Dabigatran Treatment of Acute Non-Cardioembolic Ischaemic Stroke: A Randomised Controlled Trial

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl <50 ml/min) or aspirin (81 mg OD). Magnetic resonance imaging was performed prior to randomisation and was repeated at day 30, with clinical assessments at 30 and 90 days. Imaging endpoints were ascertained centrally by readers blinded to treatment. The primary endpoint was symptomatic HT within 37 days of randomisation. Secondary endpoints included asymptomatic HT and recurrent cerebral infarcts. Findings: A total of 305 patients, mean age 66±13.21 years, were randomised to dabigatran or aspirin a mean of 40.10±19.44 hours after symptom onset. The qualifying event was a TIA in 21%, and ischaemic stroke in79% of patients. Median NIHSS (IQR) was 1 (0-2), and mean infarct volume 3.2±6.5 ml. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (RR=2.32, 95% CI 0.78, 6.85). Baseline infarct volume predicted incident HT (OR 1.07; 95% CI 1.03-1.12, p=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran and 14/142 (9.8%) of aspirin patients (RR=0.62, 95% CI 0.26, 1.48). There were no major bleeding events with either treatment. Interpretation: Dabigatran given to patients with acute minor non-cardioembolic ischaemic stroke/TIA was safe and was associated with a risk of HT similar to aspirin. Trial Registration Number: clinicatrials.gov NCT02295826 Funding Statement: DATAS II was funded by the Canadian Institutes for Health Research (G327075). Declaration of Interests: Dr. Butcher has served as an advisory board consultant and received speaker’s fees and investigatorinitiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Sharma has served as an advisory board consultant and or received speaker’s fees and investigator-initiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo and Servier. Dr. Benavente has served as an advisory board consultant and or received speaker’s fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Field has served as an advisory board consultant and received speaker’s fees from BoehringerIngelheim, Bayer, BMS-Pfizer and Servier and investigator-initiated grant support from BoehringerIngelheim and Bayer (study medication). Dr. Hill has served as a consultant for Boehringer-Ingelheim. He has received grants to the University of Calgary from Medtronic, Stryker, Boehringer-Ingelheim Canada, Bayer Canada. Dr. Gioia has received speaker honoraria from Bayer, and BMS Pfizer and has served as an advisory board consultant for Bayer, and Servier Inc. Dr. Coutts has served as an advisory board consultant for BMS-Pfizer. Boehringer-Ingelheim is providing study drug for an investigator-initiated study led by Dr. Coutts. Ethics Approval Statement: The trial was approved by research ethics review boards at each institution.