Bivalirudin and Ecarin Clotting Time

Bivalirudin and Ecarin Clotting Time
Apr 10, 2016 12:08am

Maria Grana asks, who uses the ecarin clotting test? Can the ecarin clotting test be used for bivalirudin (Angiomax) monitoring?  Is the ecarin clotting test FDA approved? We are having complaints from MDs that the activated clotting time (ACT ) is not responding to administration of heparin on some patients. Can these patients have antithrombin (AT , ATIII ) deficiency? Some of these patients are on Angiomax but the ACT is not FDA approved for angiomax monitoring and the package insert for the I-STAT says that other anticoagulants/drugs on board can interfere. Thank you for your help.


Hello, Maria, and thank you. The ecarin clotting time assay is available from Esoterix Coagulation, a LabCorp Company, and is offered for investigational or research use only. It is not FDA-approved, and for that reason I know of no local laboratories that offer the assay. Diagnostica Stago, Inc. has developed their Ecarin Chromogenic Assay, which may be used to measure the direct thrombin inhibitors (DTIs) Angiomax, Argatroban and the direct oral anticoagulant, dabigatran (Pradaxa), however it, too awaits FDA approval, though it has been available for several years in Europe. Aniara offers the Hyphen Biomed Hemoclot Thrombin Inhibitor assay, which is a plasma-diluted thrombin time. It may also be used to measure all three DTIs, however it, too, awaits FDA approval. The only assay that is currently FDA-approved for measuring any of the three DTIs is the PTT , which is also prolonged by heparin, and thus not useful when heparin and Angiomax are used together. The PTT results vary considerably by reagent manufacturer and by coagulometer, so it must be applied cautiously.

In instances when the ACT or the PTT do not appear to respond to heparin therapy, the first consideration is AT depletion, which may occur after a few days of heparin therapy. Congenital AT deficiency is rare, but may cause the same problem, sometimes called heparin resistance. The physician may order AT activity levels and, if necessary, administer AT concentrate.

By coincidence, Lesa Nelson just sent a question about ACT response to heparin that may help, I've linked her post here. I'm sorry I can't offer definitive assistance, the best we can hope for is speedy FDA intestigation of these well-defined new assays.

 

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Maria Grana asks, who uses the ecarin clotting test? Can the ecarin clotting test be used for bivalirudin (Angiomax) monitoring?  Is the ecarin clotting test FDA approved? We are having complaints from MDs that the activated clotting time (ACT ) is not responding to administration of heparin on some patients. Can these patients have antithrombin (AT , ATIII ) deficiency? Some of these patients are on Angiomax but the ACT is not FDA approved for angiomax monitoring and the package insert for the I-STAT says that other anticoagulants/drugs on board can interfere. Thank you for your help.


Hello, Maria, and thank you. The ecarin clotting time assay is available from Esoterix Coagulation, a LabCorp Company, and is offered for investigational or research use only. It is not FDA-approved, and for that reason I know of no local laboratories that offer the assay. Diagnostica Stago, Inc. has developed their Ecarin Chromogenic Assay, which may be used to measure the direct thrombin inhibitors (DTIs) Angiomax, Argatroban and the direct oral anticoagulant, dabigatran (Pradaxa), however it, too awaits FDA approval, though it has been available for several years in Europe. Aniara offers the Hyphen Biomed Hemoclot Thrombin Inhibitor assay, which is a plasma-diluted thrombin time. It may also be used to measure all three DTIs, however it, too, awaits FDA approval. The only assay that is currently FDA-approved for measuring any of the three DTIs is the PTT , which is also prolonged by heparin, and thus not useful when heparin and Angiomax are used together. The PTT results vary considerably by reagent manufacturer and by coagulometer, so it must be applied cautiously.

In instances when the ACT or the PTT do not appear to respond to heparin therapy, the first consideration is AT depletion, which may occur after a few days of heparin therapy. Congenital AT deficiency is rare, but may cause the same problem, sometimes called heparin resistance. The physician may order AT activity levels and, if necessary, administer AT concentrate.

By coincidence, Lesa Nelson just sent a question about ACT response to heparin that may help, I've linked her post here. I'm sorry I can't offer definitive assistance, the best we can hope for is speedy FDA intestigation of these well-defined new assays.

 

By Dr. Ali Sadeghi-khomami
Apr 10, 2016 5:17pm
Regarding Angiomax monitoring, although I am not aware of any specific companion diagnostics for Angiomax, the following information which I found from Angiomax labeling indicates that ACT was mainly used in the clinical trials:
“In healthy volunteers and patients (with ≥ 70% vessel occlusion undergoing routine angioplasty), Angiomax exhibits linear dose--and concentration--dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. In 291 patients with ≥ 70% vessel occlusion undergoing routine PTCA, a positive correlation was observed between the dose of Angiomax and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an Angiomax dose of 1.0 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec. However concentration-ACT relationship was age-dependent. The primary pharmacodynamic biomarker measured was ACT (Hemochron®) using blood obtained at the same time and from the same source line used for collecting PK samples.
The approved product labeling for Angiomax states that, in adults, IV bivalirudin produces dose-dependent prolongation of anticoagulant activity as measured by activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombin time (PT), and activated clotting time (ACT). Prolongation of clotting times is positively correlated with plasma drug concentrations. The choice of ACT is reasonable given the clinical environment of the study.
ACT is an accepted method for evaluating coagulation status and assessing PD activity in adults and is considered a suitable surrogate measure for confirming the presence of anticoagulation during vascular interventions. It is important to note that although ACT is a useful indicator that the patient has received bivalirudin through a rise in ACT values from baseline, ACT levels have not been predictive of thrombotic or bleeding events in previous studies in the setting of catheter-based procedures at a fixed dose of bivalirudin.
In response to an FDA request for increased guidance for investigators with respect to ACT values, additional text was added by the applicant as a protocol amendment explaining that ACT was not a precise measure of anticoagulant status but that ACT levels below 200 seconds may indicate inadequate anticoagulation and measures should be taken to establish correct dosing and receipt of drug.
Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed. The steady state ACT with the sponsor’s proposed dosing regimen was within the target range (200–400 sec). This target range was decided after consulting with the medical reviewer and also searching literature.
The adequacy of ACT monitoring is more questionable in pediatric patients because ACT is influenced by factors more likely to occur in infants and neonates undergoing coronary bypass for congenital heart repair. However, the approved labeling for commercially available transcatheter atrial septal closure devices recommend a targeted ACT > 200 seconds. Moreover, American College of Chest Physicians recommend a target ACT between 250–350 sec in patients undergoing PCI.”

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