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Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

This study has been terminated.
(Too many barriers to enroll participants.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01547728
First Posted: March 8, 2012
Last Update Posted: July 15, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
rEVO Biologics
Information provided by (Responsible Party):
William C. Oliver, Mayo Clinic
  Purpose
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.

Condition Intervention Phase
Thrombophilia Due to Acquired Antithrombin III Deficiency Drug: Recombinant antithrombin (rhAT) Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

Resource links provided by NLM:


Further study details as provided by William C. Oliver, Mayo Clinic:

Primary Outcome Measures:
  • Percentage of Patients Whose Activated Clotting Time (ACT) is Prolonged Beyond 480 Seconds With Recombinant Human Antithrombin Concentrate (rhAT) Administration [ Time Frame: 3 minutes after the initial dose of rhAT, Day 1 of the study ]
    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.


Enrollment: 42
Study Start Date: February 2012
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Recombinant antithrombin (rhAT)
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.
Drug: Recombinant antithrombin (rhAT)
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.
Other Name: ATryn®

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.

  Eligibility

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01547728


Locations
United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
rEVO Biologics
Investigators
Principal Investigator: William Oliver, MD Mayo Clinic
  More Information

Additional Information:
Responsible Party: William C. Oliver, Consulatant Cardio/Thoracic Anesthesia, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01547728     History of Changes
Other Study ID Numbers: 11-004125
First Submitted: February 7, 2012
First Posted: March 8, 2012
Results First Submitted: April 21, 2015
Results First Posted: July 15, 2015
Last Update Posted: July 15, 2015
Last Verified: July 2015

Keywords provided by William C. Oliver, Mayo Clinic:
antithrombin
Heparin Resistant
Cardiac Surgery

Additional relevant MeSH terms:
Thrombophilia
Antithrombin III Deficiency
Hematologic Diseases
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Blood Protein Disorders
Genetic Diseases, Inborn
Calcium heparin
Heparin
Antithrombin III
Antithrombins
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors