Administration of Prothrombin Complex Concentrate vs. Standard Transfusion During/After Heart Transplantation

Heart Failure,Congestive Clinical Trial

— OPSTAHT  

Official title:

Optimized Administration of Prothrombin Complex Concentrate (PCC) vs. Standard Transfusion During/After Heart Transplantation - OPSTAHT

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03341156
• Other study ID #: STUDY19020099
• Status: Recruiting
• Phase: Phase 3
• Start date: July 11, 2018
• Est. completion date: December 1, 2024

Study information

• Verified date: January 2024
• Source: University of Pittsburgh
• Contact: Amy Monroe
• Phone: 412-623-6382
• Email: Monroeal[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is comparing the use of Kcentra vs. standard transfusion in patients undergoing heart transplantation surgery. Half of the patients will receive Kcentra, while the other half will receive fresh frozen plasma.

Description:

This study will be a randomized (1:1; PCC vs. plasma), open-label trial of hemostatic therapies during heart transplantation. The goal is to enroll 60 patients. Informed consent will be obtained from patients meeting the inclusion and exclusion criteria before the initiation of any study specific procedures. Eligible patients will be randomized to receive either PCC or plasma transfusion. The efficacy of interventions will be evaluated after 30 minutes of protamine administration. After the heart transplantation, thrombocytopenia and/or hypofibrinogenemia may worsen bleeding associated with vitamin K dependent factor deficiencies. Transfusion of platelets and/or cryoprecipitate is permitted if abnormal laboratory values are observed during the rewarming phase of CPB; platelet count <100 x 103/µl, and fibrinogen <200 mg/dl, respectively. Laboratory tests (hematocrit, platelet count, PT, PTT, POC-PT, coagulation factor and inhibitor levels (e.g., factor II, antithrombin), thromboelastometry or thromboelastography, endogenous thrombin generation) will also be obtained at baseline, twice during surgery and at 12-24 hours after surgery.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: December 1, 2024
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Be willing and able to provide written informed consent.
• Be at least 18 years of age.
• Patients with or without ventricular assist device (VAD) undergoing heart transplantation
• Patients who have been on warfarin for at least 72 hours before cardiopulmonary bypass procedures for heart transplantation.
• International normalization ration (INR) greater than or equal to 1.5
• Body temperature greater than 35.0 degrees Celsius.
• Blood pH greater than 7.2
• Hemoglobin greater than 7.0 mg/dL.

Exclusion Criteria:

• Treatment with clopidogrel, prasugrel, or ticagrelor within 5 days prior to study surgery.
• Known or suspected thrombophilia such as factor V Leiden, hereditary antithrombin III deficiency, heparin-induced thrombocytopenia, disseminated intravascular coagulation.
• Ischemic or thromboembolic events within 6 weeks of study surgery.
• Known allergy/anaphylaxis to prothrombin complex concentrate or albumin.
• Any indication that a potential subject did not comprehend the study restrictions, procedures. or consequences therein an informed consent cannot be convincingly given.
• Patients on respiratory support including extracorporeal membrane oxygenation (ECMO) .
• Life expectancy less than 48 hours.
• Excluded at the discretion of the surgeon based upon surgical safety precautions

Related Conditions & MeSH terms

• Heart Disease End Stage
• Heart Diseases
• Heart Failure
• Heart Failure,Congestive

Intervention

Drug:
• Kcentra
Kcentra will be administered in 2 divided doses; Pre-bypass (5-10 units/kg based on body weight and preoperative INR and post-protamine based of the pre-bypass dose and the preoperative INR; daily maximum dose not to exceed 5000 IU (50 IU/kg)
• Frozen Plasma Product, Human
If the patient is randomized to receive standard transfusion they will receive 2 U of fresh frozen plasma intravenously before cardiopulmonary bypass and then up to 4-8 U of plasma added to the cardiopulmonary bypass reservoir during rewarming.

Locations

Country	Name	City	State
United States	University of Maryland	Baltimore	Maryland
United States	Upmc Presbyterian Montefiore Hospital	Pittsburgh	Pennsylvania
United States	UPMC Presbyterian Shadyside	Pittsburgh	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Kathirvel Subramaniam	CSL Behring, University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (17)

Balsam LB, Timek TA, Pelletier MP. Factor eight inhibitor bypassing activity (FEIBA) for refractory bleeding in cardiac surgery: review of clinical outcomes. J Card Surg. 2008 Nov-Dec;23(6):614-21. doi: 10.1111/j.1540-8191.2008.00686.x. Epub 2008 Sep 10. — View Citation

Bolliger D, Gorlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology. 2010 Nov;113(5):1205-19. doi: 10.1097/ALN.0b013e3181f22b5a. — View Citation

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. — View Citation

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. — View Citation

Kantorovich A, Fink JM, Militello MA, Wanek MR, Smedira NG, Soltesz EG, Moazami N. Low-dose 3-factor prothrombin complex concentrate for warfarin reversal prior to heart transplant. Ann Pharmacother. 2015 Aug;49(8):876-82. doi: 10.1177/1060028015585344. Epub 2015 May 18. — View Citation

Karkouti K, McCluskey SA, Syed S, Pazaratz C, Poonawala H, Crowther MA. The influence of perioperative coagulation status on postoperative blood loss in complex cardiac surgery: a prospective observational study. Anesth Analg. 2010 Jun 1;110(6):1533-40. doi: 10.1213/ANE.0b013e3181db7991. Epub 2010 Apr 30. — View Citation

Marshall AL, Levine M, Howell ML, Chang Y, Riklin E, Parry BA, Callahan RT, Okechukwu I, Ayres AM, Nahed BV, Goldstein JN. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost. 2016 Feb;14(2):324-30. doi: 10.1111/jth.13212. Epub 2016 Feb 2. — View Citation

Mathias T, Puca KE, Downey F, Boyle AJ: Use of Vitamin K and Prothrombin Complex Concentrate as Warfarin Reversal Prior to Heart Transplant. Journal of Heart and Lung Transplantation 2012; 31: S154

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. — View Citation

Rao VK, Lobato RL, Bartlett B, Klanjac M, Mora-Mangano CT, Soran PD, Oakes DA, Hill CC, van der Starre PJ. Factor VIII inhibitor bypass activity and recombinant activated factor VII in cardiac surgery. J Cardiothorac Vasc Anesth. 2014 Oct;28(5):1221-6. doi: 10.1053/j.jvca.2014.04.015. — View Citation

Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013 Sep 10;128(11):1234-43. doi: 10.1161/CIRCULATIONAHA.113.002283. Epub 2013 Aug 9. — View Citation

Scott E, Puca K, Heraly J, Gottschall J, Friedman K. Evaluation and comparison of coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6 degrees C storage. Transfusion. 2009 Aug;49(8):1584-91. doi: 10.1111/j.1537-2995.2009.02198.x. — View Citation

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. — View Citation

Subramaniam K. Early graft failure after heart transplantation: prevention and treatment. Int Anesthesiol Clin. 2012 Summer;50(3):202-27. doi: 10.1097/AIA.0b013e3182603ead. No abstract available. — View Citation

Tanaka KA, Mazzeffi MA, Grube M, Ogawa S, Chen EP. Three-factor prothrombin complex concentrate and hemostasis after high-risk cardiovascular surgery. Transfusion. 2013 Apr;53(4):920-1. doi: 10.1111/trf.12110. No abstract available. — View Citation

Tanaka KA, Mazzeffi MA, Strauss ER, Szlam F, Guzzetta NA. Computational simulation and comparison of prothrombin complex concentrate dosing schemes for warfarin reversal in cardiac surgery. J Anesth. 2016 Jun;30(3):369-76. doi: 10.1007/s00540-015-2128-3. Epub 2016 Jan 9. — View Citation

Tholpady A, Monson J, Radovancevic R, Klein K, Bracey A. Analysis of prolonged storage on coagulation Factor (F)V, FVII, and FVIII in thawed plasma: is it time to extend the expiration date beyond 5 days? Transfusion. 2013 Mar;53(3):645-50. doi: 10.1111/j.1537-2995.2012.03786.x. Epub 2012 Jul 15. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Direct Cost Benefit	Acquisition costs for test agents and blood bank related charges (thawing, etc.)	From infusion until 30 days post heart transplant
Other	Total surgical time	Total time of surgical duration will be measured in the corresponding time frame	From anesthesia start time until anesthesia stop time
Other	Time to hospital discharge	Time until discharge from the hospital post study intervention will be measured	From patient out of room time to hospital discharge (or 30 days post heart transplant, whichever comes first)
Other	Time to Intensive Care Unit (ICU) discharge	Time until discharge from the ICU post study intervention will be measured	From patient out of room time to ICU discharge (or 30 days post heart transplant, whichever comes first)
Other	Indirect Cost Benefits	Extra costs related to study drug (PCC and plasma) related complications (volume overload, thrombotic complications)	From last intervention/infusion until 30 days post heart transplant or until discharge
Primary	Amount of Chest Tube Drainage	Primary outcome: Amount of chest tube output in the first 24 hours	From patient out of room time until 24 hours after
Secondary	Postoperative INR	INR value	30 Minutes post-treatment (after the last dose is completed)
Secondary	Blood Product Use	Total hemostatic blood product use including plasma, platelets, cryoprecipitate, and recombinant activated factor VII.	In OR (from OR entry to OR out of room time); postoperatively (patient out of room time) to 24 hours after; from 24 hours after until 30 days post surgery or until discharge (whichever comes first)
Secondary	Red Blood Cell Use	Red Blood Cell Use Intraoperatively and Postoperatively	Intraoperatively(from start of first intervention until start of second intervention;after 2nd intervention(post-bypass)until patient out of room time) & Postoperatively(from patient out of room time until 24 hours after;24 hours after until 30 days)
Secondary	Need for circulatory support	Percentage of patients who needed circulatory support (ECMO or VAD)	30 days post-operative or until discharge (whichever comes first)
Secondary	Mechanical Ventilation	Percentage of patients who needed mechanical ventilation for more than 72 hours	30 days post-operative or until discharge (whichever comes first)
Secondary	Tracheostomy	Percentage of patients who needed a tracheostomy	30 days post-operative or until discharge (whichever comes first)
Secondary	Renal Failure	Percentage of patients who experience renal failure requiring dialysis	30 days post-operative or until discharge (whichever comes first)
Secondary	Sepsis	Percentage of patients who experienced sepsis infection morbidity consisted of sepsis syndrome, septic shock, or mediastinitis. In addition, the diagnosis of sepsis included organisms isolated from the cultures along with elevated temperature and white blood cell counts.	30 days post-operative or until discharge (whichever comes first)
Secondary	Death	Percentage of patients who died	30 days post-operative or until discharge (whichever comes first)
Secondary	Stroke or postoperative neurological dysfunction	Percentage of patients who experienced a stroke or postoperative neurological dysfunction (seizures, delirium, unconsciousness, encephalopathy)	30 days post-operative or until discharge (whichever comes first)
Secondary	Gastrointestinal complication requiring bowel resection	Percentage of patients who experienced gastrointestinal complications requiring bowel resection	30 days post-operative or until discharge (whichever comes first)
Secondary	Peripheral vascular complication	Percentage of patients who experience peripheral vascular complications requiring surgery (thrombectomy, bypass, and amputations)	30 days post-operative or until discharge (whichever comes first)
Secondary	Deep Vein Thrombosis and Pulmonary Thromboembolism	Percentage of patients who develop a deep vein thrombosis and/ or pulmonary thromboembolism	30 days post-operative or until discharge (whichever comes first)
Secondary	Plasma Coagulation Factor levels	Plasma coagulator factor levels will be analyzed via blood laboratory tests	At baseline, post-bypass/pre-protamine, 30 minutes post-protamine, 12-24 hours post treatment
Secondary	Thrombin Generation Assay	Thrombin Generation assay will be analyzed via blood laboratory tests	At baseline, post-bypass/pre-protamine, 30 minutes post-protamine, 12-24 hours post treatment
Secondary	Surgical Re-exploration	Surgical Re-Exploration that is related to heart transplant surgery	30 days post-operative or until discharge (whichever comes first)