Dabigatran: Experience in standard clinical practice

Álvarez-Otero, J.; de la Fuente-Aguado, J.; Arias-Castaño, J.C.; González-González, L.; Puerta-Louro, R.; Araújo-Fernández, S.

doi:10.1016/j.rceng.2015.05.002

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Álvarez-Otero, J. de la Fuente-Aguado, J.C. Arias-Castaño, L. González-González, R. Puerta-Louro, S. Araújo-Fernández" "autores" => array:6 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Álvarez-Otero" "email" => array:1 [ 0 => "judithao@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "de la Fuente-Aguado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "J.C." "apellidos" => "Arias-Castaño" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "L." "apellidos" => "González-González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "R." 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The international normalized ratio (INR) is therefore often outside the therapeutic range.<a class="elsevierStyleCrossRef" href="#bib0130">1</a>Dabigatran is a direct thrombin inhibiting anticoagulant drug.<a class="elsevierStyleCrossRef" href="#bib0135">2</a> The drug is authorized for the prevention of ischemic stroke in adults with nonvalvular atrial fibrillation and one or more of the following factors: prior stroke, transient ischemic attack or systemic embolism; left ventricular ejection fraction <40%; symptomatic heart failure greater than grade 2 of the New York Heart Association (NYHA), age older than 75 years or younger than 65 years associated with diabetes mellitus, coronary artery disease or hypertension. The drug is administered orally, in the form of the prodrug dabigatran etexilate and has a half-life between 12 and 14h. Eighty percent of the drug is excreted by the kidneys.<a class="elsevierStyleCrossRef" href="#bib0135">2</a> Unlike VKAs, dabigatran has predictable pharmacokinetics and pharmacodynamics and therefore does not require coagulation monitoring.Given that dabigatran is indicated for long-term use in preventing ischemic stroke, it is important to conduct observational studies that compare the results of the clinical trials with those observed in standard clinical practice, both in terms of the drug's efficacy in preventing cerebral ischemic events and its tolerance and safety profile.Material and methodsA descriptive and retrospective study was conducted, which included all patients who started anticoagulant treatment with dabigatran in the specialized care setting between November 2011 and September 2012. Follow-up was performed from the start of treatment until June 2013.Given that this drug requires a prescription for dispensing, the list was provided by the Department of Pharmacy of Hospital Povisa (Vigo). The study respected the data confidentiality guarantee (Organic Law on Data Protection 15/99).The medical records of all patients who took at least one dose of the drug were reviewed. The following data were collected from each patient: age, sex, indication for anticoagulation, whether the administration of dabigatran was primary or secondary to problems with dicoumarin agents, comorbidities (arterial hypertension, heart failure, diabetes mellitus), glomerular filtration rate calculated using the modified MDRD formula (classifying the degree of renal failure as severe if <30mL/min and moderate for 30–60mL/min, according to the KDOQI guidelines of the National Kidney Foundation),<a class="elsevierStyleCrossRef" href="#bib0140">3</a> prior stroke, concomitant treatment with acetylsalicylic acid (ASA), clopidogrel or nonsteroidal anti-inflammatory drugs, and serum concentrations of hemoglobin, urea and creatinine. The CHADS2 and HAS-BLED scores for each patient were calculated.Through a medical history review and the consultation with the responsible physician, the onset of cerebral, cardiac and peripheral ischemic events was determined. Furthermore, we reported the hemorrhagic complications and the location and severity of the bleeding. Bleeding was classified as major (a reduction >2g/dL in hemoglobin) or minor (reduction <2g/dL of hemoglobin).The statistical analysis was performed using version 15 of the SPSS application. Descriptive statistics were conducted using frequencies and percentages for the qualitative variables and mean and standard deviation for the quantitative variables. The comparison among qualitative variables was performed using the chi-squared test, with Fisher correction when necessary, calculating the odds ratio (OR) with 95% confidence intervals (CI). A multivariate binary logistic regression was performed to control for confounding factors or interactions related to the bleeding in the univariate analysis. The comparison of quantitative variables between the patients with and without bleeding was performed using Student's t-test when the distribution was normal or the Mann Whitney U-test otherwise. To compare the evolution of the patients’ laboratory results, we used Student's t-test for paired data. Statistical significance was considered at p<.05.ResultsWe analyzed 316 patients who started treatment with dabigatran during the study period. The mean age was 76.46±8.37 years; 53.5% of the patients were men. The most common personal antecedents were arterial hypertension (79.7%), diabetes mellitus (19.2%), ischemic stroke (13.3%), heart failure (10.8%) and renal failure, with a glomerular filtration rate of 30–60mL/min (8%). Additionally, 16 (5%) patients were undergoing concomitant treatment with ASA, and 5 (1.6%) were taking clopidogrel. The mean CHADS2 and HAS-BLED scores were 1.97±1.04 and 2.36±0.87, respectively.Fifty-four percent of the patients took a 150-mg dose, and 46% took 110mg. The indication for the lower dose was a glomerular filtration rate of 30–60mL/min for 57.1% of the patients and advanced age for 42.9% of the patients. There were no differences between the groups’ characteristics according to dose, except for a larger proportion of patients with heart failure among those taking the 150-mg dose (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The indication for anticoagulation was atrial fibrillation confirmed by electrocardiography, ruling out a valvular origin through echocardiography. Dabigatran was the initial treatment for 262 patients (83%). In 47 (14.8%) cases, the drug replaced acenocoumarol for various reasons, including the onset of hemorrhagic events and the maintenance of an INR below the therapeutic range in more than 60% of the controls. In 7 cases (2.2%), dabigatran was prescribed at the patient's request. The median overall follow-up was 14 months (range, 12–16 months). Among the patients who had no hemorrhagic complications, the median follow-up was 15 months (range, 12–17 months). Among those who did have hemorrhagic complications, the median follow-up was 7 months (range, 5–12 months). Fourteen patients died during the follow-up period. In none of the cases was the cause of death considered related to dabigatran.Twenty-six (8.2%) patients stopped the treatment, 10 (3.16%) of whom stopped due to dyspepsia and 16 (5.06%) of whom stopped due to administrative causes (no renewal of the prescription due to restrictions in the administration of the drug).In terms of the ischemic events that occurred during follow-up, 2 patients (0.55/100 patient-years) had an ischemic stroke. One had amaurosis fugax and another had a left middle cerebral artery stroke, at 5 and 10 months respectively. Eight patients (2.18/100 patient-years) had an adverse ischemic event; 5 cases had a cardiac origin (1.58%; 1.36/100 patient-years), and 3 had a peripheral origin (0.94%; 0.81/100 patient-years), including an iliac occlusion, a femoropopliteal ischemia and a bilateral distal ischemia of the legs. The 8 patients with cardiac ischemia had acute coronary syndrome with no ST-segment elevation. None of them had undergone prior antiplatelet therapy. For 2 of these patients, the treatment consisted of a stent implantation; 1 patient underwent surgical revascularization, and the other 2 were only administered medical treatment. Four of the patients maintained the anticoagulation and antiplatelet treatment on a permanent basis. Double antiplatelet treatment was suspended for 1 patient after the first month, due to the patient's high hemorrhagic risk. There were no differences in the rate of coronary events between those who started the anticoagulation with dabigatran and those who changed from acenocoumarol to dabigatran (1.60 vs. 2.22, respectively; p=.794).Bleeding complications occurred in 40 patients (10.91/100 patient-years). A total of 32 patients presented minor hemorrhaging (8.73/100 patient-years), and 8 presented major hemorrhaging (2.18/100 patient-years). The most common hemorrhagic location was urological in 15 patients and gastrointestinal in 12 patients (2 of whom had a gastric neoplasm and a tubulovillous adenomatous polyp, respectively). One patient experienced a cerebral hemorrhage. Other bleeding locations included the lungs (2 patients), genitals (1 patient), nose (1 patient) and hematoma (3 patients). The location of the bleeding could not be determined for 5 patients. The administration of dabigatran was suspended for 12 patients (30%) after hemorrhagic episodes but was maintained for the remaining 28 patients (70%). Of these, 1 patient required a dosage reduction to 110mg every 12h. For 2 other patients, heparin was initially administered, and the use dabigatran was subsequently resumed.The variables associated with an increased risk of bleeding were the prior administration of ASA (31.3% vs. 11.6%; p=.021), the initial urea concentration (58.78mg/dL±30.08 vs. 50.03mg/dL±19.8; p=.026) and the CHADS2 score (2.3±1.2 vs. 1.9±1.03; p=.007). The risk of bleeding was double in the patients with CHADS scores >2 (p=.021). We observed a nonsignificant trend toward more frequent bleeding in patients with creatinine levels>1.4mg/dL (25% vs. 12.2%) and in those who were treated with the 110-mg dose (16.4% vs. 10.2%).<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the data from the univariate analysis. In the multivariate analysis, only concomitant treatment with antiplatelet agents was significantly associated with an increased risk of bleeding (OR: 3.32; [1.08–10.19]; p=.036).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>DiscussionClinical trials have shown that dabigatran at dosages of 110 and 150mg twice daily is not inferior to warfarin in preventing embolic stroke and that, at a dose of 110mg, the hemorrhagic risk is less than that with VKA.<a class="elsevierStyleCrossRef" href="#bib0145">4</a> It is important to conduct postlaunch studies to confirm that the data from the clinical trials corresponds with those from daily practice, especially due to the increase in direct costs that these drugs represent. We found no original study in the literature review that focused on this topic in Spain.The annual rate of ischemic stroke in our cohort (0.55% per 1000 patients/year) is similar to that of a Danish registry of patients in standard clinical practice<a class="elsevierStyleCrossRef" href="#bib0150">5</a> and lower than that of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) study, with 1.53% events per year with the 110-mg dose and 1.11% with the 150-mg dose.<a class="elsevierStyleCrossRef" href="#bib0140">3</a> The increase in the incidence of coronary events among patients treated with dabigatran has been the subject of controversy. In our study, 5 patients (1.36% per year) presented a cardiac ischemic event, readings that are slightly higher than those of the RELY study.<a class="elsevierStyleCrossRef" href="#bib0145">4</a> The onset of coronary events has been demonstrated in the RELY study and in a subsequent meta-analyses.<a class="elsevierStyleCrossRef" href="#bib0155">6</a> However, the onset does not seem to be attributable to a specific effect of dabigatran but rather to all thrombin inhibitors,<a class="elsevierStyleCrossRef" href="#bib0160">7</a> due to their influence on anticoagulation and the inflammatory response, which are increased by these drugs.<a class="elsevierStyleCrossRef" href="#bib0165">8</a> One study suggested that patients who switch from acenocoumarol to dabigatran could have an increased risk of ischemic cardiac episodes.<a class="elsevierStyleCrossRef" href="#bib0170">9</a> However, we have not found this association in our series, although the retrospective design of the analysis and the limited sample size do not allow us to make statements that confirm or refute this issue. Nevertheless, in a post-launch surveillance study of more than 130,000 patients, the Food and Drug Administration found no greater risk of cardiac ischemia with the use of dabigatran than with warfarin.<a class="elsevierStyleCrossRef" href="#bib0175">10</a>Hemorrhage is the main complication resulting from the use of dabigatran. In our series, 8.73% of the patients per year had an episode of minor hemorrhage, a figure lower than that of the RELY study, which had a rate of 13.16% per year with the 110-mg dose and 14.84% per year with the 150-mg dose. In our series, 2.18% of the patients per year had an episode of major hemorrhage, compared with 2.71% per year with the 110-mg dose and 3.11% per year with the 150-mg dose in the RELY study. The hemorrhagic events in our cohort were mostly episodes of minor bleeding, of gastrointestinal or urological origin, with no clinical, hemodynamic or analytical repercussion. In the meta-analyses by Holster et al., new oral anticoagulants were associated with an increased risk of gastrointestinal hemorrhaging, especially among patients who had prior colon disease.<a class="elsevierStyleCrossRef" href="#bib0180">11</a> Intracranial hemorrhage is one of the complications with highest morbidity and mortality. The Danish cohort<a class="elsevierStyleCrossRef" href="#bib0145">4</a> and a meta-analysis performed by Bloom et al.<a class="elsevierStyleCrossRef" href="#bib0185">12</a> concluded that the risk is lower with dabigatran than with VKAs.The risk factors associated with hemorrhage included advanced age, low body weight and renal failure.<a class="elsevierStyleCrossRefs" href="#bib0190">13,14</a> Although age by itself is a risk factor for bleeding due to the increased bioavailability of the drug<a class="elsevierStyleCrossRefs" href="#bib0195">14,15</a> and the greater prevalence of renal failure,<a class="elsevierStyleCrossRefs" href="#bib0200">15,16</a> age was not a determinant in our study for the onset of hemorrhagic complications, despite being higher than that of the patients in the RELY study (76 vs. 71 years, respectively). The only risk factor for hemorrhage among our patients was the concomitant administration of ASA, an already known consequence of combining antiplatelet therapy with any anticoagulant.<a class="elsevierStyleCrossRef" href="#bib0210">17</a>Part of the reluctance to use new anticoagulants is the fear of hemorrhagic complications, given that there is no clearly established pattern of action. To date, there are no approved antidotes. The recommendations in the event of a hemorrhage therefore consist of hemodialysis<a class="elsevierStyleCrossRef" href="#bib0215">18</a> or the intravenous administration of fluids or blood products, as necessary, to stop the bleeding.<a class="elsevierStyleCrossRef" href="#bib0220">19</a> An analysis of several published studies has shown that patients treated with dabigatran who experienced hemorrhagic complications required more packed red blood cells and less plasma than those who were treated with acenocoumarol, and their mean hospital stay and mortality were lower.<a class="elsevierStyleCrossRef" href="#bib0225">20</a> Nevertheless, idarucizumab (a fully human monoclonal antibody fragment) was presented in 2013 as an antidote for dabigatran. The results of the phase I study showed that the reversal of the anticoagulant effect was complete and sustained in 7 of the 9 participants who were treated with the 2-g dose and in all those who were treated with the 4-g dose.<a class="elsevierStyleCrossRef" href="#bib0230">21</a>The adverse gastrointestinal effects of the drug appeared in the clinical trials as one of the most common.<a class="elsevierStyleCrossRef" href="#bib0145">4</a> In our experience, only 3% of the patients presented dyspepsia to a degree that required discontinuing dabigatran. This should be interpreted with caution since this was an observational retrospective study, and this datum is not always reflected in the patients’ medical records. In our study, the most common cause for discontinuing the treatment was the lack of prescription renewal. The drug's direct cost is one of the main reasons for discontinuing the treatment,<a class="elsevierStyleCrossRef" href="#bib0235">22</a> despite the fact that various studies have shown that dabigatran can be cost effective in preventing ischemic stroke in patients with atrial fibrillatio.<a class="elsevierStyleCrossRefs" href="#bib0240">23–25</a>This study has two main limitations, those inherent in retrospective studies and the relatively short follow-up time, which could bias the results in favor of the drug, given that both the onset of new ischemic events and the complications and adverse effects are time dependent.In conclusion, this study provides information on the safety and efficacy of dabigatran in standard clinical practice and supports the view that, in this context, the results of its use are similar to those obtained in the clinical trials.Conflict of interestJudith Álvarez Otero received funding to attend Boehringer Ingelheim congresses. Javier de la Fuente Aguado received honoraria as speaker and for his expert testimony for Boehringer Ingelheim and funding to attend Boehringer Ingelheim congresses. Juan Carlos Arias received honoraria as speaker and funding to attend Boehringer Ingelheim congresses. Rubén Puerta Louro received honoraria as speaker and funding to attend Boehringer Ingelheim congresses.The other authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres563524" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction 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" => "xpalclavsec580067" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres563525" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción 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" => "xpalclavsec580068" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec580067" "palabras" => array:5 [ 0 => "Dabigatran" 1 => "Atrial fibrillation" 2 => "Anticoagulation" 3 => "Ischemic stroke" 4 => "Hemorrhage" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec580068" "palabras" => array:5 [ 0 => "Dabigatrán" 1 => "Fibrilación auricular" 2 => "Anticoagulación" 3 => "Ictus isquémico" 4 => "Hemorragia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesDabigatran is an anticoagulant drug and a direct thrombin inhibitor and has been approved for the prevention of ischemic stroke secondary to nonvalvularauricular auricular fibrillation.The aim of this study was to determine the efficacy of dabigatran in clinical practice for preventing cerebral ischemic events associated with nonvalvularauricular auricular fibrillation, as well as its tolerance and safety profile. Material and methodsA descriptive and retrospective study was conducted, which included all patients who started anticoagulant treatment with dabigatran between November 2011 and September 2012. Follow-up was performed from the start of treatment until June 2013. The incidence of ischemic events of cerebral, cardiac and peripheral origin was recorded, as was the onset of adverse effects and hemorrhagic complications, whose location and severity were determined. ResultsWe analyzed 316 patients, with a mean age of 76.46±8.37 years, of whom 53.5% were men. Two patients (0.55/100 patient-years) presented ischemic stroke (including one amaurosis fugax). Eight (2.18/100 patient-years) patients had an adverse ischemic event, whose origin was cardiac in 5 (1.36/100 patient-years) cases and peripheral in 3 (0.81/100 patient-years). Forty (10.91/100 patient-years) patients had a hemorrhagic complication: 32 minor (8.73/100 patient-years) and 8 major (2.18/100 patient-years) hemorrhages. ConclusionsDabigatran is effective in standard clinical practice in preventing stroke and has a safety profile similar to that reported in the clinical trials." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction 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" => "Introducción y objetivosDabigatrán es un fármaco anticoagulante, inhibidor directo de la trombina, aprobado para la prevención de ictus isquémico secundario a fibrilación auricular no valvular.El objetivo de este estudio fue determinar la eficacia de dabigatrán en la práctica clínica para la prevención de eventos isquémicos cerebrales asociados a fibrilación auricular no valvular, así como su perfil de tolerancia y seguridad. Material y métodosEstudio descriptivo y retrospectivo en el que se incluyó a todos los pacientes que iniciaron tratamiento anticoagulante con dabigatrán entre los meses de noviembre de 2011 y septiembre de 2012. Se realizó seguimiento desde el comienzo del tratamiento hasta junio de 2013. Se determinó la incidencia de eventos isquémicos de origen cerebral, cardíaco y periférico, así como la aparición de efectos adversos y complicaciones hemorrágicas, determinando su localización y gravedad. ResultadosSe analizó a 316 pacientes con una edad media de 76,46±8,37 años, de los que el 53,5% eran varones. Dos pacientes (0,55/100 pacientes-año) presentaron ictus isquémico (incluyendo una amaurosis fugax). Ocho (2,18/100 pacientes-año) tuvieron un evento adverso isquémico, que fue de origen cardíaco en 5 (1,36/100 pacientes-año) casos y periférico en 3 (0,81/100 pacientes-año). Cuarenta (10,91/100 pacientes-año) tuvieron una complicación hemorrágica: 32 hemorragias menores (8,73/100 pacientes-año) y 8 mayores (2,18/100 pacientes-año). ConclusionesDabigatrán en la práctica clínica habitual es eficaz en la prevención de ictus y presenta un perfil de seguridad similar al reportado en los ensayos clínicos." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción 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: Álvarez-Otero J, de la Fuente-Aguado J, Arias-Castaño JC, González-González L, Puerta-Louro R, Araújo-Fernández S. Dabigatrán: Experiencia en la práctica clínica habitual. Rev Clin Esp. 2015;215:385–390." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">110-mg 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">150-mg 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">Total \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 " align="left" valign="top">Age, y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.6±7.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.2±8.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.4±8.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Male sex, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Arterial hypertension, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">83.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Heart failure, %<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Diabetes mellitus, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Prior stroke, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ASA, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Clopidogrel, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CHADS2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.95±0.90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.15±1.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.97±1.09 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HASBLED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.30±0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.41±0.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.36±0.87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline Hb, g/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.78±3.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.75±1.58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.77±2.38 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline creatinine, mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97±0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97±0.26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97±0.26 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Baseline urea, mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50.46±20.15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.02±22.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50.7±21.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab913739.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "Statistical significance: p<.05." ] ] ] "descripcion" => array:1 [ "en" => "Demographic characteristics of the study population." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR \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">95% CI \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">p-value \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 " align="left" valign="top">Age >75 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.81–3.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.174 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.31–1.23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.172 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">110-mg dose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.89–3.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.068 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ASA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.13–10.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Creatinine >1.4mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.89–6.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.076 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CHADS>2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.12–4.59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.021 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HAS-BLED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.99–3.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.055 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab913738.png" ] ] ] ] 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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anticoagulation with vitamin K antagonists &#40;VKA&#41; presents significant individual variability and a narrow therapeutic window&#44; which requires periodic dosage adjustments&#46; The international normalized ratio &#40;INR&#41; is therefore often outside the therapeutic range&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Dabigatran is a direct thrombin inhibiting anticoagulant drug&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> The drug is authorized for the prevention of ischemic stroke in adults with nonvalvular atrial fibrillation and one or more of the following factors&#58; prior stroke&#44; transient ischemic attack or systemic embolism&#59; left ventricular ejection fraction &#60;40&#37;&#59; symptomatic heart failure greater than grade 2 of the New York Heart Association &#40;NYHA&#41;&#44; age older than 75 years or younger than 65 years associated with diabetes mellitus&#44; coronary artery disease or hypertension&#46; The drug is administered orally&#44; in the form of the prodrug dabigatran etexilate and has a half-life between 12 and 14<span class="elsevierStyleHsp" style=""></span>h&#46; Eighty percent of the drug is excreted by the kidneys&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">2</span></a> Unlike VKAs&#44; dabigatran has predictable pharmacokinetics and pharmacodynamics and therefore does not require coagulation monitoring&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Given that dabigatran is indicated for long-term use in preventing ischemic stroke&#44; it is important to conduct observational studies that compare the results of the clinical trials with those observed in standard clinical practice&#44; both in terms of the drug&#39;s efficacy in preventing cerebral ischemic events and its tolerance and safety profile&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">A descriptive and retrospective study was conducted&#44; which included all patients who started anticoagulant treatment with dabigatran in the specialized care setting between November 2011 and September 2012&#46; Follow-up was performed from the start of treatment until June 2013&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Given that this drug requires a prescription for dispensing&#44; the list was provided by the Department of Pharmacy of Hospital Povisa &#40;Vigo&#41;&#46; The study respected the data confidentiality guarantee &#40;Organic Law on Data Protection 15&#47;99&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The medical records of all patients who took at least one dose of the drug were reviewed&#46; The following data were collected from each patient&#58; age&#44; sex&#44; indication for anticoagulation&#44; whether the administration of dabigatran was primary or secondary to problems with dicoumarin agents&#44; comorbidities &#40;arterial hypertension&#44; heart failure&#44; diabetes mellitus&#41;&#44; glomerular filtration rate calculated using the modified MDRD formula &#40;classifying the degree of renal failure as severe if &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min and moderate for 30&#8211;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#44; according to the KDOQI guidelines of the National Kidney Foundation&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> prior stroke&#44; concomitant treatment with acetylsalicylic acid &#40;ASA&#41;&#44; clopidogrel or nonsteroidal anti-inflammatory drugs&#44; and serum concentrations of hemoglobin&#44; urea and creatinine&#46; The CHADS2 and HAS-BLED scores for each patient were calculated&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Through a medical history review and the consultation with the responsible physician&#44; 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including the onset of hemorrhagic events and the maintenance of an INR below the therapeutic range in more than 60&#37; of the controls&#46; In 7 cases &#40;2&#46;2&#37;&#41;&#44; dabigatran was prescribed at the patient&#39;s request&#46; The median overall follow-up was 14 months &#40;range&#44; 12&#8211;16 months&#41;&#46; Among the patients who had no hemorrhagic complications&#44; the median follow-up was 15 months &#40;range&#44; 12&#8211;17 months&#41;&#46; Among those who did have hemorrhagic complications&#44; the median follow-up was 7 months &#40;range&#44; 5&#8211;12 months&#41;&#46; Fourteen patients died during the follow-up period&#46; In none of the cases was the cause of death considered related to dabigatran&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Twenty-six &#40;8&#46;2&#37;&#41; patients stopped the treatment&#44; 10 &#40;3&#46;16&#37;&#41; of whom stopped due to dyspepsia and 16 &#40;5&#46;06&#37;&#41; of whom stopped due to administrative causes &#40;no renewal of the prescription due to restrictions in the administration of the drug&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In terms of the ischemic events that occurred during follow-up&#44; 2 patients &#40;0&#46;55&#47;100 patient-years&#41; had an ischemic stroke&#46; One had amaurosis fugax and another had a left middle cerebral artery stroke&#44; at 5 and 10 months respectively&#46; Eight patients &#40;2&#46;18&#47;100 patient-years&#41; had an adverse ischemic event&#59; 5 cases had a cardiac origin &#40;1&#46;58&#37;&#59; 1&#46;36&#47;100 patient-years&#41;&#44; and 3 had a peripheral origin &#40;0&#46;94&#37;&#59; 0&#46;81&#47;100 patient-years&#41;&#44; including an iliac occlusion&#44; a femoropopliteal ischemia and a bilateral distal ischemia of the legs&#46; The 8 patients with cardiac ischemia had acute coronary syndrome with no ST-segment elevation&#46; None of them had undergone prior antiplatelet therapy&#46; For 2 of these patients&#44; the treatment consisted of a stent implantation&#59; 1 patient underwent surgical revascularization&#44; and the other 2 were only administered medical treatment&#46; Four of the patients maintained the anticoagulation and antiplatelet treatment on a permanent basis&#46; Double antiplatelet treatment was suspended for 1 patient after the first month&#44; due to the patient&#39;s high hemorrhagic risk&#46; There were no differences in the rate of coronary events between those who started the anticoagulation with dabigatran and those who changed from acenocoumarol to dabigatran &#40;1&#46;60 vs&#46; 2&#46;22&#44; respectively&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;794&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Bleeding complications occurred in 40 patients &#40;10&#46;91&#47;100 patient-years&#41;&#46; A total of 32 patients presented minor hemorrhaging &#40;8&#46;73&#47;100 patient-years&#41;&#44; and 8 presented major hemorrhaging &#40;2&#46;18&#47;100 patient-years&#41;&#46; The most common hemorrhagic location was urological in 15 patients and gastrointestinal in 12 patients &#40;2 of whom had a gastric neoplasm and a tubulovillous adenomatous polyp&#44; respectively&#41;&#46; One patient experienced a cerebral hemorrhage&#46; Other bleeding locations included the lungs &#40;2 patients&#41;&#44; genitals &#40;1 patient&#41;&#44; nose &#40;1 patient&#41; and hematoma &#40;3 patients&#41;&#46; The location of the bleeding could not be determined for 5 patients&#46; The administration of dabigatran was suspended for 12 patients &#40;30&#37;&#41; after hemorrhagic episodes but was maintained for the remaining 28 patients &#40;70&#37;&#41;&#46; Of these&#44; 1 patient required a dosage reduction to 110<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&#46; For 2 other patients&#44; heparin was initially administered&#44; and the use dabigatran was subsequently resumed&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The variables associated with an increased risk of bleeding were the prior administration of ASA &#40;31&#46;3&#37; vs&#46; 11&#46;6&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;021&#41;&#44; the initial urea concentration &#40;58&#46;78<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#46;08 vs&#46; 50&#46;03<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;8&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;026&#41; and the CHADS2 score &#40;2&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;2 vs&#46; 1&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;03&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41;&#46; The risk of bleeding was double in the patients with CHADS scores &#62;2 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;021&#41;&#46; We observed a nonsignificant trend toward more frequent bleeding in patients with creatinine levels<span class="elsevierStyleHsp" style=""></span>&#62;1&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;25&#37; vs&#46; 12&#46;2&#37;&#41; and in those who were treated with the 110-mg dose &#40;16&#46;4&#37; vs&#46; 10&#46;2&#37;&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the data from the univariate analysis&#46; In the multivariate analysis&#44; only concomitant treatment with antiplatelet agents was significantly associated with an increased risk of bleeding &#40;OR&#58; 3&#46;32&#59; &#91;1&#46;08&#8211;10&#46;19&#93;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;036&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Clinical trials have shown that dabigatran at dosages of 110 and 150<span class="elsevierStyleHsp" style=""></span>mg twice daily is not inferior to warfarin in preventing embolic stroke and that&#44; at a dose of 110<span class="elsevierStyleHsp" style=""></span>mg&#44; the hemorrhagic risk is less than that with VKA&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> It is important to conduct postlaunch studies to confirm that the data from the clinical trials corresponds with those from daily practice&#44; especially due to the increase in direct costs that these drugs represent&#46; We found no original study in the literature review that focused on this topic in Spain&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The annual rate of ischemic stroke in our cohort &#40;0&#46;55&#37; per 1000 patients&#47;year&#41; is similar to that of a Danish registry of patients in standard clinical practice<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">5</span></a> and lower than that of the Randomized Evaluation of Long-Term Anticoagulation Therapy &#40;RELY&#41; study&#44; with 1&#46;53&#37; events per year with the 110-mg dose and 1&#46;11&#37; with the 150-mg dose&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">3</span></a> The increase in the incidence of coronary events among patients treated with dabigatran has been the subject of controversy&#46; In our study&#44; 5 patients &#40;1&#46;36&#37; per year&#41; presented a cardiac ischemic event&#44; readings that are slightly higher than those of the RELY study&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> The onset of coronary events has been demonstrated in the RELY study and in a subsequent meta-analyses&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">6</span></a> However&#44; the onset does not seem to be attributable to a specific effect of dabigatran but rather to all thrombin inhibitors&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">7</span></a> due to their influence on anticoagulation and the inflammatory response&#44; which are increased by these drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">8</span></a> One study suggested that patients who switch from acenocoumarol to dabigatran could have an increased risk of ischemic cardiac episodes&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">9</span></a> However&#44; we have not found this association in our series&#44; although the retrospective design of the analysis and the limited sample size do not allow us to make statements that confirm or refute this issue&#46; Nevertheless&#44; in a post-launch surveillance study of more than 130&#44;000 patients&#44; the Food and Drug Administration found no greater risk of cardiac ischemia with the use of dabigatran than with warfarin&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Hemorrhage is the main complication resulting from the use of dabigatran&#46; In our series&#44; 8&#46;73&#37; of the patients per year had an episode of minor hemorrhage&#44; a figure lower than that of the RELY study&#44; which had a rate of 13&#46;16&#37; per year with the 110-mg dose and 14&#46;84&#37; per year with the 150-mg dose&#46; In our series&#44; 2&#46;18&#37; of the patients per year had an episode of major hemorrhage&#44; compared with 2&#46;71&#37; per year with the 110-mg dose and 3&#46;11&#37; per year with the 150-mg dose in the RELY study&#46; The hemorrhagic events in our cohort were mostly episodes of minor bleeding&#44; of gastrointestinal or urological origin&#44; with no clinical&#44; hemodynamic or analytical repercussion&#46; In the meta-analyses by Holster et al&#46;&#44; new oral anticoagulants were associated with an increased risk of gastrointestinal hemorrhaging&#44; especially among patients who had prior colon disease&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">11</span></a> Intracranial hemorrhage is one of the complications with highest morbidity and mortality&#46; The Danish cohort<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> and a meta-analysis performed by Bloom et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">12</span></a> concluded that the risk is lower with dabigatran than with VKAs&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The risk factors associated with hemorrhage included advanced age&#44; low body weight and renal failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">13&#44;14</span></a> Although age by itself is a risk factor for bleeding due to the increased bioavailability of the drug<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">14&#44;15</span></a> and the greater prevalence of renal failure&#44;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">15&#44;16</span></a> age was not a determinant in our study for the onset of hemorrhagic complications&#44; despite being higher than that of the patients in the RELY study &#40;76 vs&#46; 71 years&#44; respectively&#41;&#46; The only risk factor for hemorrhage among our patients was the concomitant administration of ASA&#44; an already known consequence of combining antiplatelet therapy with any anticoagulant&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">17</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Part of the reluctance to use new anticoagulants is the fear of hemorrhagic complications&#44; given that there is no clearly established pattern of action&#46; To date&#44; there are no approved antidotes&#46; The recommendations in the event of a hemorrhage therefore consist of hemodialysis<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">18</span></a> or the intravenous administration of fluids or blood products&#44; as necessary&#44; to stop the bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">19</span></a> An analysis of several published studies has shown that patients treated with dabigatran who experienced hemorrhagic complications required more packed red blood cells and less plasma than those who were treated with acenocoumarol&#44; and their mean hospital stay and mortality were lower&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">20</span></a> Nevertheless&#44; idarucizumab &#40;a fully human monoclonal antibody fragment&#41; was presented in 2013 as an antidote for dabigatran&#46; The results of the phase I study showed that the reversal of the anticoagulant effect was complete and sustained in 7 of the 9 participants who were treated with the 2-g dose and in all those who were treated with the 4-g dose&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">21</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The adverse gastrointestinal effects of the drug appeared in the clinical trials as one of the most common&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">4</span></a> In our experience&#44; only 3&#37; of the patients presented dyspepsia to a degree that required discontinuing dabigatran&#46; This should be interpreted with caution since this was an observational retrospective study&#44; and this datum is not always reflected in the patients&#8217; medical records&#46; In our study&#44; the most common cause for discontinuing the treatment was the lack of prescription renewal&#46; The drug&#39;s direct cost is one of the main reasons for discontinuing the treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">22</span></a> despite the fact that various studies have shown that dabigatran can be cost effective in preventing ischemic stroke in patients with atrial fibrillatio&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">23&#8211;25</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">This study has two main limitations&#44; those inherent in retrospective studies and the relatively short follow-up time&#44; which could bias the results in favor of the drug&#44; given that both the onset of new ischemic events and the complications and adverse effects are time dependent&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion&#44; this study provides information on the safety and efficacy of dabigatran in standard clinical practice and supports the view that&#44; in this context&#44; the results of its use are similar to those obtained in the clinical trials&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">Judith &#193;lvarez Otero received funding to attend Boehringer Ingelheim congresses&#46; Javier de la Fuente Aguado received honoraria as speaker and for his expert testimony for Boehringer Ingelheim and funding to attend Boehringer Ingelheim congresses&#46; Juan Carlos Arias received honoraria as speaker and funding to attend Boehringer Ingelheim congresses&#46; Rub&#233;n Puerta Louro received honoraria as speaker and funding to attend Boehringer Ingelheim congresses&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The other authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "palabras" => array:5 [
            0 => "Dabigatran"
            1 => "Atrial fibrillation"
            2 => "Anticoagulation"
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            0 => "Dabigatr&#225;n"
            1 => "Fibrilaci&#243;n auricular"
            2 => "Anticoagulaci&#243;n"
            3 => "Ictus isqu&#233;mico"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Dabigatran is an anticoagulant drug and a direct thrombin inhibitor and has been approved for the prevention of ischemic stroke secondary to nonvalvularauricular auricular fibrillation&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to determine the efficacy of dabigatran in clinical practice for preventing cerebral ischemic events associated with nonvalvularauricular auricular fibrillation&#44; as well as its tolerance and safety profile&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A descriptive and retrospective study was conducted&#44; which included all patients who started anticoagulant treatment with dabigatran between November 2011 and September 2012&#46; Follow-up was performed from the start of treatment until June 2013&#46; The incidence of ischemic events of cerebral&#44; cardiac and peripheral origin was recorded&#44; as was the onset of adverse effects and hemorrhagic complications&#44; whose location and severity were determined&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We analyzed 316 patients&#44; with a mean age of 76&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;37 years&#44; of whom 53&#46;5&#37; were men&#46; Two patients &#40;0&#46;55&#47;100 patient-years&#41; presented ischemic stroke &#40;including one amaurosis fugax&#41;&#46; Eight &#40;2&#46;18&#47;100 patient-years&#41; patients had an adverse ischemic event&#44; whose origin was cardiac in 5 &#40;1&#46;36&#47;100 patient-years&#41; cases and peripheral in 3 &#40;0&#46;81&#47;100 patient-years&#41;&#46; Forty &#40;10&#46;91&#47;100 patient-years&#41; patients had a hemorrhagic complication&#58; 32 minor &#40;8&#46;73&#47;100 patient-years&#41; and 8 major &#40;2&#46;18&#47;100 patient-years&#41; hemorrhages&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Dabigatran is effective in standard clinical practice in preventing stroke and has a safety profile similar to that reported in the clinical trials&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0005"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Dabigatr&#225;n es un f&#225;rmaco anticoagulante&#44; inhibidor directo de la trombina&#44; aprobado para la prevenci&#243;n de ictus isqu&#233;mico secundario a fibrilaci&#243;n auricular no valvular&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio fue determinar la eficacia de dabigatr&#225;n en la pr&#225;ctica cl&#237;nica para la prevenci&#243;n de eventos isqu&#233;micos cerebrales asociados a fibrilaci&#243;n auricular no valvular&#44; as&#237; como su perfil de tolerancia y seguridad&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estudio descriptivo y retrospectivo en el que se incluy&#243; a todos los pacientes que iniciaron tratamiento anticoagulante con dabigatr&#225;n entre los meses de noviembre de 2011 y septiembre de 2012&#46; Se realiz&#243; seguimiento desde el comienzo del tratamiento hasta junio de 2013&#46; Se determin&#243; la incidencia de eventos isqu&#233;micos de origen cerebral&#44; card&#237;aco y perif&#233;rico&#44; as&#237; como la aparici&#243;n de efectos adversos y complicaciones hemorr&#225;gicas&#44; determinando su localizaci&#243;n y gravedad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se analiz&#243; a 316 pacientes con una edad media de 76&#44;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;37 a&#241;os&#44; de los que el 53&#44;5&#37; eran varones&#46; Dos pacientes &#40;0&#44;55&#47;100 pacientes-a&#241;o&#41; presentaron ictus isqu&#233;mico &#40;incluyendo una amaurosis fugax&#41;&#46; Ocho &#40;2&#44;18&#47;100 pacientes-a&#241;o&#41; tuvieron un evento adverso isqu&#233;mico&#44; que fue de origen card&#237;aco en 5 &#40;1&#44;36&#47;100 pacientes-a&#241;o&#41; casos y perif&#233;rico en 3 &#40;0&#44;81&#47;100 pacientes-a&#241;o&#41;&#46; Cuarenta &#40;10&#44;91&#47;100 pacientes-a&#241;o&#41; tuvieron una complicaci&#243;n hemorr&#225;gica&#58; 32 hemorragias menores &#40;8&#44;73&#47;100 pacientes-a&#241;o&#41; y 8 mayores &#40;2&#44;18&#47;100 pacientes-a&#241;o&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Dabigatr&#225;n en la pr&#225;ctica cl&#237;nica habitual es eficaz en la prevenci&#243;n de ictus y presenta un perfil de seguridad similar al reportado en los ensayos cl&#237;nicos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; &#193;lvarez-Otero J&#44; de la Fuente-Aguado J&#44; Arias-Casta&#241;o JC&#44; Gonz&#225;lez-Gonz&#225;lez L&#44; Puerta-Louro R&#44; Ara&#250;jo-Fern&#225;ndez S&#46; Dabigatr&#225;n&#58; Experiencia en la pr&#225;ctica cl&#237;nica habitual&#46; Rev Clin Esp&#46; 2015&#59;215&#58;385&#8211;390&#46;</p>"
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                  <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">Variable&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">110-mg 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">150-mg 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">Total&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  " align="left" valign="top">Age&#44; y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;3&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="left" valign="top">Male sex&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;5&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="left" valign="top">Arterial hypertension&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">83&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79&#46;7&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="left" valign="top">Heart failure&#44; &#37;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;8&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="left" valign="top">Diabetes mellitus&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#46;1&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="left" valign="top">Prior stroke&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;3&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="left" valign="top">ASA&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;1&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="left" valign="top">Clopidogrel&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;9&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="left" valign="top">CHADS2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;15<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;09&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="left" valign="top">HASBLED&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;87&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="left" valign="top">Baseline Hb&#44; g&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;38&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="left" valign="top">Baseline creatinine&#44; mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;26&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="left" valign="top">Baseline urea&#44; mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#46;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51&#46;02<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Statistical significance&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Demographic characteristics of the study population&#46;</p>"
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                  <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">Variable&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">OR&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">95&#37; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Age &#62;75 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;81&#8211;3&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;174&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="left" valign="top">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;31&#8211;1&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;172&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="left" valign="top">110-mg dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;89&#8211;3&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;068&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="left" valign="top">ASA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;13&#8211;10&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;021&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="left" valign="top">Creatinine &#62;1&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;89&#8211;6&#46;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;076&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="left" valign="top">CHADS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;12&#8211;4&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;021&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="left" valign="top">HAS-BLED&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;92&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;99&#8211;3&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;055&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Univariate analysis of the variables associated with an increased risk of bleeding&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:25 [
            0 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitamin K antagonist treatment in patients with atrial fibrillation and time in therapeutic range in 4 European countries"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;E&#46; Cott&#233;"
                            1 => "H&#46; Benhaddi"
                            2 => "I&#46; Duprat-Lomon"
                            3 => "A&#46; Doble"
                            4 => "N&#46; Marchant"
                            5 => "A&#46; Letierce"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clinthera.2014.07.016"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Ther"
                        "fecha" => "2014"
                        "volumen" => "36"
                        "paginaInicial" => "1160"
                        "paginaFinal" => "1168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25151574"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dabigatran etexilate&#58; a new oral thrombin inhibitor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46;J&#46; Hankey"
                            1 => "J&#46;W&#46; Eikelboom"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.110.004424"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2011"
                        "volumen" => "123"
                        "paginaInicial" => "1436"
                        "paginaFinal" => "1450"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21464059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "National Kidney Foundation practice guidelines for chronic kidney disease&#58; evaluation&#44; classification&#44; and stratification"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;S&#46; Levey"
                            1 => "J&#46; Coresh"
                            2 => "E&#46; Balk"
                            3 => "A&#46;T&#46; Kausz"
                            4 => "A&#46; Levin"
                            5 => "M&#46;W&#46; Steffes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Intern Med"
                        "fecha" => "2003"
                        "volumen" => "139"
                        "paginaInicial" => "137"
                        "paginaFinal" => "147"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12859163"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
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