August 13, 2010 (Miami, Florida) — Researchers believe they may have found a truly reversible anticoagulant system to control bleeding during PCI that consists of one agent to anticoagulate and another to halt the first drug’s effects . The product, known for the time being as REG1 (Regado Biosciences, Basking Ridge, NJ) includes two nuclease-stabilized RNA aptamers: an aptamer inhibiting coagulation factor IXa called RB006 (pegnivacogin) and its matched active control agent, RB007 (anivamersen).
"Having a reversible anticoagulant or an anticoagulant you can control has been the holy grail of anticoagulant therapy, especially in PCI," Dr Mauricio Cohen (University of Miami, FL) told heartwire . "We understand that while we need intense anticoagulation during the procedures, we also need to be in control and make sure we don't overshoot anticoagulation, because if the patient bleeds, they are at a higher risk of mortality."
Currently, the only reversal agent available now is protamine, which works only with unfractionated heparin (UFH), but many cath labs are switching from unfractionated heparin to bivalirudin, which does not have a specific reversal agent, Cohen said. Also, protamine is not titratable and can induce direct mast-cell degranulation, complement activation, and antibody formation that can lead to potentially catastrophic adverse reactions, according to Cohen et al.
"The beauty of this system is that you can inject the drug and, depending on the ratio of the drug and the control agent, RB006 and RB007, you can actually titrate to the level of the anticoagulation that you want . . . and you can dial the anticoagulation according to the individual need of the patient," Cohen said. He pointed out that access-site bleeding accounts for about 70% of bleeding in PCI, so the ability to control anticoagulation right after the intervention is complete and the sheath is pulled will prevent many of these events. Also, in PCI cases where the coronary is accidentally perforated, being able to reverse the anticoagulant is vital.
The results of the randomized REVERSAL-PCI phase 2a trial of REG1, led by Cohen, are published in the August 10, 2010 issue of Circulation. The open-label, multicenter, randomized study compared REG1 with UFH during elective PCI.
In the study, 10 patients were assigned to RB006 that was partially reversed with RB007 post-PCI and fully reversed four hours later; 10 patients were assigned to RB006 that was fully reversed with RB007 immediately post-PCI; and four patients were on unfractionated heparin.
Stents were deployed in 28 of the 30 lesions treated in the study, and drug-eluting stents were used in half the cases. There were six cases of two-vessel PCI. All patients were pretreated with aspirin and clopidogrel. Trial end points included major bleeding within 48 hours, a composite end point of death, MI, or urgent target vessel revascularization within 14 days, plus pharmacodynamic measures.
The median activated clotting time (ACT) values rose from 151 to 236 seconds after taking RB006. Administration of the partial RB007 dose reversed anticoagulation to an ACT of 186 seconds, and complete reversal with RB007 returned the median ACT value to 144 seconds.
The femoral sheaths were removed after complete reversal, and all cases were deemed successful, because there were no angiographic thrombotic complications and reperfusion was complete (TIMI 3). There were no deaths, but one patient in the partial-reversal group had a periprocedural MI after two-vessel disease and one patient in the complete-reversal group received another stent proximal to the first one after coming back with chest pain within a week. One patient in the UFH group had an uncomplicated enzymatic MI.
Cohen is part of a group currently conducting the REG1 Anticoagulation System Compared Heparin in Subjects with Acute Coronary Syndrome (RADAR) study. RADAR is comparing four blinded ratios of RB006 and RB007 with heparin in 800 acute coronary syndrome patients. The primary outcome measure is composite incidence of major and minor bleeding 30 days after cardiac catheterization. The study began about a year ago and is scheduled to be completed by the end of this year.
The study was funded by Regado Biosciences. Cohen has received consulting and research funding from Regado Biosciences. Disclosures for the coauthors are listed in the paper.
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: Two-Part Reversible Anticoagulant Performs Well With PCI in Small Trial - Medscape - Aug 13, 2010.