A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial
Key result
REG1 with ≥50% reversal matches heparin bleeding in ACS, but 25% reversal drives ~65% bleeding rates.
- n=640
Why the study?
The REG1 anticoagulation system had not been studied in invasively managed ACS patients, and the optimal level of reversal to allow safe sheath removal was undefined.
Does the REG1 system with variable anivamersen reversal safely provide anticoagulation and mitigate bleeding compared to heparin in NSTE-ACS patients undergoing early invasive management?
Study Design
Type
RCT (n=640)
Blinding
partially blinded
Randomization
2:1:1:2:2
Structured PICO
Does the REG1 system with variable anivamersen reversal safely provide anticoagulation and mitigate bleeding compared to heparin in NSTE-ACS patients undergoing early invasive management?
P
Population
640 patients with non-ST-elevation ACS planned for early cardiac catheterization via femoral access, followed for 30 days.
I
Intervention
REG1 system (pegnivacogin, an RNA aptamer selective factor IXa inhibitor, with 25%, 50%, 75%, or 100% anivamersen reversal)
C
Comparator
Heparin
O
Outcome
Total ACUITY bleeding through 30 dayssafety
In NSTE-ACS patients undergoing early cardiac catheterization, at least 50% reversal of pegnivacogin with anivamersen is required to achieve bleeding rates comparable to heparin, though the trial was stopped early due to allergic-like reactions.
Limitations
- Enrolment was stopped after three patients experienced allergic-like reactions.
- Enrolment in the 25% reversal arm was suspended after 41 patients
- Overall enrolment was stopped early after three patients experienced allergic-like reactions
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“The Phase 2b RADAR trial for REG1 has demonstrated a paradigm shift to provide physicians with a more effective option to control bleeding and ischemic events in ACS patients. REG1 provides physicians the ability to titrate the intensity of anticoagulation according to specific patient needs, which are not currently met with existing drugs.”
“These findings further support our belief that the REG1 Anticoagulation System may possess many advantages over currently available anticoagulants by providing a high level of anticoagulation that is controllable and fully reversible. While further studies are needed to determine whether anticoagulation with REG1 and early sheath removal following cardiac catheterization will translate into improved time to ambulation, shorter hospital stays and reduced costs for certain patients, we are very pleased to report these findings, which support REG1's remarkable safety and its broad potential impact for cardiologists, patients and payors.”
Implication
REG1 reversal feasible in invasively managed ACS; leaves open optimal dosing, safety, and efficacy for randomized trials.
Abstract
AIMS: We sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined. METHODS AND RESULTS: Non-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively. CONCLUSION: At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation.
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Cite This Study
Povsic et al. (2012) conducted an RCT in Non-ST-elevation acute coronary syndrome (n=640). REG1 (pegnivacogin and anivamersen) vs. heparin was evaluated on total ACUITY bleeding through 30 days. REG1 with at least 50% reversal resulted in similar 30-day bleeding rates (30-35%) compared to heparin (31%) in ACS patients, whereas 25% reversal led to excess bleeding (65%).