Novel Anticoagulation System Fails to Best Bivalirudin in Setting of PCI

A randomized phase 3 trial of a factor IXa inhibitor and its complementary reversal agent (REG1 Anticoagulation System) in patients undergoing percutaneous coronary intervention (PCI) was terminated early due to an excess of serious allergic reactions. So reported investigators with the multicenter REGULATE-PCI study today at the American College of Cardiology’s 64th Annual Scientific Session.

The REG1 Anticoagulation System consists of an RNA aptamer, pegnivacogin, that reversibly inhibits factor IXa with high specificity, and its antidote, anivamersen, which binds to pegnivacogin to inhibit its effect within a few minutes of administration.

The system was tested in the REGULATE-PCI trial, which had a planned enrollment of 13,200 patients with coronary artery disease undergoing PCI. Patients were randomized in an open-label fashion to REG1 or bivalirudin.

A quest for rapid reversal of anticoagulation

“We could use very high levels of anticoagulation during the procedure because we knew that as soon as the procedure was over, we could reverse it, and we did by 80 percent,” says REGULATE-PCI co-principal investigator A. Michael Lincoff, MD, Vice Chair of Cleveland Clinic’s Robert and Suzanne Tomsich Department of Cardiovascular Medicine. The hope was that the rapid reversal would reduce the rate of bleeding associated with PCI.

The dosage of the antidote can be titrated to adjust the degree of reversal of anticoagulation. “Previous studies have shown that if you could reverse the effect by 50 percent or more, you could comfortably take the vascular sheaths out at the end of the procedure without bleeding,” notes Dr. Lincoff, who also directs the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).

Study stopped early due to allergic reactions

The study was terminated after enrolling only 3,323 patients. Serious allergic events occurred within 24 hours in 10 of 1,605 patients randomized to REG1, including one fatal event and nine anaphylactic reactions. “It became clear to the study’s data safety monitoring committee that the risk of these allergic reactions was outweighing any potential benefit, so they stopped the trial,” Dr. Lincoff explains.

In a prior phase 2 study of REG1 in 900 patients, three patients experienced allergic reactions during the final week of enrollment. These reactions were unexpected, as RNA aptamers are not thought to be allergenic, according to Dr. Lincoff. They are bound to polyethylene glycol (PEG), a polyether compound that has many commercial and medical applications, to prolong circulating half-life and extend the anticoagulant effect. The speculation is that the allergic component in REG1 is the PEG, but definitive answers await further analysis.

No better than bivalirudin, with higher bleeding rates

When compared with bivalirudin, the REG1 Anticoagulation System offered no advantage on the primary efficacy end point of REGULATE-PCI, a composite of all-cause death, myocardial infarction, stroke or unplanned target revascularization through day 3 after randomization. Surprisingly, however, REG1 caused a higher rate of overall bleeding compared with bivalirudin (6.5 vs. 4.1 percent; P = .002), although not a significant excess of serious or fatal bleeding.

Dr. Lincoff says the reason for the significantly higher rate of overall bleeding is not clear. “Maybe 80 percent anticoagulation reversal isn’t enough, although it seemed to be enough in previous, smaller trials,” he notes.

The road ahead

Factor IX plays a fundamental role in tissue factor-mediated thrombin generation. It is involved in the initiation and propagation phases of coagulation, which makes it a promising target for an anticoagulant.

REGULATE-PCI puts an end to consideration of REG1 as an alternative to bivalirudin in patients with coronary artery disease undergoing PCI, Dr. Lincoff says, but the aptamer technology may still be useful for other coagulation factor targets.

In addition, he notes, the use of heparin alone in this setting has become more attractive with the powerful antiplatelet agents that are now available.