Evidence for Idarucizumab (Praxbind) in the Reversal Of the Direct Thrombin Inhibitor Dabigatran: Review Following the RE-VERSE AD Full Cohort Analysis.
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SUBMITTER: Hutcherson TC
PROVIDER: S-EPMC5642158 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
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Evidence for Idarucizumab (Praxbind) in the Reversal Of the Direct Thrombin Inhibitor Dabigatran: Review Following the RE-VERSE AD Full Cohort Analysis.
Hutcherson Timothy C TC Cieri-Hutcherson Nicole E NE Bhatt Rajvi R
P & T : a peer-reviewed journal for formulary management 20171101 11
Idarucizumab is the first reversal agent approved for the direct thrombin inhibitor dabigatran. The authors summarize the findings from the clinical trial series and describe case reports, post-marketing data, and ongoing studies. ...[more]
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Project description:Background and Purpose: Idarucizumab achieves instant reversal of anticoagulation and enables intravenous thrombolysis (IVT) in dabigatran-treated acute ischemic stroke (AIS) patients. AIS in dabigatran-treated patients is a rare event, therefore the experience is limited. A review of all published cases was performed to evaluate the safety and effectiveness of this therapeutic strategy. Methods: We searched PubMed and Scopus for all published cases of IVT after reversal with idarucizumab in dabigatran-treated AIS patients. The outcomes were safety assessed by hemorhagic transformation (HT), symptomatic intracranial hemorrhage (SICH) and death, and efficacy assessed by National Institutes of Health Stroke Scale (NIHSS) reduction. Results: We identified 251 AIS patients (39,9% females) with an average age of 74 years. HT, SICH, and death were reported in 19 (7.6%), 9 (3.6%), and 21 (8.4%) patients, respectively. Patients experiencing HT presented with more severe strokes (median NIHSS on admission: 21 vs. 8, p < 0.001; OR: 1.12, 95% CI: 1.05-1.20). After IVT there was a significant NIHSS reduction of 6 points (IQR:3-10, p < 0.001) post-stroke and linear regression revealed a correlation of admission NIHSS to NIHSS reduction (p < 0.001). Conclusions: In this systematic review of all published cases of IVT in dabigatran-treated AIS patients after reversal with idarucizumab the rates of HT, SICH and mortality, as well as NIHSS reduction, were comparable with previous studies in non-anticoagulated patients. This provides reassuring evidence about the safety and efficacy of this therapeutic strategy.
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Project description:BACKGROUND:Idarucizumab is a monoclonal antibody fragment that reverses dabigatran anticoagulation. Pharmacokinetics (PK) of idarucizumab have been described in healthy, elderly, or renally impaired (RI) volunteers, but PK data in patients are lacking. OBJECTIVES:This analysis describes the PK of idarucizumab and its target dabigatran in bleeding/surgical patients. PATIENTS AND METHODS:Results from the Reversal Effects of Idarucizumab on Active Dabigatran study, a prospective, multicenter, single-arm study demonstrated the reversal of dabigatran anticoagulation by idarucizumab in patients with uncontrollable bleeding (group A) or who needed urgent surgery (group B). Idarucizumab and unbound dabigatran concentrations, immunogenicity, and pharmacodynamics were assessed. RESULTS:Total and unbound dabigatran levels at baseline were 165 ng/mL vs 110 ng/mL and 103 ng/mL vs 69.5 ng/mL in group A and B patients, respectively. Maximum plasma concentrations and area under the curves (AUC0-24 ) of idarucizumab in group A vs B, respectively, were 24 900 nmol/L vs 25 000 nmol/L and 76 600 nmol/h/L vs 68 000 nmol/h/L. Idarucizumab AUC0-24 increased by 38% in mild, 90% in moderate, and 146% in severe RI patients vs normal renal function. Hepatic impairment or geographical region had no relevant effect on idarucizumab PK. Idarucizumab immediately decreased unbound dabigatran concentration (<20 ng/mL). A linear correlation was observed between unbound dabigatran and diluted thrombin time and ecarin clotting time. Antidrug antibody titers were low (1-64 at day 30; 0-16 at day 90) and had no impact on idarucizumab PK and pharmacodynamics. CONCLUSION:Idarucizumab PK in target patients was consistent with phase I data. Patient characteristics had no impact on PK, whereas RI increased the exposure of idarucizumab and dabigatran. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov NCT02104947.
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Project description:Idarucizumab is the first targeted antidote of dabigatran, a direct oral anticoagulant used for prevention and treatment of venous thromboembolism and prevention of stroke in atrial fibrillation. Idarucizumab is a humanized fragment of a monoclonal antibody, which binds dabigatran reversibly with high affinity and, when administered intravenously, immediately neutralizes its anticoagulant effect. It is rapidly cleared by the kidney with captured dabigatran. In Phase I and II trials, no significant adverse events have been reported. Specifically, idarucizumab has no anticoagulant or procoagulant effect by itself. Idarucizumab is currently being evaluated in an ongoing Phase III trial, in patients treated with dabigatran presenting with severe active bleeding or requiring emergency surgery or an invasive procedure and are at high risk of bleeding. The results of the interim analysis confirm the ability of idarucizumab to neutralize dabigatran instantaneously, without rebound effect, except in rare patients with very high baseline levels of anticoagulant. Although not definitely proving clinical efficacy, due to the noncontrolled design of the trial and the heterogeneity of patient conditions, these promising results on an intermediate criterion with strong rationale have led to the approval of idarucizumab for these indications. However, several questions are unresolved. First, activity measurement of dabigatran in blood, useless in current practice, could be useful to guide the treatment and avoid over- or underutilization of the antidote; but so far, it has not been largely available in real time. Second, the translation of anticoagulant neutralization to an effect on mortality and better outcome is highly dependent on the global management of these patients, especially rapid diagnosis, supportive care, and easy access to antidote administration. Although idarucizumab represents a remarkable achievement in drug design and development, whether it will be an important step toward improved safety of patients treated with dabigatran in the real world will have to be demonstrated in the postmarketing phase.
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Project description:AIMS:Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. METHODS:Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA. RESULTS:Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre-existing ADA had no impact on dose-normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran-induced anticoagulation by idarucizumab. Treatment-emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C-terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions. CONCLUSION:Pre-existing and treatment-emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre-existing ADA.
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Project description:Background: Idarucizumab has been included in guidelines for the management of bleeding or surgical procedure in dabigatran-treated patients without need for biological monitoring. The aim of the study was to assess the prognostic value of dabigatran plasma level before reversal to test the hemostatic efficacy of idarucizumab. The secondary objectives were (i) to analyze plasma dabigatran level according to the risk of rebound and (ii) to evaluate the incidence of post-reversal non-favorable clinical outcomes (including thromboembolism, bleeding, antithrombotic, and death) and antithrombotic resumption. Methods and Results: This was an observational multicentric cohort study, which included all French patients who required idarucizumab for dabigatran reversal. Between May 2016 and April 2019, 87 patients from 21 French centers were enrolled. Patients received idarucizumab for overt bleeding (n = 61), urgent procedures (n = 24), or overdose without bleeding (n = 2). Among patients with major bleeding (n = 57), treatment with idarucizumab was considered effective in 44 (77.2%) of them. Patients who did not achieve effective hemostasis after reversal had a significantly higher mean level of plasma dabigatran at baseline (524.5 ± 386 vs. 252.8 ng/mL ± 235, p = 0.033). Furthermore, patients who did not achieve effective hemostasis after reversal had less favorable outcomes during follow-up (46.2 vs. 81.8%, p = 0.027). ROC curve identified a cutoff of 264 ng/mL for dabigatran level at admission to be predictive of ineffective hemostasis. No plasma dabigatran rebound was observed after reversal in patients with dabigatran plasma level < 264 ng/mL at baseline. Conclusion: This retrospective study shows that dabigatran level before reversal could predict hemostatic effectiveness and dabigatran plasma rebound after idarucizumab injection.
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Project description:BackgroundNovel oral anticoagulants are used in atrial fibrillation. Idarucizumab has been approved for reversal of dabigatran in situations of life-threatening hemorrhage or emergency surgery.ObjectivesWe report a single center experience of ten patients on dabigatran therapy who were given idarucizumab prior to heart transplantation.Methods & resultsThe mean plasma concentration of dabigatran prior to reversal was 139 ± 89 ng/ml. Hemoglobin, hematocrit and platelet levels were decreased after surgery. Surgical procedures were successfully performed with no increased risk, especially regarding bleeding complications. All patients were alive after 90 days.ConclusionDabigatran reversal with idarucizumab in contexts of emergency surgery/urgent procedures is an attractive and safe option to be taken into consideration for patients with end stage heart disease awaiting transplantation and indication of anticoagulant therapy.
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Project description:BackgroundIdarucizumab is a humanized monoclonal antibody fragment that specifically binds with high affinity to dabigatran.ObjectivesThis study investigated the safety, tolerability and pharmacokinetics of idarucizumab alone and with dabigatran at steady state, and the effects of idarucizumab on dabigatran-induced anticoagulation.Patients/methodsThis was a two-part, phase I, randomized, placebo-controlled, double-blind, rising-dose trial in healthy Japanese males. Part 1: 32 subjects (males) received single idarucizumab doses (1, 2, 4 or 8 g [n=6/dose group]) or placebo (n=2/dose group). Part 2: 48 males received dabigatran (220 mg bid) followed by idarucizumab (n=9/dose group) 1, 2, 4 or 5 g (2×2.5 g), or placebo (n=3/dose group). Anti-idarucizumab antibodies (ADAs) and idarucizumab effect on anticoagulation parameters (diluted thrombin time [dTT], ecarin clotting time [ECT], activated partial thromboplastin time [aPTT] and thrombin time [TT]) were assessed.ResultsNo adverse events were reported in subjects receiving idarucizumab. After single doses of idarucizumab (alone or at steady state of dabigatran), maximum plasma concentration was achieved around the end of each infusion. Mean all anticoagulation parameters fell below the upper limit of normal immediately after idarucizumab infusion in all dose groups; the effect was sustained at 4 and 2×2.5 g over the entire measurement period until 72 h. At 1- and 2-g doses, partial return of the anticoagulant effect occurred. Idarucizumab alone had no effect on coagulation parameters. Treatment-emergent ADAs occurred in 6/60 males receiving idarucizumab.ConclusionsIdarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-induced anticoagulation in Japanese volunteers. Idarucizumab was well tolerated with no procoagulant effects. Trial registration number: ClinicalTrials.gov NCT02028780 (completed).
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Project description:IntroductionIdarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein.MethodsThis multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT).ResultsThe final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%.ConclusionsThe final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan.Trial registrationThis study is registered with ClinicalTrials.gov (NCT02946931).
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