Tranexamic acid after aneurysmal subarachnoid hemorrhage is associated with worse outcome in males: post hoc analysis of the ULTRA trial

BACKGROUND: The ULTRA trial demonstrated no improvement in clinical outcome at 6 months in patients with subarachnoid hemorrhage (SAH) when treated with ultra-early and short-term tranexamic acid (TXA). In this post hoc analysis, we evaluated the effect of TXA in females and males on clinical outcome after aneurysmal SAH (aSAH).

METHODS: The ULTRA trial was a prospective, randomized, controlled, open-label trial, conducted between 2013 and 2020. Patients with spontaneous SAH were assigned to ultra-early, short-term TXA in addition to usual care, or usual care only. In this study, we only included ULTRA participants with radiologically proven aSAH. We analyzed the potential effect of sex on the association between treatment group and clinical outcome by assessing effect modification, and evaluated the effect of TXA separately in females and males. The primary endpoint was clinical outcome at 6 months, assessed by the distribution of the modified Rankin Scale (mRS). Odds ratios (OR) and adjusted OR (aOR) with 95% confidence intervals (CI) were calculated using ordinal regression analyses. Secondary outcomes included good (mRS score 0-3) and excellent (mRS score 0-2) clinical outcome at 6 months, all-cause mortality at 30 days, all-cause mortality at 6 months, and in-hospital complications.

RESULTS: Of the 812 patients, 577 (71%) were female, of whom 286 (50%) received TXA. Of the 235 males, 109 (46%) received TXA. Significant effect modification of sex on the relation between treatment group and clinical outcome was observed (p = 0.044) in all aSAH patients. No significant differences in outcomes were observed among females. In males, ordinal regression analysis showed a difference in mRS distribution at 6 months to the detriment of males treated with TXA (aOR 1.94; 95% CI 1.20-3.14). No significant differences were observed between male treatment groups in secondary outcome measures.

DISCUSSION: In this post hoc analysis of the ULTRA trial, we observed a potential association between ultra-early, short-term TXA treatment and worse clinical outcomes in males at 6 months. Conversely, we did not observe a significant association between TXA treatment and clinical outcome in females. Consequently, these findings reinforce that routine use of TXA cannot be recommended in either females or males.

TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT02684812).