STOP-AUST
(2020)Objective
To assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute spot sign-positive ICH treated within 4.5 hours of symptom onset.
Study Summary
• Tranexamic acid did not significantly reduce ICH growth at 24 hours compared to placebo in spot sign-positive patients: 44% vs 52% (OR 0.72, 95% CI 0.32–1.59, p=0.41).
• No increase in thromboembolic complications with TXA (2% vs 4% placebo); mortality was numerically higher with TXA (26% vs 16%, p=0.19) though not statistically significant and none attributed to drug.
• The trial was underpowered and slow to recruit; larger trials with simpler protocols and earlier treatment windows are warranted.
• No increase in thromboembolic complications with TXA (2% vs 4% placebo); mortality was numerically higher with TXA (26% vs 16%, p=0.19) though not statistically significant and none attributed to drug.
• The trial was underpowered and slow to recruit; larger trials with simpler protocols and earlier treatment windows are warranted.
Intervention
IV tranexamic acid 1 g over 10 min followed by 1 g over 8 hours vs matching placebo (0.9% NaCl), initiated within 4.5 hours of symptom onset.
Inclusion Criteria
Adults ≥18 years, acute non-traumatic ICH with CT angiography spot sign, treatable within 4.5 hours of onset and within 1 hour of CTA, GCS >7, ICH volume <70 mL, no anticoagulant use.
Study Design
Arms: Tranexamic acid (1 g IV bolus + 1 g IV over 8 h) vs Placebo (matched 0.9% NaCl)
Patients per Arm: Tranexamic acid: n=50; Placebo: n=50
Outcome
• Primary (ICH growth >33% or >6 mL at 24h): 44% TXA vs 52% placebo (OR 0.72, 95% CI 0.32–1.59, p=0.41).
• Absolute ICH growth (median): 1.9 mL TXA vs 3.4 mL placebo (adjusted difference −1.8 mL, 95% CI −5.2 to 1.5, p=0.28).
• mRS 0–3 or back to prestroke at 90 days: 56% TXA vs 46% placebo (OR 1.64, 95% CI 0.63–4.24, p=0.31).
• Death by 90 days: 26% TXA vs 16% placebo (OR 2.38, 95% CI 0.66–8.67, p=0.19).
• Major thromboembolic events: 2% TXA vs 4% placebo (OR 0.49, 95% CI 0.04–5.58, p=0.57).
• Absolute ICH growth (median): 1.9 mL TXA vs 3.4 mL placebo (adjusted difference −1.8 mL, 95% CI −5.2 to 1.5, p=0.28).
• mRS 0–3 or back to prestroke at 90 days: 56% TXA vs 46% placebo (OR 1.64, 95% CI 0.63–4.24, p=0.31).
• Death by 90 days: 26% TXA vs 16% placebo (OR 2.38, 95% CI 0.66–8.67, p=0.19).
• Major thromboembolic events: 2% TXA vs 4% placebo (OR 0.49, 95% CI 0.04–5.58, p=0.57).
Bottom Line
Tranexamic acid did not significantly reduce ICH growth at 24 hours in spot sign-positive patients (44% vs 52%, OR 0.72, p=0.41). The treatment was safe with no increase in thromboembolic complications. Larger trials with simpler recruitment methods and an earlier treatment window are justified.
Major Points
- STOP-AUST (Spot sign and Tranexamic acid On Preventing ICH growth — AUSTralasia) was the first RCT of tranexamic acid in patients with confirmed ongoing ICH at time of recruitment, identified by the CT angiography spot sign as a biomarker of active haemorrhage.
- 100 patients were enrolled across 13 hospitals in Australia (10), Finland (1), and Taiwan (2) between March 2013 and August 2019 — a 6-year recruitment period reflecting the challenge of requiring CTA for spot sign confirmation before randomisation.
- Primary outcome (ICH growth >33% relative or >6 mL absolute by 24 h) was not significantly different: 22/50 (44%) in TXA vs 26/50 (52%) in placebo (OR 0.72, 95% CI 0.32–1.59, p=0.41). The trial observed an 8% absolute difference (vs the 30% difference it was powered to detect), consistent with the 4% difference seen in the non-selected TICH-2 trial.
- Absolute ICH growth (median) was 1.9 mL (IQR 0.2–9.5) with TXA vs 3.4 mL (IQR 0.0–16.0) with placebo; adjusted median difference −1.8 mL (95% CI −5.2 to 1.5, p=0.28). One TXA patient without a follow-up scan was assigned growth per the statistical analysis plan.
- Functional outcomes at 90 days were not significantly different. mRS 0–3 or return to prestroke: 56% TXA vs 46% placebo (OR 1.64, 95% CI 0.63–4.24, p=0.31). mRS 0–4: 68% TXA vs 80% placebo (OR 0.33, 95% CI 0.09–1.23, p=0.10). Generalised OR for full mRS distribution: 1.01 (95% CI 0.63–1.61, p=0.97).
- Mortality at 90 days was numerically higher in TXA: 13/50 (26%) vs 8/50 (16%) (OR 2.38, 95% CI 0.66–8.67, p=0.19). All deaths were due to stroke progression (one due to sepsis); none was considered drug-related by site investigators or independent assessor. Death at 7 days: 6/50 (12%) TXA vs 4/50 (8%) placebo (OR 1.43, p=0.66).
- Safety was reassuring: major thromboembolic events occurred in 1/50 (2%) TXA vs 2/50 (4%) placebo (OR 0.49, 95% CI 0.04–5.58, p=0.57). One pulmonary embolism in placebo, zero in TXA. One ischaemic stroke in each arm. No myocardial infarctions in either group.
- None of the predefined subgroup analyses showed a statistically significant interaction with treatment effect. A post-hoc interaction test for time to treatment as a continuous variable had p=0.059, and patients treated within 3 hours showed OR 0.44 (95% CI 0.16–1.19) vs those treated after 3 hours OR 2.07 (95% CI 0.43–10.05), consistent with a possible early time-window benefit.
- Recruitment was difficult: of 3325 ICH patients admitted to 7 reporting sites, only 88 (2.6%) were enrolled. Late presentation and absence of spot sign ruled out ~40% each. The complex CTA-based protocol limited generalisability, with two-thirds of patients coming from just two sites, and seven sites unable to recruit a single patient.
- Compared to TICH-2 (2325 patients, TXA up to 8 h, no spot sign selection), STOP-AUST used the same TXA dose within a tighter 4.5-h window with biomarker-selected patients. The similar point estimate (OR 0.72 vs TICH-2 OR 0.80) suggests spot sign selection may enrich the population but the narrow target may sacrifice statistical power and recruitment feasibility.
Study Design
- Study Type
- Prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, staff, and outcome assessors all masked)
- Sample Size
- 100
- Follow-up
- 90 days (±7 days) for adverse events; 24 h for primary imaging outcome
- Centers
- 13
- Countries
- Australia, Finland, Taiwan
Primary Outcome
Definition: ICH growth (>33% relative or >6 mL absolute) at 24 hours
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 26/50 (52%) | 22/50 (44%) | 0.72 (0.32-1.59) | 0.41 |
Limitations & Criticisms
- Severely underpowered: 100 patients over 6 years; powered for a 30% absolute risk reduction which was overoptimistic given the 8% difference observed.
- Median delay from CTA to treatment was 41 minutes, meaning much haematoma growth may have already occurred before drug administration (haematoma growth peaks early after onset).
- Complex CTA-based protocol severely limited recruitment: two-thirds of patients came from just 2 of 13 sites; 7 sites could not recruit a single patient. Results may not be generalisable.
- Numerically higher mortality in TXA arm (26% vs 16%) raised concern, though not statistically significant and no biological mechanism was identified; likely reflects chance imbalance in small trial.
- Control group haematoma growth rate (52%) was lower than the 61% expected based on the PREDICT study, reducing statistical power.
- Only 3-month follow-up; 6-month mRS would be preferred in ICH trials given slow recovery trajectories.
- Spot sign may not be the optimal biomarker for trial enrichment: many patients without spot sign also have haematoma growth, narrowing the target population excessively.
- Per-protocol population (39 placebo, 35 TXA) mirrored ITT results, confirming robustness but did not resolve underpowering.
- Phase 2 design precludes definitive efficacy conclusions; enrolled population too small for subgroup inferences.
Citation
Meretoja A, et al. Lancet Neurol. 2020;19(12):980–987.