Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The aim of the study is to show that first line treatment with concentrated fibrinogen has superiority over the conventional therapy with fresh frozen plasma (FFP), platelets, and cryoprecipitate in perioperative management of bleeding after complex cardiac surgery.
All patients will be recruited from the Queen Elizabeth II (QEII) Health Sciences Center, Halifax, Nova Scotia, which is the sole tertiary cardiac surgical referral center in Nova Scotia that performs approximately 1000 open heart surgical procedures yearly, including more than 700 isolated coronary artery bypass graft (CABG) procedures.
Inclusion criteria: All patients who are scheduled for elective complex cardiac surgical procedures including, double procedures (aortic valve replacement+coronary artery bypass graft , mitral valve replacement+coronary artery bypass graft , aortic valve replacement+mitral valve replacement), redo-sternotomies, and aortic root repair +/-aortic valve replacement.
Exclusion criteria: Any known congenital or preexisting bleeding disorder, preexisting clinically significant abnormal fibrinogen level, severe liver disease (alanine aminotransferase or aspartate aminotransferase > 150 U/l), inability of providing informed consent, emergency surgery, pregnancy or nursing, age under 18 years, intake of anti-platelet drugs within the last 2- 5 days before surgery (low dose aspirin is allowed) allergy to concentrated fibrinogen or other components in the product, anemia (Hb < 110), diagnosed deep venous thrombosis, pulmonary embolism, acute stroke or acute myocardial infarction.
The primary outcome: Cumulative perioperative amount (number of units and total volume) of blood components used between the start of surgery and 24 hours after administration of the study drug or placebo. 'Blood Components' are defined as all fresh components of blood (RBCs, plasma, platelets, and Cryo).
The secondary outcomes: Fibrinogen levels, hematocrit, prothrombin time (PT), partial prothrombin time (PTT), INR, platelet count, Hemoglobin (Hb), Thromboelastometry (ROTEM®, clotting time (CT), clot formation time (CFT), Angle, maximum clot firmness (MCF), Cardiovascular intensive care unit (CVICU-stay), Hospital-stay, In-Hospital Mortality, Hemoglobin, adverse events (anaphylaxis, stroke, myocardial infarction, pulmonary embolism, and deep vein thromboembolism) and usage of factor VII concentrate and human prothrombin complex (factors II, VII,IX, X), total avoidance of transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RiaSTAP | Active Comparator | Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula |
|
| Intravenous saline | Placebo Comparator | Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fibrinogen | Drug | Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative Transfusion Units | Including packed red cells, frozen plasma, platelets, cryoprecipitates | 24 hours after administration of study drug |
| Measure | Description | Time Frame |
|---|---|---|
| Fibrinogen Plasma Concentration (g/L) | 24h after infusion of study drug | |
| Hematocrit (%) | 24h after infusion of study drug | |
| Hemoglobin Concentration (g/L) |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Numbers of Patients Receiving Blood Products | Including Packed Red Cells, Fresh Frozen Plasma, Platelets, Cryoprecipitate and coagulation factor concentrates. The study was not sufficiently powered to test differences between this outcome. | 24 hours after administration of study drug |
Inclusion Criteria:
All patients who are scheduled for elective complex cardiac surgical procedures including
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Myron Kwapisz, MD | Nova Scotia Health Authority | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CapitalDHACanada | Halifax | Nova Scotia | B3H3A7 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31889306 | Background | Kwapisz MM, Kent B, DiQuinzio C, LeGare JF, Garnett S, Swyer W, Whynot S, Mingo H, Scheffler M. The prophylactic use of fibrinogen concentrate in high-risk cardiac surgery. Acta Anaesthesiol Scand. 2020 May;64(5):602-612. doi: 10.1111/aas.13540. Epub 2020 Jan 17. |
Not provided
Not provided
Not provided
The investigation included 62 patients (>18 years old) for elective, high-risk cardiac surgery (double procedures (aortic valve replacement (AVR)+coronary artery bypass grafting (CABG), mitral valve repair/replacement (MVR)+CABG, AVR+MVR), redo-sternotomies, and aortic root repair±AVR) with a pre-operative fibrinogen level of ≤3.8 g/L.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | RiaSTAP | Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula Fibrinogen: Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM) |
| FG001 | Intravenous Saline | Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula Placebo: Intravenous saline will be administered with the same volume as study drug |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | RiaSTAP | Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula Fibrinogen: Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM) |
| BG001 | Intravenous Saline |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cumulative Transfusion Units | Including packed red cells, frozen plasma, platelets, cryoprecipitates | Posted | Median | Inter-Quartile Range | Transfusion Units | 24 hours after administration of study drug |
|
All study patients were followed with a phone call interview after 6 weeks, 3, and 6 months post-operatively. All patients were assessed for the following events: angina, re-admission (congestive heart failure [CHF], acute myocardial infarction [AMI], acute coronary syndrome [ACS], and percutaneous coronary intervention [PCI]), incisional wound infection, thromboembolic complications (pulmonary embolism, deep venous thrombosis), repeated cardiac surgery, and cardiac mortality.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | RiaSTAP | Intravenous fibrinogen(RiaSTAP) will be administered according to FIBTEM based calculation formula Fibrinogen: Intravenous concentrated fibrinogen will be infused according to a hemostatic algorithm based on ROTEM (FIBTEM) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Re-Operation | Surgical and medical procedures | Systematic Assessment | Re-exploration with Re-sternotomy because of acute cardiac tamponade or diffuse or surgical bleeding |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Incisional wound infection | Skin and subcutaneous tissue disorders | Systematic Assessment |
The study was limited by a less than expected transfusion rate and the inability to reach the planned sample size.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Myron Kwapisz | Department of Anesthesia, Dalhousie University, Halifax, Canada | +1 902 473 4326 | myron.kwapisz@nshealth.ca |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 23, 2015 | Feb 22, 2020 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D006470 | Hemorrhage |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D005340 | Fibrinogen |
| ID | Term |
|---|---|
| D000209 | Acute-Phase Proteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| 24h after infusion of study drug |
| Platelet Count (10^3/μL) | 24h after infusion of study drug |
| Partial Thromboplastin Time (s) | 24h after infusion of study drug |
| International Normalized Ratio | International normalized ratio (INR) is calculated based on the prothrombin time (PT) test results.The PT is usually measured in seconds and is compared to a normal range that reflects PT values in healthy individuals. Because the reagents used to perform the PT test vary from one laboratory to another and even within the same laboratory over time, the normal ranges also will fluctuate. To standardize results across different laboratories in the world, a World Health Organization (WHO) committee developed and recommended the use of the Internationalized Normalized Ratio (INR). The INR is calculated with the ratio of the patient's prothrombin time (PT test) to a normal prothrombin time (control) sample (PT normal): INR=PT test:PT normal. The normal range is from 0.9 to 1.2. The higher the value the more is the patient anticoagulated. This means the patient's blood is thinner with a lower concentration of coagulation factors. | 24h after infusion of study drug |
| Prothrombin Time (s) | The prothrombin time (PT) test evaluates how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade work together. Included are: factors I (Fibrinogen), II (Prothrombin), V, VII and X. | 24h after infusion of study drug |
| EXTEM Clotting Time (s) | EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | 24h after infusion of study drug |
| EXTEM Maximum Clot Firmness (mm) | EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | 24h after infusion of study drug |
| INTEM Clotting Time (s) | INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | 24h after infusion of study drug |
| INTEM Maximum Clot Firmness (mm) | INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | 24h after infusion of study drug |
| FIBTEM Clotting Time (s) | FIBTEM = rotational thrombelastometry (measurement of functional fibrinogen); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | 24h after infusion of study drug |
| FIBTEM MCF (Maximum Clot Firmness) | Rotational thrombelastometry (measurement of functional fibrinogen). Rotational thrombelastometry (ROTEM) is a point-of-care viscoelastic coagulation test. The device provides four channels for simultaneous assays. With the so called "FIBTEM" assay coagulation is activated by a small amount of tissue thromboplastin (tissue factor) and platelets are blocked with cytochalasin D. The resulting clot is therefore only depending on fibrin formation and fibrin polymerisation. The maximum clot firmness (MCF) is the amplitude in mm on the result graph representing the increasing stabilisation of the clot. | 24 hours after study drug administration |
| HEPTEM Clotting Time (s) | HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase);clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | 24h after infusion of study drug |
| HEPTEM Maximum Clot Firmness (mm) | HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | 24h after infusion of study drug |
| Total Avoidance of Transfusions | Total avoidance of any transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo. | 24h after infusion of study drug |
| Missing data at primary outcome time poi |
|
Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula Placebo: Intravenous saline will be infused with the same volume of the study drug. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
|
|
|
| Secondary | Fibrinogen Plasma Concentration (g/L) | Six patients had missing data in the fibrinogen group (RiaStap) at 24h after infusion of study drug. Six patients had missing data in the placebo group at 24h after infusion of study drug. | Posted | Mean | Standard Deviation | g/L | 24h after infusion of study drug |
|
|
|
|
| Secondary | Hematocrit (%) | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Two patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Mean | Standard Deviation | Hematocrit percent | 24h after infusion of study drug |
|
|
|
|
| Secondary | Hemoglobin Concentration (g/L) | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Two patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Mean | Standard Deviation | g/L | 24h after infusion of study drug |
|
|
|
|
| Secondary | Platelet Count (10^3/μL) | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Two patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Mean | Standard Deviation | cells*10^3/μL | 24h after infusion of study drug |
|
|
|
|
| Secondary | Partial Thromboplastin Time (s) | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Two patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | International Normalized Ratio | International normalized ratio (INR) is calculated based on the prothrombin time (PT) test results.The PT is usually measured in seconds and is compared to a normal range that reflects PT values in healthy individuals. Because the reagents used to perform the PT test vary from one laboratory to another and even within the same laboratory over time, the normal ranges also will fluctuate. To standardize results across different laboratories in the world, a World Health Organization (WHO) committee developed and recommended the use of the Internationalized Normalized Ratio (INR). The INR is calculated with the ratio of the patient's prothrombin time (PT test) to a normal prothrombin time (control) sample (PT normal): INR=PT test:PT normal. The normal range is from 0.9 to 1.2. The higher the value the more is the patient anticoagulated. This means the patient's blood is thinner with a lower concentration of coagulation factors. | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Three patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Full Range | Ratio | 24h after infusion of study drug |
|
|
|
|
| Secondary | Prothrombin Time (s) | The prothrombin time (PT) test evaluates how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade work together. Included are: factors I (Fibrinogen), II (Prothrombin), V, VII and X. | Four patients in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. Three patients in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | EXTEM Clotting Time (s) | EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | EXTEM Maximum Clot Firmness (mm) | EXTEM = rotational thrombelastometry (measurement of extrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | mm | 24h after infusion of study drug |
|
|
|
|
| Secondary | INTEM Clotting Time (s) | INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | INTEM Maximum Clot Firmness (mm) | INTEM = rotational thrombelastometry (measurement of intrinsic coagulation pathway); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | mm | 24h after infusion of study drug |
|
|
|
|
| Secondary | FIBTEM Clotting Time (s) | FIBTEM = rotational thrombelastometry (measurement of functional fibrinogen); clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | FIBTEM MCF (Maximum Clot Firmness) | Rotational thrombelastometry (measurement of functional fibrinogen). Rotational thrombelastometry (ROTEM) is a point-of-care viscoelastic coagulation test. The device provides four channels for simultaneous assays. With the so called "FIBTEM" assay coagulation is activated by a small amount of tissue thromboplastin (tissue factor) and platelets are blocked with cytochalasin D. The resulting clot is therefore only depending on fibrin formation and fibrin polymerisation. The maximum clot firmness (MCF) is the amplitude in mm on the result graph representing the increasing stabilisation of the clot. | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | mm | 24 hours after study drug administration |
|
|
|
|
| Secondary | HEPTEM Clotting Time (s) | HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase);clotting time: time from start of the measurement until initiation of clotting (thrombin formation, start of clot polymerisation). | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | seconds | 24h after infusion of study drug |
|
|
|
|
| Secondary | HEPTEM Maximum Clot Firmness (mm) | HEPTEM = rotational thrombelastometry (measurement of INTEM with heparinase); maximum clot firmness: increasing stabilisation of the clot by the polymerised fibrin, platelets as well as factor XIII. | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Median | Inter-Quartile Range | mm | 24h after infusion of study drug |
|
|
|
|
| Secondary | Total Avoidance of Transfusions | Total avoidance of any transfusion after cardiopulmonary bypass (CPB) 24h after administration of study drug or placebo. | One patient in the fibrinogen group (RiaStap) had missing data at 24h after infusion of study drug. One patient in the placebo group had missing data at 24h after infusion of study drug. | Posted | Count of Participants | Participants | 24h after infusion of study drug |
|
|
|
|
| Other Pre-specified | Overall Numbers of Patients Receiving Blood Products | Including Packed Red Cells, Fresh Frozen Plasma, Platelets, Cryoprecipitate and coagulation factor concentrates. The study was not sufficiently powered to test differences between this outcome. | The placebo group had one dropout during the study because of a study protocol violation and one patient with missing data at the primary outcome time point (29pt). The fibrinogen group hat three dropouts during the study because of two study protocol violation, one death and one patient with missing data at the primary outcome time point (27pt). | Posted | Count of Participants | Participants | 24 hours after administration of study drug |
|
|
|
| 1 |
| 27 |
| 5 |
| 27 |
| 1 |
| 27 |
| EG001 | Intravenous Saline | Intravenous saline (placebo) will be calculated according to FIBTEM based calculation formula Placebo: Intravenous placebo will be infused with the same volume as the study drug. | 0 | 29 | 9 | 29 | 2 | 29 |
|
| Stroke | Nervous system disorders | Systematic Assessment | Upper extremity weakness |
|
| Postoperative Delirium | Psychiatric disorders | Systematic Assessment |
|
| Death | Nervous system disorders | Systematic Assessment | Generalized, diffuse brain edema on postop. day 1 after hemi aortic arch repair |
|
Not provided
Not provided
| D001779 |
| Blood Coagulation Factors |
| D011498 | Protein Precursors |
| D001685 | Biological Factors |
| Superiority |