Trial of RiaSTAP Versus Cryoprecipitate to Lower Operative Transfusions

Study Overview
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Brief Summary
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The study aligns with the strategic plan of New York-Presbyterian Hospital (NYPH) to reduce allogeneic blood product use and decrease unnecessary laboratory costs. One of the NYPH Quality and Patient Safety Goals for 2013 was to improve the appropriate use of transfusion guidelines and reduce unnecessary red blood cell (RBC) transfusions. Further, this study will help to answer whether RiaSTAP is a more effective product to treat bleeding than cryoprecipitate. In addition, this trial will provide investigators with preliminary data to apply for future federal funding opportunities, such as the National Heart Lung and Blood Institute sponsored R21 grant (PAR-13-025) that encourages research grant applications from investigators who propose to study research topics in blood banking and transfusion medicine aimed at improving the safety and availability of the blood supply and the practice of transfusion medicine. The investigators anticipate future follow-on studies further investigating fibrinogen concentrate and other similar therapeutics in other perioperative populations, such as in postpartum hemorrhage or surgical ICU settings. Finally, this study involves the use of a safer therapeutic, fibrinogen concentrate, to improve patient care and patient safety. This product does not require the time-intensive process of thawing; therefore, delays in patient care can be avoided by having the product readily available in the OR.

Detailed Description
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All eligible subjects undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) at New York Presbyterian Hospital-Weill Cornell Medical College will be invited to participate. Consenting subjects will be enrolled and treated according to the protocol. Study investigators anticipate that by consenting all eligible cardiovascular surgical subjects, investigators will not omit the results of subjects who may present with microvascular bleeding after CPB. It is well known that microvascular bleeding occurs more often in reoperations or complex, open cardiac procedures, such as coronary revascularization and valve repair/replacement, or aortic replacements under deep hypothermic circulatory arrest. Enrolled subjects will receive intraoperative anesthetic, anticoagulation, laboratory testing, and hemodynamic management according to WCMC standards of practice. The need for blood products, including fibrinogen supplementation (CRYO/FIB), will be assessed using a point-of-care (ROTEM) based transfusion algorithm (Appendix A) to ensure consistency and accuracy of treatment. The cardiac anesthesiologists and surgeons are currently using the ROTEM algorithm for the treatment of bleeding during cardiovascular surgery with CPB as part of routine clinical practice at WCMC. The algorithm will have been in place for greater than 9 months prior to study initiation. Randomization will occur in the blood bank when study product (CRYO/FIB) is requested to treat intraoperative acquired hypofibrinogenemia (based on ROTEM tracings). Transfusion of the randomized study product (CRYO/FIB), however, will only occur when the surgeon declares the presence of microvascular bleeding. Surgeons will be blinded to the subject's ROTEM results and randomized study arm. Intraoperative anesthesiologists will not be blinded as the two products require different preparation and administration techniques and cannot be blinded easily. Once the subject is randomized to their study intervention they will receive that product at all subsequent points during the procedure when fibrinogen replacement is required. If microvascular bleeding occurs and there is no indication by the ROTEM algorithm to administer CRYO/FIB, the subject will revert to standard of care treatment guided by ROTEM or traditional laboratory testing. The subject will not be randomized in the study. In the case of abnormal ROTEM parameters but no clinical evidence of microvascular bleeding as evaluated by the cardiac surgeon, the subject will continue to be monitored carefully for bleeding for the remainder of the procedure. If non-surgical bleeding is subsequently observed prior to chest closure and the consensus is that fibrinogen is needed based on ROTEM results (FIBTEM A10 less than or equal to 10 mm), the subject will be treated with their randomized study product according to the algorithm. Following completion of the procedure, postoperative coagulation management will be according to standard practice and guided by standard laboratory testing, when possible. Unless persistent bleeding is noted, all subjects will receive aspirin (300 mg per rectum) 6 hours postoperatively. Subjects with mechanical or mitral tissue valves will be anticoagulated with warfarin (no heparin bridge) starting on postoperative day two (POD#2). Any subjects experiencing significant arrhythmias (e.g. atrial fibrillation in the perioperative setting) will also be anticoagulated with warfarin. Pharmacologic deep vein thrombosis (DVT) prophylaxis will follow the usual standard of care. Subjects enrolled, randomized, and transfused study product will be observed until hospital discharge (total observation time). Research staff from the Department of Anesthesiology will collect outcomes data, including transfused blood products, laboratory results, evidence of perioperative thrombosis or infection, returns to the OR, length of stay, and mortality using case report forms reports and enter all collected data into a secure REDCap database.

Official Title
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Trial of RiaSTAP Versus Cryoprecipitate to Lower Operative Transfusions (TOP-CLOT)

Conditions
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Coagulopathy

Intervention / Treatment
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* Device: ROTEM
* Other: Cryoprecipitate
* Drug: RiaSTAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects age 18 and older who have given written informed consent Undergoing cardiac surgery cardiopulmonary bypass (CBP) at Weill Cornell Medical Center Exclusion Criteria: Subjects on anticoagulation medications including: Clopidogrel, ticagrelor, prasugrel with platelet function analyzer-100 assay closure time (CT) prolonged greater than 15% Last doses of dabigatran, rivaroxaban, apixaban within 72 hours Warfarin with international normalized ratio (INR) greater than 1.5 Positive pregnancy test, pregnancy or lactation Thrombocytopenia: platelet count less than 100,000 u/L Emergency procedures Proof or suspicion of a congenital or acquired coagulation disorder (e.g. von Willebrand Factor or via severe liver disease) Participation in another randomized clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RiaSTAP Arm<br>Subjects will be infused with RiaSTAP if the ROTEM FIBTEM A10 value is less than or equal to 10 mm and microvascular bleeding is present. | Device: ROTEM<br>* ROTEM delta will be used to identify intraoperative coagulation abnormalities. A blood sample and reagents are placed into a small cup. A pin suspended from a wire is immersed into the sample. The pin rotates back and forth at a fixed angle. The movement of the pin is optically monitored and converted into a real time measurement that is represented graphically. Prior to clot formation, pin rotation is unhindered and is graphically represented as a straight line. As the subject's blood sample starts to clot, strands of clot form between the pin and the cup wall, restricting the movement of the pin depending on the strength of the clot. Graphically, this is represented as a symmetrical widening of the curve.<br>* Other names: ROTEM delta;Drug: RiaSTAP<br>* Subjects with hypofibrinogenemia who are randomized to the RiaSTAP arm will be transfused with concentrated fibrinogen<br>* Other names: Concentrated Fibrinogen;|
| Active Comparator: Cryopreciptiate Arm<br>Subjects will be infused with cryoprecipitate if the ROTEM FIBTEM A10 value is less than or equal to 10 mm and microvascular bleeding is present. | Device: ROTEM<br>* ROTEM delta will be used to identify intraoperative coagulation abnormalities. A blood sample and reagents are placed into a small cup. A pin suspended from a wire is immersed into the sample. The pin rotates back and forth at a fixed angle. The movement of the pin is optically monitored and converted into a real time measurement that is represented graphically. Prior to clot formation, pin rotation is unhindered and is graphically represented as a straight line. As the subject's blood sample starts to clot, strands of clot form between the pin and the cup wall, restricting the movement of the pin depending on the strength of the clot. Graphically, this is represented as a symmetrical widening of the curve.<br>* Other names: ROTEM delta;Other: Cryoprecipitate<br>* Subjects with hypofibrinogenemia who are randomized to the Cryoprecipitate arm will be transfused with Cryoprecipitate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative Blood Transfusion Total | The combined number of allogeneic blood products (platelets + Fresh Frozen Plasma (FFP) + RBCs) administered to subjects intraoperatively after study intervention. | Procedure length, the average for participants is approximately 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour Blood Transfusion Total | Number of units of RBC, Platelets, cryoprecipitate, FFP, or other blood products administered to subjects receiving study product within the first 24 hours after procedure end | 24 hours | 
| Fibrinogen Repletion | Fibrinogen repletion as measured by ROTEM FIBTEM >10mm after study product administration. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment | Procedure length, the average for participants is approximately 6 hours | 
| Incidence of Zero Transfusions | Number of patients who receive no allogeneic blood transfusions following study product administration and first 24 hours after procedure end. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment | 24 hours | 
| Correction of Microvascular Bleeding | Difference in surgeon's assessment of microvascular bleeding from approximately 15 minutes before to approximately 15 minutes after administration of study medication. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment |  30 min intraoperatively | 
| CTICU Length of Stay | Number of days subject spends in cardiothoracic intensive care unit from procedure end to hospital discharge. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Hospital Length of Stay | Number of days subject spends in the hospital from procedure end to hospital discharge. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Thrombosis and Transfusion Reactions | Incidence of intraoperative or postoperative (during hospital admission only) thrombosis (symptomatic only) and transfusion reactions from procedure to hospital discharge. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Infection and Respiratory Failure | Incidence of any infection or respiratory failure from procedure end to hospital discharge. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Blood Loss | Quantity of intraoperative and postoperative blood loss as recorded in the anesthesia record and in chest tube outputs (blood drainage volume). Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Length of Hospital Stay, the average for participants is approximately 7 days, | 
| Incidence of Re-exploration | Incidence of subjects requiring a return to the OR for re-exploration. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Mortality Rate | Rate of hospital death during initial hospital admission. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment | Length of Hospital Stay, the average for participants is approximately 7 days | 
| Correlation of Laboratory and ROTEM Data | Correlation of fibrinogen, von Willebrand Factor (vWF), and factor VIII levels measured in traditional lab with intraoperative ROTEM parameters. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Procedure length, the average for participants is approximately 6 hours | 
| Time to Product Administration | Time from request to administration of study product. Trial terminated prior to the collection of this data due to feasibility issues preventing completion of recruitment. | Procedure length, the average for participants is approximately 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypofibrinogenemia, ROTEM, Cardiac Surgery, Concentrated Fibrinogen