A Prospective, Randomized Trial of Topical Hemostasis Patch Use following Percutaneous Coronary and Peripheral Intervention

ABSTRACT: The use of topical hemostasis patches has grown rapidly despite a paucity of evidence supporting their clinical utility. We performed a randomized, controlled trial to assess the efficacy of a topical hemostasis patch as a means to accelerate vascular hemostasis following percutaneous intervention. One hundred fifty (150) patients undergoing coronary or peripheral intervention through a 6 Fr femoral arterial sheath were randomized to sheath removal with either: (1) manual pressure and adjunctive use of a patch incorporating a polysaccharide based procoagulant material (SafeSeal Patch, Possis Medical Inc.); or (2) conventional manual pressure alone. Sheaths were removed when the activated clotting time (ACT) fell to ≤ 250 seconds. Patients ambulated 2 hours after hemostasis was achieved. Time to hemostasis (duration of compression required until cessation of bleeding following sheath removal) was significantly lower in the hemostasis patch arm (11.8 ± 3.6 vs. 13.8 ± 5.8 minutes; p = 0.02). Attainment of hemostasis in Methods Patients. Patients 18 years of age or older who underwent percutaneous coronary or peripheral arterial intervention through a 6 Fr femoral arterial sheath at our institution from May, 2007 to October, 2007 were eligible. The protocol was approved by the Research Subjects Review Board at our institution. Patients gave written informed consent for participation in the trial prior to their catheterization procedure, and randomization occurred immediately following completion of the endovascular intervention. Patients were excluded from the study if any of the following conditions were present: 1) presence of a large (> 4 cm) hematoma or persistent bleeding around the vascular sheath prior to randomization; 2) previous arteriovenous fistula or pseudoaneurysm in the ipsilateral femoral artery; 3) history of bleeding diathesis or coagulopathy; 4) preprocedural hemoglobin level 180 or diastolic blood pressure > 110); or 10) current enrollment in another ongoing investigational drug/device trial. Study protocol. All patients were treated with aspirin therapy prior to their procedure, and the selection of additional anticoagulation and antiplatelet therapy during the procedure was at the discretion of the operating physician. Patients were randomized in a 1:1 fashion in permuted blocks of 20 patients to sheath removal using either: 1) manual pressure with adjunctive use of the SafeSeal hemostasis patch, or 2) conventional manual pressure alone. Prior to sheath removal, all patients underwent angiographic imaging of the femoral artery access site to document the location of sheath insertion within the femoral artery. An activated clotting time (ACT) was obtained and the arterial sheath was removed immediately if the ACT was 250 seconds, the ACT was repeated on an hourly basis until the 250-second threshold was reached. The SafeSeal patch was used in accordance with the manufacturer’s instructions. In both study groups, compression was performed by experienced catheterization laboratory personnel who were not study investigators; strict adherence to the following protocol was observed: Manual pressure was applied continuously for 10 minutes. After 10 minutes, pressure was decreased, and if hemostasis (defined as the complete absence of any bleeding or oozing from the access site) had not been achieved, pressure was continued and the site was reassessed for hemostasis in a similar fashion every 5 minutes. After complete hemostasis was achieved, patients were kept on bed rest with the head of bed elevated to an angle of ≤ 30 degrees for 2 hours. The groin site was monitored by the nursing staff in accordance with hospital protocol. Vital signs, the groin site and distal extremity pulses were monitored during bed rest every 15 minutes for the first hour and every 30 minutes during the second hour. If bleeding reoccurred such that manual pressure was required for a period of > 5 minutes to reestablish hemostasis, bed rest was extended for an additional 2 hours from the time that hemostasis was reestablished. All patients ambulated ≥ 25 feet under supervision 2 hours after final hemostasis had been obtained. No patient was unable to ambulate at 2 hours. A complete blood count was checked and the groin site assessed the morning following the procedure. Any patient with a visible and/or palpable hematoma > 4 cm in diameter, a new femoral bruit or a drop in hemoglobin or hematocrit of > 20% relative to baseline underwent duplex ultrasound examination of the access site. All patients remained in the hospital overnight following their intervention. Definition of endpoints. The prespecified primary endpoint was the time to hemostasis, defined as the time interval from sheath removal to termination of bleeding or oozing from the femoral artery access site. If recurrent bleeding from the sheath site occurred following initial hemostasis, the timing and duration of additional compression required to reestablish complete hemostasis were also recorded. The secondary endpoints included the time to ambulation and the incidence of major and minor hemorrhagic complications in each study arm. Time to ambulation was defined as the time interval from the end of the angioplasty procedure (as determined by the time that the final angiographic image was obtained) to the time that the patient ambulated. Thrombolysis in myocardial infarction (TIMI) major bleeding was defined as a a postprocedural drop in hemoglobin of ≥ 5 g/dl or an absolute decrease in hematocrit of ≥ 15%.3 In addition, the occurrence of any of the following clinical events was also considered to represent major bleeding: the development of a large hematoma (> 4 cm in diameter); formation of an arteriovenous fistula or pseudoaneurysm confirmed by vascular ultrasound; retroperitoneal hemorrhage; or need for surgical repair of the access site for any reason. TIMI minor bleeding was defined as a postprocedural drop in hemoglobin of 3–5 g/dl or an absolute decrease in hematocrit of ≥ 9% not associated with any of the above clinical events. The incidence of small hematoma formation, defined as a visible or palpable mass of ≤ 4 cm in diameter at the sheath insertion site without associated sequelae, was also recorded. Statistics. To provide at least 80% power to detect a difference of 2.5 minutes in the average time to hemostasis between the two treatment arms at the 0.05 significance level, and assuming a standard deviation of 5 minutes or less for each arm, a total of 150 patients (75 per treatment arm) was required. Univariate comparisons between the study arms for categorical variables were performed using the chi-square test or Fisher’s exact test when at least one expected cell count was Results Patient population. A total of 150 patients were enrolled, with 75 patients randomized to each treatment arm. All patients received their assigned treatment with no crossovers. Baseline demographic characteristics are displayed in Table 1 and procedural variables are provided in Table 2. While the treatment groups were well matched for most variables, there was a significantly lower proportion of women and patients with a history of hypertension in the hemostasis patch group. Despite the gender difference, there were no differences in mean body weight or body mass index between the groups, and there were no differences in systolic or diastolic blood pressure between the study groups at the time of arterial sheath removal. In addition, the mean ACT at the time of sheath removal was significantly higher among patients randomized to the hemostasis patch arm (213 ± 26 vs. 202 ± 27 seconds; p = 0.01). Primary endpoint. The mean time to hemostasis following sheath removal, which represented the primary study endpoint, was significantly lower in the hemostasis patch compared to the conventional manual compression group (11.8 ± 3.6 vs. 13.8 ± 5.8 minutes; p = 0.023). As demonstrated in Figure 1, the likelihood of achieving hemostasis with the minimum (10 minutes) duration of compression was significantly greater among patients randomized to adjunctive hemostasis patch use rather than to manual compression alone (73 vs. 55%; odds ratio = 2.5; 95% confidence interval 1.2, 5.1; p = 0.014). Use of the hemostasis patch was statistically equivalent or superior to conventional manual compression in reducing time to hemostasis among all patient subgroups examined (Figure 2). Secondary endpoints. The median time to ambulation, which represented the duration from the end of the angioplasty procedure to ambulation, was 1 hour shorter in the hemostasis patch compared to the conventional manual compression group (2.8 vs. 3.8 hours; p = 0.03), as depicted in Figure 3. The mean time to ambulation, which is more subject than the median to influence by extreme outliers, was also significantly shorter among patients in the hemostasis patch arm (4.0 ± 3.7 vs. 4.5 ± 3.8 hours; p = 0.03). As shown in Table 3, the time to ambulation reflects a composite of multiple events including 1) the interval from the end of the interventional procedure to sheath removal; 2) the time to hemostasis; 3) the potential need for additional compression and prolongation of bed rest should recurrent bleeding occur, and; 4) the requisite 2 hour interval of bed rest between final hemostasis and ambulation. One TIMI major bleeding event, a retroperitoneal hematoma requiring surgical repair, occurred in the hemostasis patch arm and no major bleeding complications developed in the control arm. TIMI minor bleeding occurred in 1 patient in each arm. Minor hematomas were observed in 6 patients in the hemostasis patch group and in 10 patients in the control group (p = 0.29). The incidence of recurrent bleeding or oozing from the access site after initial hemostasis had been achieved was similar between the study groups (16 vs. 18 patients; p = 0.70). Among the subset of patients who experienced recurrent bleeding, the duration of additional compression required to achieve final hemostasis did not differ significantly between the hemostasis patch and control groups (9.9 ± 5.0 vs. 12.8 ± 7.9 minutes, respectively; p = 0.29). Recurrent bleeding following ambulation was uncommon and similar among the groups (4 vs. 3 patients, respectively). Multivariate analysis. Because of the unanticipated baseline differences between treatment groups with respect to gender, history of hypertension, and ACT at the time of sheath pull, multivariate logistic regression was performed to assess the potential influence of these variables on the relationship between treatment assignment and the primary study endpoint (Figure 4). Multivariate analysis demonstrated that randomization to the hemostasis patch arm remained a statistically significant independent predictor of reduced time to hemostasis when controlling for these variables. Neither gender nor history of hypertension was predictive of time to hemostasis. A lower ACT at the time of sheath removal was a significant predictor of reduced time to hemostasis. Because the mean ACT at the time of sheath removal was slightly but significantly higher in hemostasis patch arm compared to the control arm, the relationship between hemostasis patch use and reduced time to hemostasis remained significant after adjusting for the difference in ACT between the study groups. Discussion In this trial, the use of a polysaccharide-based hemostasis patch as an adjunct to manual compression following endovascular intervention was associated with accelerated times to both hemostasis and ambulation compared to conventional manual compression alone. Interestingly, while hemostasis patch use was associated with a statistically significant, but modest, reduction in mean time to initial hemostasis, the relative benefit of the patch became even more apparent in the median time to ambulation, which was 60 minutes lower in the hemostasis patch versus the control group. This magnification of the initial benefit was related to nonsignificant trends all favoring: 1) a lower likelihood of recurrent bleeding; 2) an earlier occurrence of rebleeding; and 3) more rapid control of recurrent bleeding in the hemostasis patch group. Bleeding complications were rare in both groups, with an overall 0.7% incidence of major bleeding and a 1.3% incidence of minor bleeding in the study population. These low complication rates were present despite a study protocol that called for both sheath removal at higher-than-conventional ACT levels and an early ambulation strategy. There has been extraordinary growth in the production and use of topical hemostasis patches over the past few years, with competing devices from 10 separate manufacturers currently available in the United States. Despite the rapid increase in clinical application, the level of scientific evidence documenting the incremental clinical benefit of hemostasis patches relative to conventional manual compression has remained limited. The majority of currently-marketed hemostasis patches incorporate glucosamine-based compounds, typically in the form of poly-n-acetyl glucosamine or chitosan, which is a heteropolymer of poly-d-glucosamine and poly-n-acetyl-d-glucosamine.4–7 Many of these agents were initially introduced as a means to control hemorrhage following traumatic battlefield-related and civilian injuries.8–10 The use of glucosamine-impregnated hemostasis patches among patients undergoing diagnostic coronary angiography11–14 or peripheral arterial diagnostic and interventional procedures15 has been evaluated to a limited degree. A retrospective analysis of 1,000 consecutive patients who underwent diagnostic or interventional cardiac catheterization or electrophysiology study with 4–12 Fr femoral arterial sheaths demonstrated that the use of a hemostasis patch incorporating poly-n-acetyl glucosamine was associated with a low incidence of major and minor vascular complications, however, the relative safety and efficacy of hemostasis patch use compared to conventional manual compression was not assessed.16 The largest study of hemostasis patch use to date retrospectively examined time to hemostasis and vascular complication rates among 2,464 patients who underwent diagnostic catheterization and 1,000 patients who underwent PCI at a single center.17 All patients underwent sheath removal using manual compression with or without adjunctive use of a thrombin-based hemostasis patch (D-Stat Dry, Vascular Solutions, Minneapolis, Minnesota). In this analysis, patch use was associated with a significantly shorter time to hemostasis among the PCI (but not the diagnostic catheterization) group, and with a lower incidence of vascular complications among the overall study cohort. A study by our group involving patients undergoing PCI demonstrated a significant reduction in time to hemostasis with the use of either of two chitosan-based patches compared to manual compression alone, however, hemostasis patch use was not associated with a reduction in time to ambulation.18 Because this previous study mandated prolonged (6 hours) bed rest following hemostasis, a potential advantage of hemostasis patch use with respect to time to ambulation may have been obscured. The SafeSeal patch used in the current trial utilizes a proprietary bioabsorbable plant-derived polysaccharide material produced in the form of microporous polysaccharide hemospheres (MPH). These microscopic spheres, which range from 10–200 microns in size, have porous surfaces that when in contact with blood favor the absorption of water and low molecular weight compounds, thereby locally concentrating platelets and clotting proteins and accelerating hemostasis.19 The procoagulant properties of MPH have been demonstrated experimentally,19,20 but the ability of this material to accelerate hemostasis following arterial sheath removal had not been examined previously. Little objective information exists regarding the ideal ACT level at which arterial sheaths should be removed following percutaneous intervention, or the optimal duration of bed rest following sheath removal.21 When using manual compression to achieve hemostasis following endovascular intervention, most laboratories have traditionally delayed sheath removal until the ACT falls below 150–170 seconds. One recent study suggested that sheath removal at higher levels of anticoagulation (ACT threshold of ≤ 250 seconds) was safe and not associated with an increased time to hemostasis compared to sheath removal at a lower ACT threshold of ≤ 170 seconds.18 In addition, while 4–6 hours of bed rest is typically prescribed in most institutions after removal of a 6 Fr femoral sheath post-PCI, the safety of a shorter 2-hour bed rest duration has been suggested.22 In an attempt to optimally evaluate the procoagulant effects of the hemostasis patch utilized in our trial, sheath removal was performed at the higher ACT threshold of ≤ 250 seconds, and bed rest duration was limited to 2 hours after hemostasis was established. While time to hemostasis did increase slightly when sheaths were removed at higher ACT levels, the aggressive sheath removal and early ambulation protocol employed in the current trial was associated with a low incidence of bleeding events in both the treatment and control arms and warrants continued investigation. Study limitations. While randomized, as is the case for many device-related trials, it was not possible to incorporate a blinded study design because of the distinctive appearance of the hemostasis patch. The cost, time and regulatory requirements to manufacture a “placebo” patch were prohibitive, and the polysaccharide hemospheres that constitute the patch’s active ingredient have a characteristic appearance when released during patch deployment, making blinding even more difficult. In an attempt to minimize potential bias related to the lack of blinding, strict objective criteria were established regarding determination of when hemostasis had been achieved and when ambulation could occur. The personnel in charge of obtaining hemostasis were permitted to release pressure to check for hemostasis only at 10 minutes and every 5 minutes thereafter, and strict objective criteria were used to determine when hemostasis had occurred regardless of treatment assignment. Likewise, strict objective criteria were in place for access site assessment for personnel caring for patients after the procedure. Additionally, despite randomization, differences in the frequency of some baseline variables between the two study groups occurred. Multivariate logistic regression modeling was performed and indicated that these variations did not influence the observed relationship between hemostasis patch use and the study endpoints. While hemostasis patch use was equivalent or statistically superior to conventional manual compression in reducing time to hemostasis among all patient subgroups examined, the study was not powered to examine individual subgroups, which would be more appropriately assessed in a dedicated study. Likewise, while bleeding events were uncommon in both study arms, the sample size was too small to permit definitive conclusions on vascular complications. Conclusions In this prospective, randomized trial, use of the polysaccharide-based SafeSeal hemostasis patch was safe and associated with enhanced access site hemostasis compared to manual compression alone following endovascular intervention. In addition, sheath removal at higher-than-conventional levels of anticoagulation, coupled with an early ambulation strategy, was associated with a low incidence of bleeding events.

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