Original Contribution

Comparison of the FemoSeal Vascular Closure Device With Manual Compression After Femoral Artery Puncture – Post hoc Analysis of a Large-Scale, Randomized Clinical Trial

Nader Mankerious, MD1*;  Katharina Mayer, MD1*;  Senta M. Gewalt, MD1;  Sandra M. Helde, MD1,2;  Tareq Ibrahim, MD3;  Lorenz Bott-Flügel, MD2;  Karl-Ludwig Laugwitz, MD3,4;  Heribert Schunkert, MD1,4;  Adnan Kastrati, MD1,4;  Stefanie Schüpke, MD1,4;  for the Instrumental Sealing of ARterial puncture site – CLOSURE device versus manual compression (ISAR-CLOSURE) Trial Investigators

Nader Mankerious, MD1*;  Katharina Mayer, MD1*;  Senta M. Gewalt, MD1;  Sandra M. Helde, MD1,2;  Tareq Ibrahim, MD3;  Lorenz Bott-Flügel, MD2;  Karl-Ludwig Laugwitz, MD3,4;  Heribert Schunkert, MD1,4;  Adnan Kastrati, MD1,4;  Stefanie Schüpke, MD1,4;  for the Instrumental Sealing of ARterial puncture site – CLOSURE device versus manual compression (ISAR-CLOSURE) Trial Investigators

Abstract: Objectives. To assess the safety and efficacy of arteriotomy closure with the intravascular FemoSeal vascular closure device (VCD; St. Jude Medical) compared to manual compression in patients undergoing diagnostic cardiac catheterization via the common femoral artery. Background. There is limited evidence on the performance of individual contemporary VCDs compared to manual compression. Methods. This is a subanalysis of 3018 patients who underwent transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either the intravascular FemoSeal VCD or manual compression within the investigator-initiated, large-scale, randomized, multicenter, open-label ISAR-CLOSURE trial. Primary endpoint was the composite of access-site related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat manual compression. Results. Vascular access-site complications were lower in patients assigned to the FemoSeal VCD compared to manual compression (6.0% vs 7.9%; P=.04), driven by a lower incidence of hematomas in the FemoSeal group (4.3% vs 6.8%; P<.01). Pseudoaneurysm rates were comparable in both groups (1.5% vs 1.5%; P=.88). Time to hemostasis was significantly shortened with the FemoSeal VCD compared to manual compression (0.5 min [IQR, 0.2-1.0 min] vs 10 min [IQR, 10-15 min]; P<.001). However, repeat manual compression was increased with the FemoSeal VCD (1.5% vs 0.7%; P=.03). Conclusion. In patients undergoing transfemoral diagnostic coronary angiography, the use of the FemoSeal VCD is associated with shortened time to hemostasis and a reduction in vascular access-site complications driven by fewer hematomas when compared to manual compression.  

J INVASIVE CARDIOL 2018;30(7):235-239. Epub 2018 May 15.

Key words: vascular closure device, coronary angiography, femoral access, randomized clinical trial


The safety of percutaneous procedures is highly dependent on the avoidance of vascular access-site complications.1 Use of the radial access site is an established method for reducing vascular and bleeding complications.2,3 Yet, the femoral route remains the most commonly used access site worldwide (in particular in the United States), and even in experienced high-volume radial access centers, about 20%-30% of patients still undergo catheterization via the femoral route for various reasons.4

Manual compression (MC) has traditionally been used to achieve hemostasis after femoral artery puncture. Vascular closure devices (VCDs) were introduced into clinical practice about 20 years ago in order to improve efficacy and safety. While efficacy has been a consistent finding of VCDs, their safety in terms of vascular access-site complications has remained quite controversial.5-8 However, available meta-analyses are limited by the small size, variable quality, and significant heterogeneity of included trials.

The investigator-initiated, large-scale, multicenter, randomized, open-label ISAR-CLOSURE (Instrumental Sealing of ARterial puncture site – CLOSURE device vs manual compression) trial proved that in patients undergoing transfemoral diagnostic coronary angiography, two contemporary VCDs using either an extravascular or intravascular closure mechanism are non-inferior to MC in terms of vascular access-site complications.9 A secondary comparison of the two different VCDs showed that vascular access-site complications were numerically lower in patients assigned to the intravascular FemoSeal VCD (St. Jude Medical) compared to the extravascular ExoSeal VCD (Cordis).9

There is limited evidence on the performance of individual contemporary VCDs compared to MC from large-scale randomized trials. We therefore aimed to compare the FemoSeal VCD with MC in patients enrolled in the ISAR-CLOSURE trial in terms of vascular access-site complications.

Methods

Study design. A detailed description of the study design and main results of the ISAR-CLOSURE trial have been published.9,10 The trial was performed with the approval of the ethics committee at each participating center and all patients provided written informed consent. The current analysis aims to assess the value of the intravascular FemoSeal VCD compared with MC in patients enrolled in ISAR-CLOSURE.

Study population. Patients were enrolled from April 2011 to May 2014 if they had given their written informed consent and underwent diagnostic coronary angiography with a 6 Fr sheath via the common femoral artery, which had to have a diameter of >5 mm (proven by angiography). Main exclusion criteria were previous implantation of a VCD, symptomatic leg ischemia, prior thromboendarterectomy, patch plastic of the common femoral artery, planned invasive diagnostic/interventional procedure, heavily calcified vessel, active bleeding, bleeding diathesis, severe arterial hypertension, local infection, autoimmune disease, allergy to resorbable suture, and pregnancy.10

Study treatment. Eligible patients were randomized in a 1:1:1 fashion to arteriotomy closure with one of the following techniques: (1) the intravascular FemoSeal VCD; (2) the extravascular ExoSeal VCD; or (3) MC. Allocation to treatment was performed with sealed opaque envelopes containing a computer-generated sequence. In patients randomized to VCD treatment, the VCDs were deployed according to the instructions for use under strictly sterile conditions. Investigators participating in the trial were instructed and certified from the manufacturer of the respective VCD. In patients assigned to MC, the sheath was removed by a physician and groin compression was performed until adequate hemostasis was achieved. Bed rest was recommended for all treatment groups. A pressure bandage was applied for 2 hours after VCD implantation and 6 hours after MC. There was no routine anticoagulation during coronary angiography procedures.

Follow-up. After removing the pressure bandage, the access site was clinically inspected and mobilization was allowed when considered appropriate. All patients were scheduled to undergo color-coded duplex sonography of the access site before hospital discharge. At 30 days after randomization, patients were contacted by letter, telephone, or outpatient visit for clinical follow-up. In case of any complaints related to the access site, patients were invited for further clinical and duplex sonographic examination.

Endpoints and definitions. The primary endpoint is the incidence of vascular access-site complications, defined as the composite of hematoma ≥5 cm, arteriovenous fistula, pseudoaneurysm, access-site related major bleeding, acute ipsilateral leg ischemia, need for vascular surgical or interventional treatment (for hematoma evacuation or acute ipsilateral leg ischemia), or local infection at 30 days after randomization. Secondary endpoints are time to hemostasis and repeat MC. Access-site related major bleeding definition is per the REPLACE-2 criteria11 and includes a reduction in hemoglobin of ≥3 g/dL with evident bleeding, a reduction in hemoglobin of ≥4 g/dL with or without evident bleeding, or bleeding requiring blood transfusion.12

Statistical analysis. Categorical data are presented using frequencies and proportions and were analyzed with the use of Chi-square test or Fisher’s exact test, as appropriate. Continuous variables are summarized using median with interquartile range (IQR; 25th-75th percentiles) and compared using nonparametric Wilcoxon rank-sum test. All analyses were conducted in a blinded manner regarding the randomly assigned treatment and were performed on an intention-to-treat principle. A P-value <.05 was considered to indicate statistical significance. Statistical analyses were conducted using S-PLUS software, version 4.5 (Insightful). 

Results

Patients and procedures. Among the 4524 patients enrolled in the ISAR-CLOSURE trial, a total of 3018 were assigned to either puncture-site closure with the intravascular FemoSeal VCD (n = 1509) or MC (n = 1509). In all, 92% of patients underwent duplex sonography of the access site before hospital discharge. Clinical follow-up at 30 days was available for 92% of patients. Only 17 patients (0.6%) underwent neither duplex sonographic examination of the access site nor clinical follow-up at 30 days.

Baseline clinical and demographic characteristics according to treatment allocation to the FemoSeal VCD or MC are shown in Table 1, and the antithrombotic medication on admission is summarized in Table 2. A total of 68% of patients received aspirin, about 39% received an adenosine-diphosphate receptor blocker, and 14% were on oral anticoagulant. Angiographic and procedural characteristics are presented in Table 3.

Clinical outcomes. During 30-day follow-up, one patient assigned to the FemoSeal VCD died of malignancy and 1 patient assigned to MC died of renal failure. Clinical outcomes according to treatment allocation to the FemoSeal VCD vs MC are displayed in Table 4, Figure 1, and Figure 2. The primary composite endpoint of access-site related vascular complications was lower in patients assigned to the FemoSeal VCD compared with MC (90 FemoSeal patients [6.0%] vs 119 MC patients [7.9%]; P=.04), which was driven by a lower incidence of hematomas in patients assigned to the FemoSeal VCD (65 FemoSeal patients [4.3%] vs 102 MC patients [6.8%]; P<.01). There was no difference in pseudoaneurysm occurrence (22 FemoSeal patients [1.5%] vs 23 MC patients [1.5%]; P=.88). No patient required interventional treatment or vascular surgery and no patient suffered from acute ipsilateral leg ischemia. There was 1 case of an access-site infection within 30 days in the FemoSeal VCD group.

Regarding the secondary endpoints, time to hemostasis was significantly shortened with the use of the FemoSeal VCD compared to MC (0.5 min [IQR, 0.2-1.0 min] vs 10 min [IQR, 10-15 min], respectively; P<.001). However, repeat MC after initial hemostasis was more frequent in the FemoSeal VCD group than in the MC group (22 FemoSeal patients [1.5%] vs 10 MC patients [0.7%]; P=.03).

Discussion

This post hoc analysis reports the largest randomized comparison of a single VCD with MC. The main findings can be summarized as follows: (1) In patients undergoing transfemoral diagnostic coronary angiography, the FemoSeal VCD reduces the incidence of vascular access-site complications compared to MC. (2) This reduction is driven by a significant decrease in hematomas ≥5 cm. (3) Time to hemostasis is shortened with the FemoSeal VCD compared to MC. (4) However, repeat MC is increased with the use of the FemoSeal device.

Manual compression has been the traditional technique to achieve arteriotomy-site closure after femoral artery puncture. From 1995 on, numerous VCDs were introduced and rapidly adopted into clinical practice. Importantly, approval studies required demonstration of efficacy but not safety. Later, meta-analyses based on small-scale randomized trials (ranging from 100-500 patients) with variable quality and significant heterogeneity found concerning safety signals of more vascular complications with VCDs. In 2010, the American Heart Association (AHA) released a warning statement that VCDs should not be used routinely for the specific purpose of reducing vascular complications in patients undergoing invasive cardiovascular procedures via the femoral artery approach (class III, level of evidence B).8 However, the current analysis of 3018 patients enrolled in a large-scale randomized clinical trial found a reduction in the composite of vascular access-site complications (mainly driven by hematomas) with the use of the FemoSeal VCD compared to MC in selected patients undergoing diagnostic coronary angiography.

The FemoSeal VCD is an intravascular VCD consisting of two bioresorbable polymer discs – an inner anchor plate and an outer disc – that are pulled together by a bioabsorbable filament and thereby sandwich and seal the arteriotomy site. Resorption is expected to be complete within about 3 months.10

The results of our analysis confirm and extend the results of the previous CLOSE-UP (CLOSure dEvices Used in everyday Practice) study.13 This randomized single-center trial of 1001 patients undergoing coronary angiography found improved outcome with the intravascular FemoSeal VCD over MC in terms of large groin hematomas, while other vascular complications were rare and not different between both study groups.5 Therefore, both randomized clinical trials, CLOSE-UP and ISAR-CLOSURE, showed a consistent reduction in hematomas with the FemoSeal VCD compared to MC in a total of 4019 patients. This is noteworthy because it was an increased rate of hematomas as well as pseudoaneurysm that generated safety concerns about the use of VCDs in a previous meta-analysis of 4000 patients including various VCD types.5

Compared to the CLOSE-UP trial, the overall rates of hematoma and in particular pseudoaneurysm are higher in our analysis. The most likely explanation is the meticulous follow-up of patients enrolled in the ISAR-CLOSURE trial, which included not only clinical but also routine duplex sonographic examination.

Of note, we also found an increased rate of repeat MC with the FemoSeal VCD. This increase was not seen in the CLOSE-UP trial, in which the overall rate of repeat MC was significantly higher. Immobilization protocols differ largely between both trials. In CLOSE-UP, bed rest for 1 hour was required in both groups, the use of sandbags was discouraged, and patients were allowed to raise their head to 45°. In ISAR-CLOSURE, a pressure bandage had to be worn for 2 hours in patients assigned to the FemoSeal VCD and for 6 hours in patients assigned to MC. Unfortunately, there are no prospective data available to guide the optimal timing of mobilization after VCD closure or MC, and the relative contribution of immobilization protocols to the rate of repeat MC remains speculative.

Importantly, there is increasing evidence for heterogeneity regarding the performance of different VCD types. In the ISAR-CLOSURE trial, device failure was significantly increased with the extravascular ExoSeal VCD compared to the intravascular FemoSeal VCD. Moreover, there was a trend for worse outcome with the ExoSeal VCD vs the FemoSeal VCD in terms of vascular access-site complications. In line with this, safety concerns were also found with other extravascular VCDs, including the early-generation VasoSeal VCD (St. Jude Medical)5-7 and recently with the Mynx VCD (Cardinal Health).14 Therefore, the conclusions derived with the new-generation intravascular FemoSeal device should not be generalized to other VCD types.

Study limitations. The ISAR-CLOSURE trial was powered to assess non-inferiority of two different types of VCD, including the intravascular FemoSeal VCD and the extravascular ExoSeal VCD, compared to MC in terms of vascular access-site complications. The current analysis is a post hoc analysis consisting of two-thirds of the patients enrolled in the ISAR-CLOSURE trial. Results should therefore be considered hypothesis-generating. Furthermore, this analysis suffers from the same limitations as previously described for the ISAR-CLOSURE trial, ie, its open-label nature and the exclusion of high-risk patients, in particular those undergoing percutaneous coronary intervention.9 Finally, the improvement in efficacy achieved with the FemoSeal VCD is reflected by the decreased time to hemostasis compared with MC (0.5 min for FemoSeal [IQR, 0.2-1.0 min] vs 10 min for MC [IQR, 10-15 min]; P<.001). However, we did not measure time to ambulation or time to discharge.

Conclusion

In patients undergoing transfemoral diagnostic coronary angiography, the use of the intravascular FemoSeal VCD compared to MC not only reduces time to hemostasis but also provides superior outcomes in terms of vascular access-site complications, driven by a reduction in hematomas. The current analysis thereby confirms the efficacy and safety of the contemporary intravascular FemoSeal VCD. More data are required to assess the value of VCDs in patients undergoing PCI.

References

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10.    Xhepa E, Byrne RA, Schulz S, et al. Rationale and design of a randomised clinical trial comparing vascular closure device and manual compression to achieve haemostasis after diagnostic coronary angiography: the Instrumental Sealing of ARterial puncture site - CLOSURE device versus manual compression (ISAR-CLOSURE) trial. EuroIntervention. 2014;10:198-203.

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*Joint first authors.

From the 1Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; 2Klinikum Landkreis Erding, Abteilung Kardiologie und Pneumologie, Erding, Germany; 3Medizinische Klinik 1, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; and 4German Center for Cardiovascular Diseases (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 28, 2018, provisional acceptance given February 5, 2018, final version accepted February 12, 2018.

Address for correspondence: Stefanie Schüpke, ISAResearch Center, Deutsches Herzzentrum München, Lazarettstr. 36, 80636 Munich, Germany. Email: schuepke@dhm.mhn.de

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