46; The safety profile of these antithrombotic agents could favour their use&#44; since they demonstrated a significant reduction in the risk of recurrent VTD or major bleeding&#44; compared to VKA &#40;level of evidence IIb&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a></p><p id="par0635" class="elsevierStylePara elsevierViewall">There is no evidence of the use of DOAC in patients with NVAF and active cancer&#44; since many of them were excluded from the main studies because they present a high risk of haemorrhage or a short life expectancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#8211;4</span></a></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Considerations</span><p id="par0640" class="elsevierStylePara elsevierViewall">A DOAC can always be considered under the ATU&#39;s monitoring and taking into account&#58;<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0430"><span class="elsevierStyleLabel">&#8226;</span><p id="par0645" class="elsevierStylePara elsevierViewall">Pharmacological interactions with antineoplastic&#44; antifungals and drugs that induce or inhibit CYP3A4 or P-gp &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0435"><span class="elsevierStyleLabel">&#8226;</span><p id="par0650" class="elsevierStylePara elsevierViewall">A correct oral tolerance&#46;</p></li><li class="elsevierStyleListItem" id="lsti0440"><span class="elsevierStyleLabel">&#8226;</span><p id="par0655" class="elsevierStylePara elsevierViewall">Possibility of thrombocytopaenia secondary to toxicity due to antineoplastic treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0445"><span class="elsevierStyleLabel">&#8226;</span><p id="par0660" class="elsevierStylePara elsevierViewall">Possibility of nephrotoxicity by some antineoplastics such as platinum-based agents&#46;</p></li></ul></p><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Recommendations</span><p id="par0665" class="elsevierStylePara elsevierViewall">The current indication in the patient with active cancer is LMWH&#44; although the use of DOAC in selected situations and in specific cancer patients can be assessed&#44; which requires a multidisciplinary assessment&#44; given the lack of clinical evidence&#46; Some of these situations are the following&#58;<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0450"><span class="elsevierStyleLabel">&#8226;</span><p id="par0670" class="elsevierStylePara elsevierViewall">In patients with NVAF and active cancer&#44; it is recommended to assess the use of DOAC taking into account the considerations previously discussed &#40;grade 2B recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0455"><span class="elsevierStyleLabel">&#8226;</span><p id="par0675" class="elsevierStylePara elsevierViewall">The use of DOAC in cancer-related VTD should be considered during the extended treatment after the initial 6-month therapy &#40;grade 2B recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0460"><span class="elsevierStyleLabel">&#8226;</span><p id="par0680" class="elsevierStylePara elsevierViewall">In patients with active antineoplastic treatment and DOAC&#44; the platelet count &#40;making sure it does not decrease below 501<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>0<span class="elsevierStyleSup">9</span>&#47;L&#41; and renal function &#40;grade 2B recommendation&#59; consensus recommendation based on the clinical experience observed after the use of LMWH in cancer patients under active treatment&#41; should be monitored&#46;</p></li></ul></p></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Renal failure</span><p id="par0685" class="elsevierStylePara elsevierViewall">The coexistence of chronic renal failure &#40;CRF&#41; in patients with atrial fibrillation is common&#44; since both entities frequently develop with age&#46; CRF is a known risk factor for the development of VTD and severe bleeding with or without anticoagulant therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a> DOACs have different degrees of renal clearance and&#44; although patients with severe renal failure were excluded from the trials&#44; the indirect comparison between DOACs shows certain differences depending on CrCl&#46;</p><p id="par0690" class="elsevierStylePara elsevierViewall">Patients with mild renal failure treated with DOAC had a lower rate of stroke and systemic embolism&#44; with a reduction of major or clinically relevant bleeding compared to VKA&#44; and similar rates of bleeding compared to LMWH&#46; In the case of moderate renal failure&#44; a significant reduction in thrombotic risk was also demonstrated&#44; without bleeding differences compared to VKA&#44; LMWH or anti-platelet agents &#40;level of evidence Ia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Considerations</span><p id="par0695" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0465"><span class="elsevierStyleLabel">&#8226;</span><p id="par0700" class="elsevierStylePara elsevierViewall">DOACs have different degrees of renal clearance &#40;dabigatran 80&#37;&#44; edoxaban 50&#37;&#44; rivaroxaban 33&#37; and apixaban 27&#37;&#41; and the indirect comparison between them shows certain differences in the case of renal failure &#40;level of evidence Ia&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a></p></li><li class="elsevierStyleListItem" id="lsti0470"><span class="elsevierStyleLabel">&#8226;</span><p id="par0705" class="elsevierStylePara elsevierViewall">In mild renal failure &#40;GF 50&#8211;79<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;&#44; apixaban and dabigatran 110<span class="elsevierStyleHsp" style=""></span>mg were associated with lower rates of major bleeding &#40;level of evidence Ia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a></p></li><li class="elsevierStyleListItem" id="lsti0475"><span class="elsevierStyleLabel">&#8226;</span><p id="par0710" class="elsevierStylePara elsevierViewall">In moderate renal failure &#40;GF 25&#8211;49<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;&#44; apixaban presented a better safety profile &#40;but not efficacy&#41; compared to dabigatran 110<span class="elsevierStyleHsp" style=""></span>mg and rivaroxaban &#40;level of evidence Ia&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a></p></li><li class="elsevierStyleListItem" id="lsti0480"><span class="elsevierStyleLabel">&#8226;</span><p id="par0715" class="elsevierStylePara elsevierViewall">In patients with NVAF who presented a continuous worsening of renal function &#40;decrease in CrCl &#62;20&#37; in patients with GF &#62;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;&#44; rivaroxaban was associated with lower rates of stroke and systemic embolism compared to patients on warfarin&#44; without showing a higher risk of bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">37</span></a></p></li><li class="elsevierStyleListItem" id="lsti0485"><span class="elsevierStyleLabel">&#8226;</span><p id="par0720" class="elsevierStylePara elsevierViewall">In patients with GFR between 30 and 50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; edoxaban was not lower than warfarin in stroke prevention and showed a significant reduction in bleeding &#40;level of evidence IIa&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a></p></li></ul></p><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Recommendations</span><p id="par0725" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0490"><span class="elsevierStyleLabel">&#8226;</span><p id="par0730" class="elsevierStylePara elsevierViewall">If CrCl &#62;50<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#58; DOAC should be prescribed according to comorbidities and concomitant medication &#40;grade 2A recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0495"><span class="elsevierStyleLabel">&#8226;</span><p id="par0735" class="elsevierStylePara elsevierViewall">If CrCl 31&#8211;49<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#58; apixaban 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h &#40;if creatinine &#8805;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and&#44; besides&#44; associates &#8805;80 years of age or weight &#8804;60<span class="elsevierStyleHsp" style=""></span>kg&#44; reduce dose to 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; rivaroxaban 15<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; or edoxaban 30<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46; As for dabigatran&#44; a dose of 110<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h is recommended &#40;grade 1 recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0500"><span class="elsevierStyleLabel">&#8226;</span><p id="par0740" class="elsevierStylePara elsevierViewall">If CrCl 15&#8211;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; it can be used with caution&#58; apixaban 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; rivaroxaban 15<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h edoxaban 30<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46; Dabigatran is contraindicated &#40;grade 2A recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0505"><span class="elsevierStyleLabel">&#8226;</span><p id="par0745" class="elsevierStylePara elsevierViewall">If CrCl &#60;15<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#58; contraindication for any DOAC &#40;grade 1 recommendation&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0510"><span class="elsevierStyleLabel">&#8226;</span><p id="par0750" class="elsevierStylePara elsevierViewall">Haemodialysis&#58; there are no efficacy and safety data&#46;</p></li></ul></p></span></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Practical management during bleeding</span><p id="par0755" class="elsevierStylePara elsevierViewall">If any bleeding occurs in the context of anticoagulation with a DOAC&#44; the measures to be considered are the withdrawal of the drug and quantifying the time elapsed since the last dose of anticoagulant&#46; The management of bleeding according to its severity includes the usual support measures&#46; The renal function and the basic haemostasis study should be determined to assess the possible anticoagulant effect in cases where it may be useful&#46;</p><p id="par0760" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a> outlines the recommended management from the TROMBOC&#64;T group in case of bleeding and depending on its severity&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Reversing agents</span><p id="par0765" class="elsevierStylePara elsevierViewall">The monoclonal antibody&#44; idarucizumab&#44; is the specific antidote for dabigatran&#46; It achieves a dose-dependent&#44; irreversible inhibition of both free and thrombin-bound dabigatran&#46; It has a biphasic renal clearance&#44; with a half-life of approximately 45<span class="elsevierStyleHsp" style=""></span>min &#40;level of evidence IIa&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a></p><p id="par0770" class="elsevierStylePara elsevierViewall">After the results of the RE-VERSE AD study&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a> it has been approved for hospital use&#44; both by the FDA and by the EMA&#46; It is available in Spain since December 2015&#46;</p><p id="par0775" class="elsevierStylePara elsevierViewall">In case of severe bleeding or emergency surgery&#44; requiring the immediate reversion of the anticoagulant effect of dabigatran&#44; the use of idarucizumab will be assessed taking into account the time elapsed since the last administration of DOAC&#44; CrCl according to the Cockcroft&#8211;Gault formula and the extension of the aPTT and TT &#40;grade 2A recommendation&#41;&#46; See <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a> on the protocol of use&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0780" class="elsevierStylePara elsevierViewall">Andexanet alfa &#40;PRT064445&#41;&#44; an anti-Xa anticoagulant reversal agent&#44; including heparins and fondaparinux&#44; is currently in the clinical trial phase&#44; like ciraparantag&#44; which seems effective in the reversal of all DOACs&#44; fondaparinux and heparins&#46;</p></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Conclusions</span><p id="par0785" class="elsevierStylePara elsevierViewall">The progressive increase in the use of DOACs requires the establishment and standardization of clinical practice guidelines for the benefit of patients anticoagulated with these antithrombotic agents in both ATU and PCC&#46; The present work corresponds to the consensus guidelines of the TROMBOC&#64;T working group on the management and follow-up of patients receiving DOAC&#46; To this end&#44; the available medical literature has been thoroughly reviewed and a series of meetings have been held with experts in the field of anticoagulation to identify the areas where data with a high degree of evidence exist and those where consensus is required based on clinical experience&#46; The work includes novel aspects&#44; not mentioned in other guidelines&#44; to carry out an interdisciplinary and bidirectional management between ATUs and PCCs&#46; A set of practical recommendations has been established as a result of the project&#44; which will facilitate the management and follow-up of patients on DOAC therapy&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0240">Conflict of interests</span><p id="par0790" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In recent years&#44; direct oral anticoagulants &#40;DOACs&#41; have become an alternative to vitamin K antagonists &#40;VKA&#41; for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation &#40;NVAF&#41; as well as for the prevention and treatment of deep venous thrombosis&#46; Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin&#44; which increases the options of anticoagulant treatment&#46; In our setting&#44; the anticoagulant treatment units &#40;ATUs&#41; and primary care centres &#40;PCCs&#41; play an important role in the education&#44; follow-up&#44; adherence control and management in special situations of anticoagulated patients&#46; These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A group of experts from the Catalan Thrombosis Group &#40;TROMBOC&#64;T&#41; reviewed all published literature from 2009 to 2016&#44; in order to provide recommendations based on clinical evidence&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">As a result of the project&#44; a set of practical recommendations have been established that will facilitate treatment&#44; education&#44; follow-up and management in special situations of anticoagulated patients with ACODs&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Progressive increase in the use of DOACs calls for measures to establish and homogenize clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En los &#250;ltimos a&#241;os los anticoagulantes orales directos &#40;ACOD&#41; se han convertido en una alternativa a los antagonistas de la vitamina K &#40;AVK&#41; para la prevenci&#243;n del ictus y embolia sist&#233;mica en pacientes con fibrilaci&#243;n auricular no valvular &#40;FANV&#41;&#44; as&#237; como para la prevenci&#243;n y tratamiento de la trombosis venosa profunda&#46; Los ensayos cl&#237;nicos han demostrado la no inferioridad y la potencial superioridad en comparaci&#243;n con la warfarina&#44; lo cual permite ampliar las opciones de anticoagulaci&#243;n&#46; En nuestro medio&#44; las Unidades de Tratamiento Anticoagulante &#40;UTA&#41; y los Centros de Atenci&#243;n Primaria &#40;CAP&#41; son los encargados de la educaci&#243;n&#44; seguimiento&#44; control de adherencia y del manejo en situaciones especiales de los pacientes anticoagulados&#46; Estas consideraciones han motivado la preparaci&#243;n del presente documento de consenso&#44; que tiene como objetivo establecer recomendaciones que incorporen los hallazgos de la investigaci&#243;n cient&#237;fica a la pr&#225;ctica cl&#237;nica para mejorar la calidad asistencial en el &#225;mbito de la anticoagulaci&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Un grupo de expertos del Grupo Catal&#225;n de Trombosis &#40;TROMBOC&#64;T&#41; ha revisado la bibliograf&#237;a publicada entre 2007 y 2016 para poder establecer recomendaciones basadas en la evidencia cl&#237;nica&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Como resultado del proyecto se han establecido un conjunto de recomendaciones de car&#225;cter pr&#225;ctico que facilitar&#225;n el tratamiento&#44; educaci&#243;n&#44; seguimiento y manejo en situaciones especiales de los pacientes anticoagulados con ACOD&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El aumento progresivo del uso de los ACOD requiere establecer y homogeneizar las directrices de actuaci&#243;n cl&#237;nica en el paciente anticoagulado con estos antitromb&#243;ticos tanto en las UTA como en los CAP&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; Olivera P&#44; Gabilondo M&#44; Constans M&#44; T&#224;ssies D&#44; Plensa E&#44; Pons V&#44; et al&#46; Recomendaciones del Grupo Catal&#225;n de Trombosis &#40;Tromboc&#64;t Working Group&#41; para el tratamiento de los pacientes que reciben anticoagulantes orales directos&#46; Med Clin&#46; 2018&#59;151&#58;210&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Considerations for the start of treatment with DOAC in VTD&#46;</p>"
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      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 3130
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            "Tamanyo" => 736378
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Main pharmacological interactions of DOAC&#46; <elsevierMultimedia ident="201810040626358081"></elsevierMultimedia>&#58; contraindicated&#59; <elsevierMultimedia ident="201810040626358082"></elsevierMultimedia>&#58; use with caution&#59; <elsevierMultimedia ident="201810040626358083"></elsevierMultimedia>&#58; no interaction&#46; Positive &#40;&#43;&#41;&#58; enhances the effect&#59; negative &#40;&#8722;&#41;&#58; decreases the effect&#59; NK&#58; not known&#46; &#42;Decrease from 12&#37; to 30&#37;&#44; without reducing efficacy in clinical trials&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 3099
            "Ancho" => 2383
            "Tamanyo" => 725352
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Perioperative approach for patients anticoagulated with DOAC&#46;<span class="elsevierStyleSup">&#42;</span>Assess DOAC withdrawal one more day&#44; depending on the risk of bleeding&#46; &#42;&#42;Assess delaying the restart of DOAC one more day&#44; depending on haemostatic safety&#46; Do not administer LMWH or UFH after the discontinuation of DOAC in the preoperative period&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 3979
            "Ancho" => 2917
            "Tamanyo" => 814228
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Algorithm for the management of bleeding in patients anticoagulated with DOAC&#46; <span class="elsevierStyleSup">&#42;</span>Classification of bleeding according to ISTH and GUSTO scores&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 4105
            "Ancho" => 2917
            "Tamanyo" => 464119
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Protocol for the use of idarucizumab&#46; <span class="elsevierStyleSup">&#42;</span>Classification of bleeding according to the ISTH&#46;</p>"
        ]
      ]
      5 => 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"
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        "tabla" => array:1 [
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              "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" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Levels of evidence</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>Level Ia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis of controlled&#44; randomized&#44; well-designed trials&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Level Ib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At least one randomized controlled trial&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Level IIa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At least&#44; a well-designed controlled study without randomizing&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Level IIb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">At least&#44; a study not completely experimental&#44; well designed&#44; like the cohort studies&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Level III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-experimental&#44; well-designed descriptive studies such as comparative studies&#44; correlation studies or case-control studies&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Level IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Documents or opinions of expert committees or clinical experiences of prestigious authorities or case series studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" 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="2" align="left" valign="top"><span class="elsevierStyleItalic">Degrees of recommendation</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>Category 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The available evidence is of high quality and there is consensus among the experts&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Category 2A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The available evidence is of moderate quality and there is unanimous consensus among experts&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Category 2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The available evidence is of moderate quality and there is no unanimous consensus among experts&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Category 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The available evidence may have any grade&#44; but there is no consensus among experts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1864487.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Levels of evidence and degrees of recommendation&#46;</p>"
        ]
      ]
      6 => 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"
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        ]
        "tabla" => array:2 [
          "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">Characteristics&nbsp;\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">Dabigatran&nbsp;\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">Rivaroxaban&nbsp;\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">Apixaban&nbsp;\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">Edoxaban&nbsp;\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"><span class="elsevierStyleItalic">Mechanism of action</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FIIa inhibitor &#40;thrombin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct FXa inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct FXa inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct FXa inhibitor&nbsp;\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"><span class="elsevierStyleItalic">Dosage &#40;mg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#46;30<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">110&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\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"><span class="elsevierStyleItalic">Frequency</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\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"><span class="elsevierStyleItalic">Bioavailability&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;5 &#40;pH-dependent&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80 &#40;100&#37; with food&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&nbsp;\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"><span class="elsevierStyleItalic">Renal clearance &#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 &#40;active metabolite&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#8211;50&nbsp;\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"><span class="elsevierStyleItalic">Metabolic pathway</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">P-gP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CYP 3A4&#47;2J2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">P-gP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">P-gP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">P-gP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Half-life &#40;hours&#41;</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>CrCl&#62;80<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>CrCl 50&#8211;80<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>CrCl 30&#8211;49<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#8211;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></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="elsevierStyleItalic">Hours to reach Cmax</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;2&nbsp;\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"><span class="elsevierStyleItalic">Absorption with Ibp</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" 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="5" align="left" valign="top"><span class="elsevierStyleItalic">Practical points</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>Interactions with food or alcohol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Dyspepsia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8211;10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Dialyzable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Possible&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Antidote&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Idarucizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Andexanet alfa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Andexanet alfa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Andexanet alfa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Primary prevention for VTD&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Treatment for NVAF&#47;DVT and PTE&#59; Andexanet alfa still in clinical trial phase&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Decrease from 12&#37; to 30&#37;&#44; without reducing efficacy in clinical trials&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Most relevant DOAC characteristics&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 3"
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                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">Moderate or severe mitral stenosis &#40;usually of rheumatic aetiology&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Contraindicated&nbsp;\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">Mechanical prosthetic valves in any position&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Contraindicated&nbsp;\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">Severe aortic stenosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indicated&nbsp;\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">Mild or moderate disease of another native valve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Indicated&nbsp;\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">Valvular bioprosthesis<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From the third postoperative month&nbsp;\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">Mitral valve repair<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From the third postoperative month&nbsp;\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">Percutaneous Transluminal Aortic Valvuloplasty and Transcatheter Aortic Valve Stent Implantation &#40;TAVI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To be assessed&#44; considering the bleeding risk&#44; because they can associate simple or double antiplatelet therapy &#40;no prospective data available&#41;&nbsp;\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">Hypertrophic cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">To be assessed&#44; given that there is no prospective data&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">The American guidelines do not recommend the use of DOAC in patients with valvular repair or after valve replacement with biological prostheses&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Indications and contraindications in patients with NVAF&#46;</p>"
        ]
      ]
      8 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
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        "tabla" => array:1 [
          "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">Patient characteristics&nbsp;\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">Recommended dose&nbsp;\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">Comments&nbsp;\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  " rowspan="4" align="left" valign="top">Patients with NVAF at high risk of thrombosis&#58; CHA2DS2-VASc &#8805;3 or previous stroke</td><td class="td" title="table-entry  " align="left" valign="top">Dabigatran 150<span class="elsevierStyleHsp" style=""></span>mg orally every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">This dose of dabigatran associated a greater reduction in the risk of stroke compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a>&nbsp;\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">Rivaroxaban 20<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The pivotal study with rivaroxaban had a higher number of patients with previous stroke&#46; Compared to warfarin&#44; patients with a previous myocardial infarction assigned to rivaroxaban had a nonsignificant 14&#37; reduction in the risk of ischaemic heart events<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&nbsp;\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">Apixaban 5<span class="elsevierStyleHsp" style=""></span>mg orally every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">This dose associated a greater reduction in the risk of stroke compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a>&nbsp;\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">Edoxaban 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In patients with NVAF&#44; both doses were not inferior to warfarin in the prevention of stroke and systemic embolism<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Patients with NVAF at high risk of bleeding &#40;HAS-BLED &#62;3&#41;</td><td class="td" title="table-entry  " align="left" valign="top">Apixaban 5<span class="elsevierStyleHsp" style=""></span>mg orally every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">This dose of apixaban associated a decrease in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a>&nbsp;\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">Dabigatran 110<span class="elsevierStyleHsp" style=""></span>mg orally every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">This dose of dabigatran associated a decrease in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a>&nbsp;\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">Rivaroxaban 20<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No significant difference was found in the risk of major bleeding compared to warfarin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>0&#46;44&#41;&#44; however&#44; intracranial and fatal bleeding occurred less frequently in the rivaroxaban group<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&nbsp;\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">Edoxaban 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Both doses were significantly associated with a lower rate of bleeding&#46; The dose of 30<span class="elsevierStyleHsp" style=""></span>mg was significantly associated with a lower mortality rate from all causes<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a>&nbsp;\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">Patients with dyspepsia or other gastrointestinal complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rivaroxaban&#44; apixaban and edoxaban&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">These drugs have been associated with less dyspepsia than dabigatran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Patients with NVAF and in whom difficulties of treatment adherence are expected</td><td class="td" title="table-entry  " align="left" valign="top">Rivaroxaban and edoxaban&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dosing once a day could allow a better medication compliance in the long term&nbsp;\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">Dabigatran or apixaban&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Real-life data support DOACs adherence when these have a posology of every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Elderly patients &#62;80 years of age&#44; frail&#44; with severe deterioration of renal function &#40;e&#46;g&#46; CrCl &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#41;</td><td class="td" title="table-entry  " align="left" valign="top">Apixaban 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Apixaban was associated with a decrease in bleeding in patients with impaired renal function<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a>&nbsp;\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">Rivaroxaban 15<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No significant difference was found in the risk of major bleeding compared to warfarin<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a>&nbsp;\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">Edoxaban 30<span class="elsevierStyleHsp" style=""></span>mg orally every 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Only a small amount of edoxaban is metabolized through carboxylesterase<span class="elsevierStyleHsp" style=""></span>1 and CYP3A4&#44; being less susceptible to drug interactions&#44; so polypharmacy patients show an adequate profile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Considerations for the initiation of DOAC according to the clinical characteristics of the patient&#46;</p>"
        ]
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dabigatran versus warfarin in patients with atrial fibrillation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;J&#46; Connolly"
                            1 => "M&#46;D&#46; Ezekowitz"
                            2 => "S&#46; Yusuf"
                            3 => "J&#46; Eikelboom"
                            4 => "J&#46; Oldgren"
                            5 => "P&#46;A&#46; Reilly"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa0905561"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2009"
                        "volumen" => "361"
                        "paginaInicial" => "1139"
                        "paginaFinal" => "1151"
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