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Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor that has been shown to prevent stroke in patients with atrial fibrillation. Idarucizumab is a humanised monoclonal antibody fragment developed to reverse the anticoagulant effects of dabigatran. Idarucizumab binds dabigatran 350 times more avidly than dabigatran binds thrombin, and completely reverses dabigatran’s biological activity within a few minutes.1 To date there have been only a handful of patients in whom dabigatran have been reversed with idarucizumab prior to treatment with intravenous alteplase, and none prior to endovascular clot retrieval.2 3
All New Zealand patients treated with alteplase must be entered into a national database, and this has noted whether idarucizumab was used prior to alteplase or clot retrieval since 2016. All patients treated with dabigatran and presenting within the 4.5-hour alteplase, or 6-hour endovascular clot retrieval treatment windows, had blood samples taken for thrombin clotting time (TCT) and activated partial thromboplastin time (APTT). Idarucizumab 5g was given intravenously if either the APTT or TCT was prolonged above the normal range for the laboratory. Patients were then treated with standard-dose alteplase or endovascular clot retrieval.
The National Institutes of Health Stroke Scale (NIHSS) was performed at baseline and at 24 hours. The modified Rankin Scale (mRS) was used to determine functional outcome at 90 days. Safety measures included thrombotic complications of idarucizumab, symptomatic intracranial haemorrhage (sICH) and death at 90 days. sICH was defined as large parenchymal haematoma (>30% of infarct volume with mass effect) and ≥4 point increase in NIHSS score.
There were 276 patients treated with alteplase in New Zealand between 1 July and 31 December 2016. Over this period there were 3252 ischaemic and ‘strokes unspecified’ patients (used as the denominator for calculating thrombolysis rates), giving a national thrombolysis treatment rate of 8.5%. Idarucizumab was used in seven patients; 6 of 276 (2%) patients were treated with alteplase, one of whom went on to have endovascular clot retrieval, and one treated with clot retrieval alone (table 1). At baseline, six of the patients had a prolonged APTT and all seven had prolonged TCT. Dabigatran was used for atrial fibrillation in six patients and for left ventricular thrombus in one. All seven patients had middle cerebral artery territory ischaemic strokes.
Six patients (mean (range) 68 (52–78) years) were treated with alteplase. These patients had severe neurological deficit at presentation with a median (range) NIHSS score of 21 (6–28). The time from stroke onset to administration of idarucizumab was 180 (165–273) min, and to alteplase was 211 (165–285) min. The median door to needle time was 106 min. One patient developed sICH following alteplase and one patient died from the complications of ischaemic cerebral oedema. At day 90, five of six patients were alive, four were living at home and two were independent (mRS 0–2). Two patients were treated with clot retrieval, one of whom had been treated with alteplase, and at day 90 both were living at home and one was independent.
In a national cohort, the anticoagulant effects of dabigatran were reversed with idarucizumab in 2% of all thrombolysed patients, and in two patients prior to endovascular clot retrieval. This case series represents a small but useful addition to the number of patients treated with idarucizumab prior to acute stroke therapy. Post-thrombolysis complications, including thrombotic complications, are collected and were not seen in the seven patients treated.
An algorithm has been proposed to determine whether dabigatran-treated patients should be given idarucizumab prior to acute stroke therapy.4 In this algorithm, alteplase is given without idarucizumab if the clinical team is confident that dabigatran was taken more than 24 hours earlier. If dabigatran was taken within 24 hours, the algorithm recommends that idarucizumab is administered followed by alteplase. Where the clinical team is not confident of dabigatran dose timing, idarucizumab is given prior to alteplase if either APTT or TCT is prolonged.
This study has shown that idarucizumab may be used safely, and we suggest it could be administered without waiting for test results where the timing of last dabigatran dose is unclear. In the algorithm, it was suggested that patients who were otherwise eligible could be transferred immediately for clot retrieval without reversing the anticoagulant effects with idarucizumab and treating with alteplase.
In our own centre, two-thirds of clot retrieval patients are transferred from other hospitals, leading to inevitable delays in the time to groin puncture.5 In light of this study, we now give idarucizumab followed by alteplase, which is continued in the ambulance, if the estimated time to groin puncture is more than 20 min and doing this will not delay transfer. The number of patients in this report is small, and it is possible that outcomes may be worse than would be usually expected. It is therefore important to continue careful collection of registry data to define whether the use of idarucizumab in this way is safe and improves patient outcomes.
Contributors DMYT acquired the data and drafted the manuscript; LY, AR and PAB were involved in critical review and approval of manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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