Open Label Use Of RiaStap During Aortic Reconstruction

Study design Open-label observational 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

1. Baseline Anesthesia induction

2. Pre RiaSTAP After separation from cardio pulmonary bypass (CPB), after desired
protamine given

3. Post RiaSTAP Ten minutes after RiaSTAP administered

4. Post op On admission to intensive care unit (ICU)

5. 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 Fibrinogin 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.

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.