Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial - Polymeris, A. A.; Karwacki, G. M.; Siepen, B. M.; Schaedelin, S.; Tsakiris, D. A.; Stippich, C.; Guzman, R.; Nickel, C. H.; Sprigg, N.; Kagi, G.; Vehoff, J.; Barinka, F.; et al. (Stroke, 2023)
BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as >/=33% relative or >/=6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (P(interaction)=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.
Keywords: journalArticle; (Alexion) Advisory board (fees paid to the institution); (SAMS)/Bangerter-Rhyner-Foundation, Swiss Heart Foundation (SHF). Dr Siepen:; (SNSF), Prof Dr med Karl und Rena Theiler-Haag Stiftung. Dr Traenka: research; (Wissenschaftsfonds) University Hospital Basel, University of Basel,; (Wissenschaftspool) of the University Hospital Basel; (https://clinicaltrials.gov; *Antifibrinolytic Agents/adverse effects; *Hemostatics/therapeutic use; *Thromboembolism/drug therapy; *Tranexamic Acid/adverse effects; Administration, Oral; Aged, 80 and over; Anticoagulants/adverse effects; AstraZeneca; BMS/Pfizer; Bangerter-Rhyner Foundation, and University of Basel; Bangerter-Rhyner-Stiftung; Basel; Bayer; Bayer Foundation; Bayer, Novartis; Cerebral Hemorrhage/drug therapy/complications; Data Safety Monitoring Board for the IN EXTREMIS trial, TITAN trial; DeQuervain; Dr Fischer: financial support for the SWIFT DIRECT trial from Medtronic; Dr Gensicke: research support from SNSF; Felix Platter, Freiwillige Akademische Gesellschaft Basel, SHF, SNSF. Dr Seiffge:; Female; Fondazione Dr. Ettore Balli; Hematoma/drug therapy; Humans; Industry payments made to the research; Ingelheim, AstraZeneca, Novo Nordisk for other services. Dr Lyrer: research; Male; Medtronic, Stryker, CSL Behring (fees paid to the institution); NCT04304508); Nachwuchsforderung Klinische Forschung, University of Basel; Nordisk, Vifor Pharma for expert witness services; Novartis grant; Phenox, Inc, for end point review committee services; Portola; Portola/Alexion/AstraZeneca, Bayer, VarmX. Dr Peters: research support from SHF,; ProPatient Foundation; Rapid Medical, Penumbra; Research; SHF; SNSF; SNSF, Swiss Society of Neurology, Bangerter-Rhyner-Foundation, Daiichi Sankyo,; Sankyo; Science Funds; Spezialprogramm; Springer, Teva Pharma; Stago (compensation for educational efforts); Stago (compensation for educational efforts), Daiichi Sankyo, Science Funds; Stroke; Swiss Neurological Society; Swisslife Jubilaumsstiftung for Medical; Takeda. Dr Sprigg: grants from the National Institute of Health Research. Dr; Thermo Fisher GmbH