Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

Thrombophilia Due to Acquired Antithrombin III Deficiency Clinical Trial

Official title:

Response of Recombinant Antithrombin in Heparin Resistant Patients Undergoing Cardiac Surgery

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01547728
• Other study ID #: 11-004125
• Status: Terminated
• Phase: Phase 4
• First received: February 7, 2012
• Last updated: July 13, 2015
• Start date: February 2012
• Est. completion date: February 2014

Study information

• Verified date: July 2015
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Antithrombin III Deficiency
• Thrombophilia
• Thrombophilia Due to Acquired Antithrombin III Deficiency

Intervention

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.

Locations

Country	Name	City	State
United States	Mayo Clinic in Rochester	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	rEVO Biologics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No

External Links

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