Prospective, randomized, double blind trial. The rationale of the study is the concept that fresh frozen plasma (FFP) is still largely used in cardiac surgery, despite the fact that prothrombin complexes and fibrinogen are available.The experimental hypothesis is that cardiac surgery patients may be operated with no use of FFP and with a coagulation factors replacement based on fibrinogen and prothrombin complexes (when needed).

Primary endpoint: Transfusion avoidance Secondary endpoints: Transfusion limitation, massive blood transfusion, bleeding.

Study population: high-risk adult cardiac surgery patients Sample size : 2 groups of 60 patients each

Study design Randomized, placebo-controlled, double-blinded study Endpoints Primary: Transfusion avoidance of every allogeneic blood product Secondary: Reduction in the number of allogeneic blood products used, reduction in massive blood transfusion events incidence, reduction in postoperative bleeding.

Patient population This study is focused on the role of coagulation factors substitutes in avoiding transfusions. Therefore, the patient population should be composed by patients being at high-risk for transfusions due to bleeding and not to hemodilution. Moreover, bleeding should be primarily due to a coagulation factors deficiency, rather than to other causes (namely, drug-induced platelet dysfunction).

The major determinant of coagulation factors consumption during cardiac operations is the length of CPB. Only patients undergoing operations with a predictable CPB duration > 90 minutes will be admitted. This includes patients undergoing complex cardiac operations (double valve; CABG+valve; ascending aorta; adult congenital patients). Adult congenital patient may be of particular interest, since they usually have a preoperative reduced hepatic coagulation factors synthesis, due to venous stasis and polycythemia.

To avoid the effects of hemodilution in determining transfusional needs, patients with an expected lowest HCT < 23% during CPB will not be admitted to the study. This means excluding patients with a preoperative HCT < 35%, and patients with a small BSA (< 1.7 m2). Hemodilution during CPB will be checked, and in case of a HCT value < 23% the patient will be withdrawn from the study.

Power analysis and sample size

Data from our Institutional database (about 15,000 patients) have been retrieved according to the above reported selection criteria. 1,535 patients (10%) fulfill the randomization and no-withdrawal criteria.

Within this group, we could calculate the following outcome variables:

Variable Incidence Mean with SD Transfusion rate (any kind) 61% Packed red cells 57% FFP 31% Platelets 8% Big bleeders (> 800 mL) 20% Postoperative bleeding 560±501 Surgical revision 5.7%

Based on these data, we could perform a power analysis based on an alpha value of 0.05 and a beta value of 0.20. According to these values, the required number of patients to be enrolled varies according to the experimental hypothesis:

Transfusion rate control group Hypothesis for transfusion rate in treatment group Number of patients per each group Total number of patients 60% 30% 40 80 60% 35% 58 116 60% 40% 94 188

The study size will be 116 patients (58 per group).

Study protocol

Patients in the control group will receive the standard treatment available in our Hospital for blood management and hemostasis and coagulation control. This includes antifibrinolytic administration (tranexamic acid 15 mg/kg before CPB and 15 mg/kg after protamine) Patients in both groups will be transfused according to our standard protocol (attachment 1)

Randomization: sealed envelopes. Enveloped placed in the pharmacy. Preparation of the drug vs. placebo by a dedicated biologist. Blinded vials sent to the OR.

Dosing protocol

All the patients randomized and not withdrawn will be tested 20 minutes before removal of aortic cross clamping with a thromboelastometry fibrinogen test FIBTEM (Rotem) . They will all receive either human fibrinogen concentrate (according to the formula: (22 [mm] - MCF [mm]) * body weight [kg] / 140 [m] = whole g fibrinogen to be dosed as HFC) (treatment group) or placebo (control group). Study drug or placebo has to be administered after protamine.

After 15min from study drug administration and in presence of ongoing microvascular bleeding, we run a CT EXTEM. In case of prolonged CT time at EXTEM as long as 80 seconds [M1] , they will receive coagulation factors concentrates (Confidex) at a weight-based dose of 7 U/kg b.w. (treatment group) or placebo.

In presence of ongoing microvascular bleeding intraoperatively or during the first 6 hours in the ICU, the patients will be treated with other drugs and products to control bleeding according to our standard protocol (see "Transfusion protocol").

After dosing, a blood sample will be withdrawn, centrifuge, and frozen plasma will be stored for subsequent Thrombin Generation Test.

Blinding:

An unblinded biologist will follow the drug randomization process, open the sealed envelope, drug preparation, and ROTEM analysis.

All the other Investigators will be blinded.

Transfusion protocol

1. Definition of bleeding: Intraoperatively: delayed sterna closure due to microvascular bleeding Postoperatively: 2 mL/kg for 2 consecutive hours; or 1.5 ml/kg for 4 consecutive hours

Packed red cells will be transfused (one unit at a time) under the following conditions:

1. Always if Hb < 7 g/dL
2. Possible if Hb between 7 and 8 g/dL
3. Possible but with medical justification (hemodynamic instability; high oxygen extraction rate; signs of organ ischemia…) if Hb between 8 and 9 g/dL
4. Never if Hb ≥ 9 g/dL

Fresh frozen plasma in case of bleeding if

1. INR > 1.5
2. R time at TEG (with heparinase) > 12 minutes

Platelets in case of bleeding if

1. Platelet count < 50.000/mmc
2. Pre-treatment with thienopyridinies (not applicable in this study)

In case of intractable bleeding determining hemodynamic instability, and for all life-saving conditions, the above mentioned conditions may be not considered, and an empirical rescue therapy is allowed.

Funding This study will be funded internally with the IRCCS Policlinico San Donato Research Fund.

The drugs (fibrinogen concentrate and PCC) will be provided free of charge by CSL Behring, as well as the reagents for ROTEM analysis,

Inclusion Criteria:

• The patients will be screened according to a modified TRUST1 Transfusion Score. This score attributes 1 point to each of the following conditions:

  • Hb level < 13.5 g/dL

  • Weight < 77 kg

  • Female sex

  • Age > 65 years

  • Non elective surgery

  • Serum creatinine > 1.36 mg/dL

  • Redo operation

  • Non isolated surgery

  • Factors are hemodilution-related factors, and will not be included. Non isolated surgery is mandatory for inclusion. Patients will be included in presence of at least 1 within the remaining 4 risk factors:

  • Age > 65 years

  • Non elective surgery

  • Serum creatinine > 1.36 mg/dL '8Redo operation INCLUSION CRITERIA (patients randomized)

    1. Combined cardiac operation with expected CPB duration > 90 minutes
    2. At least one additional risk factor within the following: Age > 65 years; Non elective surgery; Serum creatinine > 1.36 mg/dL; Redo operation

Exclusion Criteria:

1. Age < 18 years
2. Patients under thienopyridines
3. Known coagulopathy
4. Known autoimmune disorders
5. Participation in another RCT
6. Pregnancy
7. Emergency operation
8. Baseline HCT < 35%
9. Baseline Antithrombin < 80%
10. BSA < 1.7 m2

WITHDRAWAL CRITERION:

1. Lowest HCT on CPB < 23%

2. Transfusions during CPB

   • Patients randomized and not withdrawn will be DOSED with the investigational drugs.