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Intravenous Thrombolysis After Dabigatran Reversal by Idarucizumab: A Systematic Review of the Literature.

ABSTRACT: 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.

SUBMITTER: Frol S

PROVIDER: S-EPMC8209294 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:Current guidelines do not recommend the use of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who receive direct oral anticoagulants. While the humanized monoclonal antibody idarucizumab can quickly reverse the anticoagulant effects of the thrombin inhibitor dabigatran, safety data for subsequent tissue plasminogen activator treatment are sparse. Here, we review current knowledge about dabigatran reversal prior to systemic reperfusion treatment in acute ischemic stroke.We performed a systematic review of all published cases of intravenous tissue plasminogen activator treatment following the administration of a dabigatran antidote up to June 2017 and added five unpublished cases of our own. We analyzed clinical and radiological outcomes, symptomatic post-thrombolysis intracranial hemorrhage, and other serious systemic bleeding. Additional endpoints were allergic reaction to idarucizumab, and venous thrombosis in the post-acute phase.We identified a total of 21 patients (71% male) with a median age of 76 years (interquartile range 70-84). The median National Institute of Health Stroke Scale score at baseline was 10 (n = 20, interquartile range 5-11) and 18/20 patients (90%) had mild or moderate stroke severity. The time from symptom onset to start of tissue plasminogen activator was 155 min (n = 18, interquartile range 122-214). The outcome was unfavorable in 3/19 patients (16%). There was one fatality as a result of a symptomatic post-thrombolysis intracranial hemorrhage, and two patients experienced an increase in the National Institute of Health Stroke Scale compared with baseline. One patient had a recurrent stroke. No systemic bleeding, venous thrombosis, or allergic reactions were reported.Experience with idarucizumab administration prior to tissue plasminogen activator treatment in acute ischemic stroke is limited. Initial clinical experience in less severe stroke syndromes and short time windows seems favorable. Larger cohorts are required to confirm safety, including bleeding complications and the risk of thrombosis.

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Intravenous Thrombolysis After Dabigatran Reversal by Idarucizumab: A Systematic Review of the Literature.

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