Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiopulmonary Bypass
Condition: Cardiac Surgery; Cardiopulmonary Bypass
Intervention: AT-III (Human); Placebo
Intervention description: AT-III (Human) is an antithrombin concentrate prepared from pooled human plasma. AT-III (Human) is provided as a freeze-dried preparation for intravenous use. The AT-III (Human) preparation is reconstituted in 10 or 20 mL of sterile water for injection prior to intravenous administration.; 0.9% Sodium Chloride for Injection, United States Pharmacopeia
Intervention MeSH terms: Antithrombins; Antithrombin III
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 425.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Antithrombin; Cardiopulmonary bypass

Summary:

      This is a prospective, multicenter, randomized, double-blind, placebo-controlled study. The
      purpose of this study is to determine the safety and effectiveness of human-derived
      antithrombin III (AT-III [Human]) supplementation prior to high-risk, non-emergency, cardiac
      surgery with cardiopulmonary bypass (CPB). A total of 404 adult subjects undergoing CPB who
      meet the study eligibility criteria were planned to be randomized to receive either AT-III
      (Human) or placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female.

          2. At least 18 years of age.

          3. Subject needed non-emergency cardiac surgery with CPB.

          4. Types of cardiac operations permitted: complex/combined procedures (CABG+valve),
             double/triple valve repair/replacement, ascending aorta/aortic arch surgeries.
             Isolated CABG or single valve repair/replacements were allowed only if subject had
             received preoperative heparin >2 days.

             - Following the incorporation of Protocol Version 4.0 (Amendment 3 dated 02 Apr 2015),
             this criterion was revised to include complex/combined procedures (CABG+valve),
             double/triple valve repair/replacements, ascending aorta/aortic arch surgeries
             (without baseline AT level restriction or preoperative heparin requirement). OR
             isolated CABG or single valve repair/replacements were allowed only if either (a) AT
             level was less than 80% OR (b) preoperative heparin was received ([UFH for at least 12
             hours; LMWH for more than 5 days).

          5. Subject had a baseline AT level of less than 80%.

               -  Following incorporation of Protocol Version 3.0 (Amendment 2 dated 02 Sep 2014)
                  this was changed to Subject had a Prescreening/Screening and baseline local lab
                  AT level of less than 80%.

               -  Following the incorporation of Protocol Version 4.0 (Amendment 3 dated 02 Apr
                  2015) this criterion was deleted and noted as "Not applicable - intentionally
                  left blank for data management purposes (consistency in eCRF capture of
                  eligibility criteria historically)."

          6. Subject had signed informed consent form.

          7. Subject was willing to comply with all aspects of the protocol, including blood
             sampling, for the total duration of the study.

        Exclusion Criteria:

          1. Subject needed emergency surgery.

          2. Subject needed heart transplantation.

          3. Subject needed the use of minimally invasive surgery.

          4. Subject had previous cardiac operation.

          5. Subject had infective endocarditis.

          6. Subject had thromboembolic events, stroke, or ST-elevated MI within 7 days of surgery.

          7. Subject had cardiogenic shock at the time of surgery.

          8. Subject had renal dysfunction: creatinine levels >2 mg/dL or chronic dialysis.

          9. Subject had liver dysfunction: aspartate aminotransferase (AST), alanine
             aminotransferase (ALT) increase ≥2-fold above the upper-limit of local lab normal
             ranges.

         10. Subject had treatment with Clopidogrel® and Ticagrelor® within 5 days before surgery,
             Prasugrel® within 7 days before surgery, glycoprotein IIb/IIIa receptor blockers
             within 24 hours of surgery.

         11. Subject had treatment with new oral anticoagulants (Apixaban®, Rivaroxaban®,
             Dabigatran®) within 48 hours before surgery.

         12. Subject had Vitamin K antagonist therapy and an international normalized ratio (INR)
             >1.3 on the day of surgery.

         13. Subject had platelet count <120,000/μL.

         14. Subject had history or suspicion of a congenital or acquired coagulation disorder.

         15. Subject had history of anaphylactic reaction(s) to blood or blood components.

         16. Subject had allergies to excipients in the study drug.

         17. Subject had refused to receive allogenic transfusion of blood-derived products.

         18. Subject had received AT treatment within the last 3 months prior to Screening Visit.

         19. Subject was pregnant. Subject had participated in any another investigational study
             within the last 3 months prior to Screening Visit.