JC: The TOP-ART study: Artesunate for bleeding trauma patients

Estimated reading time: 7 minutes

It’s tricky to see a direct relationship between malaria and trauma, but that is in fact what we have this week. Here at St Emlyn’s, we are always interested in potential therapies to improve the outcome of patients with significant bleeding from trauma​1​. Partly because it’s a group of patients where we have seen high quality science make a difference to outcomes in recent decades, but also because St Emlyn’s University Hospital is a major trauma centre that sees a fair number of these patients. We have previously reported how trends in trauma deaths have changed over the years​1​, with a ‘right-shift’ to mortality occurring later in the patient’s journey as prehospital, emergency department, early surgical and early critical care interventions have improved. Certainly, there are significant numbers of patients who initially recover from severe hemorrhagic shock from trauma, but who then go on to develop an inflammatory syndrome and multiple organ dysfunction syndrome​2​ (MODS).

This is where artesunate becomes of interest. Artesunate is a drug that is primarily used to treat malaria. In addition to antimalarial properties it has powerful anti-inflammatory effects and in animal models has shown promise as an adjuvant to standard therapies in severe haemorrhagic shock. However, as regular readers of St Emlyn’s will know we are always sceptical about transferring animal data in the lab to the weird, wild and highly variable experience of trauma in humans. I’d heard about this trial a few years back and have been anxiously awaiting the results as there appeared to be some confidence that it might be a game-changer.

Fortunately, we now have a clinical trial that can help us with the question of whether artesunate works in humans. The abstract is below, but as always please do read the full paper and make your own decisions. Thanks to @JoannaPoole for spotting this one.

Abstract –  Safety and efficacy of artesunate treatment in severely injured patients with traumatic hemorrhage. The TOP-ART randomized clinical trial​3​

Purpose: This study aimed at determining whether intravenous artesunate is safe and effective in reducing multiple organ dysfunction syndrome in trauma patients with major hemorrhage.

Methods: TOP-ART, a randomized, blinded, placebo-controlled, phase Ila trial, was conducted at a London major trauma center in adult trauma patients who activated the major hemorrhage protocol. Participants received artesu-nate or placebo (2:1 randomization ratio) as an intravenous bolus dose (2.4 mg/kg or 4.8 mg/kg) within 4 h of injury. The safety outcome was the 28-day serious adverse event (SAE) rate. The primary efficacy outcome was the 48 h sequential organ failure assessment (SOFA) score. The per-protocol recruitment target was 105 patients.

Results: The trial was terminated after enrolment of 90 patients because of safety concerns. Eighty-three participants received artesunate (n=54) or placebo (n=29) and formed the safety population and 75 met per-protocol criteria (48 artesunate, 27 placebo). Admission characteristics were similar between groups (overall 88% male, median age 29 years, median injury severity score 22), except participants who received artesunate were more shocked (median base deficit 9 vs. 4.7, p=0.042). SAES occurred in 17 artesunate participants (31%) vs. 5 who received placebo (17%). Venous thromboembolic events (VTE) occurred in 9 artesunate participants (17%) vs. 1 who received placebo (3%). Superiority of artesunate was not supported by the 48 h SOFA score (median 5.5 artesunate vs. 4 placebo, p=0.303) or any of the trial’s secondary endpoints.

Conclusion: Among critically ill trauma patients, artesunate is unlikely to improve organ dysfunction and might be associated with a higher VTE rate.

Shepherd, J.M., Ross, J., Anton, L. et al. Safety and efficacy of artesunate treatment in severely injured patients with traumatic hemorrhage. The TOP-ART randomized clinical trial. 

What kind of paper is this?

This is a randomised controlled trial (RCT), which is an ideal design to look at a therapeutic intervention in a defined patient group.

Tell me about the patients

In this study, patients with major bleeding from trauma, as defined by the need for a massive haemorrhage protocol (MHP) were eligible for the trial. The study was only in adults and at a single centre in London. There is some subjectivity on the need for an MHP protocol and practice varies around the world, but for this study the MHP was triggered if all of the following three factors were present.

  • SBP < 90mmHg
  • Suspected haemorrhage
  • Minimal response to small volume fluid resuscitation

Interestingly the patient numbers in this study were small. This is because this study appears to be primarily about efficacy and safety rather than clinical outcomes that we might recognise from other trauma studies. This trial does not look to have been designed as a definitive study.

What was the intervention?

Participants received artesunate or placebo (2:1 randomization ratio) as an intravenous bolus dose (2.4 mg/kg or 4.8 mg/kg or placebo) within 4 h of injury. This is a bit confusing as the study was done in a sequential manner. Early participants in the treatment arm received the 2.4mg/Kg dose, later participants received a 4.8mg/Kg dose based on new data. It does not look as this was planned to be the case on the original protocol, so the change is interesting.

What outcomes did they look for?

The principal outcome was the SOFA score at 48h post admission. A number of secondary endpoints were looked at, including the Serious Adverse Event (SAE) rate in the first 28 days. They also took serial blood samples to look at the pharmacokinetics of the drug in this population.

What did they find?

Interestingly the trial was stopped early. This was a result of the data monitoring committee raising concerns about the number of SAEs in the intervention groups. In total 90 patients had been recruited by this point.

Of those recruited, they fitted a typical profile for bleeding trauma patients in the UK. Predominantly male, young, and over half with penetrating injury. The mean ISS was 22 indicating a significant burden of injury.

The reason to stop the trial was the number of SAEs, 28 in the treatment group vs. 8 in the placebo group. In terms of patients that was 31% vs. 17% of patients experiencing an SAE. Of note it was the increased number of VTE events in the treatment group that raised concerns. There was no difference in mortality, in 48h SOFA score or any of the secondary outcome measures.

The data was further examined and there are some issues with the patient populations that might explain the discrepancies. Notably that more patients in the placebo group were treated with LMWH than in the treatment groups.

So should we abandon Artesunate as a potential treatment in bleeding major trauma?

This is a complex question to ask, and I don’t think this paper adequately answers this. The VTE increase is not seen in other indications (e.g. in malaria patients), and the fact that we are looking at small numbers, differential VTE prophylaxis and a non-systematic approach to looking for DVT makes me less confident that there is truly a safety issue here. The discussion and the associated editorial expand on these issues and leave the door open for further work looking at the inflammatory response to bleeding major trauma patients. The animal work that provided the background to this trial is reasonably convincing that by modifying the inflammatory response we may be able to translate that into a mortality benefit, but there is always that complexity of moving from lab to human populations. The principle of inflammatory modulation remains good, but the right drug, the right patients and the right timing is yet to be determined.

References

  1. 1.
    Simon C. JC: Why do bleeding trauma patients die? St Emlyn’. St Emlyn’s Blog. Published February 13, 2019. https://www.stemlynsblog.org/jc-why-do-bleeding-trauma-patients-die-st-emlyns/
  2. 2.
    Billiar TR, Hunt BJ, Bailly S. Targeting inflammation in traumatic injury: entering a new era. Intensive Care Med. Published online July 19, 2023:977-978. doi:10.1007/s00134-023-07152-2
  3. 3.
    Shepherd JM, Ross J, Anton L, et al. Safety and efficacy of artesunate treatment in severely injured patients with traumatic hemorrhage. The TOP-ART randomized clinical trial. Intensive Care Med. Published online July 20, 2023:922-933. doi:10.1007/s00134-023-07135-3

Cite this article as: Simon Carley, "JC: The TOP-ART study: Artesunate for bleeding trauma patients," in St.Emlyn's, July 27, 2023, https://www.stemlynsblog.org/jc-the-top-art-study-artesunate-for-bleeding-trauma-patients-st-emlyns/.

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