TICH-2: Tranexamic Acid for ICH Yields Mixed Results

Damian McNamara

June 19, 2018

GOTHENBURG, Sweden — Tranexamic acid for intracranial hemorrhage failed to significantly improve functional status compared with placebo at 90 days in a randomized controlled study.

However, the antifibrinolytic agent was associated with a decrease in deaths in the first week and attenuation of hematoma expansion.

The primary outcome of the phase 3 Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2) study, reported at the 4th European Stroke Organisation Conference (ESOC) 2018 and published online in The Lancet, was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 2 or less at 90 days.

The trial failed to demonstrate superiority for active treatment: 29% of the 1152 patients treated with tranexamic acid and 29% of the 1155 who received placebo achieved this endpoint.  

"However, when we looked at secondary outcomes, there were significant changes, both in hematoma growth, with attenuation in the tranexamic acid group…and a reduction in death at day 2 and day 7 that was statistically significant and favored the tranexamic acid group," said Nikola Sprigg, DM, Stroke Trials Unit in the Division of Clinical Neuroscience at the University of Nottingham, United Kingdom.

Some distinctions did not persist, however. "At day 90, this effect disappeared and there was no significant difference between the groups in death, discharge, or functional status," Sprigg added.

Table. TICH-2: Functional Status at 90 Days

Modified Rankin Scale Score Tranexamic Acid Group (n = 1152) (%) Placebo Group (n = 1155) (%)
0 2 2
1 10 11
2 17 16
3 16 17
4 19 19
5 14 14
6 (death) 22 21

 "We showed no significant benefit on the primary outcome [adjusted odds ratio, 0.88] despite an early benefit related to hemostatic effect," Sprigg said. "It is possible that the anticipated treatment effect — an odds ratio of 0.79 — was too large, and the trial was unable to detect this magnitude of treatment effect."

Attenuation of Hematoma Expansion

"We all know that intracranial hemorrhage can be devastating, particularly when patients have hematoma expansion that occurs early," Sprigg said.

 

Hematoma expansion was experienced by a smaller proportion of patients treated with tranexamic acid, 25%, compared with 29% of placebo recipients. The investigators defined hematoma expansion as an increase in blood in the brain by 6 mL or by 33% or more.

"It's possible that even though we showed an effect on hematoma growth, this was too modest to translate to clinical outcome," she said. 

Sprigg and colleagues enrolled adults within 8 hours of spontaneous intracranial hemorrhage symptom onset. Patients randomly assigned to active treatment received a 1-g bolus of tranexamic acid injected intravenously over 10 minutes, followed by an intravenous bolus infusion of 1 g over 8 hours.

The cohorts did not differ significantly at baseline; both groups featured National Institutes of Health Stroke Severity scores of 13 and similar hematoma volumes. Patients presented with a Glasgow Coma Scale score of 13 to 14, signifying moderate to severe clinical severity, and a median hematoma volume of 14 mL. About one third had an intraventricular hemorrhage. The average age of participants was 69 years.  

The only significant prespecified outcome was blood pressure, Sprigg said. Participants who had a systolic blood pressure of 170 mm Hg or less at baseline were more likely to benefit from tranexamic acid treatment than other participants (P = .0188). In contrast, health-related quality of life, cognition, radiologic findings, length of hospital stay, and other factors did not differ between groups.

Time to treatment was a prespecified subanalysis. Again, researchers found no significant differences on this metric, although they reported a trend toward better outcomes among patients treated with tranexamic acid within 4.5 hours.

"Despite our efforts to include patients as soon as possible after diagnosis, the mean time to treatment was still above 3 hours for 70%," Sprigg said. This is important, she added, because a recent meta-analysis associated treatment with antifibrinolytics within 3 hours with greater benefit for patients with acute severe hemorrhage.

Further studies to explore patient subgroups that might benefit from tranexamic acid treatment are warranted, she added.

Strengths, Limits, and Safety

TICH-2 is the largest randomized controlled trial of a hemostatic agent in intracerebral hemorrhage, Sprigg said, a strength of the study. However, "we had broad inclusion criteria to try to reflect the broad population we treat, but that may be a weakness as we had a very heterogeneous population."

The serious adverse event rate did not increase in the tranexamic acid group compared with placebo. "In particular, there was no increase in venous thromboembolism, which is a concern for people when they are giving tranexamic acid," Sprigg said.

"We have shown the drug is safe, which is very reassuring given that most tranexamic acid studies were conducted in much younger populations."

"This was a neutral finding…and a perfectly reasonable thing to test," Kennedy Lees, MD, from the University of Glasgow, United Kingdom, said when asked by Medscape Medical News to comment on the study.

"Did we expect it to be positive? We had previously tested a more powerful agent, recombinant factor VIIa, that did show reduction in hemorrhage growth, and yet we failed to see that translate into benefit," he added.

"I'm disappointed by it because it's always nice to see positive trials," Lees added.

The National Institute for Health Research (NIHR) in the United Kingdom and the Swiss Heart Foundation sponsored the study. Sprigg received a grant from the NIHR Health Technology Assessment Programme Project. Lees has disclosed no relevant financial relationships.

4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018.

Lancet. 2018;391:2107-2115. Abstract

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