Importance of appropriate clinical management of direct oral anticoagulants

Millón Caño, Juan Antonio; Vilalta Setó, Noelia; Mateo Arranz, José; Souto Andrés, Juan Carlos
doi:10.1016/j.medcle.2016.04.046
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Although the most currently used oral anticoagulants are antivitamin K &#40;AVK&#41; drugs&#44; the use of direct oral anticoagulants &#40;DOACs&#41; dabigatran&#44; rivaroxaban and apixaban is gradually spreading&#46; They offer certain advantages over AVK agents&#44; such as more stable plasma levels&#44; fewer drug and food interactions&#44; and a lower incidence of intracranial bleeding&#46; They also present certain drawbacks when compared to AVK drugs&#44; such as greater accumulation in renal failure&#44; increased incidence of gastrointestinal bleeding&#44; shorter experience in its use and a potential risk of lower adherence as it does not require frequent checks to monitor its effect&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> Still&#44; numerous clinical trials have demonstrated the efficacy and safety of the DOACs&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a> In addition&#44; data are beginning to be available on &#8220;real life&#8221; complications associated with DOACs in some countries&#44; obtained from national registers&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">3&#44;4</span></a> However&#44; there is a lack of data on these drugs&#8217; efficacy and safety in our country&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In the Haemostasis and Thrombosis Unit of the Hospital de Sant Pau a total of 223 patients under treatment with dabigatran &#40;137&#41; and rivaroxaban &#40;86&#41; received follow-up visits from January 2011 to April 2014&#46; The indications of anticoagulant therapy included prevention of embolic events by non-valvular atrial fibrillation&#44; and the treatment and prevention of recurrent venous thromboembolism&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The incidence of serious complications observed was significantly higher compared to those reported in clinical trials&#46; Bleeding complications were classified according to the <span class="elsevierStyleItalic">Bleeding Academy Research Council</span> &#40;BARC&#41; scale and bleeding of grade 3&#8211;5 was classified as severe&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">During follow-up&#44; the incidence of serious bleeding complications was 2&#46;1 per 100 patients&#47;year with dabigatran and 11&#46;2 per 100 patients&#47;year with rivaroxaban&#46; As for thrombotic complications&#44; an incidence of 4&#46;1 cases was observed in 100 patients&#47;year with dabigatran and 2&#46;8 per 100 patients&#47;year with rivaroxaban &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The following problems were detected in half of all hemorrhagic and thrombotic complications&#58; inadequate dose &#40;5&#41;&#44; poor adhesion &#40;2&#41;&#44; inadequate monitoring of the patient &#40;3&#41; or DOACs withdrawal too many days before an invasive procedure&#44; according to clinical guidelines &#40;1&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Within its whole health area&#44; the Haemostasis and Thrombosis Unit of the Hospital de Sant Pau controls only 26&#37; of dabigatran patients and 21&#46;9&#37; rivaroxaban patients&#46; It is not known whether the remaining patients are receiving an appropriate follow-up&#46; This results in a selection bias in the sample&#44; as patients who did not receive follow-up by the unit were referred to the same after having suffered a serious thrombotic or hemorrhagic event&#44; while those who did not suffer it and who did not receive follow-up by this unit were not included in their observational data &#40;they were not visited in the unit&#41;&#46; Therefore&#44; these retrospective observational data probably overstate the actual proportion of serious complications with DOACs&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">1&#46;5&#37; of patients with dabigatran and 14&#37; of patients with rivaroxaban initiated anticoagulant treatment with inadequate doses&#46; 6&#37; of patients had to reduce the dose or withdraw DOACs due to a glomerular filtration rate deterioration during follow-up&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A quarter of all ischemic complications had to do with poor adherence to treatment&#44; with unjustified dose omissions by the patient in the days prior to the complication&#46; In another quarter of these ischemic complications there was a withdrawal of DOACs too many days before an invasive procedure&#44; according to clinical guidelines or unjustified withdrawal by medical personnel&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion&#44; in the sample described&#44; half of the serious complications were related to factors which were independent to the pharmacological effect of DOACs&#58; poor adhesion&#44; poor clinical monitoring&#44; inadequate dose adjustment as per renal function and unjustified drug withdrawal or too many days &#40;according to clinical guidelines&#41; before an invasive procedure&#46; DOACs prescription should be made according to the dosage schedule of the Summary of Product Characteristics &#40;SmPC&#41;&#44; the patient needs to be trained and appropriate clinical follow-up through periodic assessments of renal function and blood counts has to be implemented&#44; and if DOACs withdrawal is indicated in order to perform an invasive procedure&#44; this should be done according to clinical guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> These measures should be undertaken by units that have experience with antithrombotic treatments&#46; As it happens with AVK&#44; poor administration&#44; lack of patient training and improper monitoring carry increased bleeding and thrombotic risks&#44; otherwise avoidable&#46;</p></span>"
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                  \t\t\t\t</th><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical trials</th><th class="td" title="table-head  " colspan="5" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Studies in &#8220;real life&#8221;</th></tr><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  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">RE-LY<span class="elsevierStyleSup">&#174;</span> &#40;Dabigatran&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">ROCKET-AF &#40;Rivaroxaban&#41;&nbsp;\t\t\t\t\t\t\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">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</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">110<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</th><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="" 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">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</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">110<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</th><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
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6076&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7131&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9120&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2239&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2739&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3654&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">86&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">Stroke&#47;systemic embolism<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;53&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">1&#46;27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;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">Severe bleeding<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;11&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;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;6&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;13&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;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;3&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">11&#46;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">Total complications<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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