Clinical considerations on the posology of direct oral anticoagulants

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ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "I. Torres-Courchoud, H.H. Chen" "autores" => array:2 [ 0 => array:2 [ "nombre" => "I." "apellidos" => "Torres-Courchoud" ] 1 => array:2 [ "nombre" => "H.H." "apellidos" => "Chen" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887416300479?idApp=WRCEE" "url" => "/22548874/0000021600000007/v2_201704020050/S2254887416300479/v2_201704020050/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2254887416300480" "issn" => "22548874" "doi" => "10.1016/j.rceng.2016.04.004" "estado" => "S300" "fechaPublicacion" => "2016-10-01" "aid" => "1260" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI)" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Rev Clin Esp. 2016;216:372-83" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Autoimmune hepatitis: From mechanisms to therapy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "372" "paginaFinal" => "383" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La hepatitis autoinmune: de los mecanismos al tratamiento" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1502 "Ancho" => 2481 "Tamanyo" => 170596 ] ] "descripcion" => array:1 [ "en" => "Mechanisms of liver damage. Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule (MHC) by professional antigen presenting cells (APCs). The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells (Th0). IL-6 and IL-1β lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17. Th17 cells promote hepatocyte secretion of IL-6, which in turn further enhances Th17 development. Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-γ, which induces monocyte (MΦ) differentiation, activates cytotoxic CD8 T-cells and promotes NK cell killing. IFN-γ also increases MHC class I and induces class II expression by hepatocytes, further exacerbating inflammation. Exposure to IL-4 leads to Th2 differentiation. Th2 cells secrete IL-13, IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies. Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Liberal, G. Mieli-Vergani, D. Vergani" "autores" => array:3 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Liberal" ] 1 => array:2 [ "nombre" => "G." "apellidos" => "Mieli-Vergani" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Vergani" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887416300480?idApp=WRCEE" "url" => "/22548874/0000021600000007/v2_201704020050/S2254887416300480/v2_201704020050/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Clinical considerations on the posology of direct oral anticoagulants" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "384" "paginaFinal" => "392" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Sáez-Peñataro, C. Avendaño-Solá, J.R. González-Juanatey" "autores" => array:3 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Sáez-Peñataro" "email" => array:2 [ 0 => "jsaez@clinic.ub.es" 1 => "jsaezp@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Avendaño-Solá" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J.R." "apellidos" => "González-Juanatey" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Farmacología Clínica, Hospital Clínic de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Farmacología Clínica, Hospital Puerta de Hierro Majadahonda, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Cardiología, Hospital Clínico Universitario de Santiago de Compostela , Santiago de Compostela, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Medicina, Facultad de Medicina y Odontología, Universidad de Santiago de Compostela, Santiago de Compostela, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Consideraciones clínicas sobre la posología de los anticoagulantes orales de acción directa" ] ] "textoCompleto" => "BackgroundThe characterization of the dose–response and dose–safety profile of medicinal products is an essential element in their development. The dose–concentration–response assessment increases the chances of obtaining a favorable risk–benefit ratio. For oral anticoagulants, an optimal treatment regimen should maintain an appropriate anticoagulant activity and safety profile over time, with no oscillations or the need for periodic laboratory monitoring.<a class="elsevierStyleCrossRefs" href="#bib0260">1,2</a>The assessment of the dose–concentration–effect relationship has varied dramatically in recent years, such that the classical approach (phase II of the clinical development of medicinal products) is less delimited now and is frequently accelerated due to the need to optimize clinical development in a highly competitive environment. Techniques such as pharmacokinetic–pharmacodynamic (PK/PD) modeling<a class="elsevierStyleCrossRefs" href="#bib0270">3,4</a> and the assessment of 2 dosage regimens in “pivotal” studies tend to replace the classical dose-finding studies. However, the time and cost savings is coupled with a notable increase in uncertainty. In these circumstances, the safety and efficacy studies on the target population are the ones that determine whether the chosen dosage regimen shows a favorable risk–benefit profile. However, we cannot rule out the possibility that other alternative regimens could have been reasonable.Direct oral anticoagulants (DOAs), both thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban and edoxaban), are not exempt from this complexity. The accepted dosage regimens for each of them (which are different one from the other) reflect the previously mentioned uncertainties. In this review, we analyze the evidence underlying the final selection of the dosage regimen, taking into account its relevance for guiding the clinical decision-making process for prescribers in daily clinical practice. To this end, we address the general foundations for selecting the dosage, subsequently analyzing the selection of the dosage regimen during the clinical development of each drug.General pharmacokinetic and pharmacodynamic principles for selecting the dosage regimenFor the characterization of PK/PD, we must consider 2 fundamental factors: the concentration reached in plasma, in the target organ or the target tissue (biophase) and the duration of the effect. The course of the plasma concentrations is determined by the processes of absorption, distribution, metabolism and excretion.<a class="elsevierStyleCrossRef" href="#bib0280">5</a> From the plasma, the drug must be distributed to the biophase to cause its effect. Therefore, the concentration and half-life in the biophase will determine the temporal profile of the effect to a greater degree than the plasma concentration. There are numerous factors (genetic, physiological and pathological) that determine the degree of variability in the pharmacokinetic processes. The dosage needs to be adjusted for each individual situation when these factors of variability involve relevant intrapatient and interpatient changes in plasma concentrations and the biophase, and these changes have clinical repercussions.In the case of DOAs, given that the target consists of plasma coagulation factors, the plasma concentrations constitute a direct measure of concentrations in the biophase. However, the temporal profile of the effect not only depends on the pharmacokinetic factors but also on the mechanism of action, given that based on this mechanism, the effect could last longer than the presence of the drug. An example of this is antivitamin K drugs, whose anticoagulant effect is maintained sufficiently long so that once the antagonism on the vitamin K disappears sufficient quantities of new active coagulation factors are synthesized. In addition to the mechanism of action, there are other pharmacodynamic factors such as potency, intrinsic activity, pharmaceutical tolerance and genetic polymorphisms<a class="elsevierStyleCrossRef" href="#bib0280">5</a> that can affect the magnitude and duration of the effect regardless of the plasma concentrations and elimination half-life.It is also important to consider the relationship of pharmacokinetic and pharmacodynamic factors. Studies on DOAs in healthy volunteers observed an acceptable parallelism between the curve of plasma concentrations and pharmacodynamic parameters, such as the activated partial thromboplastin time (aPTT), the thrombin time and the ecarin clotting time. Despite this parallelism, however, the concentration–time and effect–time curves were not similar. In these cases, the anticoagulant effect persisted into the terminal phase of the curve of elimination.<a class="elsevierStyleCrossRefs" href="#bib0285">6–9</a>It is important to note that the concentration–effect relationship is not always linear and direct and is not equal for all pharmacodynamic parameters.<a class="elsevierStyleCrossRef" href="#bib0305">10</a> In studies with healthy volunteers, for example, the aPTT analysis showed a pharmacodynamic behavior compatible with a sigmoid Emax model (the graphical representation of the concentration–effect relationship shows a sigmoid curve), while other parameters such as thrombin time, ecarin clotting time and prothrombin time (PT) fit with greater precision to a linear Emax model. Although the tendency was similar, differences were observed in the average values depending on the drug, dosage and study.<a class="elsevierStyleCrossRefs" href="#bib0310">11–20</a> Therefore, the variations in the effect are not always linearly proportional to the plasma concentration, and this relationship can be different depending on the parameter pharmacodynamic and drug considered.Lastly, the pharmacological effect observed for each of the plasma concentrations does not necessarily have a direct translation in the prediction of the clinical effect, dependent per se on numerous pharmacokinetic and pharmacodynamic factors, which is variable for each drug and should be ultimately confirmed by actual clinical data.Dosage and dosage regimen selection for direct oral anticoagulantsThe selection of the dosage regimen has considered kinetic, dynamic, clinical, safety and efficacy data. In a number of cases, as with rivaroxaban, the decision concerning the dosage regimen for nonvalvular atrial fibrillation (NVAF) was extrapolated from the prophylaxis data on deep vein thrombosis (DVT).<a class="elsevierStyleCrossRefs" href="#bib0360">21–23</a> In other cases, a specific dose search was performed for each indication, or as with dabigatran, more than one dose was assessed in the “pivotal” study in NVAF.<a class="elsevierStyleCrossRef" href="#bib0285">6</a>DabigatranDabigatran selectively and reversibly inhibits thrombin, with high affinity. After the administration of a single dose to healthy volunteers in phase I clinical trials, the maximum plasma concentration (Cmax) was observed between 0.5 and 2h,<a class="elsevierStyleCrossRef" href="#bib0375">24</a> with an elimination half-life of 7–9h. Although the maximum effect was consistent with Cmax, showing a close PK/PD relationship and a parallel evolutionary course,<a class="elsevierStyleCrossRefs" href="#bib0310">11,12</a> the anticoagulant activity persisted even into the elimination phase 12h after its administration (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0290">7,25</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The BISTRO-I clinical trial assessed dosages of 12.5, 25, 50, 100, 150, 200, 300mg twice daily and 150 and 300mg in a single daily dose for 6–10 days in patients who underwent orthopedic hip surgery, with the drug used as prophylaxis for DVT.<a class="elsevierStyleCrossRef" href="#bib0385">26</a> Although the power of the study was insufficient to demonstrate differences among the dosages, better results (but not significant) were observed in the point estimates of safety and efficacy with the fractionated administration. A post hoc PK/PD analysis of this study observed a parallel temporal kinetic and dynamic course in the first hours. However, the pharmacological effect persisted beyond the total plasma clearance of dabigatran, with a time to a 50% reduction in effect of 1.6 days for aPTT and 2.9 days for ecarin clotting time.<a class="elsevierStyleCrossRef" href="#bib0390">27</a> Although this tendency had already been confirmed in the preliminary studies in healthy volunteers (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), the data showed much longer time periods, especially in the first hours after surgery, with a slow subsequent reduction. The authors concluded that a number of confounding factors, including perioperative transfusions, could be contributing to these results (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Based on this evidence, the BISTRO-II study assessed the total dose of 300mg administered once a day compared with the same fractionated dose in preventing DVT after total hip or knee replacement.<a class="elsevierStyleCrossRef" href="#bib0395">28</a> The 300-mg dose administered once a day showed greater fluctuations between Cmax and Cmin. However, there were no significant differences with respect to the fractionated dose in terms of safety and efficacy. In a subsequent logistic regression subanalysis that integrated the pharmacokinetic and pharmacodynamic results with the safety and efficacy data, the authors’ suggested that Cmax could be a reasonable predictor of clinical results in the dose interval between 100 and 300mg, more than the fluctuations between Cmax and Cminper se.<a class="elsevierStyleCrossRef" href="#bib0395">28</a> However, the single-dose daily regimen was selected for this indication.The phase II and III clinical trials in patients with NVAF only assessed the fractionated dose regimen,<a class="elsevierStyleCrossRefs" href="#bib0400">29,30</a> given that, unlike prophylaxis after surgery, the objective in NVAF is not so much the start of rapid action in the first hours but rather maintaining the anticoagulant effect over the course of the treatment, preserving an appropriate safety and efficacy profile over time. Assuming that Cmax has been related to the risk of hemorrhage, the fractioning of the dose was considered to provide the best safety and efficacy profile, with a reduction in the incidence of hemorrhagic events associated with the reduction in the Cmax peak, maintaining long-term anticoagulant efficacy at clinically significant levels. The dosages evaluated in the RE-LY phase III clinical trial were 110 and 150mg, twice daily,<a class="elsevierStyleCrossRefs" href="#bib0320">13,31</a> compared with warfarin.RivaroxabanRivaroxaban is a selective and reversible inhibitor of FXa. Its elimination half-life has been estimated at 5–9h in young individuals and 11–13h in elderly individuals.<a class="elsevierStyleCrossRef" href="#bib0415">32</a> Studies in healthy volunteers have shown PK/PD relationship results similar to those obtained with dabigatran, indicating a close correlation between the course of the plasma concentrations and the inhibition of aPTT and PT, although the anticoagulant activity persisted beyond 12h after the administration of doses greater than 5mg (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0380">25,26,33</a>The phase I clinical trials ODIXa-DVT and EINSTEIN DVT<a class="elsevierStyleCrossRefs" href="#bib0360">21,22</a> assessed the safety and efficacy of rivaroxaban, in a dose range of 20–40mg, administered one or twice daily, compared with the standard treatment (initial administration of low-molecular-weight heparins followed by maintenance treatment with vitamin K antagonists) in patients with DVT. The study ODIXa-DVT observed a lower persistence of thrombus at 21 days of treatment with the fractionated dose. However, the recurrence of thromboembolic events at 84 days of follow-up was similar in the 2 dosage regimes. Therefore, no definitive conclusions could be extracted from the study on the better dosage regimen.The EINSTEIN-DVT study found no significant differences between the 2 dosage regimens. The authors suggested that, based on the results of the previous ODIXa-DVT study and considering that the fractionated administration increased the minimum concentration levels throughout the day, the treatment regimen should include an initial 3-week period of fractionated administration in the acute phase of DVT, followed by a single daily maintenance dose. A subsequent population pharmacokinetics study, performed with the data from these 2 studies, showed that the single daily administration increased the Cmax levels by 20% and decreased the Cmin levels by 60%.<a class="elsevierStyleCrossRef" href="#bib0370">23</a> Although the 5–95 percentile range overlapped for these 2 parameters, a clear tendency was observed in the reduction of Cmin with the single administration, confirming the findings of the ODIXa-DVT study. The data suggested that Cmin was a predictor of safety in terms of hemorrhagic events.No formal dose-finding studies were performed for the NVAF indication. However, given the extended duration of the effect on the aPTT and PT and the association of a Cmin with a lower risk of bleeding, a single-dose 20mg/d regimen was chosen for the long-term maintenance treatment, a dosage subsequently evaluated in the phase III clinical trial ROCKET AF.<a class="elsevierStyleCrossRef" href="#bib0425">34</a>ApixabanApixaban is another selective and reversible FXa inhibitor, with a pharmacokinetic and pharmacodynamic profile similar to that of rivaroxaban<a class="elsevierStyleCrossRefs" href="#bib0300">9,35</a> and a half-life of 12h.<a class="elsevierStyleCrossRef" href="#bib0435">36</a> In healthy volunteers, the anticoagulant activity significantly persisted at 12h after the administration of a dose >2.5mg (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0440">37</a> During its phase II implementation, 3 doses were assessed: 5, 10 and 20mg administered once or twice daily for the indication of prophylaxis in orthopedic surgery. The study was not designed to detect significant differences in the 2 treatment regimens. However, a tendency towards a reduction in the incidence rate of thrombosis was observed for each dose in the fractionated dose group compared with the single-dose group.<a class="elsevierStyleCrossRef" href="#bib0445">38</a> The final decision on the dosage regimen was performed based on the exposure–clinical response modeling, along with previous clinical data.<a class="elsevierStyleCrossRef" href="#bib0330">15</a> In this study, the therapeutic utility index, which integrates the safety and efficacy predictions based on the systemic exposure or area under the curve in steady state for each dosage regimen, showed that the fractionated regimen had a more favorable profile. Based on these previous data, the fractionated regimen was selected for the confirmation studies AVERROES and ARISTOTLE for the NVAF indication.<a class="elsevierStyleCrossRefs" href="#bib0335">16–18</a>EdoxabanEdoxaban is a reversible FXa inhibitor. The anticoagulant activity, measured using aPTT and PT in the studies with healthy volunteers, showed a direct and proportional relationship with the evolution of the plasma concentration curves, with persistence of the anticoagulant activity beyond 24h postadministration (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0350">19,20,39–42</a>The subsequent development of edoxaban showed novel results in terms of the pharmacokinetic justification for the dose administration frequency. A phase II clinical trial that assessed the safety of 30 and 60-mg doses, administered once or twice daily to patients with NVAF, showed that the incidence rate of bleeding was significantly higher with the fractionated administration.<a class="elsevierStyleCrossRefs" href="#bib0470">43,44</a> In this study and in a related PK/PD study,<a class="elsevierStyleCrossRef" href="#bib0480">45</a> the higher incidence of hemorrhagic events in the fractionated-dose groups was more precisely correlated with Cmin, a result also suggested by the clinical studies with rivaroxaban. Considering that the initial phase I studies had shown that the anticoagulant activity of edoxaban persisted beyond its mean elimination time, the single daily administration was chosen for the phase III clinical trial ENGAGE AF-TIMI 48.<a class="elsevierStyleCrossRefs" href="#bib0485">46,47</a>Therefore, the regimen selection for NVAF showed a differential evolution for each drug. We also must consider that the phase III clinical trials had significant differences in terms of the included population, design and measurement of clinical events and pharmacodynamic parameters.Differential characteristics of the confirmatory clinical trialsRisk of hemorrhagic and thrombotic eventsThe studies presented differences in terms of baseline risk of thrombotic events, defined by the CHADS2 score. For example, the mean CHADS2 score in the ROCKET-AF study was 3.5, while in the other studies the score was between 2.1 and 2.8 (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Definition of safety variablesWhile all studies considered a drop in hemoglobin levels ≥2g/dL to be a major hemorrhage, this reduction was only considered in the ARISTOTLE study when it persisted for 24h.<a class="elsevierStyleCrossRefs" href="#bib0335">16,18</a> Similarly, only transfusions of packed red blood cells were considered (not whole blood transfusions). This less restrictive safety assessment criterion could have resulted in detecting a different number of hemorrhagic events in the ARISTOTLE study.<a class="elsevierStyleCrossRefs" href="#bib0335">16,18</a>Design differencesThe phase III studies had notable differences in their design. Firstly, the ROCKET-AF,<a class="elsevierStyleCrossRef" href="#bib0425">34</a> ARISTOTLE,<a class="elsevierStyleCrossRefs" href="#bib0335">16,18</a> and ENGAGE TIMI-AF 48<a class="elsevierStyleCrossRefs" href="#bib0485">46,47</a> studies allowed for dosage adjustments based on the baseline renal function. However, the RE-LY study<a class="elsevierStyleCrossRefs" href="#bib0320">13,31</a> did not allow for dosage adjustments (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), despite the fact that 80% of dabigatran is eliminated renally. Secondly, the RE-LY study<a class="elsevierStyleCrossRefs" href="#bib0320">13,31</a> was open, while the other studies used a blinded design. Finally, the dosage range for the experimental arm was substantially different. While the RE-LY<a class="elsevierStyleCrossRefs" href="#bib0320">13,31</a> and ENGAGE TIMI-AF48 studies<a class="elsevierStyleCrossRefs" href="#bib0485">46,47</a> assessed 2 doses, the ROCKET<a class="elsevierStyleCrossRef" href="#bib0425">34</a> and ARISTOTLE<a class="elsevierStyleCrossRefs" href="#bib0335">16,18</a> and AVERROES<a class="elsevierStyleCrossRef" href="#bib0340">17</a> studies assessed single-dose regimens of the experimental drug. The control arm was also dramatically different among the studies, as shown by the different time in therapeutic range values (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Differences in the measurement of pharmacodynamic parametersThe clinical trials presented considerable heterogeneity in terms of the measurement of pharmacodynamic parameters (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), limiting the comparability of the pharmacodynamic conclusions and their correlation with the clinical data among drugs and taking into account the different sensitivities of the pharmacodynamic tests used to measure the anticoagulant activity.In conclusion, the pharmacokinetic data from the phase II clinical trials showed that the anticoagulant activity remained at significant levels, even during the elimination phase, regardless of the administration regimen. Despite the conclusions derived from the PK/PD characterization, the clinical development of phases II and III and thereby the safety and efficacy conclusions were different for each drug. The final dosage selection was based, in short, on the analysis adjusted to each drug and indication assessed, according to the clinical context, and not so much on the initial PK/PD predictions (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The confirmatory clinical trials, even when sharing common characteristics, presented marked differences that hinder in large measure the indirect comparisons among DOAs.Determining the relative benefit of the various dosage regimens for DOAs is therefore complex. On one hand, single daily administration improves therapeutic adherence (although there are still no data in clinical practice that support this, a number of publications on patients with NVAF suggest this conclusion).<a class="elsevierStyleCrossRef" href="#bib0495">48</a> On the other hand, the fractionated dosage regimen contributes to a decrease in the fluctuations in the drug's plasma concentrations. Considering that the biophase is found in plasma and that the temporal profile of plasma concentrations is associated, in principle, with the temporal profile of its pharmacological action, achieving stable levels theoretically contributes to maintaining the long-term anticoagulant effect even at the expense of a potential increase in the risk of bleeding associated with a higher Cmin. However, this fact does not always hold true for all drugs. With DOAs, the data from studies with healthy volunteers indicate that, despite the short half-life (between 7 and 14h), the anticoagulant activity is maintained significantly beyond 12–24h (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Therefore, a pharmacokinetic argument cannot be used as the only foundation for selecting the dosage regimen.In the context of anticoagulant therapy, there is no pharmacodynamic parameter that can be considered a fully valid predictor of clinical safety and efficacy. Therefore, the final decision on the chosen dosage regimen should be tested during the clinical development, adapting the initial predictions to the data obtained with each drug. For DOAs, despite presenting a similar PK/PD profile (with certain differences in the point estimates), the conclusions on the risk-benefit relationship have to be limited to the assessment of the actual safety and efficacy data and not as much on the PK/PD results. For example, despite the fact that both dabigatran and rivaroxaban maintain certain anticoagulant activity 12h after the dose administration, the results of the phase II studies in patients with DVT varied for each drug and administration regimen. The final dosage regimen for NVAF did not always coincide with the regimen that showed better results in the phase II studies (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).In addition to the differences among the studies, the alternative hypothesis is also worth considering; i.e., the fact that there are subtle differences among the DOAs, shown during the clinical development. This fact could explain, for example, why Cmax has been considered a good predictor of safety and efficacy for dabigatran, while Cmin is better adjusted in the rivaroxaban and edoxaban model.Considering these differences, a number of authors have attempted to analyze the overall benefit of each dosage regimen, performing indirect comparisons among the studies. In a recent study,<a class="elsevierStyleCrossRef" href="#bib0500">49</a> different dosage regimens were compared using a meta-analysis of indirect comparisons and fixed effects, including clinical trials performed with dabigatran, rivaroxaban, apixaban and edoxaban compared with warfarin for the indication of NVAF. The individual results of each study were analyzed, calculating the index of heterogeneity and using joint estimates of several studies when the index was less than 25%. The main analysis compared the individual and joint results of each drug against warfarin for the main endpoints of safety and efficacy: stroke, all-cause mortality, intracranial hemorrhage and other major hemorrhagic events. The authors concluded that fractionated administration had the most favorable risk–benefit balance, with a reduction in thrombotic (stroke) and hemorrhagic (intracranial hemorrhage) events compared with once-daily administration. Although the statistical method for the control of heterogeneity and the analysis of results were appropriate, in our opinion the conclusions lack support, due to the lack of comparability of the analyzed studies by including different drugs, dosages and population groups, which preclude the extrapolation of their results. As has already been stated, the clinical implementation in phases II and III was different for each drug: a different reasoning in the selection of dosage, markedly different designs and patient populations in the confirmatory clinical trials, which make it extraordinarily difficult to obtain generalizable conclusions about the collection of drugs. On the limitations inherent in the meta-analysis and the systematic revisions, the meta-analyses of indirect comparisons, as is the case of the commented study, are even more likely to incur this restriction. The indirect comparisons based on individual studies with a common comparator can entail significant selection biases that seriously question the validity of the results and, in the opinion of a number of authors, should be avoided or used with caution.<a class="elsevierStyleCrossRefs" href="#bib0505">50,51</a> In fact, in the case we are discussing, the meta-analysis of indirect comparisons is still less consistent because the comparator, warfarin, is also not homogeneous among studies (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).Not only the design of the clinical trials but also the focus of PK/PD models, the measured pharmacodynamic parameters and their sensitivity show considerable heterogeneity, making it impossible to perform a consistent comparison among dosage regimens, anticoagulant activity and effect and the clinical events of safety and efficacy among the studies.Therefore, the indirect comparisons are not a reliable strategy for reaching solid conclusions about on the overall benefit of each dosage regimen and overcome the individual differences of each drug. These differences should be addressed in direct comparative clinical trials between each of the drugs.In conclusion, the overall clinical benefit of each DOA and of each dosage regimen for NVAF and, in general, for each indication should be considered individually. Lacking comparative studies, the indirect comparisons do not constitute a reliable source of evidence on the overall benefit and applicability in clinical practice. Despite their limitations, it is expected that future successive observational studies in conditions of standard clinical practice will help delimit the actual value of each drug and facilitate the decision-making process.Conflicts of interestJRGJ declares having given presentations, signed research contracts and participated in clinical trials with Boehringher Ingelheim, Bayer, BMS, Pfizer and Daichii Sankyo. CAS declares having given presentations and signed research contracts with Bayer, BMS, Pfizer and Daiichi. JSP declares having given presentations for Bayer." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres823814" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec820424" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres823815" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec820423" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Background" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "General pharmacokinetic and pharmacodynamic principles for selecting the dosage regimen" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Dosage and dosage regimen selection for direct oral anticoagulants" ] ] ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Dabigatran" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Rivaroxaban" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Apixaban" ] 8 => array:3 [ "identificador" => "sec0035" "titulo" => "Edoxaban" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0040" "titulo" => "Differential characteristics of the confirmatory clinical trials" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Risk of hemorrhagic and thrombotic events" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Definition of safety variables" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Design differences" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Differences in the measurement of pharmacodynamic parameters" ] ] ] ] ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack276326" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec820424" "palabras" => array:5 [ 0 => "Factor Xa inhibitors" 1 => "Pharmacokinetics" 2 => "Pharmacodynamics" 3 => "Administration regimen" 4 => "Atrial fibrillation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec820423" "palabras" => array:5 [ 0 => "Inhibidores del factor Xa" 1 => "Farmacocinética" 2 => "Farmacodinamia" 3 => "Esquema de administración" 4 => "Fibrilación auricular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The efficacy of dicoumarin anticoagulants has been shown in patients with nonvalvular atrial fibrillation. However, they have drawbacks such as the need to adjust the dosage and the interaction with drugs and food. Direct oral anticoagulants are an effective and safe alternative and have a less complicated clinical management. There is considerable debate on the selection criteria for the posology regimens of direct oral anticoagulants. The differences among them and their administration regimens have raised questions about the clinical, pharmacokinetic and pharmacodynamic selection criteria that support the posology. This review critically analyses the available evidence and its impact on the final selection of the dosage regimen." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los anticoagulantes dicumarínicos han demostrado su eficacia en pacientes con fibrilación auricular no valvular. Sin embargo, presentan desventajas como la necesidad de ajustar la dosis y la interacción con fármacos y alimentos. Por su parte, los anticoagulantes orales de acción directa se presentan como una alternativa eficaz y segura con un manejo clínico menos complejo. Existe un considerable debate sobre los criterios de selección de las pautas posológicas de los anticoagulantes orales de acción directa. Las diferencias entre ellos y sus pautas de administración han despertado dudas sobre los criterios de selección clínicos, farmacocinéticos y farmacodinámicos que avalan dicha posología. Esta revisión analiza de forma crítica las evidencias disponibles y su impacto en la selección final del esquema posológico." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sáez-Peñataro J, Avendaño-Solá C, González-Juanatey JR. Consideraciones clínicas sobre la posología de los anticoagulantes orales de acción directa. Rev Clin Esp. 2016;216:384–392." ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; ECT, ecarin clotting time; mTT, mean thrombin time; HepTest and Rotachrom, measurement of plasma factor Xa levels; Tmax, time to maximum concentration; IC50, half maximal inhibitory concentration (concentration at which thrombin is inhibited by 50%)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Brand name \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pradaxa® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Xarelto® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Eliquis® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lixiana® \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">Target \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Factor IIa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Factor Xa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Factor Xa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Factor Xa \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">Prodrug \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">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">Laboratory tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">aPTT, PT and ECT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PT, aPTT and HepTest \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PT, aPTT, mTT, HepTest and Rotachrom \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PT, aPTT and HepTest \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">Therapeutic dosage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">110, 150mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10, 20mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5, 5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60, 30mg/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">Thrombin inhibition (IC50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.56μM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">163μM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75–100μM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.561nM \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">Tmax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.25–3h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–4h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–3h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.5h \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">Elimination half-life \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7–9h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7–11h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8–10h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–14h \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">Persistence of anticoagulant activity beyond 12h (aPTT and PT) \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">Yes \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">Yes \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">65% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80–100% \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">66% (active form 33%, inactive form 33%) \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% \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">Patient groups who required care \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal or hepatic failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal or hepatic failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal or hepatic failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal failure \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">Interference with cytochrome \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">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><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1385102.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Synopsis of phase I studies performed with healthy volunteers described in the text." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: Cmax, maximum concentration; Cmin: minimum concentration; TUI, therapeutic utility index; iTTR, individual time within therapeutic range; PD, pharmacodynamic; PK, pharmacokinetic; aPTT, activated partial thromboplastin time; ECT, ecarin clotting time." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Evidence from phase II clinical trials \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BISTRO-I (14,15): Tendency towards greater safety and efficacy in the point estimates in the single-dose group PD parameters evaluated: aPTT and ECT BISTRO-II (16): No differences in safety and efficacy between single dose and fractionated dose. Cmax: correlation with the clinical events of safety and efficacy. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ODIXa-DVT and EINSTEIN DVT (26-28): no significant differences in safety and efficacy between single dose and fractionated dose. Cmin: correlation with the clinical events of safety and efficacy. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II trials (29,30): Fractionated dose had better safety and efficacy results than single daily dose. PK/PD modeling with TUI: fractionated dose has better safety and efficacy profile. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II trials (40-42): Fractionated dose had better safety and efficacy results than single daily dose. Cmin: correlation with the clinical events of safety and efficacy. \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 regimen evaluated in the phase III clinical trials \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RE-LY: 110 and 150mg, twice daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ROCKET AF: 20mg once daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AVERROES and ARISTOTLE: 5mg twice daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ENGAGE AF-TIMI 48: 30 and 60mg once daily \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">Blinding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Open \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \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">Prerandomization dosage adjustment Phase III studies \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">From 20 to 15mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From 5 to 2.5mg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From 60 to 30mg From 30 to 15mg \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 adjustment after randomization Phase III studies \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><td class="td" title="table-entry " align="left" valign="top">From 60 to 30mg From 30 to 15mg \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">iTTR (definition of the comparator: warfarin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">55.2% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">68.4% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1385101.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison between kinetic and dynamic activity (anticoagulant activity), based on the phase II and III clinical trials." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: CHADS2, stroke risk prediction scale for patients with atrial fibrillation; TIA, transient ischemic attack." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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 RE-LY (n=18,113) \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 ROCKET AF (n=14,264) \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 ARISTOTLE (n=18,201) \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 ENGAGE (n=21,105) \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">Mean CHADS2 score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.8 \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">Heart failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57% \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">Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">91% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">94% \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">≥75 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40% \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">Diabetes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36% \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">Previous stroke or TIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28% \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">Moderate renal failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1385103.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison of the mean CHADS2 scores of the patients included in the phase III confirmation studies for each drug." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib0260" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New anticoagulant therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L.A. 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Clinical considerations on the posology of direct oral anticoagulants

Consideraciones clínicas sobre la posología de los anticoagulantes orales de acción directa

J. Sáez-Peñataroa,

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jsaez@clinic.ub.es
jsaezp@hotmail.com

Corresponding author.

, C. Avendaño-Soláb, J.R. González-Juanateyc,d

a Servicio de Farmacología Clínica, Hospital Clínic de Barcelona, Barcelona, Spain

b Servicio de Farmacología Clínica, Hospital Puerta de Hierro Majadahonda, Madrid, Spain

c Servicio de Cardiología, Hospital Clínico Universitario de Santiago de Compostela , Santiago de Compostela, Spain

d Departamento de Medicina, Facultad de Medicina y Odontología, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

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            "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of liver damage&#46; Liver damage is initiated by the presentation of a self-antigenic peptide within a major histocompatibility molecule &#40;MHC&#41; by professional antigen presenting cells &#40;APCs&#41;&#46; The presence of appropriate costimulation alongside exposure to various cytokines drives the differentiation of uncommitted CD4 helper T-cells &#40;Th0&#41;&#46; IL-6 and IL-1&#946; lead to differentiation into pathogenic Th17 cells that secrete the proinflammatory cytokine IL-17&#46; Th17 cells promote hepatocyte secretion of IL-6&#44; which in turn further enhances Th17 development&#46; Exposure to IL-12 leads to the differentiation of Th1 cells secreting IFN-&#947;&#44; which induces monocyte &#40;M&#934;&#41; differentiation&#44; activates cytotoxic CD8 T-cells and promotes NK cell killing&#46; IFN-&#947; also increases MHC class I and induces class II expression by hepatocytes&#44; further exacerbating inflammation&#46; Exposure to IL-4 leads to Th2 differentiation&#46; Th2 cells secrete IL-13&#44; IL-4 and IL-10 that enable B cell maturation into plasma cells with the consequent production of autoantibodies&#46; Autoantibodies are in turn involved in antibody-mediated cellular cytotoxicity and complement activation&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The characterization of the dose&#8211;response and dose&#8211;safety profile of medicinal products is an essential element in their development&#46; The dose&#8211;concentration&#8211;response assessment increases the chances of obtaining a favorable risk&#8211;benefit ratio&#46; For oral anticoagulants&#44; an optimal treatment regimen should maintain an appropriate anticoagulant activity and safety profile over time&#44; with no oscillations or the need for periodic laboratory monitoring&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The assessment of the dose&#8211;concentration&#8211;effect relationship has varied dramatically in recent years&#44; such that the classical approach &#40;phase II of the clinical development of medicinal products&#41; is less delimited now and is frequently accelerated due to the need to optimize clinical development in a highly competitive environment&#46; Techniques such as pharmacokinetic&#8211;pharmacodynamic &#40;PK&#47;PD&#41; modeling<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">3&#44;4</span></a> and the assessment of 2 dosage regimens in &#8220;pivotal&#8221; studies tend to replace the classical dose-finding studies&#46; However&#44; the time and cost savings is coupled with a notable increase in uncertainty&#46; In these circumstances&#44; the safety and efficacy studies on the target population are the ones that determine whether the chosen dosage regimen shows a favorable risk&#8211;benefit profile&#46; However&#44; we cannot rule out the possibility that other alternative regimens could have been reasonable&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Direct oral anticoagulants &#40;DOAs&#41;&#44; both thrombin inhibitors &#40;dabigatran&#41; and factor Xa inhibitors &#40;rivaroxaban&#44; apixaban and edoxaban&#41;&#44; are not exempt from this complexity&#46; The accepted dosage regimens for each of them &#40;which are different one from the other&#41; reflect the previously mentioned uncertainties&#46; In this review&#44; we analyze the evidence underlying the final selection of the dosage regimen&#44; taking into account its relevance for guiding the clinical decision-making process for prescribers in daily clinical practice&#46; To this end&#44; we address the general foundations for selecting the dosage&#44; subsequently analyzing the selection of the dosage regimen during the clinical development of each drug&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">General pharmacokinetic and pharmacodynamic principles for selecting the dosage regimen</span><p id="par0020" class="elsevierStylePara elsevierViewall">For the characterization of PK&#47;PD&#44; we must consider 2 fundamental factors&#58; the concentration reached in plasma&#44; in the target organ or the target tissue &#40;biophase&#41; and the duration of the effect&#46; The course of the plasma concentrations is determined by the processes of absorption&#44; distribution&#44; metabolism and excretion&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">5</span></a> From the plasma&#44; the drug must be distributed to the biophase to cause its effect&#46; Therefore&#44; the concentration and half-life in the biophase will determine the temporal profile of the effect to a greater degree than the plasma concentration&#46; There are numerous factors &#40;genetic&#44; physiological and pathological&#41; that determine the degree of variability in the pharmacokinetic processes&#46; The dosage needs to be adjusted for each individual situation when these factors of variability involve relevant intrapatient and interpatient changes in plasma concentrations and the biophase&#44; and these changes have clinical repercussions&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the case of DOAs&#44; given that the target consists of plasma coagulation factors&#44; the plasma concentrations constitute a direct measure of concentrations in the biophase&#46; However&#44; the temporal profile of the effect not only depends on the pharmacokinetic factors but also on the mechanism of action&#44; given that based on this mechanism&#44; the effect could last longer than the presence of the drug&#46; An example of this is antivitamin K drugs&#44; whose anticoagulant effect is maintained sufficiently long so that once the antagonism on the vitamin K disappears sufficient quantities of new active coagulation factors are synthesized&#46; In addition to the mechanism of action&#44; there are other pharmacodynamic factors such as potency&#44; intrinsic activity&#44; pharmaceutical tolerance and genetic polymorphisms<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">5</span></a> that can affect the magnitude and duration of the effect regardless of the plasma concentrations and elimination half-life&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">It is also important to consider the relationship of pharmacokinetic and pharmacodynamic factors&#46; Studies on DOAs in healthy volunteers observed an acceptable parallelism between the curve of plasma concentrations and pharmacodynamic parameters&#44; such as the activated partial thromboplastin time &#40;aPTT&#41;&#44; the thrombin time and the ecarin clotting time&#46; Despite this parallelism&#44; however&#44; the concentration&#8211;time and effect&#8211;time curves were not similar&#46; In these cases&#44; the anticoagulant effect persisted into the terminal phase of the curve of elimination&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">6&#8211;9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">It is important to note that the concentration&#8211;effect relationship is not always linear and direct and is not equal for all pharmacodynamic parameters&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">10</span></a> In studies with healthy volunteers&#44; for example&#44; the aPTT analysis showed a pharmacodynamic behavior compatible with a sigmoid Emax model &#40;the graphical representation of the concentration&#8211;effect relationship shows a sigmoid curve&#41;&#44; while other parameters such as thrombin time&#44; ecarin clotting time and prothrombin time &#40;PT&#41; fit with greater precision to a linear Emax model&#46; Although the tendency was similar&#44; differences were observed in the average values depending on the drug&#44; dosage and study&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">11&#8211;20</span></a> Therefore&#44; the variations in the effect are not always linearly proportional to the plasma concentration&#44; and this relationship can be different depending on the parameter pharmacodynamic and drug considered&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Lastly&#44; the pharmacological effect observed for each of the plasma concentrations does not necessarily have a direct translation in the prediction of the clinical effect&#44; dependent <span class="elsevierStyleItalic">per</span> se on numerous pharmacokinetic and pharmacodynamic factors&#44; which is variable for each drug and should be ultimately confirmed by actual clinical data&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Dosage and dosage regimen selection for direct oral anticoagulants</span><p id="par0045" class="elsevierStylePara elsevierViewall">The selection of the dosage regimen has considered kinetic&#44; dynamic&#44; clinical&#44; safety and efficacy data&#46; In a number of cases&#44; as with rivaroxaban&#44; the decision concerning the dosage regimen for nonvalvular atrial fibrillation &#40;NVAF&#41; was extrapolated from the prophylaxis data on deep vein thrombosis &#40;DVT&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#8211;23</span></a> In other cases&#44; a specific dose search was performed for each indication&#44; or as with dabigatran&#44; more than one dose was assessed in the &#8220;pivotal<span class="elsevierStyleItalic">&#8221;</span> study in NVAF&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">6</span></a></p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Dabigatran</span><p id="par0050" class="elsevierStylePara elsevierViewall">Dabigatran selectively and reversibly inhibits thrombin&#44; with high affinity&#46; After the administration of a single dose to healthy volunteers in phase I clinical trials&#44; the maximum plasma concentration &#40;<span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#41; was observed between 0&#46;5 and 2<span class="elsevierStyleHsp" style=""></span>h&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">24</span></a> with an elimination half-life of 7&#8211;9<span class="elsevierStyleHsp" style=""></span>h&#46; Although the maximum effect was consistent with <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#44; showing a close PK&#47;PD relationship and a parallel evolutionary course&#44;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">11&#44;12</span></a> the anticoagulant activity persisted even into the elimination phase 12<span class="elsevierStyleHsp" style=""></span>h after its administration &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">7&#44;25</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The BISTRO-I clinical trial assessed dosages of 12&#46;5&#44; 25&#44; 50&#44; 100&#44; 150&#44; 200&#44; 300<span class="elsevierStyleHsp" style=""></span>mg twice daily and 150 and 300<span class="elsevierStyleHsp" style=""></span>mg in a single daily dose for 6&#8211;10 days in patients who underwent orthopedic hip surgery&#44; with the drug used as prophylaxis for DVT&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a> Although the power of the study was insufficient to demonstrate differences among the dosages&#44; better results &#40;but not significant&#41; were observed in the point estimates of safety and efficacy with the fractionated administration&#46; A <span class="elsevierStyleItalic">post hoc</span> PK&#47;PD analysis of this study observed a parallel temporal kinetic and dynamic course in the first hours&#46; However&#44; the pharmacological effect persisted beyond the total plasma clearance of dabigatran&#44; with a time to a 50&#37; reduction in effect of 1&#46;6 days for aPTT and 2&#46;9 days for ecarin clotting time&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a> Although this tendency had already been confirmed in the preliminary studies in healthy volunteers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; the data showed much longer time periods&#44; especially in the first hours after surgery&#44; with a slow subsequent reduction&#46; The authors concluded that a number of confounding factors&#44; including perioperative transfusions&#44; could be contributing to these results &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Based on this evidence&#44; the BISTRO-II study assessed the total dose of 300<span class="elsevierStyleHsp" style=""></span>mg administered once a day compared with the same fractionated dose in preventing DVT after total hip or knee replacement&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> The 300-mg dose administered once a day showed greater fluctuations between <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> and <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#46; However&#44; there were no significant differences with respect to the fractionated dose in terms of safety and efficacy&#46; In a subsequent logistic regression subanalysis that integrated the pharmacokinetic and pharmacodynamic results with the safety and efficacy data&#44; the authors&#8217; suggested that <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> could be a reasonable predictor of clinical results in the dose interval between 100 and 300<span class="elsevierStyleHsp" style=""></span>mg&#44; more than the fluctuations between <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> and <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span><span class="elsevierStyleItalic">per se&#46;</span><a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> However&#44; the single-dose daily regimen was selected for this indication&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The phase II and III clinical trials in patients with NVAF only assessed the fractionated dose regimen&#44;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">29&#44;30</span></a> given that&#44; unlike prophylaxis after surgery&#44; the objective in NVAF is not so much the start of rapid action in the first hours but rather maintaining the anticoagulant effect over the course of the treatment&#44; preserving an appropriate safety and efficacy profile over time&#46; Assuming that <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> has been related to the risk of hemorrhage&#44; the fractioning of the dose was considered to provide the best safety and efficacy profile&#44; with a reduction in the incidence of hemorrhagic events associated with the reduction in the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> peak&#44; maintaining long-term anticoagulant efficacy at clinically significant levels&#46; The dosages evaluated in the RE-LY phase III clinical trial were 110 and 150<span class="elsevierStyleHsp" style=""></span>mg&#44; twice daily&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;31</span></a> compared with warfarin&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Rivaroxaban</span><p id="par0070" class="elsevierStylePara elsevierViewall">Rivaroxaban is a selective and reversible inhibitor of FXa&#46; Its elimination half-life has been estimated at 5&#8211;9<span class="elsevierStyleHsp" style=""></span>h in young individuals and 11&#8211;13<span class="elsevierStyleHsp" style=""></span>h in elderly individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">32</span></a> Studies in healthy volunteers have shown PK&#47;PD relationship results similar to those obtained with dabigatran&#44; indicating a close correlation between the course of the plasma concentrations and the inhibition of aPTT and PT&#44; although the anticoagulant activity persisted beyond 12<span class="elsevierStyleHsp" style=""></span>h after the administration of doses greater than 5<span class="elsevierStyleHsp" style=""></span>mg &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">25&#44;26&#44;33</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The phase I clinical trials ODIXa-DVT and EINSTEIN DVT<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">21&#44;22</span></a> assessed the safety and efficacy of rivaroxaban&#44; in a dose range of 20&#8211;40<span class="elsevierStyleHsp" style=""></span>mg&#44; administered one or twice daily&#44; compared with the standard treatment &#40;initial administration of low-molecular-weight heparins followed by maintenance treatment with vitamin K antagonists&#41; in patients with DVT&#46; The study ODIXa-DVT observed a lower persistence of thrombus at 21 days of treatment with the fractionated dose&#46; However&#44; the recurrence of thromboembolic events at 84 days of follow-up was similar in the 2 dosage regimes&#46; Therefore&#44; no definitive conclusions could be extracted from the study on the better dosage regimen&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The EINSTEIN-DVT study found no significant differences between the 2 dosage regimens&#46; The authors suggested that&#44; based on the results of the previous ODIXa-DVT study and considering that the fractionated administration increased the minimum concentration levels throughout the day&#44; the treatment regimen should include an initial 3-week period of fractionated administration in the acute phase of DVT&#44; followed by a single daily maintenance dose&#46; A subsequent population pharmacokinetics study&#44; performed with the data from these 2 studies&#44; showed that the single daily administration increased the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> levels by 20&#37; and decreased the <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> levels by 60&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">23</span></a> Although the 5&#8211;95 percentile range overlapped for these 2 parameters&#44; a clear tendency was observed in the reduction of <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> with the single administration&#44; confirming the findings of the ODIXa-DVT study&#46; The data suggested that <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> was a predictor of safety in terms of hemorrhagic events&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">No formal dose-finding studies were performed for the NVAF indication&#46; However&#44; given the extended duration of the effect on the aPTT and PT and the association of a <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> with a lower risk of bleeding&#44; a single-dose 20<span class="elsevierStyleHsp" style=""></span>mg&#47;d regimen was chosen for the long-term maintenance treatment&#44; a dosage subsequently evaluated in the phase III clinical trial ROCKET AF&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Apixaban</span><p id="par0090" class="elsevierStylePara elsevierViewall">Apixaban is another selective and reversible FXa inhibitor&#44; with a pharmacokinetic and pharmacodynamic profile similar to that of rivaroxaban<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">9&#44;35</span></a> and a half-life of 12<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a> In healthy volunteers&#44; the anticoagulant activity significantly persisted at 12<span class="elsevierStyleHsp" style=""></span>h after the administration of a dose &#62;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a> During its phase II implementation&#44; 3 doses were assessed&#58; 5&#44; 10 and 20<span class="elsevierStyleHsp" style=""></span>mg administered once or twice daily for the indication of prophylaxis in orthopedic surgery&#46; The study was not designed to detect significant differences in the 2 treatment regimens&#46; However&#44; a tendency towards a reduction in the incidence rate of thrombosis was observed for each dose in the fractionated dose group compared with the single-dose group&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">38</span></a> The final decision on the dosage regimen was performed based on the exposure&#8211;clinical response modeling&#44; along with previous clinical data&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> In this study&#44; the therapeutic utility index&#44; which integrates the safety and efficacy predictions based on the systemic exposure or area under the curve in steady state for each dosage regimen&#44; showed that the fractionated regimen had a more favorable profile&#46; Based on these previous data&#44; the fractionated regimen was selected for the confirmation studies AVERROES and ARISTOTLE for the NVAF indication&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#8211;18</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Edoxaban</span><p id="par0095" class="elsevierStylePara elsevierViewall">Edoxaban is a reversible FXa inhibitor&#46; The anticoagulant activity&#44; measured using aPTT and PT in the studies with healthy volunteers&#44; showed a direct and proportional relationship with the evolution of the plasma concentration curves&#44; with persistence of the anticoagulant activity beyond 24<span class="elsevierStyleHsp" style=""></span>h postadministration &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">19&#44;20&#44;39&#8211;42</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The subsequent development of edoxaban showed novel results in terms of the pharmacokinetic justification for the dose administration frequency&#46; A phase II clinical trial that assessed the safety of 30 and 60-mg doses&#44; administered once or twice daily to patients with NVAF&#44; showed that the incidence rate of bleeding was significantly higher with the fractionated administration&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">43&#44;44</span></a> In this study and in a related PK&#47;PD study&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">45</span></a> the higher incidence of hemorrhagic events in the fractionated-dose groups was more precisely correlated with <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#44; a result also suggested by the clinical studies with rivaroxaban&#46; Considering that the initial phase I studies had shown that the anticoagulant activity of edoxaban persisted beyond its mean elimination time&#44; the single daily administration was chosen for the phase III clinical trial ENGAGE AF-TIMI 48&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">46&#44;47</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Therefore&#44; the regimen selection for NVAF showed a differential evolution for each drug&#46; We also must consider that the phase III clinical trials had significant differences in terms of the included population&#44; design and measurement of clinical events and pharmacodynamic parameters&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Differential characteristics of the confirmatory clinical trials</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Risk of hemorrhagic and thrombotic events</span><p id="par0110" class="elsevierStylePara elsevierViewall">The studies presented differences in terms of baseline risk of thrombotic events&#44; defined by the CHADS<span class="elsevierStyleInf">2</span> score&#46; For example&#44; the mean CHADS<span class="elsevierStyleInf">2</span> score in the ROCKET-AF study was 3&#46;5&#44; while in the other studies the score was between 2&#46;1 and 2&#46;8 &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Definition of safety variables</span><p id="par0115" class="elsevierStylePara elsevierViewall">While all studies considered a drop in hemoglobin levels &#8805;2<span class="elsevierStyleHsp" style=""></span>g&#47;dL to be a major hemorrhage&#44; this reduction was only considered in the ARISTOTLE study when it persisted for 24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;18</span></a> Similarly&#44; only transfusions of packed red blood cells were considered &#40;not whole blood transfusions&#41;&#46; This less restrictive safety assessment criterion could have resulted in detecting a different number of hemorrhagic events in the ARISTOTLE study&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;18</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Design differences</span><p id="par0120" class="elsevierStylePara elsevierViewall">The phase III studies had notable differences in their design&#46; Firstly&#44; the ROCKET-AF&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a> ARISTOTLE&#44;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;18</span></a> and ENGAGE TIMI-AF 48<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">46&#44;47</span></a> studies allowed for dosage adjustments based on the baseline renal function&#46; However&#44; the RE-LY study<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;31</span></a> did not allow for dosage adjustments &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; despite the fact that 80&#37; of dabigatran is eliminated renally&#46; Secondly&#44; the RE-LY study<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;31</span></a> was open&#44; while the other studies used a blinded design&#46; Finally&#44; the dosage range for the experimental arm was substantially different&#46; While the RE-LY<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">13&#44;31</span></a> and ENGAGE TIMI-AF48 studies<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">46&#44;47</span></a> assessed 2 doses&#44; the ROCKET<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a> and ARISTOTLE<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;18</span></a> and AVERROES<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">17</span></a> studies assessed single-dose regimens of the experimental drug&#46; The control arm was also dramatically different among the studies&#44; as shown by the different time in therapeutic range values &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Differences in the measurement of pharmacodynamic parameters</span><p id="par0125" class="elsevierStylePara elsevierViewall">The clinical trials presented considerable heterogeneity in terms of the measurement of pharmacodynamic parameters &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; limiting the comparability of the pharmacodynamic conclusions and their correlation with the clinical data among drugs and taking into account the different sensitivities of the pharmacodynamic tests used to measure the anticoagulant activity&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; the pharmacokinetic data from the phase II clinical trials showed that the anticoagulant activity remained at significant levels&#44; even during the elimination phase&#44; regardless of the administration regimen&#46; Despite the conclusions derived from the PK&#47;PD characterization&#44; the clinical development of phases II and III and thereby the safety and efficacy conclusions were different for each drug&#46; The final dosage selection was based&#44; in short&#44; on the analysis adjusted to each drug and indication assessed&#44; according to the clinical context&#44; and not so much on the initial PK&#47;PD predictions &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The confirmatory clinical trials&#44; even when sharing common characteristics&#44; presented marked differences that hinder in large measure the indirect comparisons among DOAs&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Determining the relative benefit of the various dosage regimens for DOAs is therefore complex&#46; On one hand&#44; single daily administration improves therapeutic adherence &#40;although there are still no data in clinical practice that support this&#44; a number of publications on patients with NVAF suggest this conclusion&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">48</span></a> On the other hand&#44; the fractionated dosage regimen contributes to a decrease in the fluctuations in the drug&#39;s plasma concentrations&#46; Considering that the biophase is found in plasma and that the temporal profile of plasma concentrations is associated&#44; in principle&#44; with the temporal profile of its pharmacological action&#44; achieving stable levels theoretically contributes to maintaining the long-term anticoagulant effect even at the expense of a potential increase in the risk of bleeding associated with a higher <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#46; However&#44; this fact does not always hold true for all drugs&#46; With DOAs&#44; the data from studies with healthy volunteers indicate that&#44; despite the short half-life &#40;between 7 and 14<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; the anticoagulant activity is maintained significantly beyond 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Therefore&#44; a pharmacokinetic argument cannot be used as the only foundation for selecting the dosage regimen&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In the context of anticoagulant therapy&#44; there is no pharmacodynamic parameter that can be considered a fully valid predictor of clinical safety and efficacy&#46; Therefore&#44; the final decision on the chosen dosage regimen should be tested during the clinical development&#44; adapting the initial predictions to the data obtained with each drug&#46; For DOAs&#44; despite presenting a similar PK&#47;PD profile &#40;with certain differences in the point estimates&#41;&#44; the conclusions on the risk-benefit relationship have to be limited to the assessment of the actual safety and efficacy data and not as much on the PK&#47;PD results&#46; For example&#44; despite the fact that both dabigatran and rivaroxaban maintain certain anticoagulant activity 12<span class="elsevierStyleHsp" style=""></span>h after the dose administration&#44; the results of the phase II studies in patients with DVT varied for each drug and administration regimen&#46; The final dosage regimen for NVAF did not always coincide with the regimen that showed better results in the phase II studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In addition to the differences among the studies&#44; the alternative hypothesis is also worth considering&#59; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; the fact that there are subtle differences among the DOAs&#44; shown during the clinical development&#46; This fact could explain&#44; for example&#44; why <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span> has been considered a good predictor of safety and efficacy for dabigatran&#44; while <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span> is better adjusted in the rivaroxaban and edoxaban model&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Considering these differences&#44; a number of authors have attempted to analyze the overall benefit of each dosage regimen&#44; performing indirect comparisons among the studies&#46; In a recent study&#44;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">49</span></a> different dosage regimens were compared using a meta-analysis of indirect comparisons and fixed effects&#44; including clinical trials performed with dabigatran&#44; rivaroxaban&#44; apixaban and edoxaban compared with warfarin for the indication of NVAF&#46; The individual results of each study were analyzed&#44; calculating the index of heterogeneity and using joint estimates of several studies when the index was less than 25&#37;&#46; The main analysis compared the individual and joint results of each drug against warfarin for the main endpoints of safety and efficacy&#58; stroke&#44; all-cause mortality&#44; intracranial hemorrhage and other major hemorrhagic events&#46; The authors concluded that fractionated administration had the most favorable risk&#8211;benefit balance&#44; with a reduction in thrombotic &#40;stroke&#41; and hemorrhagic &#40;intracranial hemorrhage&#41; events compared with once-daily administration&#46; Although the statistical method for the control of heterogeneity and the analysis of results were appropriate&#44; in our opinion the conclusions lack support&#44; due to the lack of comparability of the analyzed studies by including different drugs&#44; dosages and population groups&#44; which preclude the extrapolation of their results&#46; As has already been stated&#44; the clinical implementation in phases II and III was different for each drug&#58; a different reasoning in the selection of dosage&#44; markedly different designs and patient populations in the confirmatory clinical trials&#44; which make it extraordinarily difficult to obtain generalizable conclusions about the collection of drugs&#46; On the limitations inherent in the meta-analysis and the systematic revisions&#44; the meta-analyses of indirect comparisons&#44; as is the case of the commented study&#44; are even more likely to incur this restriction&#46; The indirect comparisons based on individual studies with a common comparator can entail significant selection biases that seriously question the validity of the results and&#44; in the opinion of a number of authors&#44; should be avoided or used with caution&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">50&#44;51</span></a> In fact&#44; in the case we are discussing&#44; the meta-analysis of indirect comparisons is still less consistent because the comparator&#44; warfarin&#44; is also not homogeneous among studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Not only the design of the clinical trials but also the focus of PK&#47;PD models&#44; the measured pharmacodynamic parameters and their sensitivity show considerable heterogeneity&#44; making it impossible to perform a consistent comparison among dosage regimens&#44; anticoagulant activity and effect and the clinical events of safety and efficacy among the studies&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Therefore&#44; the indirect comparisons are not a reliable strategy for reaching solid conclusions about on the overall benefit of each dosage regimen and overcome the individual differences of each drug&#46; These differences should be addressed in direct comparative clinical trials between each of the drugs&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In conclusion&#44; the overall clinical benefit of each DOA and of each dosage regimen for NVAF and&#44; in general&#44; for each indication should be considered individually&#46; Lacking comparative studies&#44; the indirect comparisons do not constitute a reliable source of evidence on the overall benefit and applicability in clinical practice&#46; Despite their limitations&#44; it is expected that future successive observational studies in conditions of standard clinical practice will help delimit the actual value of each drug and facilitate the decision-making process&#46;</p></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">JRGJ declares having given presentations&#44; signed research contracts and participated in clinical trials with Boehringher Ingelheim&#44; Bayer&#44; BMS&#44; Pfizer and Daichii Sankyo&#46; CAS declares having given presentations and signed research contracts with Bayer&#44; BMS&#44; Pfizer and Daiichi&#46; JSP declares having given presentations for Bayer&#46;</p></span></span>"
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              "titulo" => "General pharmacokinetic and pharmacodynamic principles for selecting the dosage regimen"
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              "titulo" => "Dosage and dosage regimen selection for direct oral anticoagulants"
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        5 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Dabigatran"
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                  "titulo" => "Definition of safety variables"
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                  "titulo" => "Design differences"
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          "palabras" => array:5 [
            0 => "Factor Xa inhibitors"
            1 => "Pharmacokinetics"
            2 => "Pharmacodynamics"
            3 => "Administration regimen"
            4 => "Atrial fibrillation"
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            0 => "Inhibidores del factor Xa"
            1 => "Farmacocin&#233;tica"
            2 => "Farmacodinamia"
            3 => "Esquema de administraci&#243;n"
            4 => "Fibrilaci&#243;n auricular"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The efficacy of dicoumarin anticoagulants has been shown in patients with nonvalvular atrial fibrillation&#46; However&#44; they have drawbacks such as the need to adjust the dosage and the interaction with drugs and food&#46; Direct oral anticoagulants are an effective and safe alternative and have a less complicated clinical management&#46; There is considerable debate on the selection criteria for the posology regimens of direct oral anticoagulants&#46; The differences among them and their administration regimens have raised questions about the clinical&#44; pharmacokinetic and pharmacodynamic selection criteria that support the posology&#46; This review critically analyses the available evidence and its impact on the final selection of the dosage regimen&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los anticoagulantes dicumar&#237;nicos han demostrado su eficacia en pacientes con fibrilaci&#243;n auricular no valvular&#46; Sin embargo&#44; presentan desventajas como la necesidad de ajustar la dosis y la interacci&#243;n con f&#225;rmacos y alimentos&#46; Por su parte&#44; los anticoagulantes orales de acci&#243;n directa se presentan como una alternativa eficaz y segura con un manejo cl&#237;nico menos complejo&#46; Existe un considerable debate sobre los criterios de selecci&#243;n de las pautas posol&#243;gicas de los anticoagulantes orales de acci&#243;n directa&#46; Las diferencias entre ellos y sus pautas de administraci&#243;n han despertado dudas sobre los criterios de selecci&#243;n cl&#237;nicos&#44; farmacocin&#233;ticos y farmacodin&#225;micos que avalan dicha posolog&#237;a&#46; Esta revisi&#243;n analiza de forma cr&#237;tica las evidencias disponibles y su impacto en la selecci&#243;n final del esquema posol&#243;gico&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; S&#225;ez-Pe&#241;ataro J&#44; Avenda&#241;o-Sol&#225; C&#44; Gonz&#225;lez-Juanatey JR&#46; Consideraciones cl&#237;nicas sobre la posolog&#237;a de los anticoagulantes orales de acci&#243;n directa&#46; Rev Clin Esp&#46; 2016&#59;216&#58;384&#8211;392&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; APTT&#44; activated partial thromboplastin time&#59; PT&#44; prothrombin time&#59; ECT&#44; ecarin clotting time&#59; mTT&#44; mean thrombin time&#59; HepTest and Rotachrom&#44; measurement of plasma factor Xa levels&#59; Tmax&#44; time to maximum concentration&#59; IC50&#44; half maximal inhibitory concentration &#40;concentration at which thrombin is inhibited by 50&#37;&#41;&#46;</p>"
          "tablatextoimagen" => 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=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Brand name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pradaxa<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Xarelto<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eliquis<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lixiana<span class="elsevierStyleSup">&#174;</span>&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">Target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Factor IIa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Factor Xa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Factor Xa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Factor Xa&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">Prodrug&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">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">Laboratory tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">aPTT&#44; PT and ECT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PT&#44; aPTT and HepTest&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PT&#44; aPTT&#44; mTT&#44; HepTest and Rotachrom&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PT&#44; aPTT and HepTest&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">Therapeutic dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">110&#44; 150<span class="elsevierStyleHsp" style=""></span>mg&#47;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">10&#44; 20<span class="elsevierStyleHsp" style=""></span>mg&#47;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">2&#46;5&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#47;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">60&#44; 30<span class="elsevierStyleHsp" style=""></span>mg&#47;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">Thrombin inhibition &#40;IC50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;56<span class="elsevierStyleHsp" style=""></span>&#956;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">163<span class="elsevierStyleHsp" style=""></span>&#956;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">75&#8211;100<span class="elsevierStyleHsp" style=""></span>&#956;M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;561<span class="elsevierStyleHsp" style=""></span>nM&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">Tmax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25&#8211;3<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">2&#8211;4<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">1&#8211;3<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">1&#46;5<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">Elimination half-life&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#8211;9<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">7&#8211;11<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">8&#8211;10<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">10&#8211;14<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">Persistence of anticoagulant activity beyond 12<span class="elsevierStyleHsp" style=""></span>h &#40;aPTT and PT&#41;&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">Yes&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">Yes&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">Bioavailability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">65&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#8211;100&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#37;&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">Renal clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66&#37; &#40;active form 33&#37;&#44; inactive form 33&#37;&#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&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#37;&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">Patient groups who required care&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal or hepatic failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal or hepatic failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal or hepatic failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Renal failure&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">Interference with cytochrome&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">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><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></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Synopsis of phase I studies performed with healthy volunteers described in the text&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#44; maximum concentration&#59; <span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">min</span>&#58; minimum concentration&#59; TUI&#44; therapeutic utility index&#59; iTTR&#44; individual time within therapeutic range&#59; PD&#44; pharmacodynamic&#59; PK&#44; pharmacokinetic&#59; aPTT&#44; activated partial thromboplastin time&#59; ECT&#44; ecarin clotting time&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Evidence from phase II clinical trials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BISTRO-I &#40;14&#44;15&#41;&#58;</span><br>Tendency towards greater safety and efficacy in the point estimates in the single-dose group<br>PD parameters evaluated&#58; <span class="elsevierStyleItalic">aPTT</span> and ECT<br><span class="elsevierStyleItalic">BISTRO-II &#40;16&#41;</span>&#58; No differences in safety and efficacy between single dose and fractionated dose&#46;<br><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf">max</span>&#58; correlation with the clinical events of safety and efficacy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ODIXa-DVT and EINSTEIN DVT &#40;26-28&#41;</span>&#58; no significant differences in safety and efficacy between single dose and fractionated dose&#46;<br><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">min</span></span>&#58; correlation with the clinical events of safety and efficacy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Phase II trials &#40;29&#44;30&#41;</span>&#58;<br>Fractionated dose had better safety and efficacy results than single daily dose&#46;<br>PK&#47;PD modeling with TUI&#58; fractionated dose has better safety and efficacy profile&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Phase II trials &#40;40-42&#41;</span>&#58;<br>Fractionated dose had better safety and efficacy results than single daily dose&#46;<br><span class="elsevierStyleItalic">C</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">min</span></span>&#58; correlation with the clinical events of safety and efficacy&#46;&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">Dosage regimen evaluated in the phase III clinical trials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">RE-LY&#58;</span> 110 and 150<span class="elsevierStyleHsp" style=""></span>mg&#44; twice daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ROCKET AF</span>&#58; 20<span class="elsevierStyleHsp" style=""></span>mg once daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">AVERROES and ARISTOTLE</span>&#58; 5<span class="elsevierStyleHsp" style=""></span>mg twice daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ENGAGE AF-TIMI 48</span>&#58; 30 and 60<span class="elsevierStyleHsp" style=""></span>mg once daily&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">Blinding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&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">Prerandomization dosage adjustment Phase III studies&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">From 20 to 15<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From 5 to 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From 60 to 30<span class="elsevierStyleHsp" style=""></span>mg<br>From 30 to 15<span class="elsevierStyleHsp" style=""></span>mg&nbsp;\t\t\t\t\t\t\n
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                  \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><td class="td" title="table-entry  " align="left" valign="top">From 60 to 30<span class="elsevierStyleHsp" style=""></span>mg<br>From 30 to 15<span class="elsevierStyleHsp" style=""></span>mg&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">iTTR &#40;definition of the comparator&#58; warfarin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; CHADS<span class="elsevierStyleInf">2</span>&#44; stroke risk prediction scale for patients with atrial fibrillation&#59; TIA&#44; transient ischemic attack&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dabigatran RE-LY &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#44;113&#41;&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 ROCKET AF &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#44;264&#41;&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 ARISTOTLE &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#44;201&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;5&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;1&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;8&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">Heart failure&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">57&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">91&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">94&#37;&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">&#8805;75 years&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">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">31&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&#37;&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">Diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&#37;&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">Previous stroke or TIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Comparison of the mean CHADS2 scores of the patients included in the phase III confirmation studies for each drug&#46;</p>"
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      "titulo" => "References"
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                  "contribucion" => array:1 [
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.04.003

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