Fibrinogen Concentrate vs Cryoprecipitate

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03014700
• Collaborator: Emory University (Other)
• Enrollment: 60
• Locations: 2
• Arms: 2
• Actual Duration (Months): 25.8
• Patients Per Site: 30
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

One of the most common hemostatic derangements in pediatric open- heart surgery is an acute acquired hypofibrinogenemia. This compromises fibrin clot generation and platelet aggregation, resulting in increased bleeding and allogenic blood transfusions.

Currently, fresh frozen plasma and cryoprecipitate are used to supplement fibrinogen in pediatric cardiac patients. We propose that replacing cryoprecipitate with fibrinogen concentrate will be as effective in treating post-CPB bleeding and will decrease total blood product exposure when used as part of a blood transfusion algorithm.

We plan to include all patients undergoing cardiac surgery on CPB less than 12 months and a fibrinogen level <250mg/dL while on bypass.

We hope to demonstrate that fibrinogen concentrate is at least as effective as the standard of care in the management of peri- operative bleeding in neonatal patients undergoing cardiopulmonary bypass. If we are able to demonstrate that fibrinogen is at least as effective as the standard of care, then we would plan a multi-center trial to demonstrate the safety and efficacy of this medication. If we are able to demonstrate that fibrinogen concentrate is effective, fibrinogen concentrate could replace allogenic products and potentially decrease transfusion related morbidity in mortality in this population.

Condition or Disease	Intervention/Treatment	Phase
Congenital Heart Disease	Biological: Fibrinogen Concentrate; Biological: Cryoprecipitate	Phase 4

Detailed Description

Patients under 12 months of age requiring cardiopulmonary bypass surgery will be approached for the study. Patients with a pre- existing coagulopathy, including unexplained bleeding or history of clotting, will be excluded. Prior to the study beginning, patients will be randomized to our standard transfusion algorithm with cryoprecipitate or fibrinogen concentrate. As is standard of care, laboratory tests will be sent at standard times points

1. after the induction of anesthesia,

2. after initiation of bypass,

3. after separation from bypass and administration of protamine, and transfusion of either fibrinogen concentrate or cryoprecipitate

4. on arrival to the ICU. These laboratory tests include hematocrit, arterial blood gas, chemistry, thromboelastogram (TEG) and fibrinogen. Additional laboratory tests will be sent as indicated by the clinical scenario to determine transfusion requirements. For patients enrolled in the study, we will standardize the anesthetic management, cardiopulmonary bypass protocol, and transfusion thresholds in the operating room and ICU. We will collect demographic data, intraop and post-op laboratory values, bypass times, intraop and post op transfusion data, chest tube output, adverse events, and length of ventilation, ICU stay and hospital stay.

For patients randomized to the study arm (fibrinogen concentrate), the fibrinogen level measured on bypass will be used to calculate the appropriate dose of fibrinogen concentrate to achieve a level of 300mg/dL after separation from bypass. Fibrinogen concentrate will replace cryoprecipitate in our post-operative transfusion algorithm. If the patient has continued bleeding based on laboratory values and clinical situation, the patient will be given cryoprecipitate as a rescue measure. Patients not on the study protocol will receive our normal transfusion algorithm.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Care Provider)
• Primary Purpose: Treatment
• Official Title: Repurposing of Fibrinogen Concentrate as a Cost-Effective and Safe Hemostatic Agent in Infants Undergoing Cardiac Surgery on Cardiopulmonary Bypass
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Apr 25, 2018
• Actual Study Completion Date: Apr 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Cryoprecipitate Arm Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Biological: Cryoprecipitate; Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group
Active Comparator: Fibrinogen Concentrate Arm Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group	Biological: Fibrinogen Concentrate; Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group

Outcome Measures

Primary Outcome Measures

1. Total Units of Intraoperative Allogenic Donor Transfusions (ADT) Administered During Procedure Through ICU Arrival. [From administration of the drug during surgery to ICU arrival postoperatively (up to 24 hours)]

   For our study, 1 donor exposure = 1 unit of blood product transfusion. A blood product includes red blood cells, fresh frozen plasma, cryoprecipitate, and platelets.

Secondary Outcome Measures

1. Chest Tube Output [From administration end of surgery to 24 hours post operatively]

   Volume of chest tube drainage evaluated over first 24 hours post operatively

2. Hours of Mechanical Ventilation [From administration of the drug during surgery to extubation in the ICU (up to 30 days)]

3. Length of Stay in Intensive Care Unit (ICU) [From administration of the drug during surgery to discharge from the ICU (up to 3 months)]

4. Length of Stay in Hospital [From administration of the drug during surgery to discharge from the hospital (up to 6 months)]

5. Count of Participants Who Died Within 30 Days Following Procedure [From administration of the drug to 30 days following surgery]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Day to 12 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Neonates of at least 32 weeks of gestational age and infants up to 12 months of age with the diagnosis of congenital heart disease, requiring open heart surgery with cardiopulmonary bypass

Exclusion Criteria:

• Pre-existing coagulopathy, including unexplained bleeding or history of clotting

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Stanford	California	United States	94305
2	Laura Downey	Emory	Georgia	United States	30322

Sponsors and Collaborators

• Stanford University
• Emory University

Investigators

• Principal Investigator: Glyn D Williams, MBChB, FFA, Stanford University
• Principal Investigator: Laura Downey, MD, Emory University

Study Documents (Full-Text)

• Study Protocol - Feb 3, 2017
• Statistical Analysis Plan - Mar 8, 2019

More Information

Publications

None provided.

• Responsible Party: Glyn David Williams, Professor, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT03014700
• Other Study ID Numbers: 36374
• First Posted: Jan 9, 2017
• Last Update Posted: May 7, 2019
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Heart Diseases; Heart Defects, Congenital

Study Results

Participant Flow

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Period Title: Overall Study
STARTED	30	30
COMPLETED	25	29
NOT COMPLETED	5	1

Baseline Characteristics

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm	Total
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group	Total of all reporting groups
Overall Participants	30	30	60
Age (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	4	4	4
Sex: Female, Male (Count of Participants)
Female	16 53.3%	9 30%	25 41.7%
Male	14 46.7%	21 70%	35 58.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.3%	3 10%	4 6.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 10%	5 16.7%	8 13.3%
White	22 73.3%	18 60%	40 66.7%
More than one race	0 0%	1 3.3%	1 1.7%
Unknown or Not Reported	4 13.3%	3 10%	7 11.7%

Outcome Measures

1. Primary Outcome

Title	Total Units of Intraoperative Allogenic Donor Transfusions (ADT) Administered During Procedure Through ICU Arrival.
Description	For our study, 1 donor exposure = 1 unit of blood product transfusion. A blood product includes red blood cells, fresh frozen plasma, cryoprecipitate, and platelets.
Time Frame	From administration of the drug during surgery to ICU arrival postoperatively (up to 24 hours)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	30	30
Median (Inter-Quartile Range) [ADT units]	5	4

2. Secondary Outcome

Title	Chest Tube Output
Description	Volume of chest tube drainage evaluated over first 24 hours post operatively
Time Frame	From administration end of surgery to 24 hours post operatively

Outcome Measure Data

Analysis Population Description

Participants who completed the protocol are included in the analysis

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	25	29
Median (Inter-Quartile Range) [ml/kg]	18.05	16.11

3. Secondary Outcome

Title	Hours of Mechanical Ventilation
Time Frame	From administration of the drug during surgery to extubation in the ICU (up to 30 days)

Outcome Measure Data

Analysis Population Description

Participants who completed the protocol are included in the analysis

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	25	29
Median (Inter-Quartile Range) [hours]	30.32	27.10

4. Secondary Outcome

Title	Length of Stay in Intensive Care Unit (ICU)
Time Frame	From administration of the drug during surgery to discharge from the ICU (up to 3 months)

Outcome Measure Data

Analysis Population Description

Participants who completed the protocol are included in the analysis

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	25	29
Median (Inter-Quartile Range) [days]	4.50	3.00

5. Secondary Outcome

Title	Length of Stay in Hospital
Time Frame	From administration of the drug during surgery to discharge from the hospital (up to 6 months)

Outcome Measure Data

Analysis Population Description

Participants who completed the protocol are included in the analysis

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	25	29
Median (Inter-Quartile Range) [days]	8.00	7.00

6. Secondary Outcome

Title	Count of Participants Who Died Within 30 Days Following Procedure
Time Frame	From administration of the drug to 30 days following surgery

Outcome Measure Data

Analysis Population Description

Participants who completed the protocol are included in the analysis

Arm/Group Title	Cryoprecipitate Arm	Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group	Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
Measure Participants	25	29
Count of Participants [Participants]	0 0%	1 3.3%

Adverse Events

Time Frame	Day of procedure through 30 days postoperatively or hospital discharge
Arm/Group Title	Cryoprecipitate Arm		Fibrinogen Concentrate Arm
Arm/Group Description	Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group Cryoprecipitate: Subject will be administered Cryoprecipitate to control bleeding after open heart surgery when randomized to Cryoprecipitate group		Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group Fibrinogen Concentrate: Subject will be administered Fibrinogen Concentrate to control bleeding after open heart surgery when randomized to Fibrinogen Concentrate group
All Cause Mortality
	Cryoprecipitate Arm		Fibrinogen Concentrate Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		1/30 (3.3%)
Serious Adverse Events
	Cryoprecipitate Arm		Fibrinogen Concentrate Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		4/30 (13.3%)
Cardiac disorders
Tamponade	0/30 (0%)		1/30 (3.3%)
General disorders
Death	0/30 (0%)		1/30 (3.3%)
Nervous system disorders
Stroke	1/30 (3.3%)		0/30 (0%)
Respiratory, thoracic and mediastinal disorders
Chest Exploration	1/30 (3.3%)		2/30 (6.7%)
Vascular disorders
Thrombosis requiring Intervention	0/30 (0%)		1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Cryoprecipitate Arm		Fibrinogen Concentrate Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/30 (26.7%)		5/30 (16.7%)
Cardiac disorders
Arrhythmia requiring treatment	6/30 (20%)		5/30 (16.7%)
Infections and infestations
Infection (with positive culture within 14 days)	1/30 (3.3%)		0/30 (0%)
Surgical and medical procedures
Repeat Surgery (less than 7 days)	2/30 (6.7%)		0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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