Clinical trial NCT02037555: Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiopulmonary Bypass
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cardiac Surgery
Cardiopulmonary Bypass
Keywords: Antithrombin
Cardiopulmonary bypass
Lead sponsor: Grifols Therapeutics LLC
Sponsor class: INDUSTRY
Collaborators: name: Covance
name: Clinipace Worldwide
First posted: 2014-01-16
Enrollment: 425
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Primary outcomes:
measure: Percentage of Subjects With Any Component of a Major Morbidity Composite
timeFrame: Up to Day 30 +/- 4 days
Secondary outcomes:
Other outcomes:
Locations:
city: Orange
country: United States
facility: UC Irvine
state: California
city: San Francisco
country: United States
facility: VA Medical Center - San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Hospital and Clinics
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Miami
country: United States
facility: Jackson Memorial Hospital at University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Fort Wayne
country: United States
facility: Indiana Ohio Heart
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Heart Center of IN, LLC
state: Indiana
city: Lexington
country: United States
facility: Kentucky Clinic
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Medical
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Lansing
country: United States
facility: Sparrow Clinical Research Institute
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Kansas City
country: United States
facility: Saint Luke's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Lincoln
country: United States
facility: CHI Health Nebraska Heart Medical Office
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: New Hyde Park
country: United States
facility: North Shore University Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Health Fargo
state: North Dakota
city: Akron
country: United States
facility: Summa Health Hospital
state: Ohio
city: Cincinnati
country: United States
facility: The Lindner Center for Research & Education - The Christ Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: ProMedica Toledo Hospital
state: Ohio
city: Toledo
country: United States
facility: University of Toledo Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Memphis
country: United States
facility: Baptist Memorial Hospital Memphis
state: Tennessee
city: Nashville
country: United States
facility: St. Thomas Health
state: Tennessee
city: Bellaire
country: United States
facility: Memorial Hermann Memorial City Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Heart
state: Texas
city: Richmond
country: United States
facility: Cardiothoracic Surgical Associates
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
Study officials:
References:
citation: 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.