RiaSTAP vs. Conventional Transfusion in Patients Having Heart Valve Surgery

Study Overview
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Brief Summary
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Heart surgery involving valve replacement often involves the use of the heart-lung machine for over 90 minutes, and bleeding tendency is frequently seen. Conventionally, platelet transfusion has been the primary therapy to treat bleeding after this type of procedure. More recently, perioperative supplementation of purified fibrinogen (RiaSTAP, CSL Behring) was shown to reduce bleeding and blood product use (plasma or platelets) after heart surgery. The objective of this trial is to demonstrate the clinical equivalency and economic utility of using fibrinogen concentrate, RiaSTAP for the mitigation of post-operative bleeding in patients in lieu of platelet transfusion. Purified fibrinogen concentrate has been approved by FDA, and it has been used for the treatment of acute bleeding episodes in patients with low fibrinogen due to hereditary causes (e.g., afibrinogenemia). Compared to the transfusion of platelets which may be associated with volume overload, bacterial/viral infection, immunological effects and excess blood clotting, purified fibrinogen has several advantages. First, it contains no liquid plasma allowing for low volume infusion. Several viral inactivation/reduction steps are used to prepare the fibrinogen concentrate, increasing its viral safety. No antibodies or white blood cells are contained in the fibrinogen concentrate; therefore transfusion reactions are rare. Although platelet transfusion is widely used after heart surgery, there has been no randomized study to endorse this practice. In this study, patients undergoing heart valve replacement will be randomized to receive either platelet (1 unit) transfusion or fibrinogen concentrate (4g) after heparin anticoagulation is reversed. Subjects will be treated only if there is evidence of significant microvascular bleeding. Fifteen minutes after the initial treatment, subjects will be reevaluated for bleeding. If bleeding continues, subjects will be treated with blood transfusion per institutional standard of care. The primary endpoints for this study are the hemostatic condition of the surgical field and 24-hour total of blood product transfusion.

Detailed Description
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Platelet and plasma transfusion remain in the mainstay hemostatic therapy for perioperative bleeding. Several studies indicate that acquired fibrinogen deficiency can be the primary cause of bleeding after cardiac surgery. The aim of the study is to compare hematologica and transfusion profiles between the first-line fibrinogen replacement and platelet transfusion in post-cardiac surgical bleeding. In this prospective randomized, open-lable study, 20 adult patients undergoing valve replacement or repair, and fulfilling preset visual bleeding scale (0=excellent hemostasis; 1=oozing; 2=moderate bleeding; 3=severe bleeding from multiple bleeding sites) are randomized to 4 g of fibrinogen or 1 unit of apheresis platelet transfusion. After the initial randomized intervention, additional transfusions are given in the presence of bleeding (>200 ml/hour) according to the institutional practie as follows; 1 apheresis platelet unit if platelet count is less than 100 x 10^9 /L, 2 units of plasma if international normalized ratio is >1.6, or 10 units of cryoprecipitate if fibrinogen level is <200 mg/dL. Primary endpoints include hemostatic condition in the surgical field and 24-hour hemostatic product usage. Hematologica data, clinical outcome, and safety date are collected up to the 28th day postoperative visit.

Official Title
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RiaSTAP vs. Conventional Transfusion for Patients Undergoing Valve Replacement Surgery: RiaCT

Conditions
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Heart Valve Disease, Coronary Artery Disease

Intervention / Treatment
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* Drug: Human fibrinogen concentrate
* Other: apheresis platelets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent Age >17 and < 86 years Patients undergoing planned cardiopulmonary bypass (CPB) for: combined coronary artery bypass grafting and valve replacement/repair surgery single valve replacement surgery mitral valve repair surgery 3. or double valve surgery (aortic and mitral) Presence of clinically relevant microvascular bleeding after protamine administration (hemostasis assessment score of 2-3) Patients should fulfill the following parameters prior to the study intervention: Body temperature > 35.0°C Blood pH > 7.2 Hb > 7.0 mg/dL Activated clotting time (ACT) < 155 seconds CPB time > 60 minutes Exclusion Criteria: Replacement of aorta Planned valve replacement without median sternotomy Previous valve replacement surgery (previous coronary artery bypass graft (CABG) acceptable) History or suspicion of a congenital or acquired coagulation disorder such as hemophilia, von Willebrand disease, and liver disease Hemodialysis dependent renal failure Liver dysfunction (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increased ≥ 2-fold above the upper limit of local laboratory normal ranges) Known allergy/anaphylaxis to fibrinogen concentrate or apheresis platelet units Clopidogrel administration within 5 days of surgery Coumadin (warfarin) administration within 5 days of surgery Participation in another clinical study in the 4 weeks preceding surgery Any indication that a potential subject did not comprehend the study restrictions, procedures, or consequences therein an informed consent cannot be convincingly given Life expectancy less than 48 hours

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: RiaSTAP<br>Human fibrinogen concentrate | Drug: Human fibrinogen concentrate<br>* 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding<br>* Other names: RiaSTAP;|
| Active Comparator: Group B: apheresis platelets<br>single apheresis unit | Other: apheresis platelets<br>* A single apheresis platelet unit will be administered as an initial therapy within 30 minutes of ACT <155 seconds post CPB with evidence of significant microvascular bleeding.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding Scores | Bleeding scores are scored on a four-point scale. A visual assessment of surgical field was performed by the senior surgical staff as follows: 0 = excellent hemostasis (dry field), 1 = mild bleeding (oozing), 2 = moderate bleeding (controllable with applied pressure), and 3 = severe bleeding (multiple diffuse bleeding sites). If the visual bleeding scale was 2 to 3, the subjects were randomly assigned to a study intervention using a closed envelope method. | intra-operatively and up to 24 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery. |  | Operative period up to 60 minutes | 
| Volume (mL) of Fresh-frozen Plasma (FFP) Transfused-during Surgery and up to 24 Hours After Surgery |  | Operative period up to 60 minutes and up to 24 hours after surgery | 
| Volume (mL) of Platelets Transfused- During Surgery and up to 24 Hours After Surgery |  | Operative period up to 60 minutes and up to 24 hours after surgery | 
| Median Blood Loss (mL) at 12 Hours After Surgery |  | From end of surgery to 12 hours after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemostasis, Cardiopulmonary bypass (heart-lung machine), Fibrinogen, platelet