PCC vs. FFP for Post Cardiopulmonary Bypass Coagulopathy and Bleeding

NCT02557672 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 14-009579
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

This will be the first prospective randomized controlled clinical trial directly comparing Prothrombin Complex Concentrate (PCC) Compared to Fresh Frozen Plasma (FFP) for post cardiopulmonary bypass microvascular bleeding and factor-mediated coagulopathy. Is there a difference in bleeding and transfusion requirements in patients received PCC versus FFP?

Conditions

Bleeding; Blood Loss, Surgical; Cardiovascular Surgical Procedures; Prothrombin Complex Concentrates; Fresh Frozen Plasma

Outcome Measures

Primary Outcomes (5)

• Chest Tube Output

  The amount of chest tube drainage output from after surgery through midnight of the next day. As measured in mL.

  24 hours

• Red Blood Cell (RBC) Blood Product Transfusion

  The number of subject's who received 0,1,2,3 or more units of RBC's transfused from completion of study drug administration though midnight of the next day.

  24 hours

• Platelets Blood Product Transfusion

  The number of subject's who received 0,1,2,3 or more units of Platelets transfused from completion of study drug administration though midnight of the next day.

  24 hours

• Cryoprecipitate (Cryo) Blood Product Transfusion

  The number of subject's who received 0,1,2,3 or more units of Cryo's transfused from completion of study drug administration though midnight of the next day.

  24 hours

• Fresh Frozen Plasma (FFP) Blood Product Transfusion

  The number of subject's who received 0,1,2,3 or more units of FFP's transfused from completion of study drug administration though midnight of the next day.

  24 hours

Study Arms (2)

Fresh frozen plasma

ACTIVE COMPARATOR

After cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given with target activated clotting time (ACT) within 10% of baseline value. After protamine administration the ACT, complete blood count (CBC), prothrombin time (PT)/ international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen, will be collected via preexisting arterial access. If ACT \>10% baseline additional protamine will be given at the anesthesiologists discretion. Evaluation and determination of excessive microvascular bleeding in the surgical field will occur 10 minutes after return of ACT to within 10% of baseline. Patients with clinical evidence of excessive microvascular bleeding in the surgical field as determined by the surgical team, along with a PT \>16.6 sec/ INR \>1.6 sec will receive fresh frozen plasma as this is standard therapy per our institutional algorithm at a dose of 10-15 mL/kg rounded up to the nearest unit.

Biological: Fresh frozen plasma (FFP)

Prothrombin complex concentrate

EXPERIMENTAL

After cardiopulmonary bypass, patients will receive protamine at dose 0.01 mg/unit of heparin given with target ACT within 10% of baseline value. After protamine administration the ACT, CBC, PT/ INR, APTT, and fibrinogen, will be collected via preexisting arterial access. If ACT \>10% baseline additional protamine will be given at the anesthesiologists discretion. Evaluation and determination of excessive microvascular bleeding in the surgical field will occur 10 minutes after return of ACT to within 10% of baseline. Patients with clinical evidence of excessive microvascular bleeding in the surgical field as determined by the surgical team, along with a PT \>16.6 sec/ INR \>1.6 sec will receive Prothrombin complex concentrate (Human) 15 units/kg.

Drug: Prothrombin complex concentrate (Human)

Interventions

Prothrombin complex concentrate (Human) DRUG

PCC (Kcentra)

Also known as: Kcentra

Prothrombin complex concentrate

Fresh frozen plasma (FFP) BIOLOGICAL

FFP

Fresh frozen plasma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects accepted for this study must:
• Be 18 years of age
• Be undergoing elective cardiac surgical procedure utilizing cardiopulmonary bypass
• Have evidence of excessive microvascular bleeding in the surgical field as determined by the surgical team in addition to a PT \>16.6 sec or INR \>1.6 sec.

You may not qualify if:

• Subjects who have one or more of the following will be excluded from the study:
• Are unable to grant informed consent or comply with study procedure
• History of hypercoagulable condition (e.g. Factor V Leiden, AT-3 deficiency, Prothrombin gene mutation, Anti-phospholipid antibody syndrome, etc) or previous unprovoked thromboembolic complications
• Coagulopathic conditions such as factor deficiencies, factor inhibitors, heparin induced thrombocytopenia, or use of intravenous anticoagulants other than heparin at the time of cardiovascular surgery
• Thromboembolic event within past 3 months
• Received oral therapy with clopidogrel, prasugrel, rivaroxaban or dabigatran within the past 5 days
• Patients taking chronic warfarin therapy who have not discontinued treatment and demonstrated an INR \<1.3 prior to surgery
• Fibrinogen level \<150 mg/dL on initial post cardiopulmonary bypass labs
• Antithrombin 3 level \< 80% control (preoperative)
• Are undergoing emergency open heart-surgery
• Cardiopulmonary bypass time is expected to be \< 30 minutes
• Age \< 18 years of age
• Are pregnant

Sponsors & Collaborators

• Mayo Clinic: lead
• CSL Behring: collaborator

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Related Publications (20)

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  PMID: 22623627 BACKGROUND

• Ballotta A, Saleh HZ, El Baghdady HW, Gomaa M, Belloli F, Kandil H, Balbaa Y, Bettini F, Bossone E, Menicanti L, Frigiola A, Bellucci C, Mehta RH. Comparison of early platelet activation in patients undergoing on-pump versus off-pump coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2007 Jul;134(1):132-8. doi: 10.1016/j.jtcvs.2007.01.055.

  PMID: 17599498 BACKGROUND

• Demeyere R, Gillardin S, Arnout J, Strengers PF. 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 Oct;99(3):251-60. doi: 10.1111/j.1423-0410.2010.01339.x.

  PMID: 20840339 BACKGROUND

• Ferreira J, DeLosSantos M. The clinical use of prothrombin complex concentrate. J Emerg Med. 2013 Jun;44(6):1201-10. doi: 10.1016/j.jemermed.2012.12.022. Epub 2013 Apr 18.

  PMID: 23602147 BACKGROUND

• Goldberg AD, Kor DJ. State of the art management of transfusion-related acute lung injury (TRALI). Curr Pharm Des. 2012;18(22):3273-84. doi: 10.2174/1381612811209023273.

  PMID: 22621274 BACKGROUND

• Gorlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, Jakob H, Peters J. 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 Dec;115(6):1179-91. doi: 10.1097/ALN.0b013e31823497dd.

  PMID: 21970887 BACKGROUND

• Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, Fukushima J, Kalil Filho R, Sierra DB, Lopes NH, Mauad T, Roquim AC, Sundin MR, Leao WC, Almeida JP, Pomerantzeff PM, Dallan LO, Jatene FB, Stolf NA, Auler JO Jr. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010 Oct 13;304(14):1559-67. doi: 10.1001/jama.2010.1446.

  PMID: 20940381 BACKGROUND

• Hanke AA, Joch C, Gorlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth. 2013 May;110(5):764-72. doi: 10.1093/bja/aes501. Epub 2013 Jan 18.

  PMID: 23335567 BACKGROUND

• Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e152S-e184S. doi: 10.1378/chest.11-2295.

  PMID: 22315259 BACKGROUND

• Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4.

  PMID: 22473649 BACKGROUND

• Levy JH, Faraoni D, Spring JL, Douketis JD, Samama CM. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology. 2013 Jun;118(6):1466-74. doi: 10.1097/ALN.0b013e318289bcba.

  PMID: 23416382 BACKGROUND

• Nuttall GA, Oliver WC, Santrach PJ, Bryant S, Dearani JA, Schaff HV, Ereth MH. Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology. 2001 May;94(5):773-81; discussion 5A-6A. doi: 10.1097/00000542-200105000-00014.

  PMID: 11388527 BACKGROUND

• Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012 May;52 Suppl 1(Suppl 1):65S-79S. doi: 10.1111/j.1537-2995.2012.03663.x.

  PMID: 22578374 BACKGROUND

• ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

  PMID: 22797452 BACKGROUND

• Thiele RH, Raphael J. A 2014 Update on Coagulation Management for Cardiopulmonary Bypass. Semin Cardiothorac Vasc Anesth. 2014 Jun;18(2):177-89. doi: 10.1177/1089253214534782.

  PMID: 24876232 BACKGROUND

• Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. doi: 10.1097/01.ccm.0000159849.94750.51.

  PMID: 15818095 BACKGROUND

• 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.

  PMID: 25822921 BACKGROUND

• Welsby IJ, Schroeder DR, Ghadimi K, Nuttall GA, Smith MM. Thrombin generation after prothrombin complex concentrate or plasma transfusion during cardiac surgery. J Thromb Thrombolysis. 2025 Feb;58(2):309-318. doi: 10.1007/s11239-024-03061-3. Epub 2024 Dec 4.

  PMID: 39633218 DERIVED

• Hayes K, Fernando MC, Jordan V. Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding. Cochrane Database Syst Rev. 2022 Nov 21;11(11):CD013551. doi: 10.1002/14651858.CD013551.pub2.

  PMID: 36408876 DERIVED

• Smith MM, Schroeder DR, Nelson JA, Mauermann WJ, Welsby IJ, Pochettino A, Montonye BL, Assawakawintip C, Nuttall GA. Prothrombin Complex Concentrate vs Plasma for Post-Cardiopulmonary Bypass Coagulopathy and Bleeding: A Randomized Clinical Trial. JAMA Surg. 2022 Sep 1;157(9):757-764. doi: 10.1001/jamasurg.2022.2235.

  PMID: 35767271 DERIVED

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Hemorrhage; Blood Loss, Surgical

Interventions

Factor IX

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Intraoperative Complications

Intervention Hierarchy (Ancestors)

Enzyme Precursors; Enzymes and Coenzymes; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Gregory A. Nuttall, M.D.
• Organization: Mayo Clinic

gnuttall@mayo.edu

(507) 255-3298

Study Officials

• Gregory Nuttall, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PI

Study Record Dates

• First Submitted: September 21, 2015
• First Posted: September 23, 2015
• Study Start: August 1, 2016
• Primary Completion: June 1, 2021
• Study Completion: January 1, 2022
• Last Updated: June 7, 2022
• Results First Posted: June 7, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)