Effectiveness and safety of antifibrinolytic agents in off-pump coronary artery bypass grafting: a systematic review and meta-analysis
Eficácia e segurança de agentes antifibrinolíticos em cirurgia de revascularização do miocárdio sem circulação extracorpórea: uma revisão sistemática e metanálise
João Lucas W.C. Marchesani, Matheus H. Leite e Silva, Matheus S. Thomaz, Davi B. Wolff, Emerson C.L. Almeida, Michelle D.S.S. Costa
Abstract
Background
Coronary Artery Bypass Grafting (CABG) is the most widely used cardiac intervention and can be accomplished without an extracorporeal circulation off-pump. The benefits of antifibrinolytics in off-pump CABG have yet to be demonstrated.
Methods
Randomized Controlled Trials (RCTs) and observational studies comparing the use of antifibrinolytic agents (tranexamic acid, aprotinin, and epsilon-aminocaproic) versus controls in patients undergoing off-pump CABG were searched in the PubMed, Embase, and Cochrane databases. Outcomes included thromboembolic events, in-hospital mortality, overall mortality, bleeding, Intensive Care Unit (ICU) length of stay, and blood product transfusions. Meta-analyses were conducted using the Inverse Variance method under a random-effects model, with p < 0.05 considered statistically significant.
Results
Of the 23,149 patients in 20 RCTs and seven observational studies, 51% received antifibrinolytic agents (tranexamic acid or aprotinin). Observational and randomized designs were analyzed separately in primary subgroup analyses. Significant reduction was found for overall mortality (RR = 0.72; [95% CI 0.54−0.95]) in the RCT subgroup. Red-blood-cell transfusion requirements were reduced (RR = 0.65; [95% CI 0.53, 0.78]) as well as Platelets (RR = 0.59; [95% CI 0.41, 0.84]) and fresh-frozen-plasma (RR = 0.39; [95% CI 0.36, 0.42]) transfusion requirement. The RCT subgroup showed a reduction in thromboembolic events (RR = 0.55; [95% CI 0.39, 0.79]).
Conclusion
In off-pump CABG, antifibrinolytics reduced the need for blood transfusion while reducing thromboembolic events and overall mortality in RCT subgroups, while pooled analyses combining RCTs and observational studies did not demonstrate significant reductions.
Prospero Link
Keywords
Resumo
Introdução
A cirurgia de revascularização do miocárdio (CRM) é a intervenção cardíaca mais amplamente utilizada e pode ser realizada sem circulação extracorpórea, na técnica off-pump. Os benefícios dos antifibrinolíticos na CRM off-pump ainda não foram completamente demonstrados.
Métodos
Ensaios clínicos randomizados (ECRs) e estudos observacionais que compararam o uso de agentes antifibrinolíticos (ácido tranexâmico, aprotinina e ácido ε-aminocaproico) versus controles em pacientes submetidos à CRM off-pump foram pesquisados nas bases PubMed, Embase e Cochrane. Os desfechos incluíram eventos tromboembólicos, mortalidade intra-hospitalar, mortalidade geral, sangramento, tempo de internação em Unidade de Terapia Intensiva (UTI) e transfusão de hemoderivados. As metanálises foram conduzidas pelo método da variância inversa sob modelo de efeitos aleatórios, considerando p < 0,05 como estatisticamente significativo.
Resultados
Dos 23.149 pacientes incluídos em 20 ECRs e sete estudos observacionais, 51% receberam agentes antifibrinolíticos (ácido tranexâmico ou aprotinina). Os delineamentos observacionais e randomizados foram analisados separadamente nas análises primárias de subgrupos. Houve redução significativa da mortalidade geral (RR = 0,72; IC 95% 0,54–0,95) no subgrupo de ECRs. A necessidade de transfusão de concentrado de hemácias foi reduzida (RR = 0,65; IC 95% 0,53–0,78), assim como a transfusão de plaquetas (RR = 0,59; IC 95% 0,41–0,84) e de plasma fresco congelado (RR = 0,39; IC 95% 0,36–0,42). O subgrupo de ECRs também demonstrou redução de eventos tromboembólicos (RR = 0,55; IC 95% 0,39–0,79).
Conclusão
Na CRM off-pump, os antifibrinolíticos reduziram a necessidade de transfusão sanguínea, além de diminuírem eventos tromboembólicos e mortalidade geral em subgrupos de ECRs. Entretanto, análises agrupadas combinando ECRs e estudos observacionais não demonstraram reduções significativas.
Registro PROSPERO
Palavras-chave
References
1. Head SJ, Milojevic M, Taggart DP, Puskas JD. Current Practice of State-of-the-Art Surgical Coronary Revascularization. Circulation. 2017;136:1331−45.
2. Woodman R, Harker L. Bleeding complications associated with cardiopulmonary bypass. Blood. 1990;76:1680−97.
3. Gielen CLI, Brand A, van Heerde WL, Stijnen T, Klautz RJM, Eikenboom J. Hemostatic alterations during coronary artery bypass grafting. Thromb Res. 2016;140:140−6.
4. Tibi P, McClure RS, Huang J, Baker RA, Fitzgerald D, Mazer CD, et al. STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management. Ann Thorac Surg. 2021;112:981−1004.
5. Boer C, Meesters MI, Milojevic M, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J Cardiothorac Vasc Anesth. 2018;32:88−120.
6. Zhang Y, Bai Y, Chen M, et al. The safety and efficiency of intravenous administration of tranexamic acid in coronary artery bypass grafting (CABG): a meta-analysis of 28 randomized controlled trials. BMC Anesthesiol. 2019;19:104.
7. Sun L, An H, Feng Y. Intravenous Tranexamic Acid Decreases Blood Transfusion in Off-Pump Coronary Artery Bypass Surgery: A Meta-analysis. Heart Surg Forum. 2020;23. E039−49.
8. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021: 372.. n71.
9. Nurozler F, Kutlu T, Küçük G. Aprotinin for Patients Exposed to € Clopidogrel before Off-Pump Coronary Bypass. Asian Cardiovasc Thorac Ann. 2008;16:483−7.
10. Poston RS, White C, Gu J, et al. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Ann Thorac Surg. 2006;81:104−11.
11. Durand M, Chavanon O, Tessier Y, et al. Effect of Aprotinin on Postoperative Blood Loss in Off-Pump Coronary Artery Bypass Surgery. J Card Surg. 2006;21:17−21.
12. Desai PH, Kurian D, Thirumavalavan N, et al. A Randomized Clinical Trial Investigating the Relationship Between Aprotinin and Hypercoagulability in Off-Pump Coronary Surgery. Anesth Analg. 2009;109:1387−94.
13. Sterne JAC, Savovic J, Page MJ, et al. RoB2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
14. Sterne JA, Hernan MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;355:i4919.
15. McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12:55−61.
16. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, AustriaAvailable from: https:// www.r-project.org/.
17. Weingarten BR, Tran DTT, Mahaffey R, Sohmer B. Tranexamic acid for primary elective off-pump coronary artery bypass grafting surgery. Can J Anesth. 2021;68:1287−9.
18. Vijay D, Gajarajan S, Sindhu S. Assessment of effect of TXA in off-pump cardiac surgery patients. Int J Acad Med Pharm. 2023;5:1604−7.
19. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased Mortality, Postoperative Morbidity, and Cost After Red Blood Cell Transfusion in Patients Having Cardiac Surgery. Circulation. 2007;116:2544−52.
20. Wang E, Yuan X, Wang Y, et al. Tranexamic Acid Administered During Off-Pump Coronary Artery Bypass Graft Surgeries Achieves Good Safety Effects and Hemostasis. Front Cardiovasc Med. 2022;9:775760.
21. Dai Z, Chu H, Wang S, Liang Y. The effect of tranexamic acid to reduce blood loss and transfusion on off-pump coronary artery bypass surgery: a systematic review and cumulative meta-analysis. J Clin Anesth. 2018;44:23−31.
22. Casati V, Gerli C, Franco A, et al. Tranexamic acid in off-pump coronary surgery: a preliminary, randomized, double-blind, placebo-controlled study. Ann Thorac Surg. 2001;72:470−5.
23. Casati V, Valle DP, Benussi S, et al. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgery: Comparison between on-pump and offpump techniques. J Thorac Cardiovasc Surg. 2004;128:83−91.
24. Grant MC, Kon Z, Joshi A, et al. Is Aprotinin Safe to Use in a Cohort at Increased Risk for Thrombotic Events: Results From a Randomized, Prospective Trial in Off-Pump Coronary Artery Bypass. Ann Thorac Surg. 2008;86:815−22.
25. Mehr-Aein A, Sadeghi M, Madani-civi M. Does Tranexamic Acid Reduce Blood Loss in Off-Pump Coronary Artery Bypass? Asian Cardiovasc Thorac Ann. 2007;15:285−9.
26. Wei M, Jian K, Guo Z, et al. Tranexamic acid reduces postoperative bleeding in off-pump coronary artery bypass grafting. Scand Cardiovasc J. 2006;40:105−9.
27. Vanek T, Jares M, Fajt R, et al. Fibrinolytic inhibitors in offpump coronary surgery: a prospective, randomized, doubleblind TAP study (tranexamic acid, aprotinin, placebo). Eur J Cardiothorac Surg. 2005;28:563−8.
28. Fergusson DA, Hebert 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.
29. Ahn SW, Shim JK, Youn YN, et al. Effect of Tranexamic Acid on Transfusion Requirement in Dual Antiplatelet-Treated Anemic Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery ‒ A Randomized Controlled Study. Circ J. 2012;76:96−101.
30. Bert C, Buck DF, Sergeant P, et al. Aprotinin Reduces Cardiac Troponin I Release and Inhibits Apoptosis of Polymorphonuclear Cells During Off-Pump Coronary Artery Bypass Surgery. J Cardiothorac Vasc Anesth. 2008;22:16−22.
31. Chakravarthy M, Muniraj G, Patil S, Suryaprakash S, Mitra S, Shivalingappa B. A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery. Ann Card Anaesth. 2012;15:105−10.
32. Englberger L, Markart P, Eckstein FS, Immer FF, Berdat PA, Carrel TP. Aprotinin reduces blood loss in off-pump coronary artery bypass (OPCAB) surgery. Eur J Cardiothorac Surg. 2002;22:545−51.
33. Hosseini H, Rahimianfar AA, Abdollahi MH, et al. Evaluations of topical application of tranexamic acid on post-operative blood loss in off-pump coronary artery bypass surgery. Saudi J Anaesth. 2014;8:224−8.
34. Murphy GJ, Mango E, Lucchetti V, et al. A randomized trial of tranexamic acid in combination with cell salvage plus a metaanalysis of randomized trials evaluating tranexamic acid in offpump coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2006;132:475−80.
35. Taghaddomi RJ, Mirzaee A, Attar AS, Shirdel A. Tranexamic Acid Reduces Blood Loss in Off-Pump Coronary Artery Bypass Surgery. J Cardiothorac Vasc Anesth. 2009;23:312−5.
36. Wei M, Jian K, Guo Z, et al. Effects of Half-dose Aprotinin in Offpump Coronary Artery Bypass Grafting. World J Surg. 2006;30 (6):1108−14.
37. Yang Y, Xiao F, Chen HY, Li Y, Shi ZH. Aprotinin reduces myocardial injury in the off-pump coronary artery bypass grafting. Zhonghua Yi Xue Za Zhi. 2003;83:2061−3.
38. Kim TW, Ju YH, Cho HW, et al. Effects of Aprotinin during OffPump Coronary Artery Bypass Grafting in Patients on Hemostasis Taking Aspirin. Korean J Anesthesiol. 2004;47:676−80.
39. Bittner HB, Lemke J, Lange M, Rastan A, Mohr FW. The Impact of Aprotinin on Blood Loss and Blood Transfusion in Off-Pump Coronary Artery Bypass Grafting. Ann Thorac Surg. 2008;85:1662−8.
40. Hulde N, Zittermann A, Deutsch MA, Von Dossow V, Gummert JF, Koster A. Tranexamic acid and convulsive seizures after offpump coronary artery bypass surgery: the role of renal insufficiency. Interact Cardiovasc Thorac Surg. 2019;29:852−4.
41. Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet. 2008;371:475−82.
42. Khadanga P, Kanchi M, Gaur P. Effectiveness of Tranexamic Acid in Reducing Postoperative Blood Loss in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting. Cureus. 2020;12: e11924.
Submitted date:
06/23/2025
Accepted date:
01/04/2026
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email