Thomas J Povsic (Duke Clinical Research Institute, Duke University Medical Center, Durham, USA) and others report in Eurointervention that the novel REG1 anticoagulation system—comprised of a single-stranded RNA factor IXa inhibitor (pegnivacogin) and its reversal agent (anivamersen)—is safe and feasible for supressing both ischaemic events and thrombotic complications with a favourable bleeding profile in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI).
According to Povsic et al, attempts to increase the intensity of anticoagulation in PCI have been limited by bleeding. They add: “One approach to achieving effective anticoagulation while mitigating bleeding is to use an anticoagulation regimen that can be actively reversed, permitting anticoagulation therapy to be tailored to the clinical circumstances and changing needs of an individual patient.”
The authors note that the REG1 anticoagulation system can be actively reversed and RADAR (a randomised, partially blinded, multicentre, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes) has already shown that it is feasible to use the system in patients with acute coronary syndromes undergoing cardiac catheterisation. However, they add that the safety of using the REG1 strategy in patients undergoing PCI has not been “thoroughly investigated”. Therefore, in the current analysis (RADAR-PCI), Povsic et al compared the safety of using the REG1 system with the safety of using heparin in patients with acute coronary syndromes undergoing PCI.
Of the 640 patients enrolled in the original RADAR study, 388 underwent PCI within 24 hours of admission to hospital. In this subgroup of patients, 277 (after randomisation) received 1mg/kg of pegnivacogin and underwent immediate sheath removal with varying amounts of reversal agent—25% reversal (22), 50% reversal (68), 75% reversal (71), and 100% reversal (116). Enrolment in the 25% reversal arm was stopped because of excess bleeding in this group as was stipulated per protocol. The 111 patients in the control group received heparin and standard care (sheath removal
The composite ischemic endpoint was numerically lower in patients in the REG1 group (4.4% vs. 7.3%, respectively; p=0.3). While not statistically powered to demonstrate an effect on this endpoint, the incidence of ischaemic events in the peri-PCI period was also lower in REG1 treated patients (2.9% vs 7.2%, p=0.06). Povsic et al reported: “Bleeding was substantial in the 25% reversal arm prior to discontinuation of enrolment, but similar among the other pegnivacogin arms and in patients randomised to heparin.” They add that although the study was not powered to compare the rates of bleeding between patients receiving pegnivacogin, there was a significantly lower rate of bleeding in patients who received the drug with 100% reversal than in patients who received 25% reversal (p=0.003 for the comparison).
The authors conclude: “When coupled with appropriate reversal, REG1 allows early femoral sheath removal without compromising bleeding. Additional studies of REG1 in large and varied patient populations undergoing interventions in which transient high-level anticoagulation with rapid post-procedural reversal is attractive are warranted.”
Povsic told Cardiovascular News: “While not adequately powered as a phase II study, our study supports the concept that controllable anticoagulation offers, for the first time, the possibility of favourably impacting both ischaemic and bleeding endpoints—or at minimum, developing a more potent anticoagulant without increasing bleeding risk. This is possible because the availability of a reversible agent allows safe targeting and achievement of very high levels of anticoagulation. This strategy may be extremely attractive not only in PCI, but in other invasive procedures (eg. coronary artery bypass grafting) or acute care settings where the need for anticoagulation may change significantly during the clinical care of a patient or transient high-level anticoagulation is needed.”