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Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

Primary Purpose

Thrombophilia Due to Acquired Antithrombin III Deficiency

Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Recombinant antithrombin (rhAT)
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thrombophilia Due to Acquired Antithrombin III Deficiency focused on measuring antithrombin, Heparin Resistant, Cardiac Surgery

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB)
  • Heparin resistant according to this definition: initial activated clotting time (ACT) after an intravenous loading dose of heparin (300 u/kg) is less than 480 seconds

Exclusion criteria:

  • current use of one or more of these medications:

    • warfarin (within 3 days of surgery);
    • streptokinase;
    • tissue plasminogen activator;
    • abciximab,
    • eptifibatide,
    • tirofiban or
    • clopidogrel.
  • known hypersensitivity to goat or goat milk proteins,
  • patients with pre-existing coagulopathy defined as a history of bleeding or laboratory bleeding disorder (e.g., von Willebrand disease, platelet disorder) and
  • patients receiving direct thrombin inhibitors

Sites / Locations

  • Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Recombinant antithrombin (rhAT)

Arm Description

Subjects will receive an intravenous bolus of 500 units of recombinant, human antithrombin (rhAT, ATRYN ®). If the subject remains heparin-resistant, one more IV bolus of 500 units rhAT is given.

Outcomes

Primary Outcome Measures

Percentage of Patients Whose Activated Clotting Time (ACT) is Prolonged Beyond 480 Seconds With Recombinant Human Antithrombin Concentrate (rhAT) Administration
Restored antithrombin level is defined as an activated clotting time > 480 seconds 3 minutes after the initial dose of 500 units of rhAT is administered. The percentage of patients who meet this criterion will be summarized using a point estimate and a 95% confidence interval.

Secondary Outcome Measures

Full Information

First Posted
February 7, 2012
Last Updated
July 13, 2015
Sponsor
Mayo Clinic
Collaborators
rEVO Biologics
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1. Study Identification

Unique Protocol Identification Number
NCT01547728
Brief Title
Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery
Official Title
Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Terminated
Why Stopped
Too many barriers to enroll participants.
Study Start Date
February 2012 (undefined)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mayo Clinic
Collaborators
rEVO Biologics

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The objective of this study is to prospectively evaluate the response of recombinant antithrombin (rAT) (ATRYN) in patients who are heparin resistant and are scheduled to undergo cardiac surgery.
Detailed Description
AT is an α2-globulin that is produced primarily in the liver. It binds thrombin, as well as other serine proteases, factors IX, X, XI, and XII, kallikrein, and plasmin irreversibly, which neutralizes their activity. However, only inhibition of thrombin and factor Xa by AT has physiologic and clinical significance.1 AT deficiency may occur as a congenital or acquired deficiency. Acquired deficiencies are secondary to increased AT consumption, loss of AT from the intravascular compartment (renal failure, nephrotic syndrome) or liver disease (cirrhosis). A normal AT level is 80% to 120% with activity below 50% considered clinically important based on the risk of venous thrombosis in patients with congenital deficiency of AT.2 However, the risk of thrombosis is higher in congenital forms than acquired forms of AT deficiency.3, 4 Unfortunately, the only abnormal coagulation test associated with this condition is the assay for AT activity, which is diagnostic but not readily available. Acquired deficiencies of AT are commonly encountered in cardiac surgical patients. Anticoagulation with heparin for CPB depends on AT to inhibit clotting as heparin alone has no effect on coagulation. Heparin catalyzes AT inhibition of thrombin over a 1000 fold by binding to a lysine residue on AT and altering its conformation. Thrombin actually attacks AT, disabling it, but in the process attaches AT to thrombin, forming a complex that can be detected and used to assess thrombin formation but has no activity. Thirty percent of AT is consumed during this process so AT levels are reduced temporarily. If AT levels are not restored, then a condition may arise called heparin resistance. There are other less frequent causes of heparin resistance besides AT deficiency such as platelets, fibrin, vascular surfaces and plasma proteins.5 There is no universally accepted definition of heparin resistance. It is broadly defined as the failure of a specific heparin dose (300 - 400 u/kg) to prolong an ACT beyond 400 - 480 seconds in preparation for initiation of CPB. Because the definition of heparin resistance may differ according to both heparin dose and target ACT, the incidence of heparin resistance in the literature is very variable. A recent randomized prospective study analyzing 2270 cardiac cases, identified 3.7% of the patients to be heparin resistant but the incidence has been reported as high as 18% - 30% The incidence of heparin resistance is likely to further increase as the use of heparin infusions prior to cardiac surgery becomes more prevalent.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thrombophilia Due to Acquired Antithrombin III Deficiency
Keywords
antithrombin, Heparin Resistant, Cardiac Surgery

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recombinant antithrombin (rhAT)
Arm Type
Experimental
Arm Description
Subjects will receive an intravenous bolus of 500 units of recombinant, human antithrombin (rhAT, ATRYN ®). If the subject remains heparin-resistant, one more IV bolus of 500 units rhAT is given.
Intervention Type
Drug
Intervention Name(s)
Recombinant antithrombin (rhAT)
Other Intervention Name(s)
ATryn®
Intervention Description
Subjects will receive an intravenous bolus of 500 units of recombinant, human antithrombin (rhAT, ATRYN ®). If the subject remains heparin-resistant, one more IV bolus of 500 units rhAT is given.
Primary Outcome Measure Information:
Title
Percentage of Patients Whose Activated Clotting Time (ACT) is Prolonged Beyond 480 Seconds With Recombinant Human Antithrombin Concentrate (rhAT) Administration
Description
Restored antithrombin level is defined as an activated clotting time > 480 seconds 3 minutes after the initial dose of 500 units of rhAT is administered. The percentage of patients who meet this criterion will be summarized using a point estimate and a 95% confidence interval.
Time Frame
3 minutes after the initial dose of rhAT, Day 1 of the study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) Heparin resistant according to this definition: initial activated clotting time (ACT) after an intravenous loading dose of heparin (300 u/kg) is less than 480 seconds Exclusion criteria: current use of one or more of these medications: warfarin (within 3 days of surgery); streptokinase; tissue plasminogen activator; abciximab, eptifibatide, tirofiban or clopidogrel. known hypersensitivity to goat or goat milk proteins, patients with pre-existing coagulopathy defined as a history of bleeding or laboratory bleeding disorder (e.g., von Willebrand disease, platelet disorder) and patients receiving direct thrombin inhibitors
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William Oliver, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Links:
URL
http://clinicaltrials.mayo.edu
Description
Mayo Clinic Clinical Trials

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Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

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