Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

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.

Study Overview

• Status: Terminated
• Conditions: Thrombophilia Due to Acquired Antithrombin III Deficiency
• Intervention / Treatment: Drug: Recombinant antithrombin (rhAT)

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: ATryn®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 minutes after the initial dose of rhAT, Day 1 of the study

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: rEVO Biologics
• Investigators: Principal Investigator: William Oliver, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: February 7, 2012
• First Submitted That Met QC Criteria: March 4, 2012
• First Posted (Estimate): March 8, 2012

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: July 13, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Cardiac Surgery; antithrombin; Heparin Resistant
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Genetic Diseases, Inborn; Blood Protein Disorders; Blood Coagulation Disorders; Thrombophilia; Antithrombin III Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Antithrombins; Antithrombin III
• Other Study ID Numbers: 11-004125