Safety and efficacy of artesunate treatment in severely injured patients with traumatic hemorrhage. The TOP-ART randomized clinical trial.
Shepherd JM., Ross J., Anton L., Rourke C., Brentnall AR., Tarning J., White NJ., Thiemermann C., Brohi K.
PurposeThis study aimed at determining whether intravenous artesunate is safe and effective in reducing multiple organ dysfunction syndrome in trauma patients with major hemorrhage.MethodsTOP-ART, a randomized, blinded, placebo-controlled, phase IIa trial, was conducted at a London major trauma center in adult trauma patients who activated the major hemorrhage protocol. Participants received artesunate 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.ResultsThe 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.ConclusionAmong critically ill trauma patients, artesunate is unlikely to improve organ dysfunction and might be associated with a higher VTE rate.