Reversion algorithm for patients anticoagulated with dabigatran in urgent surgery

Ferrandis, R.; Colomina, M.J.; Durán, L.; Gómez-Luque, A.; Hidalgo, F.; Llau, J.V.
doi:10.1016/j.redare.2018.09.012
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Direct acting oral anticoagulants &#40;DOAC&#41; are capable of inhibiting a specific factor in the coagulation cascade &#40;factor IIA or Xa&#41;&#46; In terms of their mechanism of action&#44; they are divided into direct thrombin inhibitors &#40;factor IIa&#41;&#58; dabigatran etexilate&#59; and direct factor Xa inhibitors&#58; rivaroxaban&#44; apixaban and edoxaban&#46; The main clinical indications for their use are currently similar<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a>&#58; primary prophylaxis of venous thromboembolism after total hip or knee arthroplasty&#44; treatment and secondary prevention of deep vein thrombosis and pulmonary embolism&#44; and prophylaxis for stroke and systemic embolism in nonvalvular atrial fibrillation&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Like other antithrombotic agents&#44; haemorrhage is the most frequent adverse effect associated with the use of DOACs&#46; Haemorrhage&#44; in the context of DOAC therapy&#44; can present spontaneously as a result of the therapy itself&#44; but can also occur after injury or invasive procedures&#46; In these circumstances&#44; the lack of a standard analytical method to quantitatively and effectively assess the anticoagulant effect&#44; coupled with the absence of specific neutralising antidotes&#44; have raised some concerns about DOAC management&#46; This has led to the development of agents that specifically reverse the effect of these drugs and facilitate the emergency treatment of these patients&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">A specific antidote for dabigatran&#44; idarucizumab&#44; was recently approved for use in patients who require urgent anticoagulant reversal&#46; Given the evident lack of clinical experience&#44; in this document we have collected all the information available to date&#44; and put forward a reversal protocol&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Pharmacological basis of direct oral anticoagulants</span><p id="par0020" class="elsevierStylePara elsevierViewall">All DOACs share a series of common characteristics that should be noted<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">2&#44;3</span></a>&#58; they are administered orally&#44; they exert their action directly &#40;they do not require antithrombin&#41;&#44; they have a rapid onset of action&#44; few drug interactions&#44; and a predictable anticoagulant effect&#46; Because of this&#44; they can be administered at fixed doses &#40;once or twice a day&#44; depending on the drug and the indication&#41; and routine monitoring of their anticoagulant action is unnecessary&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite their similarities&#44; some of their pharmacokinetic characteristics differ considerably&#44; and each drug needs to be analysed individually to ensure it is used correctly &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4&#8211;6</span></a> All DOACs&#44; to a greater or lesser extent&#44; are affected by impaired renal function &#40;dabigatran<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>edoxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>rivaroxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>apixaban&#41;&#44; by the presence of moderate to severe liver failure &#40;rivaroxaban<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>apixaban<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>edoxaban<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>dabigatran&#41; and by concomitant medication&#46; These characteristics justify the need for dose adjustment or limit the use of different drugs&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">One of the benefits of DOACs is their low potential for significant drug interactions&#46; Most interactions occur with drugs that inhibit or induce CYP3A4 or P-gp&#44; so concomitant treatment with these agents should be avoided&#46; The most important are&#58; antiarrhythmics &#40;dronedarone&#44; amiodarone&#44; propafenone&#44; verapamil&#44; digoxin&#44; etc&#46;&#41;&#44; antihypertensives &#40;carvedilol&#44; propranolol&#44; labetalol&#44; diltiazem&#44; nifedipine&#44; etc&#46;&#41;&#44; statins &#40;atorvastatin&#44; lovastatin&#41;&#44; anti-infectives &#40;clarithromycin&#44; rifampicin&#44; fluconazole&#44; ketoconazole&#44; etc&#46;&#41; or protease inhibitors &#40;ritonavir&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In addition&#44; concomitant administration of DOACs with drugs that interfere with haemostasis &#40;antiplatelet agents&#44; fibrinolytics&#44; etc&#46;&#41;&#44; should&#44; logically&#44; be avoided due to the high risk of bleeding&#46; However&#44; all DOACs can be used safely in patients with heparin-induced thrombocytopaenia&#44; provided the clinical indication is adequate&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">There are no data on the use of DOACs in pregnant women&#59; therefore&#44; all of them are contraindicated during pregnancy&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Dabigatran monitoring</span><p id="par0045" class="elsevierStylePara elsevierViewall">Dabigatran&#44; unlike antivitamin K&#44; does not require routine monitoring&#46; Because of this&#44; most the laboratories in Spain do not have access to a relatively easy&#44; inexpensive and reliable method to quantify their plasma concentration or their anticoagulant effect&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a> However&#44; this determination may be necessary under some circumstances&#44; such as bleeding&#44; thrombosis&#44; urgent invasive procedures&#44; or when thrombolysis is required&#46; It can also be useful to guide procedures or elective surgery &#40;in specific populations or when DOAC elimination may be altered&#41;&#44; in the event of overdose&#44; or to ensure therapeutic levels in patients with multiple factors that may interfere with the pharmacokinetics of DOAC&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1&#44;7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the absence of specific monitoring tests&#44; traditional clotting tests have been used&#44; although these have important limitations&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> Activated partial thromboplastin time &#40;aPTT&#41; or kaolin-cephalin clotting time&#44; can provide a qualitative assessment of dabigatran activity&#44; but sensitivity depends on the reagent and coagulometer used&#44; and this complicates the interpretation of results&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">9</span></a> Most patients treated with dabigatran have prolonged aPTT &#40;aPTT ratio<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#62;</span><span class="elsevierStyleHsp" style=""></span>1&#46;2&#41;&#46; Normal aPTT levels &#40;aPTT ratio<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#60;</span><span class="elsevierStyleHsp" style=""></span>1&#46;2&#41; excludes dabigatran levels above the therapeutic range&#44; but does not exclude the presence of lower levels&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">10</span></a> Conversely&#44; a normal thrombin time &#40;TT&#41; has a high negative predictive value for excluding the presence of dabigatran&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> However&#44; due to its high sensitivity&#44; a prolonged TT could indicate the presence of either clinically relevant or negligible dabigatran levels&#44; due to the fact that TT is prolonged in the presence of small plasma concentrations of dabigatran&#46; Changes in ecarin clotting time &#40;ECT&#41; are both sensitive and specific for dabigatran&#59; however&#44; this test is not systematically recommended for monitoring due to the absence of specific and standardised kits for dabigatran&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Specific tests available include the diluted thrombin time test &#40;dTT&#41; &#40;Hemoclot<span class="elsevierStyleSup">&#174;</span> thrombin inhibitor assay&#41;&#44; which determines dabigatran levels with a linear relationship and has good sensitivity in a concentration range of 50&#8211;500<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> Modified dTT tests that can determine low dabigatran concentrations are also available&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> There is also a chromogenic ecarin test that can accurately measure dabigatran concentrations both in the low range &#40;&#60;50<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#41; and the normal range &#40;50&#8211;500<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> In addition&#44; ecarin tests are not sensitive to heparins&#44; and can therefore be useful in cases of concomitant administration &#40;bridging therapy from heparins to dabigatran and vice versa&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> A chromogenic anti-IIa test has also been developed&#44; but needs to be validated in clinical studies&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Characteristics of idarucizumab</span><p id="par0060" class="elsevierStylePara elsevierViewall">Idarucizumab is a specific reversal agent for dabigatran&#46; Specifically&#44; it is a humanised&#44; monoclonal antibody fragment that binds dabigatran and its metabolites with an affinity that is 300 times stronger than its affinity for thrombin&#46; The affinity for dabigatran and its metabolites is potent and specific&#44; and therefore&#44; immediately neutralises its anticoagulant effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17&#44;18</span></a> The idarucizumab-dabigatran complex is characterised by a fast association constant and an extremely slow dissociation constant&#44; resulting in a very stable complex&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> Because of this mechanism of action&#44; reversal of dabigatran&#39;s anticoagulant action is practically instantaneous&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Idarucizumab does not only bind to free dabigatran&#44; but also to thrombin-bound dabigatran and its active metabolites&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17&#8211;19</span></a> Once the bond and the corresponding complexes &#40;idarucizumab-dabigatran&#41; have been formed&#44; the anticoagulant action of dabigatran is completely neutralised&#46; These complexes are stable and irreversible&#44; and only a minimal dissociation of dabigatran from the complex has been described&#44; with no clinical repercussion&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The antidote is only specific for dabigatran&#46; This means that idarucizumab has no effect on non-dabigatran-bound thrombin&#46; This&#44; therefore&#44; rules out the risk of adverse effects involving the actions of thrombin on platelets or fibrinogen&#44; and there is no interaction that alters the capacity of thrombin generation&#46; This is why idarucizumab has no inherent or administration-derived procoagulant or anticoagulant effects&#44; other than those that exclusively affect dabigatran&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17&#8211;21</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Pharmacokinetics</span><p id="par0075" class="elsevierStylePara elsevierViewall">The pharmacokinetics of idarucizumab were investigated in 224 healthy individuals in phase 1 trials<span class="elsevierStyleSmallCaps">&#44;</span> of which data from a representative subgroup of 6 healthy individuals aged between 45 and 64 years who received 5<span class="elsevierStyleHsp" style=""></span>g intravenous infusion for pharmacokinetic analysis are presented&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution&#46; Following the intravenous infusion of a 5<span class="elsevierStyleHsp" style=""></span>g dose&#44; the drug exhibited an initial half-life of 45<span class="elsevierStyleHsp" style=""></span>min&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#44;22&#44;23</span></a> Only about 4&#37; of the drug was present at 4<span class="elsevierStyleHsp" style=""></span>h of administration&#59; at 12<span class="elsevierStyleHsp" style=""></span>h of administration of idarucizumab&#44; plasma concentration was minimal&#44; and at 24<span class="elsevierStyleHsp" style=""></span>h it was practically undetectable&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#8211;23</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In some patients&#44; plasma dabigatran concentrations at 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h of idarucizumab administration showed slight rebound&#44; along with a small increase in dTT and ECT clotting tests&#46; This effect has been explained by the redistribution of existing dabigatran in the extravascular space &#40;therefore&#44; not initially neutralised after administration of idarucizumab&#41; to the intravascular compartment&#46; This increase in dabigatran does not reach therapeutic levels&#44; and therefore does not imply&#44; in itself&#44; the need for administration of a further doses of the antidote&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">After intravenous administration of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab&#44; 32&#46;1&#37; of the dose was recovered in urine within a collection period of 6<span class="elsevierStyleHsp" style=""></span>h and less than 1&#37; in the following 18<span class="elsevierStyleHsp" style=""></span>h&#46; The remaining part of the dose is assumed to be eliminated via protein catabolism&#44; mainly in the kidney&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">19&#44;20&#44;23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Proteinuria has been observed after treatment with idarucizumab&#44; a physiologic reaction to renal protein overflow that is reversed within 24<span class="elsevierStyleHsp" style=""></span>h of treatment&#46; The transient proteinuria usually peaked about 4<span class="elsevierStyleHsp" style=""></span>h after idarucizumab administration&#44; and normalised within 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h&#46; In isolated cases&#44; the transient proteinuria persisted for more than 24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17&#44;19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Dosage&#44; preparation and administration</span><p id="par0100" class="elsevierStylePara elsevierViewall">The recommended dose of idarucizumab is 5<span class="elsevierStyleHsp" style=""></span>g&#44; which should be administered intravenously as 2 consecutive infusions of 2&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;50<span class="elsevierStyleHsp" style=""></span>ml over 5&#8211;10<span class="elsevierStyleHsp" style=""></span>min each or as a bolus injection not mixed with other drugs&#46; It can be administered via a pre-existing intravenous line&#44; provided it has been flushed with an injectable solution of sodium chloride &#40;0&#46;9&#37;&#41; before and after perfusion&#46; No other infusion should be administered in parallel via the same intravenous access&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">As mentioned above&#44; in some patients recurrence of plasma concentrations of unbound dabigatran and concomitant prolongation of clotting tests have occurred up to 24<span class="elsevierStyleHsp" style=""></span>h after administration of idarucizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#46;</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> A maximum daily dose has not yet been investigated&#44;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">17&#44;19</span></a> but from a clinical perspective&#44; administration of a second dose of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab can be considered in the following situations&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Recurrence of clinically relevant bleeding together with prolonged clotting times&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">If potential re-bleeding would be life-threatening and prolonged clotting times are observed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">In patients requiring a second emergency surgery or urgent procedure and have prolonged clotting times that are considered likely to be related to the presence of dabigatran&#46;</p></li></ul></p><p id="par0125" class="elsevierStylePara elsevierViewall">With regard to idarucizumab management in special populations&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a> no dose adjustment is required in renally impaired patient&#44; those with hepatic injury&#44; or in patients aged over 65 years&#46; The safety and efficacy of Praxbind in children below the age of 18 years have not yet been established&#46; No data are available&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Evaluation of effectiveness</span><p id="par0130" class="elsevierStylePara elsevierViewall">The effectiveness of idarucizumab to reverse the anticoagulant effect of dabigatran is based on the results of the REVERSE-AD study&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> which shows almost complete normalisation of dTT and ECT in the 2 groups of study patients &#40;patients with uncontrolled bleeding and patients in whom reversal of dabigatran is considered necessary because they require urgent surgery&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The study also showed that haemostasis was achieved in patients with bleeding&#44; and in slightly over 90&#37; of those who received idarucizumab before urgent surgery&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">In addition&#44; since its approval by the FDA&#44; several reports of idarucizumab use in patients&#44; mainly to control critical bleeding have also shown its efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25&#8211;30</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Safety profile</span><p id="par0140" class="elsevierStylePara elsevierViewall">Safety was evaluated in 224 healthy patient<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> and in the 503 patients of the REVERSE-AD study &#40;phase 3&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a> with severe uncontrolled bleeding &#40;301&#47;503&#41; or in need of an urgent invasive procedure &#40;202&#47;503&#41;&#59; no adverse reactions directly attributable to the drug were observed&#46; Of the 503 patients treated with idarucizumab included in the REVERSE-AD study&#44; 35 died within the first 5 days after treatment &#40;19 and 16&#44; respectively&#44; in group&#41;&#46; Most of these deaths could be related to worsening of the underlying disease and existing comorbidities&#46; Thrombotic events occurred in 24 &#40;4&#46;8&#37;&#41; and 34 &#40;6&#46;8&#37;&#41; patients at 30 and 90 days&#44; respectively&#44; and the 30-day rate was similar in both groups &#40;5&#46;0 and 4&#46;6&#37;&#41;&#46; These rates are considered consistent with those reported after major surgical procedures or hospitalisation for uncontrolled bleeding&#46; In the discussion section&#44; the authors speculate that the low rate of reinitiation of anticoagulation that&#44; especially in the group of patients with bleeding&#44; could have contributed to the appearance of thrombotic events&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Mild symptoms associated with possible hypersensitivity &#40;pyrexia&#44; bronchospasm&#44; hyperventilation&#44; rash&#44; or pruritus&#41; were also reported&#46; Other adverse effects occurring in 5&#37; or more cases were hypokalaemia &#40;9&#47;123&#44; 7&#37;&#41;&#44; delirium &#40;9&#47;123&#44; 7&#37;&#41;&#44; constipation &#40;8&#47;123&#44; 7&#37;&#41;&#44; pyrexia &#40;7&#47;123&#59; 6&#37;&#41; and pneumonia &#40;7&#47;123&#44; 6&#37;&#41;&#46; In no case could a causal relationship with idarucizumab be established&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">However&#44; idarucizumab binds specifically to dabigatran and its metabolites&#44; reversing its anticoagulant effect&#44; which exposes the patient to the thrombotic risk of their underlying disease&#46; This is why it is essential to reinstate anticoagulant therapy 24<span class="elsevierStyleHsp" style=""></span>h after administration of idarucizumab&#44; once clotting times have stabilised&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22&#8211;24</span></a></p><span id="sec1040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect1040">Special precautions for use<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a></span><p id="par0160" class="elsevierStylePara elsevierViewall">Special precautions should be taken with idarucizumab administration in situations such as&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Hereditary fructose intolerance</span></p></li></ul></p><p id="par0170" class="elsevierStylePara elsevierViewall">The sorbitol content of the recommended dose of idarucizumab is 4<span class="elsevierStyleHsp" style=""></span>g&#46; In patients with hereditary fructose intolerance&#44; this amount of sorbitol has been associated with reports of hypoglycaemia&#44; hypophosphataemia&#44; metabolic acidosis&#44; increase in uric acid&#44; acute liver failure with breakdown of excretory and synthetic function&#44; and death&#46; In these patients&#44; risk of treatment must be weighed against the potential benefit&#46; If idarucizumab is administered in these patients&#44; intensified monitoring is needed for the first 24<span class="elsevierStyleHsp" style=""></span>h&#46;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Thromboembolic complications</span></p></li></ul></p><p id="par0180" class="elsevierStylePara elsevierViewall">Patients being treated with dabigatran have underlying disease states that predispose them to thromboembolic events&#46; To reduce this risk&#44; resumption of anticoagulant therapy should be considered as soon as medically appropriate&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22&#8211;24</span></a><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Urinary protein testing</span></p></li></ul></p><p id="par0190" class="elsevierStylePara elsevierViewall">Idarucizumab causes transient proteinuria as a physiologic reaction to renal protein overflow after rapid intravenous administration of 5<span class="elsevierStyleHsp" style=""></span>g&#46; The transient proteinuria is not indicative of renal damage&#44; which should be taken into account for urine testing&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Sodium content</span></p></li></ul></p><p id="par0200" class="elsevierStylePara elsevierViewall">This medicinal product contains 2&#46;2<span class="elsevierStyleHsp" style=""></span>mmol &#40;or 50<span class="elsevierStyleHsp" style=""></span>mg&#41; sodium per dose&#59; this should be taken into consideration when treating patients on a controlled sodium diet&#46;</p></span></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Therapeutic indications for idarucizumab</span><p id="par0205" class="elsevierStylePara elsevierViewall">It is important to note that most bleeding events in patients receiving treatment with DOACs&#44; due to their short half-life&#44; can be managed conservatively by temporarily suspending the drug and starting supportive measures&#59; therefore&#44; reversal agents are rarely used&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Idarucizumab was approved under an Accelerated Approval Pathway by the U&#46; S Food and Drug Administration and the European Medicines Agency for use in adult patients treated with dabigatran that require rapid reversal of its anticoagulant effect&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">31</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">It is indicated in&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Severe acute bleeding&#44; with haemodynamic instability&#44; which does not respond to general measures and persists despite local haemostatic measures&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Life-threatening bleeding or bleeding into an organ considered critical due to its sensitivity to bleeding&#44; due to its persistence&#44; or due to the risk of complications&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Urgent surgical interventions associated with high risk of bleeding that cannot be delayed by 8<span class="elsevierStyleHsp" style=""></span>h or more&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Urgent invasive diagnostic or therapeutic techniques associated with a high risk of bleeding&#46;</p></li></ul></p><p id="par0240" class="elsevierStylePara elsevierViewall">The incidence of severe bleeding is difficult to estimate&#46; In clinical practice&#44; reports of major bleeding due to dabigatran vary greatly&#44; ranging from 3&#46;2&#37;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> to 9&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a> possibly due to the patient&#39;s comorbidities&#46; Until now&#44; management of dabigatran-induced severe bleeding events has been limited to supportive measures&#44; administration of blood products&#44; haemodialysis or administration of prohaemostatic agents &#40;prothrombin complex concentrate&#41;&#46; The use of prothrombin complex concentrate can reduce DOAC-induced bleeding by providing large volumes of factors II and X&#46; This strategy is recommended when a specific antidote is not available&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The introduction of idarucizumab calls for the creation of protocols&#44; with their corresponding indications and method of administration&#44; and the specific role of this reversal agent in the clinical management of acute dabigatran-induced bleeding must be defined&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Considerations for reversal with idarucizumab</span><p id="par0250" class="elsevierStylePara elsevierViewall">It is always important to bear in mind that bleeding complications in patients receiving dabigatran should be managed on a case-by-case basis&#44; depending on the site and severity of the bleed&#44; and the patient&#39;s coexisting medical conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">35</span></a> When available&#44; idarucizumab is the treatment of choice for the urgent reversal of the anticoagulant effect of dabigatran&#44; following a protocol adapted to each institution&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Certain factors must be considered before using idarucizumab&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">1&#46;</span></span><p id="par0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Is reversal necessary&#63;</span></p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0265" class="elsevierStylePara elsevierViewall">YES&#44; in</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0270" class="elsevierStylePara elsevierViewall">bleeding from a non-compressible site that is life-threatening or can lead to irreversible injury &#40;central nervous system&#44; intraspinal&#44; intraocular&#44; intrapulmonary&#44; retroperitoneal bleeding or intramuscular bleeding with compartment syndrome&#41;&#44;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0275" class="elsevierStylePara elsevierViewall">severe bleeding that does not respond to usual measures&#44;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0280" class="elsevierStylePara elsevierViewall">urgent surgery or urgent invasive procedures that cannot be delayed by at least 8<span class="elsevierStyleHsp" style=""></span>h and that require adequate haemostasis due to a high risk of bleeding&#46; Can include haemorrhage due to multiple trauma&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0285" class="elsevierStylePara elsevierViewall">NO&#44; if</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0290" class="elsevierStylePara elsevierViewall">bleeding responds to usual support strategies&#44; is not life threatening&#44; or in patients in whom surgery or invasive procedure may be delayed by more than 8<span class="elsevierStyleHsp" style=""></span>h&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">2&#46;</span></span><p id="par0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Confirm the presence of dabigatran</span></p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0300" class="elsevierStylePara elsevierViewall">Find out the patient&#39;s dabigatran dosage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Find out when the last dose was taken&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Evaluate the possibility of an accidental or deliberate overdose&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0315" class="elsevierStylePara elsevierViewall">In each case&#44; estimate the half-life of the drug&#44; mainly on the basis of renal function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">3&#46;</span></span><p id="par0320" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Evaluate coagulation</span></p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Run specific tests&#44; whenever possible &#40;ECT&#44; dTT&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0330" class="elsevierStylePara elsevierViewall">aPTT ratio is the simplest&#44; most useful tool&#44; with the limitations already mentioned&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">4&#46;</span></span><p id="par0335" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Consider the immediate administration of idarucizumab</span></p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0340" class="elsevierStylePara elsevierViewall">In the accepted indications&#44; idarucizumab should be administered immediately without awaiting the results of laboratory tests&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">5&#46;</span><p id="par0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Maintain general support measures for bleeding management and the administration of</span> blood products and adjuvants&#44; depending on the patient&#39;s evolution&#46; Idarucizumab is not a substitute for these&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">6&#46;</span><p id="par0350" class="elsevierStylePara elsevierViewall">A <span class="elsevierStyleItalic">second dose</span> of 5<span class="elsevierStyleHsp" style=""></span>g idarucizumab could be considered if coagulation parameters remain altered&#44; and only if the clinical need to rapidly reverse the anticoagulant effect persists&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a></p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">7&#46;</span><p id="par0355" class="elsevierStylePara elsevierViewall">Evaluate the <span class="elsevierStyleItalic">resumption of anticoagulant therapy</span> on a case by case basis&#44; weighing up the risk of bleeding against the risk of thrombosis&#46; Because of the short half-life of idarucizumab&#44; dabigatran can be restarted 24<span class="elsevierStyleHsp" style=""></span>h after administration&#44; except in patients with renal failure&#44; in whom the half-life can be prolonged&#46;</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Future perspectives</span><p id="par0360" class="elsevierStylePara elsevierViewall">In the future&#44; idarucizumab could be indicated in patients with moderate bleeding in whom usual bleeding management measures fail&#46; More studies are needed&#44; and the efficacy of a lower dose of idarucizumab must be analysed&#46; It could potentially be indicated in cases in which patients with acute renal failure need urgent surgery&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">Although it has been used to reverse the effect of dabigatran prior to thrombolytic therapy in ischaemic stroke&#44; there insufficient safety data to recommend this indication&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">Further understanding of idarucizumab will eventually clarify its role in other groups of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protocol for the management of dabigatran in urgent surgery</span><p id="par0375" class="elsevierStylePara elsevierViewall">Following the development of indications for the use of idarucizumab&#44; the dabigatran management protocol shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> is recommended in patients awaiting urgent surgery or an urgent invasive procedure&#46; The protocol should only be implemented after completion of the initial steps recommended in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0380" class="elsevierStylePara elsevierViewall">The management of anticoagulated patients with bleeding or that require an urgent intervention with a moderate to high risk of bleeding is always controversial&#46; Such a complicated situation is made even worse when the anticoagulant is a DOAC&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall">The addition of idarucizumab&#44; a specific dabigatran reverser&#44; to the therapeutic arsenal will certainly facilitate the management of these patients&#46; However&#44; action protocols specific to each hospital must be developed and approved by a multidisciplinary committee&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0390" class="elsevierStylePara elsevierViewall">R&#46; Ferrandis has taken part in conferences or educational projects sponsored by Octapharma&#44; CSL Behring&#44; Boehringer Ingelheim&#44; Rovi&#44; and has received honoraria to attend Octapharma congresses&#46;</p><p id="par0395" class="elsevierStylePara elsevierViewall">M&#46;J&#46; Colomina has taken part in conferences and congresses sponsored by Baxter&#44; and has received honoraria from Vifor for attending meetings&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">J&#46;V<span class="elsevierStyleSmallCaps">&#46;</span> Llau has provided scientific consultancy services&#44; and has taken part in educational courses or conferences sponsored by Boehringer Ingelheim&#44; Octapharma&#44; Sanofi&#44; Rovi&#44; CSL Behring&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">The remaining authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Pharmacological basis of direct oral anticoagulants"
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        2 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Dabigatran monitoring"
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          "titulo" => "Therapeutic indications for idarucizumab"
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              "identificador" => "sec0050"
              "titulo" => "Considerations for reversal with idarucizumab"
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    "fechaRecibido" => "2018-09-24"
    "fechaAceptado" => "2018-09-26"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Ferrandis R&#44; Colomina MJ&#44; Dur&#225;n L&#44; G&#243;mez-Luque A&#44; Hidalgo F&#44; Llau JV&#46; Algoritmo de reversi&#243;n para los pacientes anticoagulados con dabigatr&#225;n en cirug&#237;a urgente&#46; Rev Esp Anestesiol Reanim&#46; 2019&#59;66&#58;149&#8211;156&#46;</p>"
      ]
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        "nota" => "<p class="elsevierStyleNotepara" id="npar1005">This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program&#46; An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page&#58; <a class="elsevierStyleInterRef" target="_blank" id="intr1005" href="https://www.elsevier.es/redar">https&#58;&#47;&#47;www&#46;elsevier&#46;es&#47;redar</a></p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Proposed protocol for the management of patients receiving dabigatran who need to undergo an urgent surgery or invasive procedure&#46; BR&#58; bleeding risk&#46;</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">&#42;If heavy or uncontrolled bleeding occurs during surgery&#44; it must be treating using standard management strategies&#44; including fluid replacement&#44; haemodynamic stabilisation&#44; administration of blood products and coagulants&#46; Administration of a second dose of 5<span class="elsevierStyleHsp" style=""></span>g of idarucizumab can be considered&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cmax&#58; peak plasma concentration&#59; CYP34A&#58; cytochrome P450 3A4&#59; FIIa&#58; activated factor <span class="elsevierStyleSmallCaps">ii</span>&#59; FXa&#58; activated factor <span class="elsevierStyleSmallCaps">x</span>&#59; P-gp&#58; permeability glycoprotein&#59; T1&#47;2&#58; elimination half-life&#46;</p>"
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                  \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">&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">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">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">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">Edoxab&#225;n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of action&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">FIIa inhibitor&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">FXa inhibitor&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">FXa inhibitor&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">FXa inhibitor&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">Bioavailability&#44; &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cmax&#44; 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;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T1&#47;2&#44; h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#8211;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8211;9&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;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bound to proteins&#44; &#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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55&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">Volume of distribution&#44; l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#8211;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">107&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 excretion &#40;active drug&#41;&#44; &#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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#8211;27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepatic metabolism&#44; &#37; &#40;interactions&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;P-gp&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66 &#40;CYP3A4&#44; P-gp&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">75 &#40;CYP3A4&#44; P-gp&#41;&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;30 &#40;CYP3A4&#44; P-gp&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pharmacokinetics of direct acting oral anticoagulants&#46;</p>"
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        "etiqueta" => "Table 2"
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">dTT&#58; diluted thrombin time&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Pollack et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a></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">Study variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A<br>Patients with bleeding&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">Group B<br>Patients requiring surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Primary end point</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Percentage reversal of the anticoagulant effect of dabigatran&#44; based on determination of dTT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Secondary outcomes</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Restoration of haemostasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Haemostasis was restored in 100&#37; of evaluable patients who presented severe bleeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Haemostasis was normal in 93&#46;4&#37; of patients who needed an urgent procedure&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Summary idarucizumab efficacy based on results obtained from the REVERSE-AD study&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">ECT&#58; ecarin clotting time&#59; aPTT&#58; activated partial thromboplastin time&#59; dTT&#58; diluted thrombin time&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Check that the patient is receiving dabigatran&#44; verifying the dose administered and the time of the last intake&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">Check renal function&#44; preferably by calculating creatinine clearance&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">Request hemostasis tests&#44; based on availability&#58; aPTT&#44; dTT&#44; ECT&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">Classify the bleeding risk of the surgical procedure&#58; high&#47;moderate&#47;low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                0 => "xTab1981140.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Preliminary steps before implementation of the dabigatran reversal protocol&#46;</p>"
        ]
      ]
    ]
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      "titulo" => "References"
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