STOP-AUST

Clinical Context

Hematoma expansion is a critical factor contributing to poor outcomes in acute intracerebral hemorrhage (ICH). The “spot sign,” identified on CT angiography (CTA) as foci of contrast extravasation within the hematoma, is a strong predictor of subsequent hematoma expansion and worse clinical prognosis. Patients positive for the spot sign represent a high-risk subgroup who might particularly benefit from hemostatic therapies aimed at preventing further bleeding.

Tranexamic acid (TXA), an antifibrinolytic agent, has been investigated for its potential to reduce hematoma expansion in ICH. While larger trials like TICH-2 (in a general ICH population treated within 8 hours) did not show a benefit in 90-day functional outcome despite some effect on hematoma growth and early mortality, it was hypothesized that targeting TXA to a high-risk, spot sign positive population within a very early time window might yield more substantial benefits.

The STOP-AUST (Spot Sign for Predicting and Treating ICH Growth–AUStralian Trial) was a phase 2 randomized controlled trial designed to assess whether TXA could reduce hematoma expansion in CTA spot sign positive patients with acute ICH when administered early.

Patient Population

STOP-AUST enrolled 100 adult patients (≥18 years) from multiple centers in Australia. Eligible patients had:

• Spontaneous intracerebral hemorrhage confirmed by non-contrast CT.
• At least one spot sign identified on a CTA performed within 4.5 hours of symptom onset.
• Ability to receive the study drug (TXA or placebo) within 1 hour of the qualifying CTA and within 4.5 hours of symptom onset.
• Pre-stroke modified Rankin Scale (mRS) score of 0 or 1 (no significant pre-existing disability).

Key exclusion criteria included infratentorial hemorrhage, purely intraventricular hemorrhage, known secondary causes of ICH, planned early surgical evacuation, or contraindications to TXA.

The median age of participants was approximately 68-70 years. Baseline characteristics, including median GCS and hematoma volume, were generally balanced. The median time from symptom onset to CTA was around 1.5 hours, and to treatment was around 2.5 hours.

Study Design

STOP-AUST was a multicenter, prospective, randomized, double-blind, placebo-controlled, phase 2 trial.

Protocol Details

Eligible spot sign positive patients were randomized 1:1 to receive either:

• Intervention Group (Tranexamic Acid): An intravenous loading dose of tranexamic acid 1 g administered over 10 minutes, followed immediately by a second intravenous infusion of tranexamic acid 1 g administered over the next 8 hours.
• Control Group (Placebo): Matching placebo (0.9% sodium chloride) administered intravenously with the same appearance, volume, and infusion rates as the tranexamic acid.

All patients also received standard medical care for ICH according to local and international guidelines. A follow-up non-contrast CT scan was performed at 24 (±6) hours to assess hematoma expansion.

Outcome Assessment

The primary outcome was a radiological endpoint (hematoma expansion). Clinical outcomes were assessed at 90 days by personnel blinded to treatment allocation.

Power Analysis & Statistical Approach

The primary outcome was significant hematoma expansion at 24 hours. The trial was designed as a phase 2 study to detect a signal of efficacy on this surrogate endpoint, which could then inform the design of a larger phase 3 trial. The sample size was modest, typical for a phase 2 investigation.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: Double-blind, placebo-controlled design is strong; focus on a biomarker-selected population; phase 2 nature means it’s not powered for definitive clinical efficacy.)

Results

A total of 100 patients were randomized: 50 to tranexamic acid and 50 to placebo. Baseline characteristics were well-matched.

Primary Outcome: Significant Hematoma Expansion at 24 Hours

Significant hematoma expansion (defined as >6 mL absolute increase or >33% relative increase from baseline) occurred in:

• Tranexamic acid group: 44% (22 of 50 patients)
• Placebo group: 50% (25 of 50 patients)

The adjusted odds ratio (aOR) for hematoma expansion with tranexamic acid was 0.70 (95% CI, 0.28–1.75; p=0.45). This difference was not statistically significant.

Secondary Outcomes

• Absolute Hematoma Growth (mL) at 24 hours: Median 3.5 mL (IQR 0.5–14.0) in the TXA group vs. 4.9 mL (IQR 0.8–16.5) in the placebo group (p=0.58). No significant difference.
• Relative Hematoma Growth (%) at 24 hours: Median 28% (IQR 3–111) in the TXA group vs. 37% (IQR 5–106) in the placebo group (p=0.81). No significant difference.
• Mortality at 90 days:
  • Tranexamic acid group: 14%
  • Placebo group: 18%
    (Adjusted OR 0.71, 95% CI 0.22–2.31; p=0.57). No significant difference.
• Functional Outcome (mRS distribution) at 90 days: No significant difference between groups (adjusted common OR for improvement with TXA 1.22, 95% CI 0.57–2.62; p=0.61).
• Favorable Functional Outcome (mRS 0–2) at 90 days:
  • Tranexamic acid group: 42%
  • Placebo group: 34%
    (Adjusted OR 1.42, 95% CI 0.56–3.60; p=0.46). No significant difference.

Safety Outcomes

• Thromboembolic Events: Were infrequent and occurred in similar proportions in both groups (TXA: 2%; Placebo: 4%).
• Seizures: Occurred in 6% of TXA patients and 2% of placebo patients.
• Overall rates of serious adverse events were comparable.

Final Thoughts & Critical Appraisal

The STOP-AUST trial was a well-designed phase 2 study that specifically targeted a high-risk ICH population (spot sign positive) with early tranexamic acid administration. Despite the strong rationale for using TXA in this group, the trial did not demonstrate a statistically significant reduction in the primary outcome of hematoma expansion at 24 hours, nor did it show significant benefits in 90-day clinical outcomes.

Key takeaways:

• No Significant Reduction in Hematoma Expansion in Spot Sign Positive Patients: In this specific population, TXA did not significantly reduce the rate of hematoma expansion compared to placebo. While there were numerical trends favoring TXA for some measures of growth, these did not reach statistical significance.
• Underpowered for Clinical Outcomes: As a phase 2 trial with 100 patients, STOP-AUST was not powered to definitively assess the impact of TXA on clinical outcomes like mRS or mortality. The observed numerical differences in these outcomes should be interpreted with caution.
• Safety Profile: TXA appeared to be relatively safe, with no significant increase in thromboembolic events, although seizures were numerically slightly higher in the TXA group, a known potential concern with TXA.
• Implications for Targeting Therapy: The results suggest that even in a biomarker-selected high-risk population (spot sign positive), the effect of TXA on hematoma expansion might be modest or difficult to demonstrate without a very large sample size. It raises questions about whether the spot sign alone is sufficient to identify TXA responders or if other factors are at play.
• Context with Larger TXA Trials: The findings of STOP-AUST, while focused on a specific subgroup, align with the overall neutral results of larger phase 3 trials like TICH-2 and INTREPID regarding the lack of clear functional benefit with TXA in broader ICH populations.

STOP-AUST contributed valuable data by investigating TXA in a targeted, high-risk ICH cohort. While it didn’t provide a definitive positive signal for this strategy, it underscores the ongoing challenges in finding effective hemostatic therapies that translate into improved clinical outcomes for ICH patients.

How do we reconcile the results with other studies?

(Content for this section needs to be added, comparing STOP-AUST with TICH-2, INTREPID, and other studies on spot sign or hemostatic therapies. Discuss the challenges of phase 2 trials in ICH and the potential reasons why targeting the spot sign with TXA might not have yielded a stronger signal.)

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