Page 43 - Haematologica May 2020

Tranexamic acid in acquired bleeding
Table 1. Main results of randomized clinical trials assessing the use of tranexamic acid for acute bleeding.
Trial
CRASH-227-29
CRASH-333
WOMAN38
Study design
Trauma patients with or at risk of hemorrhage randomized to receive TXA or placebo
Patients with traumatic brain injury (< 3 h) randomized to receive TXA or placebo
Women with post-partum hemorrhage randomized to receive TXA or placebo
Patients enrolled
20,211 patients (10,096 in TXA group and 10,115 in placebo group)
12,737 patients (6406 in TXA group and 6331 in placebo group)
20,060 women (10,051 in TXA group and 10,009 in placebo group)
Main results
Reduction of any cause of death in TXA group versus placebo group (RR=0.91, 95% CI: 0.85-0.97, P=0.0035); reduction of bleeding-related deaths in TXA group versus placebo group (RR=0.85, 95% CI: 0.76-0.96, P=0.0077); largest reduction when TXA was administered within 1 h after trauma
(RR=0.68, 95% CI: 0.57-0.82, P<0.0001)
Reduction of the risk of head injury-related death in patients with
mild-to-moderate head injury receiving TXA (RR 0.78, 95% CI 0.64-0.95); early TXA treatment was more effective than later TXA treatment in patients with mild and moderate head injury (P=0.005)
Reduction of deaths due to bleeding in women given TXA (RR=0.81, 95% CI: 0.65-1.00; P=0.045), especially in women given treatment within 3 h of giving birth (RR=0.69, 95% CI: 0.52-0.91; P=0.008)
TXA, tranexamic acid; RR, relative risk; CI, confidence interval.
traumatic brain injury, a leading cause of trauma deaths often associated with alterations of hemostasis with the features of hyperfibrinolysis.24,31 Meta-analysis of two randomized trials examining the effect of TXA on out- comes following traumatic brain injury showed a signifi- cant reduction in the progression of intracranial hemor- rhage.32 The results of the CRASH-3 trial were published recently.33 This trial included 12,737 patients who had iso- lated acute traumatic brain injury (which occurred within 3 h of random assignment to receive TXA (loading dose 1 g over 10 minutes ,then infusion of 1 g over 8 h) or place- bo. TXA failed to reduce the primary endpoint, i.e. the risk of head injury-related death. However, after the exclusion of patients too severe to be saved, namely those with a Glasgow Coma Scale score of 3 or unreactive bilat- eral pupils at baseline, TXA reduced the risk of head injury-related deaths compared to placebo (12.5% vs. 14.0%; RR 0.89, 95% CI: 0.80–1.00). In particular, TXA decreased the risk of injury-related deaths in patients with mild-to-moderate head injury (RR 0.78, 95% CI: 0.64–0.95) but not in those with severe head injury (Table 1). As in CRASH-2, early treatment was more effective than more delayed treatment in patients with mild and moderate head injury (P=0.005), with a 10% decrease in treatment effectiveness for every 20 min delay. The risk of vascular occlusive events was similar in the TXA and placebo groups.33 Notably, the CRASH-3 trial was the first RCT to show that a drug has neuroprotective properties for patients with traumatic brain injury and even reduced mortality. Finally, a very recently published meta-analysis of six RCT on the effect of TXA, compared with placebo, on traumatic brain injury showed that this medication was associated with a reduced mortality (RR 0.91, 95% CI: 0.85-0.97; P=0.0004).34
Very recent evidence also indicates that TXA usage results in a significant reduction of obstetric bleeding.35-37 In the landmark randomized, double blind World Maternal Antifibrinolytic (WOMAN) trial, more than 20,000 women with PPH following vaginal or Cesarean delivery were assigned to receive either TXA (1 g TXA intravenously as soon as possible, followed by a further 1 g if bleeding continued after 30 min or restarted within 24 h of the initial dose) or placebo.38 The trial showed a decreased overall mortality due to bleeding in the TXA group (RR 0.81, 95% CI: 0.65-1.00; P=0.045) (Table 1), and no differences in venous or arterial thromboembolic
events were observed between women in the two arms. Similarly to the CRASH trials, in the WOMAN trial patients receiving TXA within 3 h from delivery had the most marked mortality reduction (89 deaths in the TXA group vs. 127 deaths in the placebo group, RR 0.69, 95% CI: 0.52-0.91; P=0.008).38 Thanks to the results of this global trial, a 2017 World Health Organization recom- mendation for the treatment of PPH states that TXA should be recognized as a life-saving intervention and thus made readily available for the management of PPH in settings in which emergency obstetric care is provided, regardless of the level of healthcare system resources.39 In addition, the recent NATA consensus statement recom- mends the administration of TXA (1 g by intravenous route) as soon as possible within the first 3 h after PPH onset, with this dose repeated after 30 min if bleeding continues (grade 1B recommendation).19
All in all, these large trials document with unequivocal evidence the beneficial effect of early administration of TXA in an array of patients with acute critical bleeding, without increasing the risk of adverse events.40,41
Conclusions
Although TXA has been known for more than 50 years, its successful use never ceases to amaze us. The incredi- ble current interest in this old drug is demonstrated by the increasing number of PubMed citations (589 in 2019) and by the high number of trials listed at clinicaltrials.gov (432 at the time of writing). The current evidence in the litera- ture documents the efficacy and safety of TXA in pre- venting bleeding in a variety of at-risk conditions and thanks to this effect TXA is nowadays an essential drug in the therapeutic armamentarium of PBM-based proto- cols developed by the majority of hospitals worldwide with the aim of minimizing patients’ exposure to allo- geneic blood.42
The most recently published data show unequivocally that TXA also plays a prominent role in the management of critical bleeding. Indeed, considering the results of the CRASH-2, CRASH-3 and WOMAN trials (remarkably, CRASH-2 and CRASH-3 trials were truly independent research, not funded by pharmaceutical companies), more than 50,000 bleeding patients have been investigat- ed so far for the hemostatic effect of TXA. Although
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