Halted REGULATE-PCI Trial Has Lessons for Finding "the Perfect Anticoagulant"

Marlene Busko

March 26, 2015

SAN DIEGO, CA — Exploratory analysis of data from the phase 3 REGULATE-PCI trial that was halted last August due to concerns about serious allergic reactions with the novel agent REG1 (Revolixys Kit, Regado Biosciences) suggests that if future research can solve the allergy and bleeding complications, the drug may provide effective, reversible anticoagulation for patients undergoing PCI[1].

"This is a promising story, [and] once we figure out the safety glitch, I think this could be the holy grail that we hope to see in the future," co–principal investigator Dr Roxana Mehran (Mount Sinai School of Medicine, New York, NY) said in a media briefing following presentation of the study in a late-breaking clinical-trials session here at the American College of Cardiology 2015 Scientific Sessions.

The holy grail would be an agent that has a rapid onset of action, a predictable dose-response curve, high antithrombotic efficacy during PCI, and quick reversibility very soon after, Mehran elaborated. REG1, which is a combination of the anticoagulant pegnivacogin (which acts on factor IXa and has a very short half-life) and the reversal agent anivamersen, "could be the perfect anticoagulant," she said.

Patients in the REG1 study arm had a similar rate of ischemic events but more moderate or severe bleeding than patients randomized to bivalirudin (Angiomax, the Medicines Company), along with an unacceptably high rate (0.6%) of severe allergic reactions, Mehran reported, adding that ongoing further research is looking at deciphering why the agent caused a spike in serious allergic reactions.

Dr Eric D Peterson (Duke University, Durham, NC), the assigned discussant in the media briefing, agreed that more research is needed to see how this agent might be modified to prevent these allergic reactions. Moreover, "the signs for efficacy and safety, at least as the drug was currently used, were perhaps flat," he noted. "I think there is great promise in this field, but a fair degree of work still needs to be done," he summarized.

Still Searching for the "Perfect" Anticoagulant

"Why are we so excited about yet another antithrombotic regimen? It's probably because we feel that during PCI we still don't have it perfect," Mehran said.

The phase 2 RADAR trial had previously shown that with at least 50% reversal of pegnivacogin by anivamersen, bleeding rates were similar to those with heparin. Three of the 479 patients had allergic reactions soon after receiving REG1.

In September 2013, REGULATE PCI began recruiting patients with CAD undergoing PCI in 225 centers in 17 countries, notably in the US, Canada, Estonia, Italy, and Slovakia. However, by August 21, 2014, when only a quarter (3232) of the planned 13 200 patients had been enrolled, the trial's data safety and monitoring board stopped the trial due to excess allergic events without any offsetting benefit, as heartwire from Medscape reported at the time.

In the REG1 arm, 10 patients had severe allergic reactions and one patient died by day 3, whereas only one patient in the bivalirudin had a severe allergic reaction by day 3. Meanwhile, there was no improvement in efficacy. A similar number of patients died or had a nonfatal MI, nonfatal stroke, or urgent target lesion revascularization by day 3: 6.7% vs 6.4%, for patients in the REG1 arm vs bivalirudin arm, respectively (P=0.72). Efficacy was still similar at 30 days.

The primary safety end point, incidence of major BARC 3 or 5 bleeding by day 3, was 0.4% and 0.1% for patients in the REG1 and bivalirudin arms, respectively (P=0.10). However, more patients in the REG1 arm than in the bivalirudin arm had major and minor BARC 2, 3, or 5 bleeding by day 3: 6.5% vs 4.1% (P=0.002).

Given the early termination of the trial with only a quarter of the planned end-point events, these are exploratory findings, Mehran stressed. "The concept of high-level aptamer-based anticoagulation with active reversal is promising, and a dream, I think, for a lot of us; however, its clinical role has yet to be defined, and further improvements are needed in its safety profile," she concluded.

In reply to questions from a panel, she said that phase 2 studies showed that REG1 provided very robust, effective anticoagulation across the board, so factor IXa is definitely still a target for anticoagulant therapy.

The researchers were excited by the effectiveness of REG1 but were somewhat alarmed by the increased bleeding, she admitted. "This is an extremely effective therapy; maybe it doesn't need to be just 80% reversed, but maybe 95% reversed; but we will need to see that down the line," she said.

The study was funded by Regado Biosciences. Mehran has received consultant fees and honoraria from Abbott Vascular, AstraZeneca, Biosensors, Boston Scientific, Covidien, Johnson & Johnson, Merck, Osprey, Regado, and the Medicines Company and has worked with WebMD and Wiley Blackwell Publishing.


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