Efficacy of Prothrombin Complex Concentrate Reducing Perioperative Blood Loss in Cardiac Surgery

Efficacy of Prothrombin Complex Concentrate Reducing Perioperative Blood Loss in Cardiac Surgery, Compared With Fresh Frozen Plasma: Study Protocol for a Non-inferiority, Randomized Controlled Trial

Peking Union Medical College Hospital, Beijing Anzhen Hospital, Guizhou Provincial People's Hospital, First Affiliated Hospital of Harbin Medical University, Zunyi Medical College

This study is a non-inferiority, randomized controlled trial, based on the hypothesis that 4-factor PCC is not inferior to FFP in reducing perioperative blood loss in patients undergoing cardiac surgery under cardiopulmonary bypass. 796 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 398 cases in each group. Patients will be given 15 IU/kg 4-factor PCC in group PCC and 10 ml/kg FFP in group FFP. All the patients will be followed up respectively at 24 hours, 48 hours, 72 hours and 7 days after the surgery. The primary outcome is the volume of blood loss within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused within 7 days after surgery and (2) length of intensive care unit (ICU) stay. Adverse events and serious adverse events will be monitored as safety outcomes. Exploratory outcomes include re-exploration due to postoperative bleeding within 7 days after surgery and length of hospital stay.

Perioperative blood loss and allogeneic blood transfusion are major complications of cardiac surgery, which increase perioperative complications, perioperative mortality and medical costs.This study is a non-inferiority, randomized controlled trial, in order to determine whether PCC is no worse than FFP in reducing perioperative blood loss and allogeneic blood transfusion in patients undergoing cardiac surgery under CPB. Patients signed the informed consent, aged 18 to 80 years, receiving elective CABG or valve replacement or valvuloplasty under CPB will be included. 796 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 398 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for both groups. When APTT is prolonged (> 45 s), patients will be given 15 IU/kg PCC in group PCC and 10 ml/kg FFP in group FFP. All the patients will be followed up respectively at 24 hours, 48 hours, 72 hours and 7 days after the surgery to record observations relevant to the study and the results of laboratory testing. The laboratory tests include hemoglobin concentration, hematocrit, platelet count, INR, PT, APTT, fibrinogen levels and blood biochemistry parameters. The primary outcome is the volume of blood loss within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused within 7 days after surgery and (2) length of intensive care unit (ICU) stay. Adverse events and serious adverse events will be monitored as safety outcomes. Exploratory outcomes include re-exploration due to postoperative bleeding within 7 days after surgery and length of hospital stay. Modified intent-to-treat analysis will be used for all valid variables. All randomised subjects in the study, regardless of adherence to the study process or whether an adverse event occurs before or after the intervention, should be included in the analysis. Sensitivity analysis will be performed to assess the bias that may be introduced due to nonadherence to the protocol or missing data. Baseline characteristics will be tabulated and compared between the PCC and FFP groups using absolute standardised differences, and a value larger than 0.1 will be regarded as a clinically relevant difference between groups. Unbalanced baseline factors will be further adjusted by multivariable regression models. The primary outcome, the volume of blood loss within 24 hours after surgery, will be compared using the t-test with log transformation of the variable. Continuous secondary outcomes and the total units of allogeneic RBCs transfused during and within 7 days after surgery will be compared using a t-test with log transformation of the variable. The rate of re-exploration due to bleeding within 7 days after surgery will be compared using the chi-square test. Treatment effect will be measured by risk ratio and mean difference for binary and continuous outcomes with corresponding 95% confidence intervals. Bonferroni's correction for multiple comparisons will be conducted in the analysis of the secondary outcomes. If there exists unbalanced baseline characteristics, the primary outcome and secondary outcomes will be regressed against the group allocation and the unbalanced factors using liner regression and Cox regression models. Proportional hazard assumption will be checked by the Schoenfeld's residual plot. For safety outcomes, we will only describe the incidence of overall adverse events, SAEs, and component adverse events without statistical tests between two groups. A two-sided P-value < 0.05 was considered indicative of statistical significance.

prothrombin complex concentrate, fresh frozen plasma, perioperative blood loss, efficacy, cardiac surgery, cardiopulmonary bypass

796 patients who meet the criteria will be randomly divided into 2 groups, named prothrombin complex concentrate group (group PCC) and fresh frozen plasma group (control group, group FFP), with 398 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for all patients. Prolonged APTT (> 45 s) will be regarded as a trigger for administration of PCC or FFP, according to the randomized groups. In group PCC, patients will be given 15 IU/kg PCC. In group FFP, patients will be given 10 mL/kg FFP.

Allocation will be concealed using an interactive web response system, and nurse anaesthetists will prepare the corresponding products for each patient according to the group assignments in an anaesthesia preparation room. PCC or FFP will be pumped into 50 ml syringes firstly, covered with opaque paper to hide the contents. For group PCC, we first diluted PCC to 50ml with normal saline, and then supplemented subsequent volume using normal saline to make it equal to the corresponding required volume of FFP.

When APTT is prolonged (> 45 s) measured 20 minutes after CPB or excessive bleeding observed, patients will be given 15 IU/kg PCC.

When APTT is prolonged (> 45 s) measured 20 minutes after CPB or excessive bleeding observed, patients will be given 10 mL/kg FFP.

A 4-factor prothrombin complex concentrate (Confidex®, CSL Behring, Marburg, Germany), containing a defined concentration of the four vitamin K-dependent clotting factors (II, VII, IX and X) and the thrombo-inhibitor proteins C and S. Each vial of Confidex® contains a relatively high concentration of coagulation factor II (20-48 IU/mL), factor VII (10-25 IU/mL), factor IX (20-31 IU/mL), factor X (22-60 IU/mL), proteins C (15-45 IU/mL), proteins S (13-38 IU/mL), Heparin (0.5 IU/mL), and antithrombin (0.6 IU/mL). When APTT is prolonged (> 45 s) measured 20 minutes after CPB or excessive bleeding observed, patients will be given 15 IU/kg PCC.

When APTT is prolonged (> 45 s) measured 20 minutes after CPB or excessive bleeding observed, patients will be given 10 mL/kg FFP.

the total units of allogeneic RBC transfused during the intraoperative and postoperative the total units of allogeneic RBCs transfused during and within 7 days after surgery

Inclusion Criteria: Age between 18 and 80 years. Undergoing elective coronary artery bypass grafting (CABG) or valve replacement or valvuloplasty through CPB. Signing of the informed consent form. Developing coagulation factor deficiency or coagulopathic bleeding during the surgery, meeting the indications of PCC or FFP treatment: a) prolonged APTT (> 45 s) measured 20 minutes after CPB, and b) excessive bleeding observed. Exclusion Criteria: History of cardiac surgery. Hepatic dysfunction before surgery. Coagulopathy before surgery, including inherited or acquired coagulation factor deficiencies, thrombocytopenia, platelet dysfunction and other bleeding disorders. Use of warfarin within three days and direct oral anticoagulants within 48 hours (or 72 hours if patient has renal impairment) before surgery. Withdrawal of clopidogrel or aspirin less than 7 days and low molecular weight heparin less than 24 hours before surgery. Allergy to allogeneic blood products. Pregnancy. Other serious diseases that may affect patient survival time, such as cancers.

Parr KG, Patel MA, Dekker R, Levin R, Glynn R, Avorn J, Morse DS. Multivariate predictors of blood product use in cardiac surgery. J Cardiothorac Vasc Anesth. 2003 Apr;17(2):176-81. doi: 10.1053/jcan.2003.44.

Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg. 1996 May;111(5):1037-46. doi: 10.1016/s0022-5223(96)70380-x.

Mariscalco G, Biancari F, Juvonen T, Zanobini M, Cottini M, Banach M, Murphy GJ, Beghi C, Angelini GD. Red blood cell transfusion is a determinant of neurological complications after cardiac surgery. Interact Cardiovasc Thorac Surg. 2015 Feb;20(2):166-71. doi: 10.1093/icvts/ivu360. Epub 2014 Nov 2.

Alfirevic A, Xu M, Johnston D, Figueroa P, Koch CG. Transfusion increases the risk for vasoplegia after cardiac operations. Ann Thorac Surg. 2011 Sep;92(3):812-9. doi: 10.1016/j.athoracsur.2011.04.020. Epub 2011 Jul 23.

Sellman M, Intonti MA, Ivert T. Reoperations for bleeding after coronary artery bypass procedures during 25 years. Eur J Cardiothorac Surg. 1997 Mar;11(3):521-7. doi: 10.1016/s1010-7940(96)01111-6.

Ottino G, De Paulis R, Pansini S, Rocca G, Tallone MV, Comoglio C, Costa P, Orzan F, Morea M. Major sternal wound infection after open-heart surgery: a multivariate analysis of risk factors in 2,579 consecutive operative procedures. Ann Thorac Surg. 1987 Aug;44(2):173-9. doi: 10.1016/s0003-4975(10)62035-8.

Zacharias A, Habib RH. Factors predisposing to median sternotomy complications. Deep vs superficial infection. Chest. 1996 Nov;110(5):1173-8. doi: 10.1378/chest.110.5.1173.

Linden MD. The hemostatic defect of cardiopulmonary bypass. J Thromb Thrombolysis. 2003 Dec;16(3):129-47. doi: 10.1023/B:THRO.0000024051.12177.e9.

Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007 May;83(5 Suppl):S27-86. doi: 10.1016/j.athoracsur.2007.02.099.

Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ, Leavitt BJ, Quinn RD, Nugent WC, Birkmeyer JD, O'Connor GT. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Northern New England Cardiovascular Disease Study Group. Arch Surg. 1998 Apr;133(4):442-7. doi: 10.1001/archsurg.133.4.442.

Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion. 2008 Mar;48(1 Suppl):2S-30S. doi: 10.1111/j.1537-2995.2007.01573.x. No abstract available.

Karkouti K, Callum J, Crowther MA, McCluskey SA, Pendergrast J, Tait G, Yau TM, Beattie WS. The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study. Anesth Analg. 2013 Jul;117(1):14-22. doi: 10.1213/ANE.0b013e318292efa4. Epub 2013 May 17.

Weber CF, Klages M, Zacharowski K. Perioperative coagulation management during cardiac surgery. Curr Opin Anaesthesiol. 2013 Feb;26(1):60-4. doi: 10.1097/ACO.0b013e32835afd28.

Khuri SF MA, Valeri CR. The effects of cardiopulmonary bypass on hemostasis. Loscabo J, Schafer AI, eds. Thrombosis & Hemorrhage. Cambridge: Blackwell Science. 1993;1993:1051-1073.

Kaspereit F, Hoffmann S, Pragst I, Dickneite G. Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model. Br J Anaesth. 2010 Nov;105(5):576-82. doi: 10.1093/bja/aeq216. Epub 2010 Aug 17.

Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol. 2004 Jul;126(1):139-52. doi: 10.1111/j.1365-2141.2004.04973.x.

Sun JC, Davidson MJ, Lamy A, Eikelboom JW. Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet. 2009 Aug 15;374(9689):565-76. doi: 10.1016/S0140-6736(09)60780-7.

Eitz T, Schenk S, Fritzsche D, Bairaktaris A, Wagner O, Koertke H, Koerfer R. International normalized ratio self-management lowers the risk of thromboembolic events after prosthetic heart valve replacement. Ann Thorac Surg. 2008 Mar;85(3):949-54; discussion 955. doi: 10.1016/j.athoracsur.2007.08.071.

Safaoui MN, Aazami R, Hotz H, Wilson MT, Margulies DR. A promising new alternative for the rapid reversal of warfarin coagulopathy in traumatic intracranial hemorrhage. Am J Surg. 2009 Jun;197(6):785-90. doi: 10.1016/j.amjsurg.2008.04.003. Epub 2008 Aug 22.

Fariborz Farsad B, Golpira R, Najafi H, Totonchi Z, Salajegheh S, Bakhshandeh H, Hashemian F. Comparison between Prothrombin Complex Concentrate (PCC) and Fresh Frozen Plasma (FFP) for the Urgent Reversal of Warfarin in Patients with Mechanical Heart Valves in a Tertiary Care Cardiac Center. Iran J Pharm Res. 2015 Summer;14(3):877-85.

Cromwell C, Aledort LM. FEIBA: a prohemostatic agent. Semin Thromb Hemost. 2012 Apr;38(3):265-7. doi: 10.1055/s-0032-1309286. Epub 2012 Mar 29.

Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus. 2010 Jul;8(3):149-54. doi: 10.2450/2010.0149-09. No abstract available.

Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999 Aug 15;95(4 Suppl 1):S7-12. doi: 10.1016/s0049-3848(99)00078-x.

Cappabianca G, Mariscalco G, Biancari F, Maselli D, Papesso F, Cottini M, Crosta S, Banescu S, Ahmed AB, Beghi C. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. Crit Care. 2016 Jan 6;20:5. doi: 10.1186/s13054-015-1172-6.

Song HK, Tibayan FA, Kahl EA, Sera VA, Slater MS, Deloughery TG, Scanlan MM. Safety and efficacy of prothrombin complex concentrates for the treatment of coagulopathy after cardiac surgery. J Thorac Cardiovasc Surg. 2014 Mar;147(3):1036-40. doi: 10.1016/j.jtcvs.2013.11.020. Epub 2013 Dec 22.

Weinberger J, Cipolle M. Optimal Reversal of Novel Anticoagulants in Trauma. Crit Care Clin. 2017 Jan;33(1):135-152. doi: 10.1016/j.ccc.2016.08.005.

Ortmann E, Besser MW, Sharples LD, Gerrard C, Berman M, Jenkins DP, Klein AA. An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. Anesth Analg. 2015 Jul;121(1):26-33. doi: 10.1213/ANE.0000000000000689.

Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother. 2011 Jul;45(7-8):990-9. doi: 10.1345/aph.1Q096. Epub 2011 Jul 5.

Hellstern P, Halbmayer WM, Kohler M, Seitz R, Muller-Berghaus G. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res. 1999 Aug 15;95(4 Suppl 1):S3-6. doi: 10.1016/s0049-3848(99)00077-8. No abstract available.

Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006 Jun;37(6):1465-70. doi: 10.1161/01.STR.0000221786.81354.d6. Epub 2006 May 4.

Erber WN, Perry DJ. Plasma and plasma products in the treatment of massive haemorrhage. Best Pract Res Clin Haematol. 2006;19(1):97-112. doi: 10.1016/j.beha.2005.01.026.

Vigue B, Ract C, Tremey B, Engrand N, Leblanc PE, Decaux A, Martin L, Benhamou D. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med. 2007 Apr;33(4):721-5. doi: 10.1007/s00134-007-0528-z. Epub 2007 Jan 27.

Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology. 2008 Nov;109(5):918-26. doi: 10.1097/ALN.0b013e3181895bd8.

Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008 Feb;83(2):137-43. doi: 10.1002/ajh.21046.

Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005 Jul;89(1):1-10. doi: 10.1111/j.1423-0410.2005.00648.x.

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):160S-198S. doi: 10.1378/chest.08-0670.

Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H; Beriplex P/N Anticoagulation Reversal Study Group. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008 Apr;6(4):622-31. doi: 10.1111/j.1538-7836.2008.02904.x. Epub 2008 Jan 15.

Pabinger-Fasching I. Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate. Thromb Res. 2008;122 Suppl 2:S19-22. doi: 10.1016/S0049-3848(08)70005-7.

Nienaber U, Innerhofer P, Westermann I, Schochl H, Attal R, Breitkopf R, Maegele M. The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury. 2011 Jul;42(7):697-701. doi: 10.1016/j.injury.2010.12.015. Epub 2011 Mar 9.

Goldstein JN, Refaai MA, Milling TJ Jr, Lewis B, Goldberg-Alberts R, Hug BA, Sarode R. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015 May 23;385(9982):2077-87. doi: 10.1016/S0140-6736(14)61685-8. Epub 2015 Feb 27.

Green L, Roberts N, Cooper J, Field J, Gill R, Klein A, Agarwal S, Stanworth S, Johnston A, Monk V, O'Brien B. A pragmatic pilot phase II randomised controlled trial of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) in adult patients who are undergoing heart surgery (PROPHESY). Trials. 2019 Dec 9;20(1):684. doi: 10.1186/s13063-019-3759-8.

Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, Fries D, Gorlinger K, Haas T, Imberger G, Jacob M, Lance M, Llau J, Mallett S, Meier J, Rahe-Meyer N, Samama CM, Smith A, Solomon C, Van der Linden P, Wikkelso AJ, Wouters P, Wyffels P. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013 Jun;30(6):270-382. doi: 10.1097/EJA.0b013e32835f4d5b. Erratum In: Eur J Anaesthesiol. 2014 Apr;31(4):247.

Pei L, Sun C, Lv H, Zhang Y, Shi J. Efficacy of prothrombin complex concentrate (PCC) versus fresh frozen plasma (FFP) in reducing perioperative blood loss in cardiac surgery: study protocol for a non-inferiority, randomised controlled trial. BMJ Open. 2022 Feb 10;12(2):e051072. doi: 10.1136/bmjopen-2021-051072.