Coronary Artery Disease, Heart Valve Disease
Conditions
Keywords
Hemostasis, Cardiopulmonary bypass (heart-lung machine), Fibrinogen, platelet
Brief summary
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
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.
Interventions
4 g IV once, within 30 minutes of ACT \< 155 seconds, post CPB, with evidence of significant microvascular bleeding
OTHERapheresis platelets
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.
Sponsors
CSL Behring
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide written informed consent * Age \>17 and \< 86 years * Patients undergoing planned cardiopulmonary bypass (CPB) for: 1. combined coronary artery bypass grafting and valve replacement/repair surgery 2. single valve replacement surgery 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Scores | intra-operatively and up to 24 hours postoperatively | 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. |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Recruitment details
Enrollment started in February 2011 and the study was completed in May 2012. Subjects were recruited from Emory University. Fifty-one patients were approached after initial screening for eligibility, and 26 patients were consented.
Pre-assignment details
Two subjects were excluded due to a change in surgical plans. Two subjects had low bleeding scores and were excluded.One subject had screening labs that were out of range for the study. One subject was treated using Dabigatran treatment. Total of six subjects that were excluded prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Group A: RiaSTAP Human fibrinogen concentrate
Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT \< 155 seconds, post CPB, with evidence of significant microvascular bleeding | 10 |
| Group B: Apheresis Platelets single apheresis unit
apheresis platelets: 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. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Group A: RiaSTAP | Group B: Apheresis Platelets | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 8 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 71.3 years STANDARD_DEVIATION 5.3 | 66.1 years STANDARD_DEVIATION 8.9 | 68.7 years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 10 | 5 / 10 |
| serious Total, serious adverse events | 1 / 10 | 6 / 10 |
Outcome results
Primary
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.
Time frame: intra-operatively and up to 24 hours postoperatively
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: RiaSTAP | Bleeding Scores | Intraoperative | 2.0 units on a scale | Standard Deviation 0 |
| Group A: RiaSTAP | Bleeding Scores | Postoperative | 1.0 units on a scale | Standard Deviation 0.7 |
| Group B: Apheresis Platelets | Bleeding Scores | Intraoperative | 2.1 units on a scale | Standard Deviation 0.3 |
| Group B: Apheresis Platelets | Bleeding Scores | Postoperative | 1.7 units on a scale | Standard Deviation 0.8 |
Secondary
Median Blood Loss (mL) at 12 Hours After Surgery
Time frame: From end of surgery to 12 hours after surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: RiaSTAP | Median Blood Loss (mL) at 12 Hours After Surgery | 925 ml |
| Group B: Apheresis Platelets | Median Blood Loss (mL) at 12 Hours After Surgery | 1315 ml |
Secondary
Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery.
Time frame: Operative period up to 60 minutes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: RiaSTAP | Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery. | 4 Participants |
| Group B: Apheresis Platelets | Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery. | 10 Participants |
Secondary
Volume (mL) of Fresh-frozen Plasma (FFP) Transfused-during Surgery and up to 24 Hours After Surgery
Time frame: Operative period up to 60 minutes and up to 24 hours after surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: RiaSTAP | Volume (mL) of Fresh-frozen Plasma (FFP) Transfused-during Surgery and up to 24 Hours After Surgery | 0 ml |
| Group B: Apheresis Platelets | Volume (mL) of Fresh-frozen Plasma (FFP) Transfused-during Surgery and up to 24 Hours After Surgery | 650 ml |
Secondary
Volume (mL) of Platelets Transfused- During Surgery and up to 24 Hours After Surgery
Time frame: Operative period up to 60 minutes and up to 24 hours after surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: RiaSTAP | Volume (mL) of Platelets Transfused- During Surgery and up to 24 Hours After Surgery | 0 ml |
| Group B: Apheresis Platelets | Volume (mL) of Platelets Transfused- During Surgery and up to 24 Hours After Surgery | 500 ml |