The REG1 anticoagulant system—which includes pegnivacogin, an active anticoagulant, and anivamersen, a complementary control agent to neutralize the effect of pegnivacogin, for patients undergoing percutaneous coronary intervention (PCI)—was compared with bivalirudin in the REGULATE-PCI trial [NCT01848106], presented by Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Due to increased severe allergic reactions, including 1 death, the trial was terminated early, with only about 24% of the anticipated sample size enrolled.

While antithrombotic therapies have improved safety and efficacy outcomes of PCI, available therapies may lead to adverse events (AEs) such as bleeding [Steg PG et al. N Engl J Med. 2009]. Research continues to investigate novel antithrombotic regimens for PCI that might have the ideal balance of efficacy, safety, and ease of use.

The REG1 anticoagulant system was designed to provide rapid, predictable antithrombotic action with quick reversibility by near-complete factor IXa inhibition. The phase 2 randomized active-controlled RADAR trial [Povsic TJ et al. Eur Heart J. 2013] had showed promising results for the REG1 anticoagulant system to allow for early vascular sheath removal with similar bleeding rates to heparin. Although the study was not designed to evaluate an effect on ischemic end points, the number of adverse cardiovascular (CV) end points was lower in the REG1 arm. In the RADAR trial, 3 patients had allergic-like reactions shortly after drug administration (2 were serious).

In REGULATE-PCI, patients were randomized 1:1 to receive either the REG1 system or bivalirudin during PCI. The primary efficacy outcome was a composite rate of death, nonfatal myocardial infarction, nonfatal stroke, and urgent target-lesion revascularization through day 3 following PCI, and the primary safety end point was the rate of bleeding through day 3, unassociated with coronary artery bypass graft (CABG) surgery. Additional follow-up continued through day 30, with data on allergic AEs collected.

Patients were stratified by risk group and placed into high-, medium-, and low-risk subgroups based on indicators of CV risk. Recruitment began in September 2013 with medium- and low-risk patients; in April 2014, investigators expanded enrollment of high-risk patients following a safety review for approximately 1000 patients enrolled in the study.

However, in June 2014, the study enrollment was suspended due to increased reports of severe allergic reactions, with 3232 of the planned 13 200 patients enrolled. Ten serious allergic events, 1 fatal, were observed in the REG1 treatment group, compared with 1 in the bivalirudin treatment group (Table 1). In August 2014, upon recommendation from the Data Safety Monitoring Board, the study was permanently terminated due to excess allergic reaction rates associated with REG1 with a clear offsetting benefit to the drug.

No significant differences were observed in the primary efficacy end point with the data available; however, the exploratory end point of stent thrombosis was lower with REG1 at both days 3 and 30 (0.8% vs 0.1% with REG1; P < .01). Regarding the primary safety end point, major non-CABG-associated bleeding (BARC type 3 or 5) did not differ between the 2 groups (0.4% vs 0.1%; P = .10). Nevertheless, minor and major bleeding rates were higher in REG1, with 6.5% compared with 4.1% at day 3 (P < .002).

Dr Mehran concluded with a word of caution in interpreting the efficacy and bleeding data, as early termination limited the number of participants and events. She reiterated that REG1, as currently formulated, resulted an infrequent but unacceptably high rate of severe allergic reactions.