What is the role of tranexamic acid (TXA) in managing non-traumatic intracranial hemorrhage, as investigated by the ULTRA trial?

ULTRA Trial and Tranexamic Acid in Non-Traumatic Intracranial Hemorrhage

Direct Answer

The ULTRA trial demonstrated that ultra-early and short-term tranexamic acid (TXA) treatment does not improve clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH) and may actually worsen outcomes in patients with good-grade aSAH, providing strong evidence against its routine use in this population. 1

Key Findings from the ULTRA Trial

Primary Results in Subarachnoid Hemorrhage

• The ULTRA trial was a multicenter, prospective, randomized controlled trial that evaluated ultra-early (within 24 hours) and short-term TXA treatment in patients with aSAH 1

• In patients with good-grade aSAH (WFNS 1-3), TXA treatment resulted in significantly worse clinical outcomes compared to usual care (adjusted OR 0.68,95% CI 0.48-0.94) 1

• In patients with poor-grade aSAH (WFNS 4-5), TXA showed no clinical benefit, with comparable outcomes between treatment groups (adjusted OR 1.05,95% CI 0.70-1.56) 1

• The trial included 812 participants with confirmed aSAH: 473 patients (58%) had good-grade and 339 patients (42%) had poor-grade aSAH 1

Broader Context: TXA in Subarachnoid Hemorrhage

• While TXA reduces rebleeding risk in SAH (RR 0.6,95% CI 0.44-0.8), this benefit is offset by an increased risk of cerebral ischemia/stroke (RR 1.29,95% CI 1.01-1.67) 2

• The European Society of Intensive Care Medicine makes no recommendation for TXA use in critically ill patients with subarachnoid hemorrhage due to these mixed effects 2

• The ULTRA trial was the only recent study to report venous thrombosis rates, which were rare and similar between groups 2

TXA in Non-Traumatic Intracerebral Hemorrhage (ICH)

Evidence Summary

• Three RCTs have evaluated TXA in non-traumatic ICH, with the majority of data from the TICH-2 trial 2

• TXA shows no change in mortality (RR 1.02,95% CI 0.88-1.19) or poor functional outcomes (RR 0.98,95% CI 0.93-1.04) in non-traumatic ICH 2, 3

• Meta-analysis demonstrates that TXA reduces hematoma expansion (OR 0.79,95% CI 0.67-0.93) and hemorrhagic lesion growth (mean difference -1.97 ml, 95% CI -2.94 to -1.00), but this radiographic benefit does not translate to improved clinical outcomes 4

• The TRAIGE trial, which specifically enrolled patients susceptible to hematoma expansion (with spot sign, black hole sign, or blend sign), found no significant difference in hematoma growth between TXA and placebo groups (40.4% vs 41.5%, OR 0.96,95% CI 0.52-1.77) 5

Guideline Recommendations

• The European Society of Intensive Care Medicine makes no recommendation for or against TXA in critically ill patients with non-traumatic ICH, citing moderate evidence of no effect 2

• The American Heart Association/American Stroke Association guidelines do not support routine use of TXA for spontaneous ICH, as it reduces hematoma expansion but does not improve functional outcomes or mortality 3

Clinical Implementation Considerations

Timing Considerations

• If TXA is to be used, early administration within 3 hours of symptom onset (ideally within 1 hour) is essential 3, 6

• Administration after 3 hours may increase risk of death due to bleeding in trauma contexts 6

Patient Selection Pitfalls

• Patients with very large hemorrhages are unlikely to benefit, as reduction of further bleeding would have minimal impact on overall outcome 3

• In good-grade aSAH patients, TXA may cause harm rather than benefit, making patient selection particularly critical 1

Safety Profile

• TXA has not shown significant increases in thromboembolic events across studies of intracranial hemorrhage 3, 7

• The notable exception is the increased risk of cerebral ischemia in SAH patients, which represents a significant safety concern 2, 3

• Higher doses of TXA are associated with increased seizure risk 6

Dosing Regimen

• Standard dosing used in most ICH trials: 1g loading dose IV over 10 minutes, followed by 1g infusion over 8 hours 3, 6

Clinical Recommendation

Based on the ULTRA trial findings and current guideline evidence, TXA should not be routinely used in patients with aneurysmal subarachnoid hemorrhage, particularly those with good-grade presentations where harm has been demonstrated. 1 For non-traumatic ICH, while TXA appears safe, there is no evidence of clinical benefit despite modest reductions in hematoma expansion, and routine use cannot be recommended. 2, 3 Further high-quality trials are needed to identify specific subpopulations that might benefit from TXA therapy. 2