- Pierre-André DubéB. Pharm., Pharm. D., M. Sc., C. Clin. Tox., Pharmacien-toxicologue, Institut national de santé publique du Québec
- Pierre Olivier MonastPharm. D., M. Sc., Pharmacien, Centre universitaire de santé McGill
Until now, the new oral anticoagulants had no specific antidote in the event of an overdose or a bleed, or for reversing their anticoagulant effect for emergency surgery. Several specific antidotes are currently at the development or pre-marketing study phase, and some have undergone an accelerated review process by regulatory organizations. This article presents data available to date on the recently marketed first antidote for dabigatran, namely, idarucizumab. According to data gathered while writing this literature review on this antidote, until now, it would not appear to be justified to recommend its administration right away to patients going to hospital due to intentional overdoses of dabigatran or unintentional exposure to the drug when there was no major bleed involved. Idarucizumab is particularly interesting for reversing anticoagulation as quickly as possible following ingestion of dabigatran etexilate in patients who need emergency surgery or are experiencing a major bleed. However, studies with clinical results are necessary because, for now, human studies are reporting only analytical results.
For many decades, warfarin and nicoumalone were the only oral anticoagulants used therapeutically. Since these drugs act as vitamin-K-dependent clotting factor synthesis inhibitors, oral or parenteral administration of a vitamin K supplement can be considered for reversing their anticoagulant effect(1). Since 2008, new oral anticoagulants (NOACs) have been approved in Canada. They include dabigatran, a direct thrombin inhibitor (factor IIa), as well as rivaroxaban and apixaban, direct and specific factor Xa inhibitors. The benefits of NOACs include having a predictable anticoagulant effect and not requiring regular monitoring of lab results, compared with warfarin, for example. However, a specific antidote for NOACs should be available in the event of an overdose or a bleed or for reversing anticoagulation for emergency surgery, as a result of a trauma, for example.
Several specific antidotes for NOACs have been developed, such as idarucizumab, ciraparantag and andexanet alfa(2). More specifically, idarucizumab (Praxbind®) is a humanized mouse monoclonal antibody fragment which specifically binds to dabigatran and reverses it, with a binding affinity which is 350 times higher than thrombin’s affinity for dabigatran(3). In 2014, the U.S. Food and Drug Administration (FDA) gave idarucizumab Breakthrough Therapy Designation, and in June 2015 granted it an accelerated review process so that a decision about it could be made in the fall of the same year(4,5). It was also submitted for an accelerated review process by the European Medicines Agency and Health Canada(6). The FDA finally approved idarucizumab in October 2015, and a response from Health Canada is also expected in December 2015. This article’s objective is to present the data available so far on the first marketed antidote for dabigatran, i.e., idarucizumab.
In August 2015, a review of the scientific literature on idarucizumab was carried out using the OVIDSP platform. The databases queried using the primary keyword idarucizumab were Embase, Premedline and Medline, and the period considered was from January 1, 2010 to July 31, 2015. For inclusion in the literature review, an article had to present the results of in vitro, ex vivo, animal or human studies. Articles published in English or French were retained. In total, 56 articles were identified during the initial search. Articles which were not relevant, were in foreign languages or consisted of reviews were excluded. The articles retained are presented in this review.
In vitro, ex vivo and animal studies
In 2013, Schiele et al published the first study on idarucizumab(3). Its objective was to present data on identification, humanization and in vitro and in vivo pharmacokinetics of this antidote. Idarucizumab is a purified and humanized mouse monoclonal antibody fragment (Fab). Idarucizumab’s extraordinarily high affinity for dabigatran, which is approximately 350 times higher than thrombin’s affinity for this anticoagulant, can be explained qualitatively by the drug’s structural data (crystalline structure). A tight network of interactions, including many hydrogen bonds to all dabigatran’s polarized atoms, contributes to the strong binding affinity. The antidote mimics thrombin in its molecular recognition and its ability to bind to dabigatran. However, idarucizumab does not have thrombin’s specific enzyme activity and has proven to have neutral activity in all coagulation tests. Therefore, it binds selectively and exclusively to dabigatran molecules, thereby reversing their anticoagulant effect, without however, interfering with coagulation cascade reactions. The dabigatran-idarucizumab complex is apparently stable and does not appear to break down over time. In their in vivo study on rats, this study’s researchers showed that steady-state dabigatran blood concentrations of about 200 ng/ml were reversed in one minute after direct intravenous injection of the antidote. Reversal was maintained for 25 minutes, despite continuing IV infusion of dabigatran, demonstrating the in vivo efficacy of anticoagulant activity inhibition at equimolar doses of idarucizumab.
Honickel et al evaluated the ability of two prothrombin complex concentrates (PCCs – containing 3 or 4 factors) and idarucizumab to reverse dabigatran’s anticoagulant effects ex vivo in an animal study(7). Twelve pigs received oral dabigatran etexilate (30 mg/kg twice daily for 3 days) and IV dabigatran (0.77 mg/kg/hour for 30 minutes, then 0.2 mg/kg/hour for 60 minutes). After that, trauma was inflicted on them (bilateral femoral fractures and blunt liver injury). Six pigs received a combination of tranexamic acid and a fibrinogen concentrate (Group 1) 12 minutes after the traumatic injuries, while the other six received placebo (Group 2, saline). PCCs (30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to ex vivo blood samples from both groups. Coagulation was evaluated through several coagulation tests. All coagulation parameters were modified after IV infusion of dabigatran (plasma concentrations: 442 +/- 138 ng/ml). Both types of PCC provided majority or complete reversal of dabigatran’s effects on thrombo-elastomeric parameters (clotting time, clot formation time) and on prothrombin time (PT), but not on activated partial thromboplastin time (aPTT). For its part, idarucizumab neutralized plasma concentrations of dabigatran and reversed the drug’s effects on coagulation variables. Thrombin production showed a dose-dependent over-correction following the addition of PCC, meaning that high thrombin concentrations are required to overcome dabigatran-induced coagulopathy. On the other hand, treatment with idarucizumab showed that thrombin production returned to baseline concentrations. Following traumatism, therapy combining tranexamic acid and a fibrinogen concentrate improved coagulation parameter correction by PCCs and also improved thrombo-elastomeric parameter correction by idarucizumab. To a similar degree, all PCCs studied had a positive impact on dabigatran-induced or traumatism-induced coagulopathy correction. This study showed that all PCCs had comparable efficacy for reversing the effects of dabigatran. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with an over-correction in thrombin production.
Na et al studied the efficacy of idarucizumab in an animal model in combination with anticoagulation using dabigatran(8). A placebo or dabigatran etexilate was injected intraperitoneally in mice at doses of 4.5 or 9 mg/kg (approximately equivalent to 7.2 or 14.3 mcmol/kg), or warfarin was administered orally for 72 hours in order to obtain an international normalized ratio (INR) of 3.5 to 6. One hour later, an intrastriatal injection of collagenase caused intracerebral bleeding. Idarucizumab or placebo (saline) was injected intravenously 30 minutes after the bleed at doses of 8 or 16 mcmol/kg. The intraperitoneal injection increased the average hematoma volume after 24 hours significantly in anticoagulated animals versus non-anticoagulated animals. Idarucizumab limited the enlargement of the hematoma caused by the two doses of dabigatran etexilate; however, it did not affect the enlargement caused by warfarin. Idarucizumab’s efficacy was also demonstrated when the blood contained in the hemisphere where the bleed occurred was analyzed using a photometric technique for hemoglobin. To model the high mortality of dabigatran-induced intracerebral bleeds, the researchers then increased the dose of collagenase in some mice to obtain a mortality rate of 80% at 7 days. Administration of an equimolar dose of idarucizumab reduced the rate to 42%. This study showed that idarucizumab not only produced dose-dependent reversal of dabigatran’s systemic anticoagulation and enlargement of an intracerebral hematoma, but also reduced mortality in an animal model.
However, complementary results have been presented only in the form of abstracts at international congresses. According to one study in which researchers made use of in vitro human blood flow, idarucizumab fully restored alterations caused by dabigatran on platelet deposits and fibrin covering on damaged blood vessels(9). Moreover, it produced dose-dependent reduction in mean blood loss after a trauma experienced by pigs which had been administered dabigatran in order to maintain supratherapeutic plasma concentrations(10). Idarucizumab’s half-life was 3.2 +/- 0.1 hours in pigs in hemorrhagic shock, and administration of volume fill solutions (Ringer’s Lactate, HES, RBC) did not appear to interfere in the binding between dabigatran and idarucizumab(11).
The human studies presented in this review were funded by the manufacturer, since idarucizumab has been marketed for only a short time as this article is being written. The phase-I study conducted by Glund et al was divided into two stages. The first stage consisted of a randomized, controlled study of 110 healthy subjects in order to verify idarucizumab’s safety versus placebo and to find out the drug’s pharmacokinetic parameters and its effects on the different coagulation tests(12). Stage 2 was to evaluate safety and the potential for the various coagulation tests to return to normal in 47 healthy subjects on dabigatran(13). Subjects included in both phases of the study did not develop any adverse effects considered to be serious, either with continuous IV infusion or with rapid IV administration. The incidence of adverse effects was similar for subjects on idarucizumab and those on placebo. No immunogenic reaction was observed using tests for anti-idarucizumab antibodies. One important observation was that taking idarucizumab had no impact on coagulation tests in subjects not taking anticoagulants. When used in anticoagulated subjects on dabigatran, idarucizumab produced dose-dependent reversal of anticoagulation. At doses greater than or equal to 2 g, idarucizumab returned diluted thrombin time (dTT) to normal and maintained it there; that test is considered to be the most sensitive test validated for monitoring dabigatran(14). The same observation was made for the ecarin clotting time (ECT) test with doses of idarucizumab greater than or equal to 4 g.
The phase-3 RE-VERSE AD (REVERSal Effects of Idarucizumab on Active Dabigatran) study has attracted attention following the recent publication of preliminary results(15). This multicentre, prospective, cohort study by Pollack et al was an interim analysis including 90 patients. Recruitment is still underway and it is intended to include a total of 300 patients from more than 400 hospitals. Subjects were divided into two groups: Group A was made up of adult subjects taking dabigatran, who had major active bleeds requiring reversal of its anticoagulant effect, while adult subjects taking dabigatran who required emergency surgery were included in Group B. All subjects received 5 g of idarucizumab administered in two consecutive direct IV infusions of 2.5 g each. The study’s primary objective was to find the maximum percentage reversal of dabigatran’s anticoagulant effect, based on dTT or ECT. The choice of the observational design rather than a traditional randomized, controlled trial was explained by the lack of a treatment shown to be effective for reversing dabigatran’s effect which could act as a comparator in this type of study. In addition, as the condition to be treated, namely, major bleeds, can lead to serious complications or death, it would not have been considered ethical to carry out a study comparing an antidote to placebo. The average study patient was aged 76, Caucasian and taking reduced doses of oral dabigatran 110 mg twice daily for atrial fibrillation. The mean time since last taking dabigatran was 15.4 hours. Little information was available about the severity of the patient’s initial state which justified the use of idarucizumab. Sixteen patients were hemodynamically unstable when recruited. A maximum median percentage reversal of dabigatran’s anticoagulant effect of 100% (95%CI: 100-100) was observed. The study did not mention the proportion of subjects in whom the calculation was made with dTT or ECT, or in how many subjects both coagulation tests were completely reversed due to idarucizumab. When patients started participating in this study, the dTT value was within normal limits for 22 of them (24%), and ECT was normal in a further 9 patients (10%). However, those patients were excluded from the primary analysis. Within 24 hours following administration of idarucizumab, dTT values were below the upper limit of normal for 90% of Group A patients and 81% of Group B patients, compared with 72% of Group A patients and 54% of Group B patients with respect to ECT. A more marked effect of idarucizumab on dTT was also observed compared with its effect on ECT, although the clinical impact of that difference between the two tests remains to be demonstrated. Four hours after administration of the antidote, 96.5% of patients had achieved free dabigatran plasma concentrations near the limit of detection. However, two patients had plasma concentrations much higher than the therapeutic values normally observed. The median time for return to hemostasis, in the clinician’s judgment, was 11.4 hours in subjects in Group A. However, the time to return to hemostasis could only be determined in one quarter of subjects included in that group. In total, 18 patients died, and 5 of those deaths were due to a fatal hemorrhage. Therefore, idarucizumab failed to stop the bleeding quickly enough to prevent death in at least 5.6% of subjects. In total, 5 subjects who received idarucizumab experienced a thrombotic event. One subject developed a pulmonary embolism and deep vein thrombosis two days after receiving the antidote, while all other thrombotic events experienced by patients occurred more than one week after administration of idarucizumab. The only death related to thrombotic events occurred 26 days after administration of idarucizumab, after an ischemic stroke. No anticoagulation was restarted in 5 subjects when the complication occurred, which suggests that the previous underlying prothrombotic condition of those subjects might be the issue, particularly considering too the chronology of events versus the time when the antidote was administered. In the 51 Group A subjects, almost 65% received at least one blood product; 27.5% of subjects received at least one transfusion of fresh frozen plasma; 11.8%, platelets and 8%, tranexamic acid. No subjects received coagulation factor concentrate.
A summary of the human studies is presented in Table 1 (see article in PDF version).
Two further studies were presented only in the form of abstracts at international congresses(16,17). The first study concluded that administration of 5 g or two consecutive doses of 2.5 g of idarucizumab provided sustainable reversal of dabigatran-induced anticoagulation in healthy subjects, irrespective of age (interval not specified, but this study mentions seniors) or renal function – evaluated up to 30-60 ml/min, but no lower(16). In addition, anticoagulant therapy with dabigatran etexilate could be restarted 24 hours after the use of idarucizumab(16). The second study concluded that idarucizumab reversed inhibition of fibrin formation around wounds in healthy volunteers who received dabigatran etexilate(17).
Dabigatran is an oral anticoagulant with a different mechanism of action than the other NOACs. It acts as a direct competitive thrombin inhibitor. The oral formulation is marketed in the form of a prodrug, dabigatran etexilate, in 110 and 150 mg capsules (18). Dabigatran etexilate is rapidly absorbed and converted into dabigatran by hydrolysis catalyzed by an esterase found in plasma and in the liver(18). Its elimination half-life is approximately 12-17 hours(18). Administration of dabigatran should be avoided in patients with renal function below 30 ml/min(18). There might be an increased risk of toxicity when dabigatran is combined with drugs which are potent P-glycoprotein inhibitors or major substrates(18). According to the RE-LY study, the risk of hemorrhage and ischemic stroke was correlated with dabigatran plasma concentrations(19). Age is apparently the most important covariable to consider, and the dose of dabigatran should be adapted to patient characteristics in order to have a more favourable risk-benefit ratio(19). It is not necessary to stop taking dabigatran before a medical procedure considered to be have a very low bleed risk (e.g., dental cleaning, periodontal surgery, skin biopsy, cataract surgery, endoscopy without biopsy). However, it is recommended that dabigatran be discontinued 1-2 days before a medical procedure considered to have a low bleed risk (e.g., laparoscopy, coronary angiogram, insertion of a pacemaker or defibrillator) and 2-3 days before a medical procedure considered to have an intermediate bleed risk (e.g., any other intra-abdominal, intrathoracic, orthopedic or vascular surgery) or high bleed risk (e.g., neurological surgery, valve replacement, prostatectomy, total hip or knee replacement)(20). In addition to these recommendations, it would be preferable to discontinue taking the drug one day earlier if kidney function is 30-50 ml/min, and two days earlier if it is below 30 ml/min(20).
Idarucizumab is the first dabigatran-specific antidote to be marketed. As an antidote, it has several benefits based on studies published so far: already in the form of an injectable solution (50 mg/ml), administered as a quick IV infusion in 5 minutes, binds strongly and solely to dabigatran, rapidly reverses dabigatran’s anticoagulant effects, has no procoagulant activity and few adverse effects. However this antidote is only suitable for dabigatran, not the other NOACs, which is its main inconvenience. In addition, studies are currently limited to analytical results.
According to preliminary results for the primary endpoint of the RE-VERSE AD study, idarucizumab gets a perfect grade with an anticoagulant effect reversal rate of 100%. However, clinicians must bear in mind that this is an analytical result, which does not necessarily determine a patient’s clinical course. Is it really clinically necessary to reverse 100% of anticoagulant activity in all cases? While almost all subjects had undetectable dabigatran plasma concentrations 4 hours after administration of idarucizumab, that was only the case for 79% of them 24 hours after taking the antidote. These results, like the decrease in effect on dTT and ECT after 24 hours mentioned in the results, raise questions about the actual duration of action of the antidote. The authors do not explain or comment on the loss of efficacy. One hypothesis to explain these observations might be a loss of binding between idarucizumab and dabigatran over time or delayed intestinal absorption of dabigatran etexilate. Nevertheless, the data leads to questions about the need to re-administer the antidote, in particular to subjects in whom the half-life time is increased, e.g., kidney failure patients. Two Group B subjects had supratherapeutic dabigatran plasma concentrations 4 hours after administration of idarucizumab. No details about baseline concentrations present before reversal or about those patients’ clinical course is available. However, the data sows doubt about idarucizumab’s efficacy in a situation of severe dabigatran poisoning and the dose to use in that type of situation. We can also wonder whether there is potentially resistance to idarucizumab. The study’s inclusion criteria, although defined adequately in the protocol, are still subjective and depend on the clinician’s judgment, particularly for subjects in Group A. Not much information is available about bleed severity and patients’ condition when they started participating in the study. As a result, we can question the homogeneity of patients included in the study and wonder whether the use of idarucizumab was really indicated for those patients. Moreover, nearly one quarter of subjects included in the study had a diluted thrombin time within normal limits when they received the antidote.
Since 2012, the Centre antipoison du Québec [Quebec poison control centre] (CAPQ) has received about 30 calls a year involving potential poisonings with drugs which may include dabigatran etexilate. Of 80 calls received between 2012 and 2015, more than 90% involved therapeutic errors made by the patient (e.g., a double dose). Of the few cases of intentional ingestion of doses ranging from 770 to 4,500 mg of dabigatran etexilate, no patients experienced bleeding. According to the current CAPQ treatment protocol, any child (no matter the dose ingested) or any adult who has ingested a dose higher than three times the usual unit therapeutic dose, i.e., more than 3 capsules, should be directed to a hospital to be observed and for monitoring of coagulation parameters. This recommendation is based on the study by Stevenson et al, among others. They reported a series of cases of exposure to dabigatran etexilate or rivaroxaban identified by the California poison control centre from January 2011 to July 2013(21). None of the patients who mistakenly received an additional dose of dabigatran etexilate reported bleeding or adverse effects. Of 37 cases of dabigatran poisoning, 4 were the result of an intentional overdose of dabigatran etexilate ranging from 1,800 to 3,900 mg. Only one of those four patients experienced bleeds which were minor. As well, the coagulation parameters did not seem to correlate to the bleeds. The two dabigatran-related deaths actually involved long-term use of therapeutic doses. Administration of activated charcoal within 2 hours following ingestion should be considered. According to some authors, intermittent hemodialysis could be considered as an extracorporeal clearing measure for dabigatran. However, it appears that 4 hours of treatment would not be sufficient for returning to subtherapeutic plasma concentrations of dabigatran, even with normal kidney function(22).
The arrival of the first antidote for a NOAC is likely to give a breath of hope to healthcare professionals who, until now, were reluctant to prescribe this drug therapy for their patients. The cost of idarucizumab on the Canadian market had not been announced when this article was written. However, it is apparently $3,500 US in the United States for a kit containing two vials of 2.5 g/50 ml of idarucizumab. Other antidotes are being developed, which might eventually lead to competition in price. Nonetheless, the availability of an antidote should not replace caution and good medical and pharmaceutical practices. Clinicians should make sure they select candidates who can undertake drug therapy with an NOAC, choose the NOAC which best suits a given patient and the most appropriate dose for that patient. In addition, clinicians should make sure they have optimal pre-operative management in order to be able to discontinue administration of the NOAC within the recommended periods. The need to administer an antidote (expensive or not) to a patient who has to have elective surgery would be an indicator of poor pre-operative management. According to data currently available about idarucizumab, this antidote is of interest, because it can quickly reverse anticoagulation after taking dabigatran. It might be useful to have access to it for patients who need to have emergency surgery or presenting with major bleeds (e.g., traumatism); the other antidotes currently available on the market are not able to quickly reverse NOACs’ anticoagulant effects. However, it does not seem appropriate currently to recommend administration of this antidote right away to patients attending a hospital due to intentional overdoses of dabigatran or unintentional exposure to this drug (e.g., ingestion by a child, administration error in a nursing home), when there is no major bleed.
Please indicate which of the following statements is true concerning the RE-VERSE AD study.
A. This is an interim analysis of a large randomized, controlled, multicentre study with recruitment still underway.
B. Study patients for whom the primary endpoint was measured showed a median anticoagulant effect reversal rate of 100%.
C. Idarucizumab slightly increased the incidence of thrombotic events, as was demonstrated in phase-1 clinical trials.
D. Although the number of deaths was not initially included in the results evaluated by RE-VERSE AD, the absence of deaths in patients who received idarucizumab reinforces the antidote’s efficacy.
* Answer: B
For all correspondencePierre-André Dubé Institut national de santé publique du Québec
945, avenue Wolfe, 4e étage Québec, QC G1V 5B3
Telephone: 418 650-5115, ext. 4647
Fax: 418 654-2148
Email: [email protected]
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Dubé PA, Monast PO. Idarucizumab: a specific antidote for dabigatran. Bulletin d’information toxicologique 2013;31(4):17-25. [En ligne] https://www.inspq.qc.ca/en/toxicologie-clinique/idarucizumab-specific-an...