Carta Acesso aberto Revisado por pares

Tranexamic acid: the king is dead, long live the king!

2020; Elsevier BV; Volume: 124; Issue: 6 Linguagem: Inglês

10.1016/j.bja.2020.02.015

ISSN

1471-6771

Autores

H. Lier, Aryeh Shander,

Tópico(s)

Trauma and Emergency Care Studies

Resumo

Although the reports on the use of tranexamic acid (TXA) date back to the early 1960s, TXA experienced a renaissance after publication of the report of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 trial in 2010.1Shakur H. Roberts I. et al.Crash-trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.Lancet. 2010; 376: 23-32Abstract Full Text Full Text PDF PubMed Scopus (2112) Google Scholar Subsequently in 2011, TXA was accepted by the WHO to the list of Essential Medicines.2World Health OrganisationSummary of the Report of the 18th Meeting of the WHO Expert Committee on the Selection and Use of Essential Medicines.2011http://www.who.int/selection_medicines/committees/expert/18/en/Date accessed: February 9, 2018Google Scholar A prospective cohort study on TXA use in severely injured civilian patients showed a positive effect only in patients who presented with shock (base deficit ≥6 mE L−1).3Cole E. Davenport R. Willett K. Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study.Ann Surg. 2015; 261: 390-394Crossref PubMed Scopus (99) Google Scholar Although the authors supported use of TXA as part of major haemorrhage protocols for severely injured shocked patients, they concluded that ‘it is difficult to recommend its [TXA] use in non-shocked patients within mature civilian trauma systems’. Consequently, TXA is now recommended for patients in, or at least at risk of, haemorrhagic shock. The current Summary of Product Characteristics (SmPC) limits TXA use specifically for fibrinolysis.4Electronic Medicines Compendium (eMC)Cyklokapron Injection — Summary of Product Characteristics (SmPC).2019https://www.medicines.org.uk/emc/product/1077/smpc/Date accessed: May 29, 2019Google Scholar The efficacy of TXA for treating (hyper-)fibrinolysis (characterised by inhibition of further D-dimer and plasmin–antiplasmin complex production) has been confirmed for postpartum haemorrhage (PPH)5Ducloy-Bouthors A.S. Duhamel A. Kipnis E. et al.Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial.Br J Anaesth. 2016; 116: 641-648Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and trauma.6Stein P. Studt J.D. Albrecht R. et al.The impact of prehospital tranexamic acid on blood coagulation in trauma patients.Anesth Analg. 2018; 126: 522-529Crossref PubMed Scopus (29) Google Scholar Current guidelines recommend TXA for ‘excessive bleeding’7American Society of Anesthesiologists Task Force on Perioperative Blood ManagementPractice guidelines for perioperative blood management: an updated report by the American society of anesthesiologists task force on perioperative blood management.Anesthesiology. 2015; 122: 241-275Crossref PubMed Scopus (471) Google Scholar or a ‘patient who is bleeding or at risk of significant haemorrhage’8Spahn D.R. Bouillon B. Cerny V. et al.The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.Crit Care. 2019; 23: 98Crossref PubMed Scopus (582) Google Scholar that is ‘due to (or at least suspected) hyperfibrinolysis’.9Kozek-Langenecker S.A. Ahmed A.B. Afshari A. et al.Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016.Eur J Anaesthesiol. 2017; 34: 332-395Crossref PubMed Scopus (337) Google Scholar In this setting, TXA might help in saving a life as one component of a comprehensive haemorrhage management concept. In this issue of the British Journal of Anaesthesia, Ageron and colleagues10Ageron F.-X. Gayet-Ageron A. Ker K. Coats T. Shakur-Still H. Roberts I. The effect of tranexamic acid on death due to bleeding by baseline risk: a meta-analysis of individual patient-level data from 28,333 patients.Br J Anaesth. 2020; 124: 676-683Abstract Full Text Full Text PDF Scopus (15) Google Scholar report a meta-analysis of individual patient-level data from randomised trials that assessed anti-fibrinolytic drugs (aprotinin, TXA, epsilon aminocaproic acid [EACA], and aminomethylbenzoic acid) in acute severe bleeding. The authors examined how the effectiveness and safety of these drugs varied by the baseline risk of death caused by bleeding. They selected two randomised trials of TXA, CRASH-21Shakur H. Roberts I. et al.Crash-trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.Lancet. 2010; 376: 23-32Abstract Full Text Full Text PDF PubMed Scopus (2112) Google Scholar and WOMAN,11WOMAN Trial CollaboratorsEffect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.Lancet. 2017; 389: 2105-2116Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar which included 28 333 patients receiving treatment within 3 h. The primary outcome was death caused by bleeding, and the secondary outcomes were fatal and non-fatal vascular occlusive events. Using mathematical modelling, the authors stratified patients into four baseline categories of risk of death caused by bleeding: 0–5% (low); 6–10% (intermediate); 11–20% (high), and >20% (very high). Most patients (81%) had a baseline risk under 5%. Although deaths caused by bleeding occurred in all baseline risk categories with almost the same absolute number, the mortality rate varied from 1% in the low risk group to 30% in the very high risk group. The mortality reduction attributed to TXA did not vary by baseline risk. There was no increase in fatal or non-fatal occlusive events with TXA in any of the baseline risk categories. According to the authors, this study shows ‘that TXA treatment should be considered as an early preventive measure rather than a treatment for severe coagulopathic bleeding’, and that TXA should be given to ‘all major trauma patients whatever their apparent risk’.10Ageron F.-X. Gayet-Ageron A. Ker K. Coats T. Shakur-Still H. Roberts I. The effect of tranexamic acid on death due to bleeding by baseline risk: a meta-analysis of individual patient-level data from 28,333 patients.Br J Anaesth. 2020; 124: 676-683Abstract Full Text Full Text PDF Scopus (15) Google Scholar Of note, the authors screened 13 696 publications of different antifibrinolytics for this meta-analysis, but only two trials of TXA could be included in the analysis. Moreover, these two trials were published by the authors themselves. Unfortunately, no current or previous guidelines recommend preventive/prophylactic use of TXA. In the WOMAN trial, the authors clearly state ‘ … when used as a treatment for postpartum haemorrhage, TXA should be given as soon as possible after bleeding onset’. The updated WHO recommendations12Vogel J.P. Oladapo O.T. Dowswell T. Gulmezoglu A.M. Updated WHO recommendation on intravenous tranexamic acid for the treatment of post-partum haemorrhage.Lancet Glob Health. 2018; 6: e18-e19Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar state ‘ … in addition to standard care for women with clinically diagnosed postpartum haemorrhage after vaginal birth or Caesarean section’. The 2019 consensus statement of the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA),13Munoz M. Stensballe J. Ducloy-Bouthors A.S. et al.Patient blood management in obstetrics: prevention and treatment of postpartum haemorrhage. A NATA consensus statement.Blood Transfus. 2019; 17: 112-136PubMed Google Scholar endorsed by the International Federation of Gynaecology and Obstetrics (FIGO), the European Board and College of Obstetrics and Gynaecology (EBCOG) and the European Society of Anaesthesiology (ESA), emphasises that TXA should ‘not be used routinely for PPH prevention’. The current 5th European Trauma Guideline8Spahn D.R. Bouillon B. Cerny V. et al.The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.Crit Care. 2019; 23: 98Crossref PubMed Scopus (582) Google Scholar indicates TXA for patients with ‘significant haemorrhage’. For risk ratios (RR), the ‘no effect’ occurs when the 95% confidence interval (CI) of RR includes 1.0. As this range approaches 1 but still does not include it, there is often reduced clinical relevance despite statistically significant differences denoted by a low P-value.14Dobson G.P. Doma K. Letson H.L. Clinical relevance of a p value: does tranexamic acid save lives after trauma or postpartum hemorrhage?.J Trauma Acute Care Surg. 2018; 84: 532-536Crossref PubMed Scopus (17) Google Scholar The upper CI limit of most results of CRASH-2 and WOMAN trials are very close to or include the null value of 1.15Lier H. Maegele M. Shander A. Tranexamic acid for acute hemorrhage: a narrative review of landmark studies and a critical reappraisal of its use over the last decade.Anesth Analg. 2019; 129: 1574-1584Crossref PubMed Scopus (38) Google Scholar Statistically speaking, the reported differences might be marginal at best.14Dobson G.P. Doma K. Letson H.L. Clinical relevance of a p value: does tranexamic acid save lives after trauma or postpartum hemorrhage?.J Trauma Acute Care Surg. 2018; 84: 532-536Crossref PubMed Scopus (17) Google Scholar,16Letson H.L. Dobson G.P. Dennis A.T. et al.WOMAN trial: letters to the editor.Lancet. 2017; 390: 1581-1584Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar As the upper limits of CIs of RRs in many analyses in every large international multicentre randomised placebo-controlled trial on the topic of TXA (CRASH-2,1Shakur H. Roberts I. et al.Crash-trial collaboratorsEffects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.Lancet. 2010; 376: 23-32Abstract Full Text Full Text PDF PubMed Scopus (2112) Google Scholar CRASH-2 follow-up on time dependency,17Crash-collaborators Roberts I. Shakur H. et al.The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.Lancet. 2011; 377 (101 e1–2): 1096-1101Abstract Full Text Full Text PDF PubMed Scopus (797) Google Scholar WOMAN,11WOMAN Trial CollaboratorsEffect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.Lancet. 2017; 389: 2105-2116Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar and CRASH-318Crash-trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.Lancet. 2019; 394: 1713-1723Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar) indicated a possible ‘no effect’, the continuing positive, sometimes even euphemistic conclusions towards TXA are bewildering. If one adheres to the principles of ‘evidence-based’ medicine, one should consider the results of these statistics and discuss them critically. The CRASH-2 results noted an absolute 0.8% reduction of risk of bleeding-related deaths by TXA. This corresponds to a number-needed-to-treat (NTT) of 119. In the WOMAN trial, TXA yielded an absolute risk reduction of 0.4% (NTT=250) for death caused by bleeding, and 0.5% (NTT=200) mortality risk reduction if TXA was given within 3 h. Following the authors' conclusion in their analysis reported in the British Journal of Anaesthesia,10Ageron F.-X. Gayet-Ageron A. Ker K. Coats T. Shakur-Still H. Roberts I. The effect of tranexamic acid on death due to bleeding by baseline risk: a meta-analysis of individual patient-level data from 28,333 patients.Br J Anaesth. 2020; 124: 676-683Abstract Full Text Full Text PDF Scopus (15) Google Scholar 99% of patients in the low-risk category (with 1% death caused by bleeding) will receive TXA although they do not meet the criteria. Added to that, 92% of patients in the intermediate risk category will not need it. In the high-risk category, 86% of patients will receive TXA without any identified necessity. The data show that even within the very high risk category, 70% will receive a pharmaceutical agent outside the current indications. The authors concluded ‘many deaths are in patients at low and intermediate risk’. One might discuss the meaning of the word ‘many’. We strongly agree that every death is one too many. But 1% death caused by bleeding in the low category and 8% in the intermediate category hardly qualifies as ‘many’. In the presence of benefit for some and assuming no risk to all others, one might consider using a pharmaceutical agent as liberally as possible, but we question this approach with TXA. Seizures after TXA are predominantly seen in cardiac surgery; yet, this complication has been reported in almost every surgical setting.19Yates J. Perelman I. Khair S. et al.Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis.Transfusion. 2019; 59: 806-824Crossref PubMed Scopus (25) Google Scholar Possible thromboembolic side-effects are listed in the SmPC: ‘In patients with a history of thromboembolic diseases or in those with increased incidence of thromboembolic events in their family history (patients with a high risk of thrombophilia), TXA should only be administered if there is a strong medical indication after consulting a physician experienced in haemostaseology and under strict medical supervision’.4Electronic Medicines Compendium (eMC)Cyklokapron Injection — Summary of Product Characteristics (SmPC).2019https://www.medicines.org.uk/emc/product/1077/smpc/Date accessed: May 29, 2019Google Scholar Thromboembolic complications were noted in the early trials. For example, the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study20Morrison J.J. Dubose J.J. Rasmussen T.E. Midwinter M.J. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study.Arch Surg. 2012; 147: 113-119Crossref PubMed Scopus (512) Google Scholar reported a nine-fold (0.3% vs 2.7%) increased rate of pulmonary embolism (PE) and 12-fold (0.2% vs 2.4%) increased rate of deep vein thrombosis (DVT). Of the 20 211 patients in the CRASH-2 study, a total of 369 vascular (venous or arterial) occlusive events were reported: 168 in the TXA group vs 201 in the placebo group. In the WOMAN trial, a DVT rate of 0.03% in TXA arm vs 0.07% in the placebo arm and a PE rate of 0.2% in both arms were reported. A PE rate as much as almost 1 order of magnitude higher than the DVT rate in the same population was quite unexpected and surprising. These facts raise concerns regarding the accuracy of detecting, diagnosing and reporting these important and relevant complications. Indeed in the view of many authors,15Lier H. Maegele M. Shander A. Tranexamic acid for acute hemorrhage: a narrative review of landmark studies and a critical reappraisal of its use over the last decade.Anesth Analg. 2019; 129: 1574-1584Crossref PubMed Scopus (38) Google Scholar,21Gruen R.L. Jacobs I.G. Reade M.C. study P.A.-T. Trauma and tranexamic acid.Med J Aust. 2013; 199: 310-311Crossref PubMed Scopus (37) Google Scholar,22Benipal S. Santamarina J.L. Vo L. Nishijima D.K. Mortality and thrombosis in injured adults receiving tranexamic acid in the pst-CRASH-2 era.West J Emerg Med. 2019; 20: 443-453Crossref PubMed Scopus (10) Google Scholar as neither the CRASH-2 nor the WOMAN trial has sufficiently assessed thromboembolism in their respective cohorts, these studies may not be the best source to provide sufficient evidence against a possible effect of TXA on increased vascular occlusive events. In a recent systematic review and meta-analysis (nine studies, n=1656 patients), the pooled incidence of in-hospital thrombotic events after TXA was 5.9% (95% CI, 3.3–8.5%), vs 2.0% (95% CI, 1.8–2.3%) in the CRASH-2 trial.22Benipal S. Santamarina J.L. Vo L. Nishijima D.K. Mortality and thrombosis in injured adults receiving tranexamic acid in the pst-CRASH-2 era.West J Emerg Med. 2019; 20: 443-453Crossref PubMed Scopus (10) Google Scholar An increasing number of these side-effects are published in the trauma setting.15Lier H. Maegele M. Shander A. Tranexamic acid for acute hemorrhage: a narrative review of landmark studies and a critical reappraisal of its use over the last decade.Anesth Analg. 2019; 129: 1574-1584Crossref PubMed Scopus (38) Google Scholar An increased risk for fibrinolytic shutdown among severely injured trauma patients receiving TXA has been described.23Meizoso J.P. Dudaryk R. Mulder M.B. et al.Increased risk of fibrinolysis shutdown among severely injured trauma patients receiving tranexamic acid.J Trauma Acute Care Surg. 2018; 84: 426-432Crossref PubMed Scopus (48) Google Scholar A systematic review and meta-analysis of observational studies on the use of TXA in trauma24Nishida T. Kinoshita T. Yamakawa K. Tranexamic acid and trauma-induced coagulopathy.J Intensive Care. 2017; 5: 5Crossref PubMed Scopus (37) Google Scholar reported a pooled RR for venous thromboembolism of 1.61 (95% CI, 0.86–3.01). In the military setting, TXA administration is an independent risk factor for VTE development.25Walker P.F. Schobel S. Caruso J.D. et al.Trauma Embolic Scoring System in military trauma: a sensitive predictor of venous thromboembolism.Trauma Surg Acute Care Open. 2019; 4e000367Crossref PubMed Scopus (7) Google Scholar A systematic review and meta-analysis of 268 RCTs with 38 978 patients showed that 72% of the studies exclude patients because of major comorbidity and 59% because of a history of thromboembolic events.19Yates J. Perelman I. Khair S. et al.Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis.Transfusion. 2019; 59: 806-824Crossref PubMed Scopus (25) Google Scholar It is not unreasonable to say that the statement that TXA does not cause thromboembolic effects is based on ‘moderate-quality evidence’.19Yates J. Perelman I. Khair S. et al.Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis.Transfusion. 2019; 59: 806-824Crossref PubMed Scopus (25) Google Scholar As the authors of the current meta-analysis state themselves,10Ageron F.-X. Gayet-Ageron A. Ker K. Coats T. Shakur-Still H. Roberts I. The effect of tranexamic acid on death due to bleeding by baseline risk: a meta-analysis of individual patient-level data from 28,333 patients.Br J Anaesth. 2020; 124: 676-683Abstract Full Text Full Text PDF Scopus (15) Google Scholar their ‘estimates of the effects on adverse events are much less precise’ and TXA ‘appears’ to be safe. The results of the CRASH-2 and WOMAN trials were not reproducible in a modern, developed hospital setting in countries with high socioeconomic status.22Benipal S. Santamarina J.L. Vo L. Nishijima D.K. Mortality and thrombosis in injured adults receiving tranexamic acid in the pst-CRASH-2 era.West J Emerg Med. 2019; 20: 443-453Crossref PubMed Scopus (10) Google Scholar TXA is not a substitute for effective surgical management of any bleeding: it does not contract an atonic uterus, nor does it tie a heavily bleeding vessel or stabilise a fractured pelvis. TXA is an effective therapy for (at least suspected) fibrinolytic bleeding. Yet, despite half a century of clinical use, our current knowledge of this agent—including its pharmacokinetics (outside cardiac surgery), dosing, renal effects on dosing, side-effects, and other actions beyond coagulation—is still limited. After the withdrawal of aprotinin in 2008 (and despite its limited re-emergence in 2012 for use only in on-pump coronary artery bypass grafting), TXA is the only remaining antifibrinolytic agent with worldwide usage (as EACA is rarely used outside the USA and is thought to be less effective). The current discussion of the liberal use of TXA is reminiscent of the one we observed with liberal use of aprotinin. For more than a decade, aprotinin was recognised as ‘a wonder drug’, first in cardiac surgery, followed by liver transplantation and PPH, and then increasingly in almost every bleeding situation. The Blood Conservation using Antifibrinolytics in a Randomized Trial (BART) led to the removal of aprotinin for clinical use despite pre-existing early knowledge of adverse events that were clearly listed in its SmPC. The recently published CRASH-3 study18Crash-trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.Lancet. 2019; 394: 1713-1723Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar on TXA for traumatic brain injury is the first major randomised trial indicating higher RRs following application of TXA (if TXA <3 h): for thromboembolic complications (DVT: RR=1.22 [95% CI, 0.57–2.61]; all vascular occlusive events: RR=1.13 [95% CI, 0.80–1.59]), and for other complications (renal failure: RR=1.28 [95% CI 0.90–1.80]; stroke: RR=1.23 [95% CI, 0.71–2.13]; seizure: RR=1.21 [95% CI, 0.94–1.56]; and sepsis: RR=1.04 [95% CI, 0.89–1.22]). Turning a blind eye to any risks of an agent instead of objective risk–benefit assessment in individual scenarios might lead to its subsequent complete removal from clinical use once risks begin to gain widespread attention. Contrary to common belief, current data do not exonerate TXA from thromboembolic complications. When in doubt on where the line of benefit crosses into risk, remaining on ‘labeled indications’ provides appropriate safety for those at risk and benefit to those in need. Therefore, until proven differently, TXA should remain a pharmaceutical to treat fibrinolytic bleeding. Literature search: HL Acquisition, analysis, and interpretation of data: both authors Drafting of the manuscript: HL Contributed to editing of the manuscript: AS Revision of the manuscript: AS HL has received travel expenses and lecture fees from Bayer Vital, blood donation service west (DRK [German Red Cross]), CSL Behring, Ferring, IL Werfen, and NovoNordisk. AS has received consulting, research and lecture fees, and expenses from Masimo, CSL Behring, IL Werfen, Merck, Vifor Pharm, and HbO2 Therapeutics. Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patientsBritish Journal of AnaesthesiaVol. 124Issue 6PreviewEarly administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. Full-Text PDF Open Access

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