Safety and efficacy of Angio-Seal device for transfemoral neuroendovascular procedures: A systematic review and meta-analysis

Abstract

Introduction

Angio-Seal is a commonly used device for femoral hemostasis in neuroendovascular procedures. This meta-analysis investigates of the safety and efficacy of Angio-Seal in patients undergoing endovascular neurointerventional procedures.

Methods

A systematic review and meta-analysis on all studies evaluating the Angio-Seal device in neurointerventional procedures from inception through 2020 were performed. We studied rates of groin hematoma, retroperitoneal hematoma, pseudoaneurysm, ipsilateral DVT, and ischemic complications. Meta-analysis was performed using the random-effects model.

Results

13 studies were included in our analysis. 2250 patients with 104 complications were found {4.5% (95% CI, 2.7%–6.3%)}. Of these complications, groin hematoma was the most common with a rate of 2.4% (95% CI, 1.1%–3.6%). Retroperitoneal hematoma {0.3% (95% CI, 0%–0.5%)}, pseudo-aneurysm {0.5% (95% CI, 0.2%–0.8%), and ipsilateral DVT {0.3% (95% CI, 0.1%–0.7%) were also not in negligible rate. The rate of other complications were as follows: vessel occlusion/stenosis; 0.2% (95% CI, 0%–0.4%), vascular surgery; 0.2% (95% CI, 0%–0.5%), and infection; 0.2% (95% CI, 0%–0.5%). One patient died as result of hemorrhagic complications {0.1% (95% CI, 0%–0.3%)}. Use of anticoagulant/antiplatelet therapy was found to be positively correlated with high risk of any groin complication and groin hematoma (p ≤ .05). Female gender was associated with high risk of ipsilateral DVT (p ≤ .05). Interestingly, large sheath size was associated with low risk of groin hematoma (p ≤ .05).

Conclusion

The safety and efficacy rate of Angio-Seal was approximately 95%. The most common complication was groin hematoma. Serious complications including retroperitoneal hematoma and femoral artery occlusion were rare.

Introduction

Vascular closure devices were introduced in the early 1990s as an alternative to manual compression. These medical devices aimed mainly at decreasing complications associated with delayed hemostasis in manual compression applied to patients by reducing the time to hemostasis. One of the more commonly used closure devices in neurointerventional suites is the Angio-Seal. The Angio-Seal consists of a collagen plug, a small rectangular anchor, and a connecting polyglycolic suture and was first introduced in 2006.

Understanding the safety and efficacy of the Angio-Seal as it relates to neuroendovasuclar procedures is important given the fact that neurointerventional patients are frequently fully anticoagulated, on dual antiplatelet therapy, and, in the setting of stroke, receive tPA. A comprehensive meta-analysis of Angio-Seal related complications is also important for benchmarking femoral artery access complication rates as well. In this meta-analysis, we investigate important femoral artery access-site complications of Angio-Seal vascular closure device in the patients who treated with interventional neuro-endovascular procedures.

Materials and methods

Search strategy

A comprehensive search of several databases from inception to September 24, 2020, limited to English language and excluding animal studies, was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The key words “Angioseal ““Angio-Seal” “Vascular closure device” “neuro-interventional” “neurovascular” “cerebrovascular accident” “stroke” “cerebral Angioplasty” “aneurysm rupture” “cerebral angiography” were used in both “AND” and “OR” combinations. The search strategy was designed and conducted by an experienced librarian with input from the study’s principal investigator. Controlled vocabulary supplemented with keywords was used to search for studies describing the Angio-Seal device in neurointerventional patients. (Full search strategy is available in Appendix 1)

Eligibility criteria

Inclusion criteria were the following: 1) Study reporting a consecutive series of patients, 2) The patients were treated with interventional neuro-endovascular procedures with clear reporting of outcomes, 3) common femoral artery access with hemostasis achieved using the Angio-Seal vascular closure device, 4) Series of at least 20 patients reporting clearly the complications of the Angio-Seal vascular closure device. Review articles, guidelines, technical notes, comments, and editorials were excluded.

Study selection process

Titles and abstracts were screened for inclusion by one author using EndNote (Clarivate Analytics, Philadelphia, United States). Full-text articles were retrieved for the included abstracts and screened by the same author and were reviewed by the senior author.

Data extraction and outcome measures

We extracted the baseline characteristics of the patients from each study including patient number, gender, mean age, mean BMI, history of co-morbidities like stroke, hypertension. DM, cardiac diseases, and dyslipidemia. Information of the procedures included the sheath size, the use of tPA, anticoagulant therapy (ACT), or antiplatelet drugs (APT) were also extracted.

The number of any complication associated with Angio-Seal vascular closure device use to facilitate the hemostasis in the femoral arteriotomy in the patients who treated with interventional neuro-endovascular procedures was extracted. Nine complications were considered for extraction included; groin hematoma (any size if reported), retroperitoneal hematoma, pseudoaneurysm, ipsilateral DVT, ipsilateral limb ischemia, vessel occlusion/stenosis, vascular surgery, infection, and death. All these complications were counted under “Any groin complication”. Thus, the goal of this meta-analysis is to investigate the complications and safety of the Angio-Seal vascular closure device in the neuro-interventional procedures.

Study risk of bias

Newcastle-Ottawa Quality Assessment Scale for Case Control Studies was designed to assess the risk of bias in comparative studies. However, because none of our included studies was controlled, we selected specific items from this tool and modified it to assess the risk of bias in our included studies in this meta-analysis focusing on these questions: 1) did the study include all patients or consecutive patients versus a selected sample?; 2) was the study prospective or retrospective?; 3) were outcomes clearly reported?; and, 4) were the interventionalists treating the patients and those who assessed angiographic and clinical outcomes same?.

Statistical analysis

The cumulative incidence (event rate per patient at the end of the study) for each study was estimated and 95% CI. Because we anticipated marked heterogeneity in the populations and interventions across the various included studies, a random-effects model was used to pool incidence rates across studies.¹ The I² statistic was used to express the proportion of inconsistency that is not attributable to chance.² Meta-analysis for all outcomes, meta regression for outcomes of interest and a funnel plot for each outcome -to investigate any probable publication bias- were conducted using Jamovi 1.2 (The Jamovi Project, Sydney, Australia, 2020),³ and OpenMeta[Analyst] open source Statistical Software.⁴ Outcomes or variables which were reported in limited number were not included in meta regression according to Cochrane recommendations.⁵

Results

Study selection and characteristics

230 articles were found by the librarian search and one article was added after hand-search. 229 articles were selected for review after removing the duplicates. Upon the review of the title and abstract, 176 articles were excluded. The full text of 53 articles was screened and 12 articles^6–17 with 2478 patients were included in the qualitative synthesis. 1224 (49.4%) and 1254 (50.6%) of these patients were male and female, respectively and their mean age was 60.4 years. The mean BMI of 538 patients in 4 studies was 27.67 kg/m². 2250 patients treated with interventional neuro-endovascular procedures were included in the quantitative synthesis. The baseline characteristics of the patients including the reported co-morbidities and the procedure information are listed in Table 1.

Table 1.

Baseline characteristics.

Study			Patient characteristics									Procedure information
Study, date, (total patients no.)	Study design	Risk of bias	Patients who underwent neuro-interventional procedures with Angio-Seal device	Female gender (%)	Mean age	Mean BMI (kg/m²)	Stroke or SAH (%)	HTN (%)	DM (%)	Cardiac morbidities (%)	Dyslipidemia (%)	Sheath size -Fr- (mean)	No. of patients on tPA (%)	No. of patients on Anticoagulant (%)	No. of patients on Antiplatelet (%)
Pierot et al.6	P	Low	119	53	51.60	4 pt >30	NR	19.3	9.2	NR	NR	6.27	NR	67.2	NR
Geyik et al.15	R	Mod	640	46.4	54.50	NR	NR	NR	NR	NR	NR	6.42	NR	21.25	48.75
Wong et al.12 (153)	P	Low	90	43.8	56.10	NR	NR	NR	NR	NR	NR	6 or 8	NR	NR	NR
Shah et al.8 (472)	R	Mod	443a	50	70.00	NR	NR	NR	NR	NR	NR	8.05	55.1	12.7	2.1 (DAPT)
Shah et al.10 (234)	R	High	98b	61.5	52.50	NR	NR	NR	NR	NR	10.25	8	NR	40.6	17.1
Sato et al.16	P	Low	119	47.06	62.10	34.00	NR	52.1	13.4	NR	30.25	7.36	2.5	7.5	89.1
Aida et al.11 (141)	R	Low	141	54.6	63.07	22.99	NR	64.5	18.4	NR	31.2	6.3	NR	NR	77.3
Janssen et al.6 (72)	R	High	72	52.8	70.60	NR	100	86.1	29.2	48.6	61.1	9	63.9	20.8	33.3
Wareham et al.14 (145)]	R	Mod	145	51	69.10	NR	100	33.1	7.6	25.5	NR	8	48.3	11.7	4.8
Addepalli et al.13 (459)	R	Low	197	68.5	53.50	29.95	100	62.9	16.75	NR	NR	NR	NR	60.9	NR
Ishida et al.17 (60)	R	Mod	60	13.3	71.10	NR	NR	81.7	41.7	NR	88.3	NR	NR	100	100
Ozono et al.9 (116)	R	Mod	126	46.8	68	23.35	19	65.9	24.6	15.1	44.4	NR	NR	100	NR

HTN: Hypertension, DM: Diabetes Mellitus, P: Prospective, R: Retrospective, NR: Not reported, DAPT: Dual Antiplatelet Therapy, Pt: Patient, Mod: Moderate.

^aThe baseline characteristics of the Angio-Seal group were mixed with the data of patients with other vascular closure devices but the outcomes of each group were reported clearly.

^bThe baseline characteristics of the patients who underwent interventional procedures were mixed with the ones who underwent diagnostic procedures but the outcomes of each group were reported clearly.

Overall outcomes

Total of 104 {4.5% (95% CI, 2.7%–6.3%)} groin complications in 2250 patients were reported in 12 studies. The most common complication was groin hematoma, which occurred in 60 patients {2.4% (95% CI, 1.1%–3.6%), in 1993 patients and 10 studies. The rate of other complications was as follows: of pseudoaneurysm was 0.5% (95% CI, 0.2%–0.8%), retroperitoneal hematoma was 0.3% (95% CI, 0%–0.5%), ipsilateral DVT was 0.3% (95% CI, 0.1%–0.7%), vessel occlusion/stenosis was 0.2% (95% CI, 0%–0.4%), vascular surgery was 0.2% (95% CI, 0%–0.5%), infection was 0.2% (95% CI, 0%–0.5%), and death was 0.1% (95% CI, 0%–0.3%). No complication of ipsilateral limb ischemia was reported in the included studies. According to our meta regression results, the larger the proportion of patients who received ACT/APT, the higher the risk of any groin complication and groin hematoma was found to be exist (p < .05). Interestingly, the larger sheath size was associated with less risk of groin hematoma (p < .05). A significant correlation was found between female gender and high risk of ipsilateral DVT (p < .05). All complications rates are provided in Table 2 and Figure 2.

Table 2.

Complication rates.

Complications of Angio-Seal device in transfemoral neuroendovascular procedures
Study, date.	Patients no.	Any groin complication	Groin hematoma	Retroperitoneal hematoma	Pseudo-aneurysm	DVT (ipsilateral)	Ipsilateral limb ischemia	Vessel occlusion/stenosis	Vascular surgery	Infection	Complication-associated mortality
Pierot et al.6	119	5	4	0	1	0	0	0	0	0	0
Geyik et al.15	640	23	9	5	4	0	0	1	2	2	0
Wong et al.12	90	10	9	0	0	0	0	1	0	0	0
Shah et al.8	443	3	2	0	1	0	0	0	0	0	0
Shah et al.10	98	0	0	0	0	0	0	0	0	0	0
Sato et al.16	119	10	9	0	0	0	0	0	0	1	0
Aida et al.11	141	6	5	NR	1	NR	NR	NR	NR	NR	NR
Janssen et al.6	72	2	1	0	0	0	0	0	0	0	1
Wareham et al.14	145	2	0	0	1	0	0	0	0	1	0
Addepalli et al.13	197	15	NR	NR	NR	15	NR	NR	NR	NR	NR
Ishida et al.17	60	3	NR	3	NR	NR	NR	NR	NR	NR	0
Ozono et al.9	126	25	21	NR	4	NR	NR	NR	NR	NR	NR

NR: Not reported.

Figure 2.

Forest plots with random-effect model demonstrate the risk of following complications after use of Angio-Seal closure device in transfemoral neuroendovascular procedures; (a) Overall Groin complication. (b) Groin hematoma. (c) Retroperitoneal hematoma. (d) Pseudoaneurysm formation. (e) Ipsilateral DVT. (f) Vascular surgery. (g) vascular occlusion/stenosis. (h) Infection. (i) Complication-associated mortality.

Figure 1.

The Flow diagram of study selection process.

Heterogeneity & risk of bias

High heterogeneity was found in two outcomes; any groin complication (84.93%) and groin hematoma (81.41%). Outcome of ipsilateral DVT was associated with moderate heterogeneity (54.2%). A publication bias was found to be in all outcomes. Funnel plots of the outcomes and all the results of meta-regression are provided in Appendix 2.

Of 12 studies, the risk of bias was low in 5, moderate in 5, and high in 2 studies. The smallest study had 60 patients and the largest study had 640 patients. The included studies’ data are summarized in Table 1.

Discussion

Our meta-analysis of over 2000 patients undergoing femoral hemostasis for neurointerventional procedures using the Angio-Seal demonstrated a number of interesting findings. First, Angio-Seal resulted in complete femoral hemostasis without hematoma or other complication in over 95% of cases. Overall, this efficacy rate is satisfactory given the large sheath size and use of anti-platelet agents and anticoagulation during these neurointerventional procedures (bearing in mind that patients undergoing diagnostic angiography were excluded). The most common complication was groin hematoma, occurring in 2.5% of cases. Major complications including pseudoaneurysms, retroperitoneal hematoma, DVT, vessel occlusion, and infection occurred in a total of 2.5% of cases as well. The rate of these complications is not negligible however. These findings are important as they 1) highlight some of the complications associated with Angio-Seal that physicians should be vigilant of and 2) demonstrate that with the use of Angio-Seal, major and minor complications can occur in up to 5% of patients.

We selected specific complications because of their important impact on the clinical prognosis of the patients. Among these complications, groin hematoma was found to be the most common complication. However, groin hematoma was associated with low morbidity and usually resolved after additional treatments in most of the studies. Groin hematomas can be fatal however, as demonstrated in a study published by Janssen et al which included the only mortality in our study.⁶ Twelve pseudo-aneurysms and eight retroperitoneal hematomas were also noted. Two vascular occlusions (or stenosis) were also reported. Two surgical interventions were reported; the first was to repair a stenotic femoral artery and the second was to resect a local infection associated with groin hematoma. Four infections were seen in 1726 patients.^14–16

On review of the literature, low BMI and large sheath size were reported to be associated with a high risk of complications in the neurovascular literature. Aida et al. attributed the high risk of bleeding in patients with low BMI to the low subcutaneous tissue to cover the collagen sponge and the effect of antiplatelet therapy that they assumed to be more powerful in patients with low BMI.¹¹ However, only four studies in our systematic review reported the mean BMI. Larger sheath size was reported as an independent predictor of access site complications in the percutaneous coronary interventions.^18,19 However, in our included studies, 900 patients with sheath size smaller or equal to 7 Fr suffered from 34 (3.8%) complications while only 7 (0.9%) complications were seen in 758 patients with large size sheath (≥ 8 Fr). Meta regression of outcome of groin hematoma concerning mean sheath size also signified the correlation between the large mean sheath size and low rate of groin hematoma (p < .05).

Concomitant anticoagulant therapy, peripheral vascular disease (PVD), and older age were found to be risk factors for many complications in the Angio-Seal use on the cardiac patients.^20,21 However, in this study, the results did not show a statistically significant correlation between the mean age and any groin complication. The association between PVD and Angio-Seal complications were assessed in only a few neuro-interventional studies. Female sex, prothrombotic diseases (e.g. DM, dyslipidemia, cardiac diseases) and morbidities like stroke, hypertension were reported as predictors for access site complications in the cardiac literature.²² In our review, many of the patients were suffering from these diseases suggesting that our meta-analysis had adequate representation of these comorbidities. The female gender was found to be associated with higher risk of ipsilateral DVT according to our meta regression results. However, female gender was associated with lower risk of groin hematoma, but the results were not statistically significant (p=0.061).

The patients in the neuro-interventional procedures generally receive high doses of heparin and antiplatelet drugs before and after the procedure and occasionally lifelong. In addition, those with ischemic stroke and thromboembolic cerebrovascular diseases are often started on tPA and thrombolytic agents. Many trials and cohort studies in the cardiologic literature have drawn the attention to the complications related to high heparin doses, thrombolytic agents, and prolonged heparin treatment.^23–25 Since puncture site complications were seen to increase significantly in the patients who receive those treatments, some authors recommended to cease or reverse these drugs prior to sheath removal.^6,15 In our systematic review, most of the studies reported that their patients received anticoagulant or antiplatelet treatments. However, only four studies mentioned the use of tPA.^6,8,14,16 Geyik et al. showed in their retrospective study that the vascular closure device related complications rate in the interventional procedures is around 5 times more than in the diagnostic procedures where there is no need for the activated clotting time measurements, generally.¹⁵ However, Wong et al. reported an acceptable low level of VCD complications in patients with prolonged elevated activated clotting time (range 250–500 seconds).¹² Shah et al. evaluated the Angio-Seal device complications in non-ideal circumstances to use the device and reported no complication in the interventional group.¹⁰ In our study, a meta regression of the outcomes “any groin complication” and “groin hematoma” regarding ACT and APT use showed that the larger the proportion of patients who received ACT or APT, the higher the risk of groin hematoma.

The high heterogeneity among the included studies in outcomes of any groin complication, groin hematoma, and moderate heterogeneity in ipsilateral DVT can be referred to the variation in sheath size, use of ACT/APT, segments of femoral artery where the device has been applied, and the experience of the interventionist.

Limitations

The main limitation of this meta-analysis is that all the included studies were uncontrolled and many were retrospective and the results have high heterogeneity. There might be variability in practice patterns and operator and medical center expertise. This is evident by the wide range of antiplatelet therapy regimens that were administered to patients before and after the neurovascular interventions. Groin hematoma was listed as a complication, but many of these hematomas were clinically inconsequential. There was no reported follow-up period to assess any possible or delayed Angio-Seal device complication like DVT in most of the included studies. Another limitation is the lack of stratification of outcomes based on important variables such as the type of the neuro-endovascular intervention. Publication bias is obvious among the studies, and the role of the device manufacturer in the research is not fully clear. Lastly, we do not have specific data on baseline patient morbidity. Thus, we are unable to determine what proportion of patients with poor medical history developed the complication after procedure. Therefore, the overall certainty in the evidence at present is rated very low.²⁶

Conclusion

The complication rates associated with the use of the Angio-Seal vascular closure device in neurointerventional patients are not negligible, at around 5%. A majority of the complications was due to groin hematomas; however, complications such as pseudoaneurysm, infection and arterial stenosis occurred in slightly over 2% of cases. These findings are important to consider when benchmarking femoral artery complication rates.