Test results presented have implications for patients if they require emergency surgery.
Last month, the FDA approved idarucizumab (marketed as Praxbind) as an agent that specifically reverses the anticoagulant dabigatran (approved in 2010 as Pradaxa) to prevent stroke and systemic blood clots in patients with atrial fibrillation and to treat deep vein thrombosis and pulmonary embolism. According to FDA, the accelerated approval was granted based on an unmet need. Both Praxbind and Pradaxa are made by Boehringer Ingelheim.1
According to a presentation Monday at the American Heart Association Scientific Sessions, being held in Orlando, Florida, it remained to be seen how idarucizumab would work if a patient had already been given other coagulation factors, or how it might affect other anticoagulants on the market. In particular, the first scenario might occur in an emergency.
Joanne van Ryn, PhD, a scientist with Boehringer Ingelheim, first outlined the nature of the idarucizumab molecule, which binds to dabigatran in a 1-to-1 manner. “Dabigatran is almost completely enclosed,” she explained.
Van Ryn then reviewed results of a series of tests performed with idarucizumab and dabigatran in combination with coagulation factors 3- or 4-factor prothrombin complex (PCCs) activated PCC (aPCC) or recombinant Factor Villa (rFVlla). Van Ryn Dabigatran (0-500 ng-mL) was added to human plasma that contained these coagulants, with or without idarucizumab (3.0 mg/mL). Researchers measured the levels of anticoagulant activity.2
According to van Ryn, as well as an accompanying abstract, idarucizumab reversed anticoagulant activity of dabigatran to baseline; this reversal was not affected by presence of PCCs, aPCC or rFVIIa. Later in the session, however, both van Ryn and moderator Steven Lentz, MD, of the University of Iowa, cautioned that this was not an invitation to purposely use PCCs along with idarucizumab if a patient’s dabigatran status is known in an emergency situation.
Van Ryn then outlined another series of tests that analyzed whether idarucizumab would reverse the anticoagulant effects of several other agents. Idarucizumab did not reverse the effects of direct thrombin inhibitors (DTIs) hirudim, bivalirudin, or argatroban. There was a weak effect on melagatran, which van Ryn noted has some similarities to dabigatran.
In addition, human plasma treated with rivaroxaban, apixaban, heparin, and enoxaparin did not have their anti-FXa effects reversed when tested with idarucizumab.
The implications of the tests are important, because the highly specific effects of idarucizumab mean that patients will remain safe if other drugs are used initially in emergency surgery, van Ryn said.
Lentz called the results, “very clean.”
One trial that led to FDA approval involved 123 patients taking dabigatran who received idarucizumab due to uncontrolled bleeding or because they required emergency surgery. In this ongoing trial, based on laboratory testing, the anticoagulant effect of dabigatran was fully reversed in 89% of patients within 4 hours. In this patient trial, the most common side effects were low potassium (hypokalemia), confusion, constipation, fever and pneumonia.1
1. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa [press release]. Silver Spring, MD: FDA Newsroom; October 16, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm.
2. Van Ryn J, Schurer J, Fischer D, Goss A. Reversal of dabigatran anticoagulation by idarucizumab in the presence of coagulation factor concentrates and the lack of potential non-specific effects of idarucizumab on heparins, Factor Xa inhibitors and other direct thrombin inhibitors like bivalirudin, hirudin or argatroban. Presented at the American Heart Association Scientific Sessions; Orlando, Florida; November 9, 2015; abstract 299.