Page 42 - Haematologica May 2020

M. Franchini and P.M. Mannucci
Tranexamic acid for the prevention of bleeding
There is a growing body of evidence documenting the efficacy of TXA in preventing bleeding in a variety of major surgical procedures, especially cardiac surgery, in the frame of PBM programs.8,13 In a systematic review and meta-analysis, TXA was shown to reduce blood losses in surgical patients by nearly one-third compared to place- bo.15 These results were consistent with those of a Cochrane systematic review, including 129 trials with 10,488 participants, which showed that TXA reduced the probability of receiving a blood transfusion by one third [relative risk (RR) 0.62, 95% confidence interval (95% CI): 0.58-0.65; P<0.001).9 More recently, TXA has been widely used to minimize bleeding and exposure to allogeneic blood transfusion in major orthopedic surgery. Several large randomized controlled trials (RCT) and meta-analy- ses have consistently confirmed that the intravenous administration of this medication effectively and safely reduces perioperative blood loss and transfusion require- ments at the time of major orthopedic operations such as total hip and knee arthroplasty.10 Some concerns still remained among users over the hypothetical increased risk of thromboembolic complications following the sys- temic infusion of this anti-fibrinolytic agent, because orthopedic surgery is associated not only with a high risk of bleeding but also of thrombosis. Thus, to refute this unjustified, non-evidence-based perception which repre- sents the main obstacle to a broader use of TXA in this clinical context, we recently conducted a systematic review and meta-analysis of the literature aimed at assessing the safety of intravenous TXA in patients undergoing major orthopedic surgery.16 After a meta-ana- lytic pooling of 73 RCT involving 4,174 patients and 2,779 controls, there was a similar incidence of venous thromboembolism in patients and controls (2.1% vs. 2.0%), which established the safety of this pharmacolog- ical treatment in a PBM setting.16 In addition, a recent sys- tematic review and meta-analysis of five RCT involving 457 patients undergoing total hip arthroplasty concluded that the combined use of intravenous and topical TXA is more effective than intravenous TXA alone in terms of reduction of blood loss, hemoglobin decline and need for transfusion without increasing the rate of thromboembol- ic complications.17 The recently published Recommendations for the implementation of PBM pro- grams in orthopedic surgery, edited by the Italian National Blood Center in collaboration with several sci- entific societies, supported the preoperative and/or post- operative use of TXA in total hip and knee replacement surgery (grade 2A recommendation).18
Given the efficacy of TXA in various conditions at potential risk of severe bleeding, several groups also eval- uated its use in preventing obstetric hemorrhage.19,20 Post- partum hemorrhage (PPH) is a leading cause of premature maternal mortality globally, accounting for at least 100,000 deaths each year worldwide.21 A Cochrane sys- tematic review that evaluated TXA in the prevention of PPH was recently published. In the frame of an analysis of 12 RCT involving 3,285 women, TXA decreased post- partum blood loss, prevented PPH and lowered blood transfusion requirements.22 We have recently conducted a systematic review and meta-analysis on the use of TXA for PPH prevention in women undergoing Cesarean deliv- ery.23 After an in-depth analysis of 18 RCT involving
4,557 women, it was found that prophylactic use of TXA significantly reduced the incidence of PPH, total blood loss and transfusion requirements without increasing the risk of thromboembolic complications, thus supporting its beneficial effect in this critical clinical setting. Accordingly, the most recent multidisciplinary consensus statement on prevention and treatment of PPH from the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) rec- ommends intravenous of TXA for women at increased risk of PPH (grade 1C recommendation).19
On the whole, these multiple and consistent findings show that TXA is effective at preventing bleeding compli- cations in a variety of medical and surgical conditions without increasing the risk of thrombosis.
Tranexamic acid in acute bleeding conditions
In addition to the preventive use of TXA, a number of studies have investigated the role of this anti-fibrinolytic agent in patients presenting with acute, critical bleed- ing.5,6,24-26 In trauma patients, the largest body of evidence stems from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH) tri- als. In the CRASH-2 trial, 20,211 severely injured adults with confirmed or suspected hemorrhage were randomly assigned within 8 h from the occurrence of trauma to receive TXA (loading bolus dose of 1 g and then an infu- sion of 1 g over 8 h) or placebo.27 Despite no difference in bleeding rate and transfusion use, all-cause mortality was lower in the treatment group than in the placebo group (14.5% vs. 16%, respectively; RR 0.91; 95% CI: 0.85– 0.97, P=0.0035). Similarly, the rate of deaths attributed to bleeding was reduced from 5.7% to 4.9% (P=0.0077) (Table 1). Yet, from a sub-analysis of CRASH-2, the tim- ing of TXA administration was crucial for patients’ out- comes.28 Early infusion of TXA within 1 h after trauma was associated with the largest survival benefit (absolute reduction = 2.4%, number needed to treat = 41). TXA infused between 1 and 3 h also reduced the risk of death due to bleeding (absolute reduction = 1.3%, number needed to treat = 77), but a later administration (>3 h after trauma) was associated with an increased risk of death from bleeding compared with the risk among patients receiving placebo (RR 1.44, 95% CI: 1.12–1.84; P=0.004).28 There was no evidence that TXA increased the risk of vascular occlusive events and, in a pre-speci- fied analysis of the data collected when TXA was given within 3 h of injury, there was even a reduction in the odds of fatal and non-fatal vascular occlusive events (odds ratio = 0.69, 95% CI: 0.53-0.89; P=0.005).29 Following the publication of this study, the World Health Organization (WHO) included TXA in their list of essential medicines (available at: http://www.who.int/selection_medicines/commit- tees/expert/18/applications/tranexamic/en). Since this semi- nal study, a number of randomized clinical trials, system- atic reviews and meta-analyses on the efficacy of anti-fib- rinolytic agents have been published. The Cochrane sys- tematic review regarding anti-fibrinolytic drugs for acute traumatic injury found that, after the analysis of four tri- als involving 20,548 patients, TXA reduced the risk of death by 10% (RR 0.90, 95% CI: 0.85-0.96; P=0.002) without increasing the risk of adverse events.30
TXA has also been extensively studied in the setting of
1202
haematologica | 2020; 105(5)