Intravenous Thrombolysis after Dabigatran Reversal with a Specific Antidote Idarucizumab

Introduction

Patients with acute ischemic stroke (IS) use often oral anticoagulants, especially as a preventive treatment of embolic events for atrial fibrillation. However, intravenous thrombolysis (IVT) is not recommended generally in these patients if certain conditions are present [1–3]. In the patients, who use warfarin, the value of INR should be > 1.7. In patients using direct anticoagulants (DOAK), IVT is recommended only if DOAK are not used in last 48 hours definitely or if specific laboratory detection test for appropriate DOAK are normal. [1–3]

An immediate reversal of the anticoagulation effect of DOAK is a new possibility of the IVT treatment in these patients now. Since the end of year 2015, a specific human monoclonal antibody Idarucizumab (Praxbind^®) is available, which binds Dabigatran approx. 350× more than Dabigatran binds thrombin [4]. Standard dose 5 g of Idarucizumab reverses completely the biological effect of Dabigatranu within a few minutes [5,6]. Up to now, six cases of IVT for acute IS after previous anticoagulation reversal of Dabigatran were published only.

In the following part, we present the first documented administration of Idarucizumab followed by IVT for acute IS in Czech Republic.

Case

A 70-year-old female was admitted early December 2015 for 2 hours lasting severe left hemiparesis, lesion of facial nerve with dysartria and tactile hypesthesia of left-sided limbs and left face; score in National Institutes of Health Stroke Scale (NIHSS) were 8 points. Patient used Dabigatran in a dose 2 × 150 mg daily as a preventive treatment for atrial fibrillation (AF) and last intake was approx. 5 hours before the patient's admission. She was treated for arterial hypertension, diabetes mellitus (on oral antidiabetics), hypothyreosis and bronchial asthma.

Performed computed tomography (CT) of brain showed small hypodense lesions in white matter in proximity of lateral ventricles corresponding to old ischemic changes (Fig. 1A). CT angiography did not shoed occlusion or significant stenoses in intra and extra-cranial arteries (Fig. 1B). Thrombin time (TT) was extended over 180 seconds and activated tromboplastin time (aPTT) over 61.7 sec. All blood counts were normal, serum creatinin was elevated to 125mmol/l.

Patient was treated with 5 g of Idarucizumab (2 × 2.5 g/50 ml) according to therecommended scheme approx. 5.5 hours after last intake of Dabigatran [7]. After the end of administration of antidote, a control coagulation sample was performed and administration of 85 mg of rt-PA (Actilyse^®) was initiated immediately according to patient's declared weigh of 95 kg. The results of control coagulation sample were normal: TT was 15.1 sec and aPTT 31.9 sec.

Patient recovered clinically within 2 hours after IVT and after 24 hours, she presented with a very mild left hemiparesis only (NIHSS 2). A control brain CT was identical, means no acute ischemia or hemorrhage was present. Only non-significant atherosclerotic changes in carotid bifurcation and internal carotid arteries were observed in neurosonological exam. No adverse events and complications were recorded in association with prior treatment with antidote and IVT. In secondary prevention, patient was covered by a low weighted molecular heparin (Fraxiparine^®) in dose 0.9 ml s.c. 2× a day. Subsequently, patient was transferred to a sector hospital in her place of residency, where Dabigatran in a dose of 2 × 150 mg daily was given back her for the preventive treatment and then she was discharged home (NIHSS 2) with a score of one point in the modified Rankin Scale.

Discussion

In this article, we present the first documented case of IVT for acute IS after previous reversal of effect of Dabigatran using a specific antibody Idarucizumab in Czech Republic. Up to now, six administration of antidote before IVT was published only [8–13] and in one case only, patient used Dabigatranu 2 × 150 mg daily [9]; in resting cases, the dose 2×110 mg was used. Recently published expert opinion is based on data from 14 IVT performed after previous reversal of anticoagulation effect of Dabigatran in Germany [14].

Idarucizumab is specific human monoclonal antibody, which binds directly on Dabigatran (direct inhibitor of thrombin) and with very high affinity [4]. Antibody was approved in autumn 2015 (US Food and Drug Administration, European Medicines Agency) for use to fast reversal of anticoagulation effect in urgent cases or in case of severe or live threatening hemorrhage in patients taking Dabigatran [15]. The effect of antidote was confirmed by a prospective multi-centric study RE-VERSE-AD (Reversal Effects of Idarucizumab on Active Dabigatran), in which the patients requiring urgent surgery or patients suffering severe live threatening hemorrhage were enrolled [6].

In presented case, the reversal of Dabigatran effect with a normalization of coagulation parameters came immediately after the end of antidote application, which is well documented by the values of TT and aPTT from the control coagulation sample performed before IVT (see Case description). The benefit of Idarucizumab except immediate reversal of Dabigatran is also fact, that antidote has no pro-coagulation effect (in contrast to coagulation factors concentrates) and no interaction between antibody and rt-PA induced thrombolysis in vitro test [4,5,16].

Recently published opinion of international expert group recommends to administrate 5 g of Idarucizumab in patients using Dabigatran, who are indicated to IVT and perform coagulation tests for TT and aPTT. If the levels of coagulation parameters are extended over normal values, IVT should be stopped immediately. In case of mechanical thrombectomy without previous IVT, it is recommended to administrate Idarucizumab in case of intracranial hemorrhagic complications or in case of a great bleeding in site of catheter entry (groin) [14]. In conclusion, presented case represents a new therapeutic paradigm, when patient – user of Dabigatran – may be treated with IVT for acute IS after the reversal of effect of Dabigatran with Idarucizumab. This new therapeutic concept is supported by previous yet published cases and also by the opinion of international expert group. This new therapeutic procedure has also a substantial impact on clinical practice for an increasing number of patients – users of Dabigatran – for primary or secondary prevention of thrombembolic events.