Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiopulmonary Bypass

A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiac Surgery With Cardiopulmonary Bypass

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.

Study Overview

• Status: Completed
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass
• Intervention / Treatment: Biological: AT-III (Human); Other: Placebo

Detailed Description

The primary objective of this clinical study was to compare the percentage of subjects with any component of a 7 item major morbidity composite (postoperative mortality, stroke, acute kidney injury ([AKI]), surgical re-exploration, arterial or venous thromboembolic event, prolonged mechanical ventilation, or infection) between 2 groups of subjects randomly allocated to receive preoperative supplementation of AT-III (Human) (Antithrombin-III ([Human ]) or Placebo.

The secondary objectives of this clinical study were the following:

• To compare postoperative antithrombin III (AT) levels at the Intensive Care Unit (ICU) admission between the AT-III (Human) treatment group and Placebo control group

• To compare the following perioperative outcomes between the AT-III (Human) treatment group and Placebo control group:

  • Postoperative chest-drain blood loss in the first 12 and 24 hours after surgery
  • Transfusion requirements
  • Need for surgical re-exploration
  • Low cardiac output syndrome
  • Myocardial Infarction (MI)
  • Stroke
  • AKI
  • Arterial or venous thromboembolic events
  • Infections
  • Prolonged mechanical ventilation (>24 hours)
  • All-cause postoperative mortality
  • ICU stay duration
  • Prolonged ICU stay (>6 days)
  • Length of hospital stay

Additionally, safety objectives included the evaluation of AT III (Human) for clinical safety including adverse events (AEs), risks for bleeding, clinical laboratory testing, physical exam, and vital signs.

• Study Type: Interventional
• Enrollment (Actual): 425
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • UC Irvine
    • San Francisco, California, United States, 94121
      • VA Medical Center - San Francisco
    • Stanford, California, United States, 94305
      • Stanford University Hospital and Clinics
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School Of Medicine
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital at University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University
  • Illinois
    • Springfield, Illinois, United States, 62794
      • Memorial Medical Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Indiana Ohio Heart
    • Indianapolis, Indiana, United States, 46290
      • St. Vincent Heart Center of IN, LLC
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Kentucky Clinic
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Medical
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women'S Hospital
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Sparrow Clinical Research Institute
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68526
      • CHI Health Nebraska Heart Medical Office
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Dartmouth-Hitchcock Medical Center
  • New York
    • New Hyde Park, New York, United States, 11040
      • North Shore University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Sanford Health Fargo
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Health Hospital
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research & Education - The Christ Hospital
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
    • Toledo, Ohio, United States, 43606
      • ProMedica Toledo Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Baptist Memorial Hospital Memphis
    • Nashville, Tennessee, United States, 37205
      • St. Thomas Health
  • Texas
    • Bellaire, Texas, United States, 77401
      • Memorial Hermann Memorial City Medical Center
    • Houston, Texas, United States, 77030
      • Texas Heart
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical Center
    • Richmond, Virginia, United States, 23225
      • Cardiothoracic Surgical Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AT-III (Human); Single intravenous dose of AT-III (Human) sufficient to achieve an absolute increase of 20% (percentage points) above pretreatment AT levels according the following formula: AT-III (Human) dose (IU) required = (20) × (subject weight in kg) / 1.4	Biological: AT-III (Human); 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.; Other Names: Antithrombin
Placebo Comparator: Placebo; Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose.	Other: Placebo; 0.9% Sodium Chloride for Injection, United States Pharmacopeia; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With Any Component of a Major Morbidity Composite	Major morbidity composite defined as a composite of any one or more of the following: Postoperative mortality (deaths occurring within 30 days of the operation or occurring during the primary hospitalization).; Stroke (clinical diagnosis of focal or global neurological deficit of abrupt onset caused by disturbance in cerebral blood supply).; Acute kidney injury (increase of serum creatinine levels to >2.0 mg/dL and twice the baseline level or a new requirement for dialysis postoperatively).; Surgical reexploration (return to operating room because of bleeding, tamponade, graft occlusion or other cardiac reason).; Arterial or venous thromboembolic event (perioperative myocardial or mesenteric infarction, peripheral thromboembolism, acute coronary graft thrombosis, intracardiac thrombosis, deep vein thrombosis, pulmonary embolism).; Prolonged mechanical ventilation (>24 hours).; Infection (deep sternal-wound infection and/or bloodstream infections).	Up to Day 30 +/- 4 days

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Collaborators: Covance; Clinipace Worldwide

Publications and helpful links

General Publications

• Moront MG, Woodward MK, Essandoh MK, Avery EG, Reece TB, Brzezinski M, Spiess B, Shore-Lesserson L, Chen J, Henriquez W, Barcelo M, Despotis G, Karkouti K, Levy JH, Ranucci M, Mondou E; Clinical Thrombate Study Group. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery. Anesth Analg. 2022 Oct 1;135(4):757-768. doi: 10.1213/ANE.0000000000006145. Epub 2022 Jul 25.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2014
• Primary Completion (Actual): January 25, 2018
• Study Completion (Actual): January 25, 2018

Study Registration Dates

• First Submitted: January 14, 2014
• First Submitted That Met QC Criteria: January 14, 2014
• First Posted (Estimate): January 16, 2014

Study Record Updates

• Last Update Posted (Actual): March 15, 2019
• Last Update Submitted That Met QC Criteria: February 27, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Cardiopulmonary bypass; Antithrombin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Antithrombins; Antithrombin III
• Other Study ID Numbers: GTI1307