Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery

Giangiuseppe Cappabianca, Giovanni Mariscalco, Fausto Biancari, Daniele Maselli, Francesca Papesso, Marzia Cottini, Sandro Crosta, Simona Banescu, Aamer B Ahmed, Cesare Beghi, Giangiuseppe Cappabianca, Giovanni Mariscalco, Fausto Biancari, Daniele Maselli, Francesca Papesso, Marzia Cottini, Sandro Crosta, Simona Banescu, Aamer B Ahmed, Cesare Beghi

Abstract

Background: Bleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited.

Methods: Between January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery.

Results: After one-to-one propensity score-matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836 ± 1226 vs. 935 ± 583 ml, p < 0.0001). Propensity score-adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95% confidence interval [CI] 0.31-0.80), decreased amount of RBC units (β unstandardised coefficient -1.42, 95% CI -2.06 to -0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95% CI 0.38-0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95% CI 1.02-2.05) and renal replacement therapy (OR 3.35, 95% CI 1.13-9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95% CI 0.84-2.72).

Conclusions: In the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI.

Figures

Fig. 1
Fig. 1
Standardized differences before and after propensity score matching comparing covariate values for patients with or without PCC administration

References

    1. Mehta RH, Sheng S, O’Brien SM, Grover FL, Gammie JS, Ferguson TB, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes. 2009;2:583–590. doi: 10.1161/CIRCOUTCOMES.109.858811.
    1. Christensen MC, Krapf S, Kempel A, von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg. 2009;138:687–693. doi: 10.1016/j.jtcvs.2009.02.021.
    1. 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;116:2544–2552. doi: 10.1161/CIRCULATIONAHA.107.698977.
    1. Mariscalco G, Biancari F, Juvonen T, Zanobini M, Cottini M, Banach M, et al. Red blood cell transfusion is a determinant of neurological complications after cardiac surgery. Interact Cardiovasc Thorac Surg. 2015;20:166–171. doi: 10.1093/icvts/ivu360.
    1. Solomon C, Pichlmaier U, Schoechl H, Hagl C, Raymondos K, Scheinichen D, et al. Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery. Br J Anaesth. 2010;104:555–562. doi: 10.1093/bja/aeq058.
    1. Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL, et al. Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation. 2008;118:331–338. doi: 10.1161/CIRCULATIONAHA.108.764308.
    1. Stuklis RG, O’Shaughnessy DF, Ohri SK. Novel approach to bleeding in patients undergoing cardiac surgery with liver dysfunction. Eur J Cardiothorac Surg. 2001;19:219–220. doi: 10.1016/S1010-7940(00)00641-2.
    1. Fraser TA, Corke CF, Mohajeri M, Stevenson L, Campbell PJ. A retrospective audit of the use of Prothrombinex-HT for refractory bleeding following adult cardiac surgery. Crit Care Resusc. 2006;8:141–145.
    1. 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;105:576–582. doi: 10.1093/bja/aeq216.
    1. Demeyre R, Gillardin S, Arnout J, Strengers PFW. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251–260. doi: 10.1111/j.1423-0410.2010.01339.x.
    1. Arnékian V, Camous J, Fattal S, Rézaiguia-Delclaux S, Nottin R, Stéphan F. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg. 2012;15:382–389. doi: 10.1093/icvts/ivs224.
    1. Tanaka KA, Mazzeffi MA, Grube M, Ogawa S, Chen EP. Three-factor prothrombin complex concentrate and hemostasis after high-risk cardiovascular surgery. Transfusion. 2013;53:920–921. doi: 10.1111/trf.12110.
    1. Song HK, Tibayan FA, Kahl EA, Sera VA, Slater MS, Deloughery TG, et al. Safety and efficacy of prothrombin complex concentrates for the treatment of coagulopathy after cardiac surgery. J Thorac Cardiovasc Surg. 2014;147:1036–1040. doi: 10.1016/j.jtcvs.2013.11.020.
    1. Görlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology. 2011;115:1179–1191.
    1. Ortmann E, Besser MW, Sharples LD, Gerrard C, Berman M, Jenkins DP, et al. An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. Anesth Analg. 2015;121:26–33. doi: 10.1213/ANE.0000000000000689.
    1. 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;83:137–143. doi: 10.1002/ajh.21046.
    1. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology. 2008;109:918–926. doi: 10.1097/ALN.0b013e3181895bd8.
    1. Vigué B, Ract C, Tremey B, Engrand N, Leblanc PE, Decaux A, et al. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med. 2007;33:721–725. doi: 10.1007/s00134-007-0528-z.
    1. Mariscalco G, Bruno VD, Cottini M, Borsani P, Banach M, Piffaretti G, et al. Optimal timing of discontinuation of clopidogrel and risk of blood transfusion after coronary surgery: propensity score analysis. Circ J. 2011;75:2805–2812. doi: 10.1253/circj.CJ-11-0620.
    1. Mariscalco G, Cottini M, Zanobini M, Salis S, Dominici C, Banach M, et al. Preoperative statin therapy is not associated with a decrease in the incidence of delirium after cardiac operations. Ann Thorac Surg. 2012;93:1439–1447. doi: 10.1016/j.athoracsur.2012.02.012.
    1. Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus. 2010;8:149–154.
    1. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212. doi: 10.1186/cc2872.
    1. Austin PC. Goodness of fit diagnostics fort the propensity score model when estimating treatment effects using covariate adjustment with the propensity score. Pharmacoepidemiol Drug Saf. 2008;17:1202–1217. doi: 10.1002/pds.1673.
    1. Normand ST, Landrum MB, Guadagnoli E, Ayanian JZ, Ryan TJ, Cleary PD. Validating recommendations for coronary angiography following acute myocardial infarction in the elderly: a matched analysis using propensity scores. J Clin Epidemiol. 2001;54:387–398. doi: 10.1016/S0895-4356(00)00321-8.
    1. Görlinger K, Shore-Lesserson L, Dirkmann D, Hanke AA, Rahe-Meyer N, Tanaka KA. Management of hemorrhage in cardiothoracic surgery. J Cardiothorac Vasc Anesth. 2013;27(4 Suppl):S20–S34. doi: 10.1053/j.jvca.2013.05.014.
    1. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49:1171–1177. doi: 10.1111/j.1537-2995.2008.02080.x.
    1. Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet. 2007;370:439–448. doi: 10.1016/S0140-6736(07)61199-4.
    1. Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–982. doi: 10.1016/j.athoracsur.2010.11.078.
    1. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30:270–382. doi: 10.1097/EJA.0b013e32835f4d5b.
    1. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates – evaluation of safety and thrombogenicity. Crit Care. 2011;15:201. doi: 10.1186/cc9311.
    1. Mitterlechner T, Innerhofer P, Streif W, Lödl M, Danninger T, Klima G, et al. Prothrombin complex concentrate and recombinant prothrombin alone or in combination with recombinant factor X and FVIIa in dilutional coagulopathy: a porcine model. J Thromb Haemost. 2011;9:729–737. doi: 10.1111/j.1538-7836.2011.04211.x.
    1. Grottke O, Braunschweig T, Spronk HM, Esch S, Rieg AD, van Oerle R, et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–1951. doi: 10.1182/blood-2011-03-343046.
    1. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622–631. doi: 10.1111/j.1538-7836.2008.02904.x.
    1. Majeed A, Eelde A, Ågren A, Schulman S, Holmström M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res. 2012;129:146–151. doi: 10.1016/j.thromres.2011.07.024.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner