RiaCT: RiaSTAP vs. Conventional Transfusion in Patients Having Heart Valve Surgery

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01283321
• Collaborator: CSL Behring (Industry)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 28
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Valve Disease; Coronary Artery Disease	Drug: Human fibrinogen concentrate; Other: apheresis platelets	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: RiaSTAP vs. Conventional Transfusion for Patients Undergoing Valve Replacement Surgery: RiaCT
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: RiaSTAP Human fibrinogen concentrate	Drug: Human fibrinogen concentrate; 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding; Other Names: RiaSTAP
Active Comparator: Group B: apheresis platelets single apheresis unit	Other: 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery. [Operative period up to 60 minutes]

2. 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]

3. 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]

4. Median Blood Loss (mL) at 12 Hours After Surgery [From end of surgery to 12 hours after surgery]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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

4. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• CSL Behring

Investigators

• Principal Investigator: Gautam Sreeram, MD, Emory University
• Principal Investigator: Kenichi Tanaka, MD, MSc, University of Maryland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gautam Sreeram, MD, Emory University
• ClinicalTrials.gov Identifier: NCT01283321
• Other Study ID Numbers: IRB00036062; RiaCT 2010
• First Posted: Jan 25, 2011
• Last Update Posted: Jun 21, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Gautam Sreeram, MD, Emory University: Hemostasis; Cardiopulmonary bypass (heart-lung machine); Fibrinogen; platelet
• Additional relevant MeSH terms: Coronary Artery Disease; Heart Valve Diseases

Study Results

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 Detail	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.

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding	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.
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets	Total
Arm/Group Description	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	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.	Total of all reporting groups
Overall Participants	10	10	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	2 20%	2 10%
>=65 years	10 100%	8 80%	18 90%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.3 (5.3)	66.1 (8.9)	68.7 (7.6)
Sex: Female, Male (Count of Participants)
Female	2 20%	2 20%	4 20%
Male	8 80%	8 80%	16 80%

Outcome Measures

1. Primary Outcome

Title	Bleeding Scores
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	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	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.
Measure Participants	10	10
Intraoperative	2.0 (0.0)	2.1 (0.3)
Postoperative	1.0 (0.7)	1.7 (0.8)

2. Secondary Outcome

Title	Number of Participants in Whom Transfusion of Platelet Concentrate is Required During or After Surgery.
Time Frame	Operative period up to 60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding	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.
Measure Participants	10	10
Count of Participants [Participants]	4 40%	10 100%

3. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding	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.
Measure Participants	10	10
Median (Inter-Quartile Range) [ml]	0	650

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding	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.
Measure Participants	10	10
Median (Inter-Quartile Range) [ml]	0	500

5. Secondary Outcome

Title	Median Blood Loss (mL) at 12 Hours After Surgery
Time Frame	From end of surgery to 12 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A: RiaSTAP	Group B: Apheresis Platelets
Arm/Group Description	Human fibrinogen concentrate: 4 g IV once, within 30 minutes of ACT < 155 seconds, post CPB, with evidence of significant microvascular bleeding	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.
Measure Participants	10	10
Median (Inter-Quartile Range) [ml]	925	1315

Adverse Events

Time Frame	Reported adverse events (AEs) include events starting during the surgery (intraoperative) and on and before 30 days after surgery (post-operative).
Arm/Group Title	Group A: RiaSTAP		Group B: Apheresis Platelets
Arm/Group Description	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		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.
All Cause Mortality
	Group A: RiaSTAP		Group B: Apheresis Platelets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A: RiaSTAP		Group B: Apheresis Platelets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		6/10 (60%)
Cardiac disorders
Atrial Fibrillation	0/10 (0%)		2/10 (20%)
Acute myocardial infarction	0/10 (0%)		1/10 (10%)
Injury, poisoning and procedural complications
Excessive mediastinal bleeding	1/10 (10%)		3/10 (30%)
Other (Not Including Serious) Adverse Events
	Group A: RiaSTAP		Group B: Apheresis Platelets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		5/10 (50%)
Respiratory, thoracic and mediastinal disorders
Pulmonary edema	3/10 (30%)		5/10 (50%)

Limitations/Caveats

Early termination leading to small number of subjects analyzed

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.