Tranexamic acid versus placebo to reduce perioperative blood transfusion in patients undergoing liver resection: protocol for the haemorrhage during liver resection tranexamic acid (HeLiX) randomised controlled trial

Paul Jack Karanicolas, Yulia Lin, Stuart McCluskey, Rachel Roke, Jordan Tarshis, Kevin E Thorpe, Chad G Ball, Prosanto Chaudhury, Sean P Cleary, Elijah Dixon, Gareth Eeson, Carol-Anne Moulton, Sulaiman Nanji, Geoff Porter, Leyo Ruo, Anton I Skaro, Melanie Tsang, Alice C Wei, Gordon Guyatt, HepatoPancreaticoBiliary Community of Surgical ONcologists: Clinical, Evaluative, and Prospective Trials (HPB CONCEPT) Team, Oliver F Bathe, Natalie G Coburn, Boris Gala-Lopez, Steven Gallinger, Julie Hallet, Diederick Jalink, Shiva Jayaraman, Calvin Law, Peter Metrakos, Douglas Quan, Trevor W Reichman, Gonzalo Sapisochin, Pablo E Serrano, Francis R Sutherland, Paul Jack Karanicolas, Yulia Lin, Stuart McCluskey, Rachel Roke, Jordan Tarshis, Kevin E Thorpe, Chad G Ball, Prosanto Chaudhury, Sean P Cleary, Elijah Dixon, Gareth Eeson, Carol-Anne Moulton, Sulaiman Nanji, Geoff Porter, Leyo Ruo, Anton I Skaro, Melanie Tsang, Alice C Wei, Gordon Guyatt, HepatoPancreaticoBiliary Community of Surgical ONcologists: Clinical, Evaluative, and Prospective Trials (HPB CONCEPT) Team, Oliver F Bathe, Natalie G Coburn, Boris Gala-Lopez, Steven Gallinger, Julie Hallet, Diederick Jalink, Shiva Jayaraman, Calvin Law, Peter Metrakos, Douglas Quan, Trevor W Reichman, Gonzalo Sapisochin, Pablo E Serrano, Francis R Sutherland

Abstract

Introduction: Despite use of operative and non-operative interventions to reduce blood loss during liver resection, 20%-40% of patients receive a perioperative blood transfusion. Extensive intraoperative blood loss is a major risk factor for postoperative morbidity and mortality and receipt of blood transfusion is associated with serious risks including an association with long-term cancer recurrence and overall survival. In addition, blood products are scarce and associated with appreciable expense; decreasing blood transfusion requirements would therefore have health system benefits. Tranexamic acid (TXA), an antifibrinolytic, has been shown to reduce the probability of receiving a blood transfusion by one-third for patients undergoing cardiac or orthopaedic surgery. However, its applicability in liver resection has not been widely researched.

Methods and analysis: This protocol describes a prospective, blinded, randomised controlled trial being conducted at 10 sites in Canada and 1 in the USA. 1230 eligible and consenting participants will be randomised to one of two parallel groups: experimental (2 g of intravenous TXA) or placebo (saline) administered intraoperatively. The primary endpoint is receipt of blood transfusion within 7 days of surgery. Secondary outcomes include blood loss, postoperative complications, quality of life and 5-year disease-free and overall survival.

Ethics and dissemination: This trial has been approved by the research ethics boards at participating centres and Health Canada (parent control number 177992) and is currently enrolling participants. All participants will provide written informed consent. Results will be distributed widely through local and international meetings, presentation, publication and ClinicalTrials.gov.

Trial registration number: NCT02261415.

Keywords: blood bank & transfusion medicine; clinical trials; hepatobiliary surgery; hepatobiliary tumours.

Conflict of interest statement

Competing interests: PJK has received honorarium from Sanofi and research support from Baxter. YL has received research funding from Novartis and Canadian Blood Services and consulting fees from Pfizer. SPC has received consulting fees from Ethicon, Erbe and Olympus. They have a leadership role as Secretary for The Americas Hepato-Pancreato-Biliary Association and are the President-Elect for the Canadian Association of General Surgeons. PC has received honoraria from Ipsen, Astellas, AstraZeneca and Novartis. ACW has received consulting fees from Histosonics and honoraria from Medtronic, AstraZeneca and Celgene. They have received support for attending meeting and/or travel from Bayer and Intuitive Surgical and have participated on a data safety monitoring board or advisory board for Histosonics. Leadership roles include the following: Representative to the American College for The Americas Hepato-Pancreato-Biliary Association; Program Committee 2022 for the International Hepato-Pancreato-Biliary Association; Program Committee 2021 for the International Laparoscopic Liver Society; Board Member for the American College of General Surgeons Specialty Governor Foundation of Surgical Fellowships; and Board Member for the New York Chapter of the American College of Surgeons. No other authors have declared competing interests.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
HeLiX study schema and outline. HeLiX, haemorrhage during liver resection tranexamic acid; QoL, quality of life; TXA, tranexamic acid.

References

    1. Beard SM, Holmes M, Price C, et al. . Hepatic resection for colorectal liver metastases: a cost-effectiveness analysis. Ann Surg 2000;232:763–76. 10.1097/00000658-200012000-00005
    1. Lin TY, Lee CS, Chen KM, et al. . Role of surgery in the treatment of primary carcinoma of the liver: a 31-year experience. Br J Surg 1987;74:839–42. 10.1002/bjs.1800740931
    1. Man K, Fan ST, Ng IO, et al. . Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 1997;226:704–13. 10.1097/00000658-199712000-00007
    1. Poon RT, Fan ST, Lo CM, et al. . Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database. Ann Surg 2004;240:698–710. 10.1097/01.sla.0000141195.66155.0c
    1. Ramos E, Dalmau A, Sabate A, et al. . Intraoperative red blood cell transfusion in liver transplantation: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 2003;9:1320–7. 10.1016/jlts.2003.50204
    1. McColl RJ, Brar B, Ghali WA, et al. . Hepatic resection in Canada: rates and geographic variation. Can J Surg 2009;52:E264–8.
    1. Alkozai EM, Lisman T, Porte RJ. Bleeding in liver surgery: prevention and treatment. Clin Liver Dis 2009;13:145–54. 10.1016/j.cld.2008.09.012
    1. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999;29:1617–23. 10.1002/hep.510290639
    1. Groenland THN, Porte RJ. Antifibrinolytics in liver transplantation. Int Anesthesiol Clin 2006;44:83–97. 10.1097/01.aia.0000210804.39545.66
    1. Gurusamy K, Shethm H, Kumar Y. Methods of vascular occlusion for elective liver resections. Cochrane Database Syst Rev 2009;21:CD007632.
    1. Lesurtel M, Selzner M, Petrowsky H. A prospective randomized study in 100 consecutive patients: comparing four different transection strategies how should transection of the liver be performed. Ann Surg 2005;242:814–23.
    1. Poon RTP. Current techniques of liver transection. HPB 2007;9:166–73. 10.1080/13651820701216182
    1. McNally SJ, Revie EJ, Massie LJ, et al. . Factors in perioperative care that determine blood loss in liver surgery. HPB 2012;14:236–41. 10.1111/j.1477-2574.2011.00433.x
    1. Kooby DA, Stockman J, Ben-Porat L, et al. . Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003;237:860–70. 10.1097/01.SLA.0000072371.95588.DA
    1. Jarnagin WR, Gonen M, Maithel SK, et al. . A prospective randomized trial of acute normovolemic hemodilution compared to standard intraoperative management in patients undergoing major hepatic resection. Ann Surg 2008;248:360–9. 10.1097/SLA.0b013e318184db08
    1. Bui LL, Smith AJ, Bercovici M, et al. . Minimising blood loss and transfusion requirements in hepatic resection. HPB 2002;4:5–10. 10.1080/136518202753598672
    1. Gozzetti G, Mazziotti A, Grazi GL, et al. . Liver resection without blood transfusion. Br J Surg 1995;82:1105–10. 10.1002/bjs.1800820833
    1. Jamieson GG, Corbel L, Campion JP, et al. . Major liver resection without a blood transfusion: is it a realistic objective? Surgery 1992;112:32–6.
    1. Katz SC, Shia J, Liau KH, et al. . Operative blood loss independently predicts recurrence and survival after resection of hepatocellular carcinoma. Ann Surg 2009;249:617–23. 10.1097/SLA.0b013e31819ed22f
    1. Kusano T, Sasaki A, Kai S, et al. . Predictors and prognostic significance of operative complications in patients with hepatocellular carcinoma who underwent hepatic resection. Eur J Surg Oncol 2009;35:1179–85. 10.1016/j.ejso.2009.04.008
    1. Rees M, Plant G, Wells J, et al. . One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery. Br J Surg 1996;83:1526–9. 10.1002/bjs.1800831110
    1. Ryan JA, Faulkner DJ. Liver resection without blood transfusion. Am J Surg 1989;157:472–5. 10.1016/0002-9610(89)90637-5
    1. Mayo SC, Shore AD, Nathan H, et al. . Refining the definition of perioperative mortality following hepatectomy using death within 90 days as the standard criterion. HPB 2011;13:473–82. 10.1111/j.1477-2574.2011.00326.x
    1. Delaney M, Wendel S, Bercovitz RS, et al. . Transfusion reactions: prevention, diagnosis, and treatment. Lancet 2016;388:2825–36. 10.1016/S0140-6736(15)01313-6
    1. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg 2012;256:235–44. 10.1097/SLA.0b013e31825b35d5
    1. Amato A, Pescatori M. Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database Syst Rev 2006;1:CD005033.
    1. Heiss MM, Mempel W, Delanoff C, et al. . Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. J Clin Oncol 1994;12:1859–67. 10.1200/JCO.1994.12.9.1859
    1. Kneuertz PJ, Patel SH, Chu CK, et al. . Effects of perioperative red blood cell transfusion on disease recurrence and survival after pancreaticoduodenectomy for ductal adenocarcinoma. Ann Surg Oncol 2011;18:1327–34. 10.1245/s10434-010-1476-3
    1. Vamvakas EC. Perioperative blood transfusion and cancer recurrence: meta-analysis for explanation. Transfusion 1995;35:760–8. 10.1046/j.1537-2995.1995.35996029162.x
    1. Zakaria S, Donohue JH, Que FG, et al. . Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg 2007;246:183–91. 10.1097/SLA.0b013e3180603039
    1. Ker K, Edwards P, Perel P, et al. . Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054. 10.1136/bmj.e3054
    1. Wu C-C, Ho W-M, Cheng S-B, et al. . Perioperative parenteral tranexamic acid in liver tumor resection: a prospective randomized trial toward a "blood transfusion"-free hepatectomy. Ann Surg 2006;243:173–80. 10.1097/01.sla.0000197561.70972.73
    1. Pang YY. The Brisbane 2000 terminology of liver anatomy and resections. HPB 2000; 2:333-39. HPB 2002;4:333–9. 10.1080/136518202760378489
    1. CRASH-2 trial Collaborators, Shakur H, Roberts I, et al. . Effects 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;376:23–32. 10.1016/S0140-6736(10)60835-5
    1. WOMAN Trial Collaborators . Effect 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;389:2106–16. 10.1016/S0140-6736(17)30638-4
    1. Sentilhes L, Winer N, Azria E, et al. . Tranexamic acid for the prevention of blood loss after vaginal delivery. N Engl J Med 2018;379:731–42. 10.1056/NEJMoa1800942
    1. Kagoma YK, Crowther MA, Douketis J, et al. . Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res 2009;123:687–96. 10.1016/j.thromres.2008.09.015
    1. Karkouti K, Rampersaud Y, McCluskey S. Blood conservation in elective spine surgery. Can J Anaesth 2002;49:A12.
    1. Wang G, Xie G, Jiang T, et al. . Tranexamic acid reduces blood loss after off-pump coronary surgery: a prospective, randomized, double-blind, placebo-controlled study. Anesth Analg 2012;115:239–43. 10.1213/ANE.0b013e3182264a11
    1. Wong J, El Beheiry H, Rampersaud YR, et al. . Tranexamic acid reduces perioperative blood loss in adult patients having spinal fusion surgery. Anesth Analg 2008;107:1479–86. 10.1213/ane.0b013e3181831e44
    1. Lecker I, Wang D-S, Whissell PD, et al. . Tranexamic acid-associated seizures: causes and treatment. Ann Neurol 2016;79:18–26. 10.1002/ana.24558
    1. Fergusson DA, Hébert PC, Mazer CD, et al. . A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319–31. 10.1056/NEJMoa0802395
    1. Henry DA, Carless PA, Moxey AJ. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011;16:CD001886.
    1. Makwana J, Paranjape S, Goswami J. Antifibrinolytics in liver surgery. Indian J Anaesth 2010;54:489–95. 10.4103/0019-5049.72636
    1. Roberts I, Shakur H, Ker K. CRASH-2 trial Collaborators. antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev 2011;1:CD004896.
    1. Truong JL, Cyr DP, Lam-McCulloch J, et al. . Consensus and controversy in hepatic surgery: a survey of Canadian surgeons. J Surg Oncol 2014;110:947–51. 10.1002/jso.23748
    1. Giordano C, Deitte LA, Gravenstein N, et al. . What is the preferred central venous pressure zero reference for hepatic resection? Anesth Analg 2010;111:660–4. 10.1213/ANE.0b013e3181c76d3e
    1. Rahbari NN, Koch M, Zimmermann JB, et al. . Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. Ann Surg 2011;253:1102–10. 10.1097/SLA.0b013e318214bee5
    1. Kalavrouziotis D, Voisine P, Mohammadi S, et al. . High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg 2012;93:148–54. 10.1016/j.athoracsur.2011.07.085
    1. Murkin JM, Falter F, Granton J, et al. . High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010;110:350–3. 10.1213/ANE.0b013e3181c92b23
    1. Gross JB. Estimating allowable blood loss: corrected for dilution. Anesthesiology 1983;58:277–80. 10.1097/00000542-198303000-00016
    1. Clavien PA, Barkun J, de Oliveira ML, et al. . The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187–96. 10.1097/SLA.0b013e3181b13ca2
    1. Canadian Institute for Health Information . Patient cost estimator, 2019. Available: [Accessed 07 Oct 2019].
    1. Canadian Institute for Health Information . Cost of a standard hospital stay, 2017. Available: [Accessed 07 Oct 2019].
    1. Canadian Institute for Health Information . The cost of acute care hospital stays by medical condition in Canada, 2004-2005, 2008. Available: [Accessed 07 Oct 2019].
    1. Barber J, Thompson S. Multiple regression of cost data: use of generalised linear models. J Health Serv Res Policy 2004;9:197–204. 10.1258/1355819042250249
    1. Briggs A, Nixon R, Dixon S, et al. . Parametric modelling of cost data: some simulation evidence. Health Econ 2005;14:421–8. 10.1002/hec.941
    1. Glick HA, Doshi JA, Sonnad SS. Economic evaluation in clinical trials. 2nd edn. Oxford University Press, 2014.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera