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Novel anticoagulation system had similar CV outcomes to bivalirudin, linked to increased bleeding, allergic reactions
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SAN DIEGO — A novel anticoagulation system studied in patients undergoing angioplasty was no more effective than bivalirudin before the trial was stopped, according to data from the REGULATE-PCI study presented at the American College of Cardiology Scientific Sessions.
The system, which combines pegnivacogin and the reversal agent anivamersen (REG1, Regado Biosciences), was associated with higher rates of moderate to severe bleeding, and the trial was stopped early because of disproportionate number of allergic reactions in patients, Roxana Mehran, MD, FACC, FACP, FCCP, FESC, FAHA, FSCAI, professor of medicine in cardiology at Icahn School of Medicine at Mount Sinai and director of interventional cardiovascular research and clinical trials at Mount Sinai Heart at The Mount Sinai Hospital, said at a press conference.
Roxana Mehran
REG1 was developed as an anticoagulant that could provide rapid onset of action, predictable dose-response, high anti-thrombotic efficacy and quick reversibility or titratability, Mehran, associate medical editor of Cardiology Today’s Intervention, said.
New anticoagulants are being investigated because “we don’t feel that during PCI, we have it perfect,” she said. “Glycoprotein IIb/IIIa inhibitors inhibit platelets extremely well but are associated with more bleeding. Bivalirudin, while it’s associated with much less bleeding, does have a signal of stent thrombosis.”
The phase 2 RADAR study previously showed that patients assigned REG1 had a numerically lower incidence of 30-day mortality, nonfatal MI, urgent target vessel revascularization or recurrent ischemia in the target vessel compared with heparin, she said.
Before the REGULATE-PCI trial was stopped, the researchers enrolled 3,232 patients undergoing angioplasty at 225 centers in 17 countries; they had intended to enroll 13,200 patients. Patients were assigned to receive bivalirudin (Angiomax, The Medicines Company) or REG1.
The primary efficacy endpoint was a composite of death, nonfatal MI, nonfatal stroke and urgent TLR at 3 days. The primary safety endpoint was BARC 3 or 5 incidence of bleeding not related to CABG at 3 days. Secondary endpoints included components of the primary endpoint at 3 days, the composite primary endpoint at 30 days, bleeding endpoints at 30 days and incidence and severity of allergic adverse events, of which three had been reported in the REG1 group in the RADAR trial.
When the trial was stopped, the primary endpoint at 3 days had occurred in 6.7% of the REG1 group compared with 6.4% of the bivalirudin group (P = .72). At 30 days, it had occurred in 7.5% of both groups (P = 1). Individual efficacy endpoints at 3 days and 30 days were also similar in both groups, except for the REG1 group having a lower rate of stent thrombosis at 30 days (0.1% vs. 0.8%; P < .01), according to the researchers.
The primary safety endpoint was not significantly different in both groups at 3 days (REG1 group, 0.4%; bivalirudin group, 0.1%; P = .1) and 30 days (REG1 group, 0.7%; bivalirudin group, 0.3%; P = .07), but the REG1 group had a higher incidence of the endpoint of major or minor BARC 2, 3 or 5 bleeding at 3 days (6.5% vs. 4.1%; P = .002) and 30 days (7.6% vs. 4.8%; P = .001), Mehran said.
For the 3,206 patients for whom allergic reaction data were available when the trial was stopped, there were 10 serious allergic events (0.6%) in the REG1 group and one (< 0.1%) in the bivalirudin group, she said. Of the 10 from the REG1 group, one had a fatal event and nine had a severe anaphylactic reaction, she said. There were 14 non-serious allergic events in the REG1 group vs. nine in the bivalirudin group.
“The way [REG1] is now, because of its allergic reactions, we can’t use it, and we are working very hard to better understand how to evaluate it and why these allergic reactions happen,” Mehran said. “But I think this is a promising story, and once we figure out that safety glitch, I think this could be the holy grail [of anticoagulation], and we hope to proceed in the future.” – by Erik Swain
Reference:
Mehran R, et al. Joint ACC/JAMA Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
Disclosure: The trial was sponsored by Regado Biosciences. Mehran reports consulting for AstraZeneca, Bayer, CSL Behring, Janssen Pharmaceuticals, Merck, Osprey Medical Inc., Regado Biosciences Inc., The Medicines Company and Watermark Consulting, and serving on scientific advisory boards for Abbott Laboratories, AstraZeneca, Boston Scientific, Covidien, Janssen Pharmaceuticals, Merck, Sanofi-Aventis and The Medicines Company.
Perspective
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Thomas J. Povsic, MD, PhD
REGULATE-PCI wanted to test two hypotheses. No. 1, is factor IX inhibition a useful target for anticoagulation during PCI? No. 2, is using an anticoagulation system that is completely reversible and controllable advantageous in this setting? Unfortunately, trial enrollment was stopped due to the rate of serious allergic reactions in patients treated with pegnivacogin, which was not counterbalanced by an efficacy signal, leaving the enrollment numbers insufficient to provide definitive answers.
However, we learned three things. No. 1, inhibiting factor IX appears to be an effective target for anticoagulation and suppression of ischemic events. No. 2, reversible anticoagulation worked, but without complete reversal at the end of the procedure, and was associated with higher bleeding rates, but a trend toward lower rates of stent thrombosis. No. 3, REG1 as currently formulated is associated with severe allergic reactions at a low but unacceptable rate for this particular clinical setting. The exact mechanism is unknown and is being actively investigated.
Since REG1 is unlikely to undergo further clinical development, this will not change practice directly, but the trial I think corroborated findings from other studies that suggest that bivalirudin is a very good drug if you want to minimize bleeding, but we again observed that there was an excess of stent thrombosis events associated with its use.
I think reversible anticoagulation remains an attractive concept to proceduralists. This study ended up being too small to definitively answer whether this will translate into clinical benefit, so I would be cautious about overinterpretation and saying this would not work.
We also plan on fully investigating the allergic reactions and the trial included an extensive biomarker collection plan to allow us to investigate this fully. Oligonucleotides have not been previously been found to be antigenic, and we have reason to believe that the allergies may not be due to the aptamer itself. I believe the concept of reversible aptamers remains an attractive area of research, although the clinical application remains to be defined.
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