Antidotes for the new oral anticoagulants: Reality and expectations

Gómez-Outes, Antonio; Lecumberri, Ramón
doi:10.1016/j.medcle.2015.11.031
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Various oral anticoagulants have been marketed in the last decade&#44; dabigatran etexilate being among them&#44; a direct thrombin inhibitor &#40;Pradaxa<span class="elsevierStyleSup">&#174;</span>&#59; Boehringer Ingelheim&#41;&#44; and the direct inhibitors of <span class="elsevierStyleSmallCaps">x</span> activated factor &#40;FXa&#41;&#44; rivaroxaban &#40;Xarelto<span class="elsevierStyleSup">&#174;</span>&#59; Bayer HealthCare&#41;&#44; apixaban &#40;Eliquis<span class="elsevierStyleSup">&#174;</span>&#59; Bristol-Myers Squibb&#41; and edoxaban &#40;Lixiana<span class="elsevierStyleSup">&#174;</span>&#47;Savaysa<span class="elsevierStyleSup">&#174;</span>&#59; Daiichi Sankyo-&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> These &#40;not so new&#41; oral anticoagulants of direct action &#40;DOAC&#41; are authorized for use in various indications related to the prophylaxis and treatment of venous thromboembolism and the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation &#40;NVAF&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The DOAC have shown a positive risk&#8211;benefit relationship in such indications and a lower haemorrhagic tendency &#40;especially in the case of intracranial haemorrhage &#91;ICH&#93;&#41; than vitamin K antagonists &#40;VKA&#41;&#46; The relatively short half-life &#40;between 11 and 17<span class="elsevierStyleHsp" style=""></span>h in patients with normal renal function&#41; can be an advantage in case of bleeding&#44; as it quickly decreases its anticoagulant action between 12 and 24<span class="elsevierStyleHsp" style=""></span>h after administration&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">1</span></a> However&#44; the absence of a specific antidote and tools for the biological control of the anticoagulant effect which are well standardized and available in any emergency laboratory has generated some distrust between prescribers and patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The treatment of haemorrhage associated with DOAC is based on the interruption of all antithrombotic medications and the establishment of supportive care &#40;local haemostasis&#44; transfusion&#44; activated carbon&#44; dialysis in the case of dabigatran&#44; <span class="elsevierStyleItalic">etc&#46;</span>&#41;&#46; In the absence of specific antidotes&#44; unspecific procoagulant agents have been used &#40;prothrombin complex concentrates and recombinant factor <span class="elsevierStyleSmallCaps">vii</span>&#41; in the case of severe bleeding&#44; but with little evidence and increased risk of thrombosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Various analyses of the treatment for major haemorrhages observed during the pivotal studies have shown similar &#40;or even better in some cases&#41; results regarding bleeding associated to DOAC compared with those related to treatment with VKA&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">7&#8211;10</span></a> However&#44; mortality after severe bleeding with DOAC&#44; although not being higher than VKA in selected populations of clinical trials&#44; it remains significant&#44; ranging between 10&#37; for non-intracranial severe bleeding<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">9</span></a> and 35&#8211;45&#37; for ICH&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">8&#44;9</span></a> Therefore&#44; up to now&#44; the availability of an antidote is an unmet medical need&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Currently&#44; several DOAC-specific antidotes are being developed&#44; aiming to reverse the anticoagulant activity and restore an adequate haemostasis in cases of severe bleeding or when there is a need to perform invasive emergency procedures&#46; Among these&#44; we find Idarucizumab &#40;BI 655075&#59; Boehringer Ingelheim&#41;&#44; andexanet alfa &#40;r-Antidote&#44; PRT064445&#44; Portola Pharmaceuticals&#41; and aripazine &#40;PER977&#44; ciraparantag&#59; Perosphere Inc&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Idarucizumab is an antibody fragment that binds to dabigatran with an affinity 350 times superior to that of thrombin by acting as a specific antidote &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#8211;15</span></a> In September 2015&#44; idarucizumab received a positive European opinion in adult patients treated with dabigatran when a quick reversal of the anticoagulant effect is required&#44; both in surgery&#47;invasive emergency procedures as well as in life-threatening or uncontrolled bleeding&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">16</span></a> The positive opinion was based mainly on surrogate efficacy data obtained in healthy volunteers&#44;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">13&#44;14</span></a> and in the interim analysis of the REVERSE-AD study conducted in 90 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> These data showed the ability of the antidote&#44; at a dose of 5<span class="elsevierStyleHsp" style=""></span>g&#44; administered intravenously&#44; to decrease &#40;unbound to proteins&#41; the free fraction of dabigatran in plasma and normalize coagulation parameters altered by the treatment with dabigatran in more than 90&#37; of subjects&#44; with an acceptable safety profile&#46; The study expected to include 450 patients in total and final results are expected in 2017 &#40;ClinicalTrials&#46;gov Identifier&#58; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02104947">NCT02104947</a>&#41;&#46; Among the strengths of the REVERSE-AD study&#44; we highlight the good correlation between clotting test normalization and decreased concentrations of free dabigatran in plasma&#46; Regarding its limitations&#44; we find the lack of a control group &#40;as currently&#44; there are no other strategies available for the specific neutralization of dabigatran&#41; and the inclusion of a limited number of patients in the interim analysis&#44; inadequate to evaluate mortality&#44; making the quantification of idarucizumab regarding its contribution to improving the clinical outcome of severe bleeding associated with dabigatran in addition to the usual support treatment difficult&#46; In fact&#44; there is great variability between the 20&#37; mortality published in the interim analysis of the REVERSE-AD study<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> and previous data published on mortality rates of major bleeding with dabigatran&#44; which range from 9&#37; of major bleeding with dabigatran in an aggregate analysis of phase <span class="elsevierStyleSmallCaps">iii</span><a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">7</span></a> studies&#44; 20&#37; of ICH with dabigatran in a study conducted on routine practice&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">17</span></a> and 35&#8211;41&#37; of ICH in a <span class="elsevierStyleItalic">post hoc</span> analysis of the RE-LY study in patients with NVAF&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">10</span></a> It is therefore likely that the bleeding location and the injury degree&#44; as well the patient&#39;s concomitant disease and treatments may have a more important effect on the bleeding prognosis than the ability to quickly neutralize the anticoagulant&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">18</span></a> For practical purposes&#44; idarucizumab is therefore a complement&#44; not a replacement&#44; in the support treatment that has been in use so far&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">On the other hand&#44; a quarter of the patients in the REVERSE-AD study showed very low or undetectable levels of anticoagulant activity &#40;according to Thrombin Time Dilution Test &#91;TTDT&#93; or ecarin time&#41; on study entry&#44; probably because more than 12<span class="elsevierStyleHsp" style=""></span>h had elapsed since the last dose of dabigatran in two thirds of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">15</span></a> These patients received the antidote but were excluded from the efficacy analysis&#46; In practice&#44; the quantification of the activity of dabigatran could avoid unnecessary administration of the antidote&#46; For the specific biological control &#40;DOAC do not require routine monitoring&#41; of dabigatran&#44; currently the test of choice in our area is the TTDT&#44; but for the moment is not available in many non-specialized laboratories&#46; Alternatively&#44; the partial activated thromboplastin time may be of some help to rule out supratherapeutic levels&#46; If the TTDT is normal&#44; it is reasonable to assume that dabigatran levels are very low and the bleeding risk is not increased&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Andexanet alfa &#40;r-Antidote&#44; PRT064445&#44; Portola Pharmaceuticals&#41; is a truncated form of FXa&#44; non-functional from an hemostatic point of view&#44; and obtained by recombinant technology&#44; which competes with native FXa to bind direct FXa inhibitors&#44; reversing its anticoagulant activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;20</span></a> The results of two studies to evaluate the surrogate safety and efficacy of andexanet alpha in reversing the anticoagulant effects of apixaban 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h and rivaroxaban 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day in healthy volunteers &#40;ANNEXA-A and ANNEXA-R studies&#44; respectively&#41; have been recently published&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> Andexanet alpha&#44; administered as an intravenous bolus &#40;400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg&#41; showed a reversion<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>90&#37; of the anti-<span class="elsevierStyleSmallCaps">x</span>a activity of apixaban and rivaroxaban in all subjects after 2&#8211;5<span class="elsevierStyleHsp" style=""></span>min of bolus administration&#44; which gradually decreased to levels similar to those in the placebo group in the following 2<span class="elsevierStyleHsp" style=""></span>h &#40;first part of the studies&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> Plasma concentrations of apixaban and rivaroxaban&#44; as well as levels of thrombin generation&#44; followed a time course similar to the anti <span class="elsevierStyleSmallCaps">x</span>a activity&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> The second part of the studies showed that a longer reversal can be obtained with a continuous perfusion &#40;4&#8211;8<span class="elsevierStyleHsp" style=""></span>mg&#47;min&#41; after the initial bolus&#44; since the effect is transient &#40;&#8776;2<span class="elsevierStyleHsp" style=""></span>h&#41; following a single intravenous administration&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">21</span></a> Also&#44; there is another ongoing study&#44; open&#44; uncontrolled&#44; to assess the hemostatic efficacy and safety of andexanet alfa in patients with major bleeding due to oral direct FXa inhibitors&#44; the final results are expected for 2022 &#40;ANNEXA-4 phase 3b-4 study&#46; ClinicalTrials&#46;gov Identifier&#58; <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02329327">NCT02329327</a>&#41;&#46; However&#44; this does not mean that it cannot be authorized in advance&#44; as it was the case with idarucizumab&#44; assuming that the interim study data evaluation&#44; along with reversal data of the anti-<span class="elsevierStyleSmallCaps">x</span>a anticoagulant activity&#44; coagulation times and safety profile&#44; show a favourable risk&#8211;benefit ratio&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Finally&#44; aripazine &#40;PER-977&#44; ciraparantag&#59; Perosphere Inc&#46;&#41; It is a small synthetic molecule &#40;&#8776;500<span class="elsevierStyleHsp" style=""></span>Da&#41; with the potential to reverse both thrombin inhibitors &#40;dabigatran&#41; and oral direct FXa inhibitors&#44; as well as fondaparinux and low molecular weight heparins <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">11&#44;22</span></a> The binding is made <span class="elsevierStyleItalic">via</span> links by hydrogen bonds and charge-charge interactions&#44; which prevents the anticoagulant from binding to its target in the coagulation cascade&#46; A recent study in 80 healthy volunteers has shown that aripazine&#44; intravenously administered at doses of 100&#8211;300<span class="elsevierStyleHsp" style=""></span>mg&#44; reverses edoxaban-induced anticoagulation after the administration of 60<span class="elsevierStyleHsp" style=""></span>mg of the same&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">22</span></a> The reversal occurred in the first 10&#8211;30<span class="elsevierStyleHsp" style=""></span>min and was sustained for 24<span class="elsevierStyleHsp" style=""></span>h&#46; In this study&#44; aripazine was well tolerated and no signs of procoagulant activity were observed&#46; Several phase <span class="elsevierStyleSmallCaps">i</span>&#8211;<span class="elsevierStyleSmallCaps">ii</span> studies are currently underway to characterize the metabolism and disposition of aripazine in humans&#44; and to identify the dose of antidote required to reverse the effect of various anticoagulants&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In conclusion&#44; the advent of specific antidotes for DOAC fulfils an unmet need and will help to build confidence and improve the safe use of these anticoagulants&#46; Idarucizumab&#44; the specific antidote to dabigatran&#44; was the first of them in obtaining a positive opinion in the European Union&#46; However&#44; it is necessary to have the results of currently ongoing studies and experience of use in everyday practice to outline in more detail the real benefit of the specific reversal of DOAC regarding improving the clinical outcome of patients&#46; Among other things&#44; it will be essential to pay particular attention to the possible development of thrombotic complications associated with the reversal of the anticoagulant effect&#46; Finally&#44; the development of multidisciplinary clinical practice guidelines will help clinicians in defining the scenarios in which the use of an antidote is appropriate&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Statement</span><p id="par0055" class="elsevierStylePara elsevierViewall">The opinions and views expressed in this article are those of the authors and do not necessarily represent the official views of their institutions or any other parties&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Financing</span><p id="par0060" class="elsevierStylePara elsevierViewall">No funding has been received for the preparation of this article&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; G&#243;mez-Outes A&#44; Lecumberri R&#46; Ant&#237;dotos de los nuevos anticoagulantes orales&#58; realidad y expectativas&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;488&#8211;490&#46;</p>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">RNA&#58; ribonucleic acid&#59; FXa&#58; activated factor <span class="elsevierStyleSmallCaps">x</span>&#59; LMWH&#58; low molecular weight heparins&#59; UFH&#58; unfractioned heparin&#59; IV&#58; intravenous&#59; NA&#58; not available&#59; <span class="elsevierStyleItalic">T</span><span class="elsevierStyleInf">max</span>&#58; maximum time&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Idarucizumab&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">Andexanet alfa&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">Aripazine&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">Tradename&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Praxbind<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">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&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">Name of product under investigation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BI 655075<br>aDabi-Fab<br>UNII-97RWB5S1U6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PRT064445<br>r-Antidote&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PER977<br>Ciraparantag&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">Company&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Boehringer Ingelheim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Portola Pharmaceuticals&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Perosphere Inc&#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">Chemical characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Humanized monoclonal antibody fragment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Truncated recombinant 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">Synthetic&#44; cationic&#44; water soluble molecule&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">Potential targets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dabigatran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Direct FXa inhibitors &#40;rivaroxaban&#44; apixaban&#44; edoxaban&#41; and indirect &#40;LMWH and fondaparinux&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rivaroxaban&#44; apixaban&#44; edoxaban&#44; dabigatran&#44; UFH&#44; LMWH and fondaparinux&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">Molecular weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47&#44;800<span class="elsevierStyleHsp" style=""></span>Da&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#44;000<span class="elsevierStyleHsp" style=""></span>Da&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">512<span class="elsevierStyleHsp" style=""></span>Da&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">T</span><span class="elsevierStyleInf">max</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;30<span class="elsevierStyleHsp" style=""></span>min&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">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">45<span class="elsevierStyleHsp" style=""></span>min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8776;1<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">&#8776;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">Dosage researched in 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">5<span class="elsevierStyleHsp" style=""></span>g IV bolus or perfusion in 5&#8211;10<span class="elsevierStyleHsp" style=""></span>min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400&#8211;800<span class="elsevierStyleHsp" style=""></span>mg IV bolus&#44; followed by perfusion of 4&#8211;8<span class="elsevierStyleHsp" style=""></span>mg&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&#8211;400<span class="elsevierStyleHsp" style=""></span>mg IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Main characteristics of the antidotes of direct oral anticoagulants&#46;</p>"
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      "titulo" => "References"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "A&#46; G&#243;mez-Outes"
                            1 => "M&#46;L&#46; Su&#225;rez-Gea"
                            2 => "R&#46; Lecumberri"
                            3 => "A&#46;I&#46; Terleira-Fern&#225;ndez"
                            4 => "E&#46; Vargas-Castrill&#243;n"
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                        0 => array:2 [
                          "etal" => false
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