Ep 148 - CRASH-3

The CRASH-3 Trial: Revolutionizing Head Injury Management with Tranexamic Acid The CRASH-3 trial, a landmark study in the field of emergency medicine, has brought significant attention to the potential role of tranexamic acid (TXA) in managing traumatic brain injury (TBI). As one of the largest randomized controlled trials ever conducted on head injury patients, its findings could reshape clinical practices globally, particularly in the pre-hospital and emergency department settings. Overview of the CRASH-3 Trial The CRASH-3 trial was designed to assess the efficacy of TXA in reducing mortality among patients with traumatic brain injury. TXA is an antifibrinolytic agent commonly used to prevent excessive bleeding in various medical scenarios, such as trauma, surgery, and postpartum hemorrhage. The question posed by CRASH-3 was whether TXA could also reduce deaths in patients who had suffered a TBI, a question that had remained unanswered despite the success of the CRASH-2 trial in managing extracranial bleeding. Patient Population and Inclusion Criteria The trial focused on adults aged 16 years and older who had sustained a traumatic brain injury. To be included, patients needed to have either a Glasgow Coma Scale (GCS) score of 12 or lower or a positive CT scan indicating intracranial bleeding. Notably, patients with significant extracranial bleeding were excluded from the trial to specifically measure the effect of TXA on TBI outcomes. A critical aspect of the trial was the timing of TXA administration. Initially, the protocol allowed TXA to be administered within eight hours of injury. However, as data from other studies like the WOMAN trial and CRASH-2 became available, suggesting that the benefits of TXA diminish after three hours, the protocol was adjusted. This change meant that the majority of patients received TXA within three hours of injury, a key factor in the study's final analysis. Key Findings of the CRASH-3 Trial The CRASH-3 trial enrolled 12,737 patients across 29 countries, making it one of the most extensive studies of its kind. The primary outcome measured was all-cause mortality at 28 days post-injury. The results showed that overall mortality was slightly lower in the TXA group (18.5%) compared to the placebo group (19.8%), although this difference was not statistically significant. However, a pre-specified subgroup analysis provided more compelling evidence. When patients with a GCS of 3 and bilateral unreactive pupils (indicating very severe brain injury) were excluded, TXA demonstrated a more significant benefit. In this subgroup, the mortality rate was 12.5% in the TXA group versus 14% in the placebo group, a statistically significant reduction with a relative risk of 0.89. This finding suggests that TXA is particularly beneficial for patients with moderate head injuries (GCS 9-15) who are more likely to survive if bleeding is controlled. Number Needed to Treat (NNT) One of the critical metrics for evaluating the effectiveness of a treatment is the number needed to treat (NNT). In the CRASH-3 trial, the NNT was 67, meaning that 67 patients would need to be treated with TXA to save one additional life at 28 days post-injury. For comparison, the NNT for aspirin in acute myocardial infarction is about 42, which is widely regarded as highly effective. An NNT of 67 is therefore quite favorable in the context of emergency medicine, particularly for a condition as serious as traumatic brain injury. Timing of Administration The CRASH-3 trial strongly reinforced the importance of administering TXA as early as possible after a head injury. The data indicated a 10% reduction in TXA’s effectiveness for every 20-minute delay in patients with mild to moderate head injury. This underscores the need for TXA to be administered in the pre-hospital setting, ideally by paramedics at the scene or en route to the hospital. Delaying treatment until after arrival at the emergency department or after conducting a