Vignan Yogendrakumar, MD, MSc

Ovesen C, Jakobsen JC, Gluud C, Steiner T, Law Z, Flaherty K, Dineen RA, Christensen LM, Overgaard K, Rasmussen RS, et al. Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign. Stroke. 2021;52:2629–2636.

While occurring less frequently than its ischemic counterpart, hemorrhagic stroke (intracerebral hemorrhage [ICH]) is a dynamic disease associated with higher degrees of morbidity and mortality. Approximately a third of acute ICH patients will experience growth of their baseline hemorrhage. This phenomenon, termed hematoma expansion, is associated with worsened long-term clinical outcomes. Hemostatic therapies have been extensively trialed, in hopes of limiting hematoma expansion and improving functional outcomes.

In 2018, the TICH-2 trial evaluated tranexamic acid against placebo in patients with acute ICH presenting within 8 hours of symptom onset. The trial showed a modest reduction in hematoma expansion incidence but no clear effect on long-term functional outcome.

In a pre-planned analysis of the TICH-2 trial, Ovesen and colleagues assessed whether there is a treatment interaction in ICH patients based on their spot sign status. The spot sign is a contrast-based marker seen in a proportion of ICH patients and is generally associated with a higher risk of hematoma expansion. The authors hoped to assess whether patients who are spot sign positive benefit more with tranexamic acid treatment compared to patients who are spot sign negative. The authors used either CT angiography or contrast-enhanced CTs to assess spot sign status. No constraints on scanner setting or protocol were placed. A central laboratory, blinded to treatment outcomes, assessed spot sign status using a widely adopted methodology. Outcomes assessed by the authors included intraparenchymal hematoma expansion (>6 mL or 33%), intraventricular hemorrhage expansion (> 2mL), and 90-day clinical outcomes based on the modified Rankin Scale.

Of the 2325 patients in the TICH-2 trial population, 215 patients underwent contrast imaging and were available for primary analysis. Significant reductions in intraparenchymal hematoma expansion and intraventricular hemorrhage expansion were not observed in either spot sign positive or negative patients (Figure 2). Clinical outcomes at 90 days did not differ between spot sign positive or negative patients, regardless of what treatment patients were randomized to.

Figure 2. Figure is showing the secondary hematoma progression outcome measure and its components.
Figure 2. Figure is showing the secondary hematoma progression outcome measure and its components.

The analysis of spot sign status and tranexamic acid in the TICH-2 trial population is limited by the relatively low patient numbers. The TICH-2 trial is also notable for significant delays in time to treatment (median 61-90 minutes from time of imaging to treatment reported by study authors), as delays during this period may allow a hemorrhage to grow and stabilize before therapy can be administered. Finally, the association of spot sign status and hematoma expansion is dependent on varying factors, including the timepoint when contrast is administered and imaging is acquired. The lack of constraints on scanner setting or protocol then may add an additional degree of heterogeneity to the data.

The findings of the TICH-2 analysis mirror other trials that used spot sign status as part of their enrollment criteria (STOP-AUST, TRIAGE). With these findings, there is a growing shift away from the use of spot sign and instead a focus on hyperacute enrollment and treatment (within 2 hours of symptom onset; STOP-MSU and FASTEST trials).