Open Label Use Of RiaStap During Aortic Reconstruction

Study Overview
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Brief Summary
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The overall purpose of this study is to administer fibrinogen concentrate (RiaSTAP, CSL Behring, Marburg, Germany) with the goal of treating coagulopathic bleeding by improving hemostasis thereby reducing overall blood product transfusion after separation from cardiopulmonary bypass following aortic reconstructive surgery. With the current sample size this is a pilot study and in effect will determine the fibrinogen level response to fibrinogen concentrate administered during aortic reconstructive surgery. It will be underpowered to detect reduction in bleeding but comparison to historical controls will be included as a secondary outcome.

Detailed Description
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Study design Open-label study Inclusion criteria Elective, adult aortic reconstruction involving a hemi-arch replacement at Duke University Medical Center (DUMC). Exclusion criteria Concomitant procedures such as Coronary Artery Bypass Grafting (CABG) , stents (within the last 3 years), refusal of blood transfusion, recent Myocardial Infarction (MI) (within the last 3 months), pregnancy, INR > 1.1, platelet inhibitor drugs within 5 days of surgery (aspirin 325 mg within 48 hours of surgery), platelet count < 150,000, age <18 years, inability to obtain written informed consent, known coagulopathy including a history of recent coumadin therapy. Primary outcome variable Fibrinogen level Secondary outcome variables Total blood product units administered during post op day (POD) 0, 1, 2, 12 and 24 hour chest tube drainage, ventilator time, duration of oxygen dependency, renal dysfunction. Adverse events will be recorded. Study procedure The administration of RiaSTAP is detailed in the flowchart below. Projected milestones Based on recent surgical volume and assuming a conservative recruitment in the 60-70% range we will plan to complete the study of 22 patients as determined by budgetary constraints in a projected 12-month study period. We plan to evaluate the protocol after 11 (half of the) patients. Reevaluation and modification may include broadening the inclusion criteria and/or altering our transfusion protocol depending on the results of the first 11 patients and the projected recruitment rate. Safety monitoring Adverse events as recorded in the aortic database of historical controls will form the basis of the clinical research form (CRF) and are specifically outlined and defined below. The conduct of anesthesia and surgery will be at the discretion of the attending surgeon and anesthesiologist. Following heparin reversal with protamine sulphate and administration of 30mcg/kg DDAVP and 5g aminocaproic acid as per standard practice for these cases, surgical hemorrhage will be excluded by the attending surgeon. The dose of fibrinogen concentrate will be administered as described in the Figure. RiaSTAP will only be administered if coagulopathic bleeding is observed by the surgeon such that it will be used for the treatment, not the prevention of bleeding. It is standard practice for the surgeon to report coagulopathic bleeding (as defined by lack of visible clot in the wound, soaking of swabs with blood and/or continued aspiration of blood into the cell-saver device) before we administer blood products and/or rFVIIa after separation from bypass and following administration of protamine to reverse heparin, aminocaproic acid to inhibit fibrinolysis and DDAVP to augment platelet function. The Food and Drug (FDA) approved dose of 70mg/kg will be used. Following the dosage of fibrinogen concentrate subsequent care of the patient will not be governed by the study protocol. Specifically, transfusion of blood products are suggested in the flow diagram above and transfusion guidelines have been developed by Dr Ian Welsby and Dr Chad Hughes in August 2009 in response to difficulties managing such cases and both of these will be available for use, BUT will only be applied at the discretion of the attending anesthesiologist and surgeon. Proposed laboratory tests in addition to standard of care Time points Baseline Anesthesia induction Pre RiaSTAP After separation from cardio pulmonary bypass (CPB), after desired protamine given Post RiaSTAP Ten minutes after RiaSTAP administered Post op On admission to intensive care unit (ICU) Post op 24 hours after surgery Plasma Heparin level (to avoid misinterpretation of clot based factor assays) Thrombin clot time (as above) Fibrinogen (Clauss method) Clotting Factor Levels Endogenous thrombin potential Whole blood Rotational Thromboelastometry (ROTEM) including Fibrinogen Test (FIBTEM) but not Lysis Test (APTEM) MEA platelet aggregometry (to be provided by CSL Behring) 20ml of blood will be drawn at each timepoint, total 100ml.

Official Title
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Open Label Use Of RiaStap During Aortic Reconstruction

Conditions
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Coagulopathic Bleeding

Intervention / Treatment
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* Drug: RiaSTAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Elective, adult aortic reconstruction involving a hemi-arch replacement at DUMC. Exclusion Criteria: Concomitant procedures such as CABG , stents (within the last 3 years), refusal of blood transfusion, recent MI (within the last 3 months), pregnancy, INR > 1.1, platelet inhibitor drugs within 5 days of surgery (aspirin 325 mg within 48 hours of surgery), platelet count < 150,000, age <18 years, inability to obtain written informed consent, known coagulopathy including a history of recent coumadin therapy.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RiaSTAP<br>One time dose of 70 mg/kg will be administered intravenously. | Drug: RiaSTAP<br>* One time dose of 70 mg/kg will be administered intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibrinogen Level Change | Fibrinogen levels will be assessed only at the timepoints listed in the timeframe and for a maximum of 24 hours. | Anesthesia Induction (Baseline), Pre RiaSTAP (est. 4 hr after baseline), Post RiaSTAP (est: 10 minutes after RiaSTAP administered), ICU Admission (est. 6 hours after baseline), 24 Hour post op (est: 24-30 hr after baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Packed Red Blood Cell Transfusion |  | Anesthesia Induction (Baseline), after CPB, ICU Admission (est. 6 hours after baseline) to post op day 2 (est: 30- 54 hr after baseline) | 
| Fresh Frozen Plasma Transfusion |  | Anesthesia Induction (Baseline), after CPB, ICU Admission (est. 6 hours after baseline) to post op day 2 (est: 30- 54 hr after baseline) | 
| Platelet Transfusion |  | Anesthesia Induction (Baseline), after CPB, ICU Admission (est. 6 hours after baseline) to post op day 2 (est: 30- 54 hr after baseline) | 
| Cryoprecipitate Transfusion |  | Anesthesia Induction (Baseline), after CPB, ICU Admission (est. 6 hours after baseline) to post op day 2 (est: 30- 54 hr after baseline) |