Dabigatran overload in acute kidney injury: haemodialysis or idarucizumab? A case report and proposal for a decisional algorithm.
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ABSTRACT:
SUBMITTER: Galassi A
PROVIDER: S-EPMC8173663 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We describe a 75-year-old female patient with nonvalvular atrial fibrillation who presented with acute ischemic stroke during treatment with dabigatran 2 × 110 mg per day. After informed consent, we reversed the anticoagulant effects of dabigatran using idarucizumab and applied an intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (off-label use). An intracerebral hemorrhage was excluded after systemic thrombolysis. Despite the IVT, the patient's clinical condition deteriorated and she developed an ischemic lesion in the right pons, the right thalamus and right cerebellum. To date, the literature lacks data concerning the thrombolytic treatment of acute ischemic stroke in patients after specific reversal of the non-vitamin K oral anticoagulant dabigatran using idarucizumab. Given the rapid and sustainable efficacy of idarucizumab, the reversal of dabigatran followed by thrombolysis seems to be safe, but further studies and register data are still needed to confirm our preliminary observation, especially to provide additional data concerning the risk-benefit evaluation.
| S-EPMC4945814 | biostudies-literature
Project description:Idarucizumab is approved for patients treated with dabigatran when reversal of the anticoagulant effects is needed. Like dabigatran, idarucizumab is excreted in the urine. The effect of renal dysfunction on drug elimination is uncertain, as patients in the RE-VERSE AD trial had a median creatinine clearance of 58 mL/min. Also, dabigatran accumulation can occur if the international normalized ratio (INR) is greater than two. A 73-year-old female was admitted for lower extremity edema and increased abdominal girth. On admission, the patient was in acute kidney injury (AKI) with an estimated creatinine clearance of 34.5 mL/min. Her prothrombin time (PT) on admission was 17 seconds, her INR was 1.4, and her hemoglobin was 8.7 gm/dL (12-16 gm/dL). Throughout her admission, she was continued on her home regimen of dabigatran 150 mg twice daily for atrial fibrillation. On day 4, she had rectal bleeding and altered mental status. At this time, her PT was elevated to 25.6 seconds, her INR had increased to 2.3, and her hemoglobin had dropped to 6.8 gm/dL. Two doses of idarucizumab 2.5 gm were administered, and dabigatran was successfully reversed with cessation of bleeding and normalization of the INR to 1.5. An additional dose of idarucizumab was not required. The patient was discharged home two days later. Idarucizumab successfully reversed the bleeding and coagulopathy associated with dabigatran in a patient with AKI.
| S-EPMC6281148 | biostudies-other
Project description:BACKGROUND AND PURPOSE:Non-vitamin K anticoagulants (NOAC) such as dabigatran have become important therapeutic options for the prevention of stroke. Until recently, there were only nonspecific agents to reverse their anticoagulant effects in a case of emergency. Idarucizumab, an antibody fragment targeting dabigatran, is the first specific antidote for a NOAC to be approved, but real-world experience is limited. METHODS:We report two cases of patients on dabigatran with acute intracerebral hemorrhage who received idarucizumab. RESULTS:In both cases, idarucizumab promptly reversed the anticoagulant effect of dabigatran and there was no hematoma expansion in follow-up imaging. CONCLUSIONS:In addition to clinical and preclinical studies, our cases add to the experience regarding the safety and efficacy of idarucizumab. They show that idarucizumab may be an important safety option for patients on dabigatran in emergency situations.
| S-EPMC5121568 | biostudies-literature
Project description:Non-vitamin K antagonist oral anticoagulants, including dabigatran, are currently widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment for immediate reversal of dabigatran-induced anticoagulation, has been introduced into the market to be used in life-threatening bleeding or urgent surgery, allowing for rapid normalization of clotting parameters. The use of idarucizumab is not yet well established in patients presenting with acute ischemic stroke on dabigatran who are candidates for thrombolytic therapy.We report the case of a 71-year-old hypertensive Caucasian woman with non-valvular atrial fibrillation treated with dabigatran 150 mg twice daily, who presented with acute ischemic stroke causing right-sided hemiparesis and aphasia. Two hours after presentation to the emergency department, a decision was made to administer idarucizumab for achieving complete reversal of any potential anticoagulant effect of dabigatran and, in the absence of any contraindications, our patient underwent successful thrombolysis. At discharge, our patient was able to walk unassisted and had only residual aphasia. Twenty days later, she had completely recovered motor function of her right side, with further progressive improvement of aphasia. Repeat cranial computed tomography confirmed the absence of hemorrhage, and anticoagulant therapy with dabigatran 150 mg twice daily was resumed.Our case report adds to the evidence that idarucizumab administration is safe in the setting of patients with atrial fibrillation treated with dabigatran who develop acute ischemic stroke requiring thrombolysis.
| S-EPMC5557536 | biostudies-other
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.
| S-EPMC6852568 | biostudies-literature
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.
| S-EPMC8209294 | biostudies-literature
Project description:Direct oral anticoagulants (DOAC) are an attractive alternative over vitamin K antagonists. They have several advantages in primary and secondary prevention of thromboembolisms due to atrial fibrillation, as well as in prevention and treatment of thromboembolic venous disease. They have fast onset action, do not need laboratory controls in patients with normal renal function, and they have practically no interference with the patient's diet or medications. The strongest objection to their use was the lack of reversal agents that could be used in case of life-threatening haemorrhage or the need for emergency surgery. Dabigatran was the first DOAC to have its own specific reversal agent: idarucizumab, a monoclonal antibody. We report here the case of a patient undergoing treatment with dabigatran that suffered an expansive subdural haematoma secondary to a cranial injury. The condition was life-threatening and required emergency surgery. Anticoagulation was successfully reversed with idarucizumab. Emergency surgery in patients in treatment with DOAC is associated with an increased risk of bleeding. With the use of a specific antidote to block the action of the anticoagulant, as in the case of idarucizumab with dabigatran, the risk of complications during and after emergency surgery is reduced. This is the first case report with which the successful use of idarucizumab in Latin America is documented.
| S-EPMC6601192 | biostudies-literature
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.
| S-EPMC4876800 | biostudies-literature
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.
| S-EPMC5510069 | biostudies-literature
Project description:BACKGROUND:Application of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations. OBJECTIVES:The objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure. METHODS:The idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates. RESULTS:The established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance. CONCLUSIONS:A comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy.
| S-EPMC7292816 | biostudies-literature