A Poly-N-acetyl Glucosamine Hemostatic Dressing for Femoral Artery Access Site Hemostasis after Percutaneous Coronary Intervention: A Pilot Study

Funding for this research was provided by Marine Polymer Technologies, Inc. The authors report no additional conflicts of interest regarding the content herein.

Acknowledgments: The authors thank Laurie LaRusso, MS, ELS, for her primary contribution to the writing of this manuscript.

Manuscript submitted July 14, 2009, provisional acceptance given August 12, 2009, final version accepted October 12, 2009. Address for correspondence: David Mego, MD, Arkansas Heart Hospital, 1701 South Shackleford Road, Little Rock, AR 72211. E-mail: dmmego@gmail.com

ABSTRACT:

Background. Arterial puncture closure devices have improved time to hemostasis and ambulation after percutaneous coronary intervention (PCI) relative to traditional manual compression, though complication rates for both methods leave room for improvement. In a pilot registry, the authors evaluated a topical hemostatic dressing containing poly-N-acetyl glucosamine (p-GlcNAc) post PCI in fully anticoagulated patients.

Methods and Results. In 100 patients undergoing PCI via the common femoral artery in the short-stay unit, the p-GlcNAc hemostatic dressing was applied with 15 minutes of manual compression at arterial access sites after arterial sheath removal. Procedural antiplatelet and anticoagulation therapies were aspirin, clopidogrel and bivalirudin. Patients were observed during 2 hours of bed rest and attempted to ambulate 2 hours post hemostasis. Effectiveness was assessed based on times to hemostasis and ambulation. Data were stratified by time elapsed since bivalirudin bolus or discontinuation of infusion (30 minutes, > 30–60 minutes, > 60 minutes).

Mean time to hemostasis was 15.5 minutes. Mean time from hemostasis to ambulation was 2.08 hours; 87% of patients ambulated at 2 hours. Sheaths were removed at a mean 40.38 minutes after discontinuing bivalirudin. Anticoagulation status (as assessed by time since discontinuation of bivalirudin) did not influence time to hemostasis or ambulation. There was a single major complication (pseudoaneurysm), two minor rebleeds requiring additional manual compression, and 1 hematoma > 5 cm.

Conclusions. This p-GlcNAc topical hemostatic dressing safely achieved hemostasis at arterial access sites and early ambulation, even with nearly immediate sheath removal after PCI with systemic anticoagulation using bivalirudin.

By recent estimates, 1 million percutaneous coronary interventions (PCI) are performed annually in the United States; the worldwide estimate is approximately 2 million.¹ This noninvasive coronary revascularization procedure has greatly curtailed the need for open cardiac surgery and the subsequent care of large sternal incisions. With the increase in PCI procedures, however, have come an increase in therapeutic arterial puncture and the subsequent need to achieve hemostasis at these sites after arterial sheath removal. The current options for achieving hemostasis at femoral artery access sites after coronary catheterization include traditional manual or mechanical compression, an array of arterial puncture closure devices (APCDs), and a handful of topical hemostatic dressings.

Manual or mechanical compression is time-consuming, labor-intensive and costly in terms of in-hospital observation during the extended period of immobilization required. Although APCDs have been shown to reduce time to hemostasis and ambulation compared with manual compression,^2–7 these devices may be associated with higher complication rates than manual compression.^5,7–9 Topically applied hemostasis dressings, which are used after diagnostic catheterization, have not been widely adopted for interventional catheterization procedures due to concerns regarding their ability to achieve hemostasis in the presence of higher levels of systemic anticoagulation and platelet inhibition. When these topical products have been used in PCI, it has been standard practice to delay sheath removal until the activated clotting time (ACT) has fallen below 180 seconds.

The research demonstrating faster times to hemostasis, ambulation, and ultimately discharge with APCDs compared with manual compression is substantial.^2–7 However, implanting intravascular device components is not without potential risks, including acute complications related to placement (e.g., hematoma, pseudoaneurysm, leg ischemia, occlusion), longer-term clinical implications (e.g., residual foreign body components), infection, and the ability to re-stick or re-use APCDs in the same arterial regions.^5,7–16 A topical, noninvasive approach to PCI access-site management that rapidly induces hemostasis biochemically, rather than mechanically, may be capable of providing the shorter times to hemostasis and ambulation associated with APCDs without the potential for vascular complications when arterial plugs or suture devices are used.

Hemostasis dressings containing procoagulant agents, such as chitosan or polyprolate acetate, are used effectively to achieve hemostasis in traumatic wounds and hemorrhage,¹⁷ hemodialysis puncture site bleeding,¹⁸ and arterial puncture site hemostasis following diagnostic and peripheral intervention in which levels of systemic anticoagulation and platelet inhibition are lower than in PCI.^19–21 Furthermore, these hemostatic pads have only been effective with ACTs less than 170–180 seconds and associated postprocedure ambulation times are in the 6- to 8-hour range.^21,22

For procoagulant hemostatic dressings to equal APCDs in terms of clinical effectiveness, they would need to be usable immediately post procedure in the presence of substantial systemic anticoagulation and platelet inhibition and allow for 2-hour ambulation. A novel vascular-access hemostasis system containing poly-N-acetyl glucosamine (p-GlcNAc) fibers, a unique material purified from a marine diatom,²³ has been shown effective for achieving hemostasis in diagnostic^24,25 and interventional cardiac catheterization,^26,27 severe visceral injuries in coagulopathic patients²⁸ and elective small-bowel surgery.²⁹ Rates of major and minor vascular complication have been low and comparable to those reported for manual compression.^24,25,27

We evaluated times to hemostasis and ambulation with a topical, p-GlcNAc fiber-containing, vascular-access hemostasis dressing after PCI in fully anticoagulated patients.

Methods

Patient selection. Patients undergoing interventional cardiac catheterization via the common femoral artery between October 16, 2007 and June 10, 2008, were eligible for this prospective, single-arm pilot registry at the Arkansas Heart Hospital in Little Rock, Arkansas. Enrollment was conducted on consecutive days that the research nurse coordinating the study was working in the catheterization laboratory. Eligible patients were those > 18 years of age treated in the short-stay unit whose catheterization procedures were performed via the common femoral artery (access confirmed by fluoroscopy) using a 6 Fr or 7 Fr arterial sheath.

Patients were excluded from participation in this study for the following reasons: history of severe peripheral vascular disease (lower extremity vascular bypass or peripheral angioplasty/stent procedures or ankle/brachial index 40, systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg, activated clotting time (ACT) > 300 seconds, or difficult access requiring multiple sticks with the introducer needle.

The study protocol was approved by the Western Institutional Review Board. Written informed consent was obtained from all patients prior to starting the index procedure.

Device description. The topical hemostasis system (SyvekEXCEL®, Marine Polymer Technologies, Danvers, Massachusetts) evaluated in this study employs a polysaccharide, p-GlcNAc-, which is purified from a marine diatom and is both protein-free and nonallergenic. The long (80–100 µm) and thin (~ 0.10–0.15 µm) fibers contain individual p-GlcNAc polymer molecules in a parallel orientation held together in a unique beta-crystalline formation by means of hydrogen bonding.²³ The hemostasis system consists of a sterile, 3 x 4 cm, lyophilized pad of p-GlcNAc on foam backing (Figure 1). A reusable Plexiglas® handle and disposable polypropylene support structure are used to apply the dressing with compression. A Tegaderm® transparent adhesive bandage is applied over the p-GlcNAc dressing after hemostasis is achieved and left in place for 24 hours.

Study procedure. Per standard PCI protocol, aspirin ≥ 80 mg orally and a clopidogrel loading dose of ≥ 300 mg were administered prior to the index procedure in patients not already taking clopidogrel. A bivalirudin bolus (75 mg/kg body weight up to a maximum 75 mg) was administered at the start of the procedure. Bivalirudin infusion during the procedure was at the operator’s discretion. The interventional cardiac catheterization procedure was performed according to standard practice. Post procedure, an arteriogram through the arterial sheath was performed to determine the access site in the common femoral artery. Arterial sheaths were pulled at 30 minutes post bivalirudin discontinuation or the earliest possible time thereafter, provided the patient had been transferred to the recovery area. At the time of sheath pull, the p-GlcNAc hemostasis dressing was applied with 15 minutes of manual compression. If the site continued to bleed, cycles of manual compression were repeated until hemostasis was achieved.

Patients were observed during 2 hours of bed rest and attempted to ambulate at 2 hours post hemostasis, at which time the arteriotomy site was evaluated for hematoma formation or other complications. Catheterization nurses involved with arterial sheath removal received training from the manufacturer’s clinical representative regarding application of the p-GlcNAc hemostasis dressing after sheath removal in highly anticoagulated patients. The two-part training consisted of a 45-minute classroom module and several sheath pulls under the observation of either the research nurse in charge of the study or the manufacturer’s clinical sales representative (formerly a radiology technician), both of whom have extensive experience with arterial sheath removal.

Study assessments. Effectiveness of the p-GlcNAc hemostasis dressing was assessed based on time to hemostasis, time to ambulation and the proportion of patients who ambulated at 2 hours. Data were stratified by time elapsed since bivalirudin bolus or discontinuation of infusion (30 minutes, > 30–60 minutes, or > 60 minutes). Because bivalirudin has been shown to produce a predictable dose response, continuous ACT monitoring with bivalirudin is not required.³⁰

Safety was evaluated based on major and minor complication rates. Major complications were defined as surgical vascular repair or ultrasound-guided compression (for pseudoaneurysm, arterial-venous fistula or laceration), femoral nerve injury (sensory or motor), blood transfusion related to a groin complication, groin infection requiring intravenous antibiotics and/or prolonged hospitalization, thrombosis or loss of distal pulses. Minor complications included rebleed from the puncture site that required additional compression and hematoma > 5 cm.

Statistical analysis. This single-arm registry was designed to assess the safety and feasibility of using a p-GlcNAc dressing to achieve hemostasis in heavily anticoagulated patients following PCI. As such, formal power calculations were not performed. Patient, procedural, and outcome variables were summarized using descriptive statistics for continuous variables (e.g., mean, standard deviation) and frequency tables or proportions for discrete variables. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

Results

Patient and procedural characteristics. Between October 16, 2007 and June 10, 2008, 100 patients meeting the study criteria and undergoing PCI in the short-stay unit were enrolled in this pilot registry. As shown in Table 1, the great majority of patients were white with a tendency toward excess body weight and a greater proportion of men than women. Procedural anticoagulation regimens included aspirin, clopidogrel and bivalirudin bolus, with a small minority of patients receiving a double bolus, an additional infusion or supplemental eptifibatide. Six-French (Fr) introducer sheaths were used in all but 1 patient, in which a 7 Fr sheath was used. Twenty-six cardiac recovery nurses from the short-stay and day-patient units removed arterial sheaths in this study, 20 of whom pulled 3 or fewer sheaths. Fifty percent of patients had their sheaths removed within 30 minutes of the bivalirudin bolus or discontinuation of bivalirudin infusion.

Outcomes. Application of the p-GlcNAc dressing after arterial sheath removal resulted in a mean time to hemostasis of 15.5 minutes. After hemostasis was achieved, the mean time to ambulation was 2.08 hours with 87% of patients ambulating at 2 hours. The most common reason for not ambulating at 2 hours was lack of staff availability at exactly 2 hours post hemostasis (9 of 13 patients). Sheaths were removed at a mean 40.38 minutes after last bivalirudin administration (bolus or discontinuation of infusion).

As shown in Table 2, anticoagulation status (as assessed by time since discontinuation of bivalirudin) did not appear to influence time to hemostasis, time to ambulation or percent of patients ambulating 2 hours post hemostasis. The lower proportion of patients ambulating at 2 hours in the 30- to 60-minute group is explained by 8 patients who did not ambulate at 2 hours due to lack of staff availability at exactly 2 hours.

Major and minor access-site complications occurred infrequently. The single major complication (1%) was a pseudoaneurysm in a patient whose sheath was removed 30–60 minutes after discontinuing bivalirudin. The patient underwent surgical repair of the pseudoaneurysm 2 hours post hemostasis and recovered without sequelae. Two minor rebleeds occurred. The first patient (sheath removal at 30 minutes) had a rebleed 20 minutes post hemostasis that resolved with an additional 3 minutes of compression. A second patient (sheath removal at 30–60 minutes) had a minor rebleed at the 2-hour ambulation, which was resolved with an additional 10 minutes of compression and 2 hours of bedrest. The only hematoma measuring > 5 cm, which occurred in a patient (sheath removal at 30–60 minutes) whose groin anatomy was found to be highly unusual, resolved with additional bedrest overnight.

Discussion

In this 100-patient series, immediate hemostasis at the femoral artery access-site and 2-hour ambulation post hemostasis were consistently achieved with topical application of a p-GlcNAc hemostatic dressing in PCI patients anticoagulated with bivalirudin. Times to hemostasis and ambulation were not affected by anticoagulation status such that arterial sheath removal as early as 30 minutes after bivalirudin bolus or end of infusion appears to be possible with this topical procoagulant dressing. Safe removal of arterial sheaths at high levels of systemic anticoagulation was performed by a large number of catheterization nurses, the majority of whom had pulled 3 or fewer sheaths in the study.

As described in the introductory section, this p-GlcNAc hemostatic dressing has been used to safely achieve hemostasis not only in diagnostic^24,25 and interventional cardiac catheterization,²⁷ but also in severe visceral injuries in coagulopathic patients²⁸ and elective small-bowel surgery.²⁹ In animal studies, the p-GlcNAc hemostasis dressing has controlled lethal hemorrhage even in fully anticoagulated swine^29,31–34 and facilitated rapid hemostasis in an animal model of severe traumatic liver injury with acidosis, hypothermia and coagulopathy.³⁵

In-vitro studies have documented physiologic responses to p-GlcNAc fibers relevant to hemostasis, including rapid aggregation of red blood cells,³⁶ rapid aggregation and activation of platelets,³⁷ activation of red blood cells to participate in clot formation^38,39 and endothelium-dependent vasoconstriction.⁴⁰ APCDs are generally considered preferable to hemostatic dressings for femoral artery hemostasis following PCI based on numerous published reports of their efficacy and two systematic reviews of published reports.^5,7 Large observational studies^8,9 and one systematic review or randomized trials,⁵ however, have indicated that these devices may be associated with increased risk for complications compared with manual compression, such as the need for surgical repair, acute femoral closure, transfusion due to groin complications, readmission for groin complications and infection.

In one observational study of more than 5,000 patients undergoing PCI, APCDs were associated with higher rates of hematoma (9.3% vs. 5.1%; p 6 cm². In a study of 206 patients undergoing diagnostic catheterization, no major or minor complications were reported for the Angio-Seal STS absorbable collagen sponge with a polymer anchor and self-tightening suture system or for manual compression.² The diagnostic angiography study aside, complication rates reported for APCDs and for manual compression in PCI patients leave room for improvement. Hemostatic dressings containing chitosan or polyprolate acetate have shortened times to hemostasis compared with manual or mechanical compression in diagnostic and peripheral catheterization, where levels of systemic anticoagulation are lower and sheath sizes are typically smaller (4–5 Fr) than in PCI (6 Fr or larger).^19-21

The one evaluation of these dressings at the femoral access post PCI (n = 184) involved 6 Fr sheath removal with ACT below 250 seconds. Time to hemostasis was 3 minutes less for the chitosan-based (ChitoSeal, Abbott Vascular) and the polyprolate acetate (Clo-Sur Pad, Scion Cardio-Vascular, Miami, Florida) dressings compared with manual compression (p = 0.005), but time to ambulation (8.1–8.8 hours; p = NS) was not shortened.²²

No major bleeding events were reported; however, minor hematoma (13% ChitoSeal, 21% Clo-Sur Pad and 9% manual compression) and rebleeding requiring further compression (21%, 23% and 16%, respectively) were reported. Additionally, a new thrombin-releasing dressing (D-Stat Dry, Vascular Solutions, Inc., Minneapolis, Minnesota) has been associated with higher overall complication rates than Angio-Seal and StarClose.⁴⁴

To our knowledge, the current study of a novel p-GlcNAc hemostatic dressing is the first to show that a topical procoagulant dressing can be used immediately post PCI in the setting of systemic anticoagulation using bivalirudin. In an earlier study of 1,000 patients anticoagulated with heparin and provisional glycoprotein (GP) IIb/IIIa inhibitors, including 364 PCI patients, the p-GlcNAc dressing rapidly controlled access-site bleeding with a 1% pseudoaneurysm rate despite 76% of sheaths being removed with an ACT between 200 and 300 seconds.²⁷ This compares favorably with the recent report of pseudoaneurysm rates of 6.0%, 2.4% and 1.1% for the novel thrombin-releasing dressing (n = 281), the nitinol clip (n = 286) and the collagen plug (n = 285), respectively, in PCI patients also anticoagulated with heparin and provisional GP IIb/IIIa inhibitors.⁴⁴

Admittedly, definitive conclusions cannot be drawn from the findings of an uncontrolled study of this kind conducted at a single institution. Additionally, it is difficult to evaluate this study with its bivalirudin regimen alongside other studies using a heparin with provisional GP IIb/IIIa inhibitor regimen and reporting anticoagulation status based on ACT. Nonetheless, the currently available data in patients treated with bivalirudin or heparin and GP IIb/IIIa inhibitors indicate that this p-GlcNAc hemostatic dressing appears to offer hemostatic effectiveness similar to APCDs, with a more acceptable risk of complications than either APCDs or manual compression. Indeed, in this study there was one (1%) pseudoaneurysm and no device-induced complications such as surgery, deep vein thrombosis, infection, altered anatomy or associated hospitalizations.

Conclusions

The findings from this pilot registry suggest that the p-GlcNAc topical hemostatic dressing can safely produce vascular-access site hemostasis even with nearly immediate sheath removal after PCI with systemic anticoagulation using bivalirudin. To our knowledge, this is the first report of a manual compression-assisted topical device that can be applied immediately post PCI to achieve hemostasis and early ambulation similar to APCDs with lower risk of complications. Larger, randomized studies are needed to thoroughly evaluate this topical hemostasis system in the PCI setting.

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