Safety of Very Early Sheath Removal in Patients Treated With REG1 for Acute Coronary Syndromes: Insights From the RADAR Trial

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John P. Vavalle, MD,1 Thomas J. Povsic, MD, PhD,1 Laura H. Aberle, BSPH,1 Steven L. Zelenkofske, DO,2 Roxana Mehran, MD,3 Jaroslaw D. Kasprzak, MD,4 Christoph Bode, MD,5 Christopher E. Buller, MD,6 Gilles Montalescot, MD,7 Jan H. Cornel, MD,8 Richard C. Becker, MD,1 John H. Alexander, MD, MHS,1 Mauricio G. Cohen, MD9

Abstract: Background. RADAR compared REG1 (25%, 50%, 75%, 100% reversal) with unfractionated heparin (UFH) in 640 acute coronary syndrome (ACS) patients (479 REG1 patients, 161 UFH patients) undergoing an invasive management strategy. We sought to determine whether the REG1 anticoagulation system allows for safer early arterial sheath removal following cardiac catheterization. Methods. REG1 patients had arterial sheath removal immediately post catheterization. We measured arterial sheath management outcomes and vascular access complications in patients who had sheath removal without vascular closure device implantation; 461 patients were included (349 REG1 patients, 112 UFH patients). Results. The median (25th, 75th) time from end of catheterization to arterial sheath removal was shorter in REG1 arms regardless of reversal strategy (26 minutes [18, 46]) compared with UFH (210 minutes [102, 342]). There was no increase in median time from sheath removal to hemostasis (10 minutes [10, 20] and 10 minutes [10, 20]; P=.60); vascular access-site bleeding complications were numerically fewer with REG1 than UFH (6% vs 11%; odds ratio [OR], 0.57; 95% CI, 0.27-1.18; P=.14). There were no differences in time to ambulation or hospital length of stay between the groups. Conclusions. REG1 allows for very early arterial sheath removal following cardiac catheterization without increasing the time to hemostasis or vascular access-site bleeding complications. Further studies are needed to determine whether anticoagulation with REG1 will translate into shorter hospital lengths of stay and reduced costs in ACS patients. 

J INVASIVE CARDIOL 2013;25(11):593-599

Key words: anticoagulation, aptamer, factor IX, bleeding, cardiac catheterization, REG1, pegnivacogin

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Vascular-access complications after cardiac catheterization lead to substantial increases in cost and morbidity. Among patients undergoing percutaneous coronary intervention (PCI), a substantial proportion of bleeding events are hematomas that occur at the site of vascular access.1 Bleeding complications among patients with acute coronary syndrome (ACS) undergoing coronary angiography are associated with poor long-term outcomes and an increase in the risk of subsequent ischemic events and death.1-4 An analysis from the National Heart Lung and Blood Institute Dynamic Registry found that patients experiencing access-site hematomas requiring transfusion were approximately 9 times more likely to die in the hospital and 4.5 times more likely to die within 1 year, as compared with those not experiencing these access-site hematomas.2

Delays to arterial sheath removal following coronary angiography have been associated with an increased risk of bleeding at the site of arteriotomy.5 The use of vascular closure devices reduces time to sheath removal and ambulation following cardiac catheterization, but does not reduce vascular complications.6 Early arterial sheath removal immediately after the conclusion of the procedure may decrease the risk of bleeding, shorten the time to ambulation, decrease hospital lengths of stay, and even possibly allow for patients to be discharged on the same day. 

The REG1 Anticoagulation System (Regado Biosciences) is a novel, aptamer-based, factor IXa inhibitor that is being developed for use in patients undergoing PCI and for the treatment of ACS. Aptamers are small oligonucleotides that can be developed to inhibit specific protein targets with high affinity and used as active drugs. Because aptamers are made of oligonucleotide sequences, they code for their own antidote that can be used to inhibit their function. 

The REG1 Anticoagulation System is composed of the active aptamer drug, pegnivacogin, and an antidote, anivamersen. Pegnivacogin is a modified ribonucleic acid (RNA) made of 31 nucleotides. The antidote, anivamersen, is an RNA oligonucleotide that is 15 nucleotides in length. Anivamersen binds to pegnivacogin via traditional Watson-Crick base pairing to inhibit its function and reverse its anticoagulant effect (Figure 1). This mechanism allows for full or partial reversal of anticoagulation based on dosing of anivamersen that is titratable to clinical needs.7 Because of REG1’s controllable nature, it may allow for safer very-early arterial sheath removal following cardiac catheterization. The Randomized, Partially-Blinded, Multicenter, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation System in Patients with Acute Coronary Syndromes (RADAR) trial was designed to evaluate REG1 in ACS patients undergoing early transfemoral invasive management. Patients were randomized to REG1 with varying degrees of reversal (25%, 50%, 75%, or 100%) or unfractionated heparin (UFH) and received coronary angiography with PCI if indicated.8 Arterial sheath removal was to occur immediately following reversal in REG1 patients and per standard of care in heparin patients. 

For the purposes of this study, we sought to evaluate differences in arterial sheath management, vascular access bleeding complications, and length of stay in patients treated with the REG1 system versus UFH among patients enrolled in the RADAR trial undergoing manual sheath removal. In particular, we assessed time from end of catheterization to sheath removal, time to hemostasis, vascular access-site bleeding complications, time to ambulation following sheath removal, and hospital lengths of stay. 

Methods

Study design. The design and results of the RADAR trial have been published.8,9 Briefly, RADAR was a phase-2b, international, adaptive design, partially-blinded, dose-ranging clinical trial to assess the safety and efficacy of the REG1 anticoagulation system, compared with UFH, in patients with ACS undergoing an invasive management strategy. Eligibility criteria included 10 minutes of ischemic symptoms within 72 hours of enrollment associated with ST-segment changes, elevated cardiac biomarkers, or a previous history of coronary artery disease by angiography.8

Patients were randomized 3:1 to open-label REG1 or UFH. Glycoprotein IIb/IIIa inhibitor use was encouraged in patients assigned to UFH. Those randomized to REG1 received 1 mg/kg of open-label intravenous pegnivacogin prior to coronary angiography. They were then randomized in a 2:1:1:2 ratio to a blinded postprocedure dose of anivamersen of 0.075, 0.2, 0.4, or 1.0 mg/kg to achieve 25%, 50%, 75%, or 100% reversal, respectively.10,11 

For patients randomized to UFH, guidance regarding heparin dosing was provided in the study protocol, but the final decisions on heparin dosing were left to the discretion of the operator. We recommended heparin dosing based on a weight-based algorithm adjusted for age, sex, and renal function. During the conduct of the PCI, heparin dosing was adjusted according to activated clotting time (ACT) monitoring. Operators were provided specific instructions to target an ACT goal of greater than 200 seconds and were given detailed instructions on redosing of heparin if ACT readings were below 200 seconds. 

Detailed instructions were provided to operators regarding acceptable sheath sizes to be used for vascular access. Specifically, the planned use of sheath sizes >7 Fr was excluded from the study. RADAR did not provide any specific guidance on the use of bone landmarks (femoral head), micropuncture, ultrasound, etc. Physicians accessed the femoral artery according to their own local practices. Following the conclusion of the procedure, sheaths were removed 10 minutes after receiving anivamersen in those randomized to REG1. In UFH patients, sheaths were removed according to local standard of care.

After sheath removal, sites were instructed to hold manual pressure on the groin site for 10 minutes. If hemostasis was not achieved, manual pressure was held for another 10 minutes. If hemostasis was not achieved after 20 minutes of manual pressure in patients randomized to REG1, an additional open-label “rescue reversal” dose of 100% reversal anivamersen (1 mg/kg) could be administered to provide complete reversal of pegnivacogin. An ambulation challenge was recommended at 2 hours after sheath removal in REG1 patients and per local standard of care in UFH patients. 

The primary endpoint of the trial was total bleeding at 30 days, which was the composite of major bleeding as defined in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, plus hemarthrosis and any clinically overt bleeding not meeting the definition for ACUITY major bleeding. The ACUITY definition for major bleeding includes intracranial, intraocular, retroperitoneal bleeds, access-site hemorrhage requiring radiologic or surgical intervention, a 5-cm diameter hematoma at the puncture site, clinically overt blood loss resulting in a decrease in hemoglobin >3 g/dL, any decrease in hemoglobin >4 g/dL, re-operation for bleeding, and the use of blood products or transfusion.8,12 Secondary endpoints included major bleeding (ACUITY major bleeding plus hemarthrosis), and a composite ischemic endpoint that included death, non-fatal myocardial infarction, urgent target vessel revascularization, or recurrent ischemia in the target vessel distribution through 30 days. All bleeding and ischemic events were adjudicated by an independent clinical events committee blinded to study treatment using original source documents. 

The RADAR trial employed an adaptive design, whereby the data safety monitoring board (DSMB) reviewed both the bleeding and ischemic events after enrollment of 100, 200, and 400 patients. Based on prespecified criteria, the DSMB could recommend cessation of enrollment either into lower reversal arms if an excess of bleeding was observed, or into higher reversal arms if an excess of ischemic events was noted. As a result, at the first interim analysis, the 25% reversal arm was closed to further enrollment as an excess of bleeding in that arm was observed. 

All patients enrolled in the trial in the intention to treat population completed the predefined 48-hour follow-up and had discharge information available for the bleeding and ischemia endpoints. There were a total of 6 subjects in the REG1 group and 2 patients in the heparin group who were lost to follow-up at 30 days. The subjects were evenly distributed with 1 patient each in the 100% and 50% groups and 2 patients in the 75%, 25%, and heparin groups. If there was no information available on the patient at 30 days, the patients were removed from the denominator and not counted in the total for each REG1 group, REG1 total, or heparin patients. None of the patients with missing data at 30 days had met an endpoint at 48 hours or hospital discharge. 


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