STOP-AUST 

Clinical Trial Details

The Spot Sign and Tranexamic Acid On Preventing ICH Growth - AUStralasia Trial: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial

The aim of the study is to test if intracerebral haemorrhage (ICH) patients who have contrast extravasation on computed tomography angiography, the "spot sign", have lower rates of haematoma growth when treated with tranexamic acid within 4.5 hours of stroke onset, compared to placebo.

Trial summarized by: Vasu Saini, MD
Content reviewed by: Joe Broderick, MD

Key Findings

As demonstrated by STOP-AUST trial, there is no significant difference in ICH growth in patients with a “spot sign” who received tranexamic acid vs. placebo within 4.5 hours of stroke onset (OR adj. 0.72, 95%CI 0.32-1.59, p 0.41).

At-a-Glance

Purpose: To study whether the antifibrinolytic agent, tranexamic acid, given within 4.5 hours of stroke symptoms onset to patients with intracerebral hemorrhage on CT (spot sign) would have less hematoma growth compared to placebo.

Trial Design: Phase 2,double blinded, placebo controlled, randomized trial of IV tranexamic acid (1g given over 10 minutes and 1 g over 8 hours) compared to placebo in patients with intracerebral hemorrhage (ICH) to evaluate ICH growth by 24 +/- 3 hours. N=100. Median time to treatment from onset 150.5 minutes.

Primary Endpoints: growth of ICH at 24 +/- 3 hours. (> 33%, or > 6 ml, increase from baseline)

Endpoints TXA placebo aOR?
P value		 Notes
ICH growth? 44%
22/50
patients?		 52%
26/50
patients?		 aOR
0.72?
P=0.41		  
Median absolute hematoma growth 1.9 ml? 3.4 ml? Adjusted mean difference
-1.8 ml?
P=0.28
Treated ≤3h of onset?     aOR
0.41
 P interaction = 0.06?
Treated 3-4.5 h of onset     aOR
2.45		  
Treated ≤ 2 hours of onset     aOR
0.19
P=0.07		  

Results: The reduction seen in intracerebral hemorrhage (ICH) was not statistically significant when tranexamic acid (TXA) was given to spot sign positive patients within 4.5 hours of ICH onset. A trend toward reduced ICH growth in those treated "ultra-early" (≤3h and ≤2h) will require more study.

Impression:

There is no statistically significant difference in ICH growth in patients with “spot sign” who received TXA vs. placebo within 4.5 hours of stroke onset but there is a trend towards reduced hematoma growth in patients receiving TXA vs. placebo in the ultra-early window ≤3hr and ≤2hr, which warrants further study and research.

STOP-AUST study results

Stroke Council Chair Peter Panagos, MD interviews the principal investigator of STOP-AUST about the trial results and what they suggest for future practice.

Detailed Results

Results:

  • N=100, 50 received TXA and 50 received placebo, baseline ICH volume 13.8mL (7.8-32.0) vs 15.6mL (7.9-33.4) respectively.
  • Median (IQR) time from onset to treatment was 150.5min (118-208). Overall there is no difference in ICH growth in TXA group vs. placebo within 4.5h from stroke onset (OR adj. 0.72, 95% CI 0.32-1.59, p=0.41).
  • There is a trend towards reduced hematoma growth in the prespecified subgroup treated ≤3h from onset (OR adj. 0.41 [95% CI 0.15-1.12], n=66), but not in those 3-4.5h from onset (aOR 2.45 [95% CI 0.52-11.57]), p-interaction = 0.06.

Primary endpoints:

  • ICH growth by 24±3 hours as defined by either 33% or 6 ml increase from baseline, adjusted for baseline ICH volume
    • TXA 22/50 (44%) vs. Placebo 26/60 (52%) (OR adj. 0.72, 95%CI 0.32-1.59, p 0.41)

Secondary endpoints:

  • Absolute ICH growth volume by 24±3 hours, adjusted for baseline ICH volume [median (IQR)]
    • TXA 1.9ml (0.2-9.5) vs. Placebo 3.4ml (0-16) [Median difference adj. -1.8, (-5.2 – 1.5), p 0.41]
  • Absolute intraventricular hematoma (IVH) growth volume by 24±3 hours, adjusted for baseline IVH volume [median (IQR)]
    • TXA 0ml (0-0) vs. Placebo 0ml (0-0.6) [Median difference adj. 0, (-0.04 – 0.04), p >.99]
  • Modified Rankin Scale (mRS) score of 0-4 or return to baseline at 3 months
    • TXA 34 (68%) vs. Placebo 40 (80%) (OR adj. 0.33, 95%CI 0.09 – 1.23, p 0.099)
  • Modified Rankin Scale (mRS) score of 0-3 or return to baseline at 3 months
    • TXA 28 (56%) vs. Placebo 23 (46%) (OR adj. 1.64, 95%CI 0.63 – 4.24, p 0.31)

Safety endpoints:

  • Major thromboembolic events (myocardial infarction, ischaemic stroke, pulmonary embolism)
    • TXA 1 (2%) vs. Placebo 2 (4%) (OR 0.49, 95%CI 0.04 – 5.58, p 0.57)
  • Death* due to any cause by 3 months
    • TXA 13 (26%) vs. Placebo 8 (16%) (OR adj. 2.38, 95%CI 0.66 – 8.67, p 0.19

    *adj. for age and baseline ICH volume

Recommended and supporting content:

Background

Intracerebral hemorrhage (ICH) affects approximately 2 million people in the world every year. Mortality after ICH is ~40% in the first 30 days. Early hematoma growth after ICH is a strong predictor of mortality and poor outcome. Tranexamic acid (TXA) is an inexpensive and widely available antifibrinolytic agent. In intracerebral hemorrhage (ICH) patients treated within 8 hours of stroke onset, intravenous TXA was associated with a modest reduction in hematoma growth and reduced early mortality (TICH2).

Trial design:

  • Phase II investigator-initiated randomized, double-blind, placebo-controlled trial of tranexamic acid in spot sign positive patients within 4½ hours of ICH

Trial population:

  • N=100, 18 years and older, both males and females. Enrolled across 13 centers in Australia, Finland and Taiwan.
  • Inclusion criteria:
    • Patients with acute ICH with “spot sign” on the CTA and presenting within 4.5 hours of symptom onset are included.
  • Exclusion criteria:
    • GCS < 8
    • Brainstem ICH
    • ICH volume >70cc as measured by ABC/2
    • Any venous or arterial thrombotic event within 12 months
    • Use of heparin, low-molecular weight heparin, GPIIb/IIIa antagonist, or oral anticoagulation within the previous 14 days, irrespective of laboratory values
    • Concurrent or planned treatment with haemostatic agents

Interventions:

  • Intravenous tranexamic acid 1000 mg in 100 mL 0.9% NaCl over 10 minutes followed by 1000 mg in 500 mL 0.9% NaCl infusion over 8 hours versus placebo.

Primary endpoints:

  • ICH growth by 24±3 hours as defined by either 33% or 6 ml increase from baseline, adjusted for baseline ICH volume.

Secondary endpoints:

  • Absolute ICH growth volume by 24±3 hours, adjusted for baseline ICH volume
  • Absolute intraventricular hematoma (IVH) growth volume by 24±3 hours, adjusted for baseline IVH volume
  • Modified Rankin Scale (mRS) score of 0-4 at 3 months
  • Modified Rankin Scale (mRS) score of 0-3 at 3 months
  • Categorical shift in mRS at 3 months, subject to the validity of proportional odds assumption

Safety endpoints:

  • Major thromboembolic events (myocardial infarction, ischaemic stroke, pulmonary embolism)
  • Death due to any cause by 3 months

Exploratory endpoints:

  • From the trial itself, ClinicalTrials.gov, or other sources, what information is given about any exploratory endpoints of the trial? Leave blank if not applicable or no information is given. (Optimal word count for this is xx to xx but there is no limit.) Adjusting outcome variables, ICH growth and mRS at 90 days, based on baseline variables such as age, Glasgow Coma Scale (GCS), presence of IVH, and ICH location, and in the following subgroups: onset-to-treatment time (<3 vs. >3 hours); baseline ICH volume (<30 vs. >30 ml); anatomical location (deep, lobar, or cerebellar); IVH (absent vs. present); GCS (>12 vs. 8-12) and age (<70 vs. >70). These analyses are hypothesis generating, as the trial is not powered for them.

Sponsors and collaborators:

  • Neuroscience Trials Australia

Related Science:

References:

  • Presented by: Nawaf Yassi, MBBS BSc (Med) PhD FRACP, International Stroke Conference 2020, Los Angeles, CA
  • ClinicalTrials.gov: NCT01702636

Key Words

Intracerebral Hemorrhage, ICH, Stroke, Cerebrovascular Disorders, Tranexamic Acid, Antifibrinolytic Agents, Fibrin Modulating agents, Hemostasis, Coagulants

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Related Clinical Topics

Intracerebral Hemorrhage, Reversal of anticoagulation in patients with Intracerebral hemorrhage, Antifibrinolytic agents