Anticoagulation With Off-Switch Fails to Improve PCI Outcomes, Sparks Allergic Reactions

SAN DIEGO, CA—A novel anticoagulation system that includes a rapid reversal agent increases moderate-to-severe bleeding and serious allergic reactions without providing improvement in clinical outcomes for patients undergoing PCI, according to results of a prematurely stopped trial presented March 15, 2015, at the American College of Cardiology/i2 Scientific Session.

  “The concept of high-level aptamer-based anticoagulation with an active reversal is promising … [but] its clinical role has yet to be determined and we need further improvement in its safety profile,” said Roxana Mehran, MD, of Mount Sinai Medical Center (New York, NY).

REGULATE-PCI was a phase III trial evaluating the REG1 anticoagulation system combining the selective factor IXa inhibitor pegnivacogin and the active control agent anivamersen, which rapidly reverses the anticoagulant effect. The system was compared with bivalirudin in 3 subgroups of patients undergoing PCI:                                        

• MI in the prior week with ischemic symptoms at rest and positive cardiac biomarkers
• At least 1 of the following risk factors: ACS with positive cardiac biomarkers more than 7 days before randomization, unstable angina without positive cardiac biomarkers, age older than 70 years, diabetes, chronic kidney disease, planned multivessel PCI, prior CABG, or peripheral vascular disease
• Negative cardiac biomarkers and no risk factors

Patients randomized to REG1 received a bolus injection of pegnivacogin 1 mg/kg just prior to PCI and then anivamersen 0.5 mg/kg—providing 80% reversal of the anticoagulant effect—at the end of the procedure. In the bivalirudin group, patients received a bolus of 75 mg/kg before PCI with an infusion of 1.75 mg/kg/hour continuing until the end of the procedure.

The planned sample size was 13,200 patients at enrollment start in September 2013, but the trial was suspended on June 29, 2014, amid ongoing reports of severe allergic reactions after 3,232 patients (mean age 65 years; about three-quarters men) had been randomized at 225 centers in North America and Europe. The data and safety monitoring board permanently stopped the trial on August 21, 2014, because of the reactions and a lack of evidence of benefit.

The primary efficacy endpoint was a composite of death, MI, stroke, or urgent TLR through day 3, which occurred in 6.7% of REG1-treated patients and 6.4% of bivalirudin-treated patients (P = .72). There were no differences between groups for any of the individual components, but there was a higher rate of stent thrombosis in the bivalirudin arm (0.8% vs 0.1%; P < .01). The patterns were similar at 30 days.

The primary safety endpoint was the rate of major non-CABG-related bleeding (BARC 3 or 5) through 3 days, and that occurred infrequently in both the REG1 and bivalirudin groups (0.4% vs 0.1%; P = .10). Including milder BARC 2 bleeding, however, resulted in a significantly higher rate of moderate-to-severe bleeding in the REG1 arm (6.5% vs 4.1%; P = .002). The 30-day bleeding results were similar.

Serious allergic reactions occurred in 10 patients in the REG1 group—including 1 who died—and 1 patient in the bivalirudin group.

Search for ‘Holy Grail’ of Antithrombotic Therapy Continues

According to Dr. Mehran, the ideal antithrombotic agent for PCI—which does not yet exist—would have a rapid onset of action, a predictable dose response, high efficacy, and quick reversibility or titratability.

The REG1 system showed promise in the phase II RADAR trial, in which at least 50% reversal of pegnivacogin allowed early vascular sheath removal with a bleeding risk comparable to heparin. In addition, there was a nonsignificant reduction in death, MI, urgent TVR, or recurrent ischemia in the target vessel at 30 days with REG1 (OR 0.5; 95% CI 0.2-1.4). 

However, 3 patients in that trial had allergic reactions (2 serious) shortly after administration of pegnivacogin, mirroring the “infrequent but unacceptably high rate of severe allergic reactions” observed in REGULATE-PCI, Dr. Mehran said, adding that further research is underway to understand the causes of the reactions.

In response to a question about why there was more bleeding with REG1 despite the rapid reversal of the anticoagulant effect, she explained that a greater degree of reversal might be required. “This was … our precautionary way of trying to keep some anticoagulation on board,” she said. “This is an extremely effective therapy and maybe it doesn’t need to be just 80% reversed, but rather 95% reversed. But we will need to see that down the line.”

At a press briefing, panelist Eric D. Peterson, MD, MPH, of the Duke Clinical Research Institute (Durham, NC), said clinicians were “quite excited” about pegnivacogin. He added that the allergic reactions might have to do with the chemical background of the molecule, which could potentially be changed.

“However … the signs for efficacy and safety, at least as the drug is used currently, were perhaps flat,” he said, “and so, in fact, it will also take some modification in how the drug is given and [for] what indications to show these benefits.”

Dr. Peterson noted that “there is great promise with where we’re going with the field” but that a “fair degree of work” remains. 

Note: Dr. Mehran is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

 

 

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Source:Mehran R, Lincoff AM, Zelenkofske S, et al. A randomized, open-label, multicenter, active-controlled, parallel-group study to determine the efficacy and safety of the REG1 anticoagulation system compared to bivalirudin in patients undergoing percutaneous coronary intervention. Presented at: American College of Cardiology/i2 Scientific Session; March 15, 2015; San Diego, CA.

 

 

Disclosures:

 

• The study was sponsored by Regado Biosciences.
• Dr. Mehran reports receiving consulting fees/honoraria from multiple pharmaceutical companies, research grants from Lilly/DSI and Stentys, and having other relationships with WebMD and Wiley Blackwell Publishing.

 

 

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