Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage

Menno R Germans; Maud A Tjerkstra; René Post; Amy Brenner; Mervyn DI Vergouwen; Gabriël Je Rinkel; Yvo Bwem Roos; René van den Berg; Bert A Coert; W Peter Vandertop; Dagmar Verbaan; ULTRA Investigators

doi:10.1177/23969873241246591

Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage

Eur Stroke J. 2024 Apr 12:23969873241246591. doi: 10.1177/23969873241246591. Online ahead of print.

Authors

Menno R Germans¹, Maud A Tjerkstra^{2

3}, René Post^{2

3}, Amy Brenner⁴, Mervyn DI Vergouwen⁵, Gabriël Je Rinkel⁵, Yvo Bwem Roos^{3

6}, René van den Berg^{3

7}, Bert A Coert^{2

3}, W Peter Vandertop^{2

3}, Dagmar Verbaan^{2

3}; ULTRA Investigators

Affiliations

¹ Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland.
² Department of Neurosurgery, Amsterdam University Medical Centers Location University of Amsterdam, Amsterdam, The Netherlands.
³ Amsterdam Neuroscience, Neurovascular Disorders, Amsterdam, The Netherlands.
⁴ Clinical Trials Unit, Department of Population Health, London School of Hygiene and Tropical Medicine, London, UK.
⁵ Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁶ Department of Neurology, Amsterdam University Medical Centers location University of Amsterdam, Amsterdam, The Netherlands.
⁷ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers Location University of Amsterdam, Amsterdam, The Netherlands.

PMID: 38606724
DOI: 10.1177/23969873241246591

Abstract

Introduction: The ULTRA-trial investigated effectiveness of ultra-early administration of tranexamic acid (TXA) in subarachnoid hemorrhage (SAH) and showed that TXA reduces the risk of rebleeding without concurrent improvement in clinical outcome. Previous trials in bleeding conditions, distinct from SAH, have shown that time to start of antifibrinolytic treatment influences outcome. This post-hoc analysis of the ULTRA-trial investigates whether the interval between hemorrhage and start of TXA impacts the effect of TXA on rebleeding and functional outcome following aneurysmal SAH.

Patients and methods: A post-hoc comparative analysis was conducted between aneurysmal SAH patients of the ULTRA-trial, receiving TXA and usual care to those receiving usual care only. We assessed confounders, hazard ratio (HR) of rebleeding and odds ratio (OR) of good outcome (modified Rankin Scale 0-3) at 6 months, and investigated the impact of time between hemorrhage and start of TXA on the treatment effect, stratified into time categories (0-3, 3-6 and >6 h).

Results: Sixty-four of 394 patients (16.2%) in the TXA group experienced a rebleeding, compared to 83 of 413 patients (19.9%) with usual care only (HR 0.86, 95% confidence interval (CI): 0.62-1.19). Time to start of TXA modifies the effect of TXA on rebleeding rate (p < 0.001), with a clinically non-relevant reduction observed only when TXA was initiated after 6 h (absolute rate reduction 1.4%). Tranexamic acid treatment showed no effect on good outcome (OR 0.96, 95% CI: 0.72-1.27) with no evidence of effect modification on the time to start of TXA (p = 0.53).

Discussion and conclusions: This study suggests that the effect of TXA on rebleeding is modified by time to treatment, providing a protective, albeit clinically non-relevant, effect only when started after 6 h. No difference in functional outcome was seen. Routine TXA treatment in the aneurysmal SAH population, even within a specified time frame, is not recommended to improve functional outcome.

Keywords: Stroke; antifibrinolytic agent; randomized controlled trial; subarachnoid hemorrhage; time interval.