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Clinical Evaluation of the eSVS Mesh: First-In-Man Trial Outcomes

Emery, Robert W. M.D.*; Solien, Eric BSc; Klima, Uwe M.D.

doi: 10.1097/MAT.0000000000000187
Clinical Cardiovascular

In coronary artery bypass graft surgery, saphenous vein graft (SVG) patency is much lower than that of the internal mammary artery (IMA). To address this problem, an external support device, the eSVS Mesh was developed. A prospective randomized First-in-Man feasibility trial was conducted in 90 patients after institutional ethics committee approval at seven international centers. The left IMA was used to bypass the anterior descending artery. A mesh-supported (treated) saphenous vein was randomized to either the right or the circumflex coronary system, and an unsupported (control) vein was grafted to the opposing territory. Device diameters available for use were 3.0, 3.5, 4.0, and 4.5 mm. Primary end-points were 30 day adverse cardiac and cerebral events and angiographic patency at 9–12 months. Eighty-five of 90 patients returned for 30 day clinical follow-up (94%). Five patients refused to return, but by telephone contacts were asymptomatic. There was one late noncardiac death and 73 patients returned for angiography (82%), thus 12 additional patients were lost to follow-up at 1 year. Overall patency rate was 49% for the treated versus 81% for controls (p < 0.001). Subset analysis revealed significantly lower patency at one center and with use of the 3.0 mm device (p < 0.05). Removing these data, patency was 72% vs. 81% (p = NS). Sternal wound infection was higher than expected at 5.0%, but this was center specific. The eSVS Mesh is safe, but at up to 1 year, patency is equivalent to untreated vein grafts after removal of outlying data. This study provides insight into operative events and parameters that may optimize outcomes and point to potential improvements in the external SVG support device. Furthermore, longer term studies are pending.

From the *St. Josephs Hospital, St. Paul, MN Kips Bay Medical Inc., Minneapolis, MN; and Burjeel Hospital Abu Dhabi, Abu Dhabi, United Arab Emirates.

Submitted for consideration June 2014; accepted for publication in revised form November 2014.

Clinicaltrials.gov identifier: NCT0077777.

Disclosure: Dr. Emery is a consultant to Kips Bay Medical Inc. E. Solien is the lead scientist and a full time employee of Kips Bay Medical Inc. Funding was provided by Kips Bay Medical—there were no patient or physician incentives.

Correspondence: Robert W. Emery, 317 Groveland Ave., Minneapolis, MN55403. Email: remery1513@aol.com.

Coronary artery bypass graft surgery (CABG) is an important therapeutic option in the treatment of left main or multivessel severe atherosclerotic disease of the coronary arteries and in diabetic patients.1–3 The internal mammary arteries (IMAs) have been well demonstrated to be the conduits of choice showing excellent long-term patency.2 Although saphenous vein graft (SVG) patency is substantively lower than the IMA, the vein is used in >80% of CABG procedures to provide complete revascularization, known to be of major benefit to patient outcomes.1–3

The Achilles heel of CABG is thus the saphenous vein due to the poorer long-term patency rate compared with arterial grafting.2,4 Saphenous vein graft loss can be substantial at 1 year and up to 50% at 10 years.2,5 This is related to transposing the saphenous vein, normally subject to lower venous pressure, into the arterial system, thus exposing the graft to systemic arterial pressures, increasing the tangential wall stress. In this environment, the vein dilates and damage to the endothelium can occur, triggering smooth muscle proliferation, the formation of thrombus, and subsequent lipid deposition. The buildup of smooth muscle cells secretes inflammatory and growth factors, as well as extracellular matrix, resulting in the development of vein graft atherosclerosis plaque, thrombosis, and ultimate graft failure.6,7 In addition, the size mismatch between the SVG and the coronary artery creates abnormal flow patterns that enhance this process.8 Despite extensive research, to date, only the use of early postoperative aspirin and aggressive statin therapy have been shown to improve patency of the SVG to 1 year.5,9,10

The eSVS Mesh (Kips Bay Medical, Minneapolis, MN), a highly flexible, semicompliant, kink-resistant extravascular tubular prosthesis constructed of knitted nitinol wire was developed to address this problem of long-term SVG patency.11 Animal experimentation has documented improved graft patency with arterial-like healing, that is, uniform internal surface of the SVG without irregularities or valve sinuses.12 These studies used the mesh as an external support and to downsize the SVG to more appropriately match the size of the coronary artery to which is to be sewn.8,12 To evaluate the effects of this device in a clinical population and determine if the mesh was appropriately designed, a First-in-Man feasibility trial was undertaken at seven international sites enrolling 90 subjects.

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Material and Methods

The First-in-Man eSVS Mesh External Saphenous Vein Support Feasibility Trial was a prospective randomized clinical experience in patients undergoing first time CABG requiring a SVG to the right coronary system (RCS) and the left circumflex coronary (CCX) system with IMA bypass to the anterior descending coronary artery. Saphenous vein grafts are harvested using open or bridged technique. Vein segment selection for application of the mesh was at the discretion of the surgeon and treatment randomized to the right coronary or CCX system.

After approval by institutional ethics committees at participating institutions, enrollment began on August 25, 2008, and was completed on July 21, 2009. The investigation sites are noted in Table 1. Follow-up was conducted for primary safety and efficacy points, including the 30 day and 1 year occurrence of major adverse events including major cardiac and cerebral events (MACCEs) and follow-up angiography at 9–12 months after surgery, respectively. All angiograms completed were sent to a core laboratory (Beth Israel Hospital, Boston, Massachusetts, under the direction of Dr. Jeffrey Popma) for interpretation.

A patent graft was defined as having <50% stenosis at all points in the vessel. Thus, patients served as their own control for meshed versus unmeshed grafts, and meshed and unmeshed grafts could be compared throughout the trial.

The eSVS Mesh was deployed over the vein much akin to a sleeve over an arm. Deployment and surgical technique have been previously published.13 The diameter range of the treated SVG is assessed for selection of the appropriately sized device (3.0, 3.5, 4.0, or 4.5 mm) as shown in Figure 1A. The device was then deployed over the vein and adhered to it with a thinly sprayed coating of Tisseel (Baxter Inc., Westlake Village, California). The mesh implanted by size is shown in Table 2.

All procedures were primary isolated CABG and, in this clinical trial, were conducted on cardiopulmonary bypass with cardioplegic arrest. Results are cited as mean ± standard deviation. Statistical analysis was conducted independently. Comparison between grafts in the individual patients was conducted using a Student’s paired t-test and between covered and uncovered grafts within the study group as a whole using a Student’s unpaired t-test. When these were not applicable, the Fischer exact test was used.

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Results

Ninety patients were enrolled in the trial; the demographics are shown in Table 3. There were no operative deaths. Four veins required replacement to a larger mesh (3.0–3.5 mm). Eighty-five patients (94%) returned for 30 day reoperative follow-up visits; five patients who refused to return were contacted by phone and interviewed, there were no adverse events in this group. There was one late noncardiac–related death at 8 months postoperative.

Twenty-three subjects had a total of 30 adverse early events of which 21 were serious; these and events from 30 days to trial completion are shown in Table 4. Four of the early adverse events were considered MACCE: two were perioperative myocardial infarctions and two were cerebral vascular accidents. Of note, sternal wound infection (SWI) occurred in 5.6% of patients, higher than objective performance criteria, and was predominantly related to a single center. Twelve of the 84 patients to return at 1 year were lost to follow-up; thus, 73 (82%) eligible patients had angiograms with both grafts evaluated. There were three SVGs that were present on aortogram that were unable to be selectively catheterized but were patent. Of the anastomoses studied, 36 of 73 covered (49%) and 59 of 73 controls (81%) were patent (p < 0.001). Patency data related to size of the mesh used and of the control grafts is shown in Table 5. Mesh size graft patency is represented in Figure 2. It is important to note that one site only had a 23% patency rate, significantly different from the other centers (p < 0.05). Patency analyses with this site included and with this site excluded are shown in Tables 5 and 6. Data on anatomic site (RCS vs. CCX) and device size for inclusive data are shown in Table 7. The 3.0 device also had significantly poorer patency (Tables 6 and 7) than the 4.0 mm mesh (p = 0.05) and the poorer patency rate nearly reached significance compared with the 3.5 mm device (p = 0.053). Data for patency with the one aberrant site and with the 3.0 mm device excluded are shown in Table 8 and Figure 3. Statistical equivalence between the treated and control grafts was noted, and MACCE was consistent with accepted objective performance criteria.4,5 There was also no difference in patency when individual patients were compared between treated and untreated grafts with patients serving as their own controls.

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Discussion

The eSVS Mesh is expected to positively impact SVG patency by two mechanisms: First, the vein is downsized by up to 35% (Figure 1A) to more appropriately size match the artery to which the bypass is created. This improves flow patterns and reduces turbulence to create more arterial-like healing (Figure 4, A and B).8,11 Second, the mesh restricts radial expansion reducing vessel wall stress and obviating endothelial damage from acute and chronic exposure to arterial pressure, which can lead to the development of SVG atherosclerotic disease.6,8,12 Because of downsizing and prevention of radial expansion, early patency was thought to be impacted.7,8 Unexpectedly, the eSVS Mesh in this clinical trial had patency equivalent to the non-eSVS–treated controls after subset analysis revealed outlying data and those points removed. From data analysis, three lessons were taken from this experience in preparation for further clinical trials: First, too much saphenous downsizing was suspected.14 This effect may have been more pronounced in smaller diameter veins. The closure rate with the 3.0 mm mesh was most impacted (Table 5). Second, veins with a double wall thickness >1.4 mm should not be downsized as the lumen is compromised by the thicker vessel wall, again, more problematic in the smaller size mesh. Residual lumen diameter after downsizing should be a minimum of 2 mm. Thus, the size 3.0 eSVS Mesh device, that with the worst performance, is no longer available. Third, one investigational site had a significantly poorer treated graft patency rate than other sites for all sizes (Table 5).14 These poor outcomes were possibly because of overly aggressive downsizing, especially in smaller grafts, lack of resection of redundant tissue between the vein and mesh, or lack of construction of a cobrahead for the construction of the proximal and distal anastomoses.14,15 It is important that recommended surgical technique13 be followed as the saphenous veins cut to nearly 90° for both proximal and distal anastomoses can result in a perpendicular anastomosis and can create an experience similar to that of the St. Jude Medical Symmetry device (St. Jude Medical Inc., St. Paul, MN) where if the 90° angle is not maintained, kinking at the anastomotic site occurs.16 Thus, it is important that the saphenous vein and mesh be incised to create a “cobrahead” anastomosis to allow the graft to lie properly and not restrict inflow. The mesh will not unravel when cut.13,17 Strict SVG selection criteria should also be followed. Removing the data from this center improved results (Table 6). With this analysis in hand, the measurement tool was redesigned to add a slot for assessment of double wall thickness that should be <1.4 mm and discontinuation of the 3.0 mm device. The currently used new measurement tool is shown in Figure 1B compared with the measurement tool used in the First-in-Man Feasibility trial.

The results of the trial showed statistical equivalency with the unmeshed vein graft and the adverse event rate not different from that seen in other large series after removal of outlying data. Thus, the eSVS Mesh is safe when sized and implanted appropriately.18,19 The incidence of SWI was related to a single center and has not been found in other reports (personal communication).17

Early postoperative computed tomographic angiography has shown the mesh-treated grafts to have excellent predischarge patency, indicating that the mesh as a foreign body does not compromise early outcomes.17 Importantly for patient safety, the current data show that the eSVS Mesh does not negatively impact 9–12 month graft patency.

Although the hope was that there would be improved 1 year patency related to downsizing alone, this may not occur because SVG atherosclerotic disease develops over time and a single year time frame may not be long enough to see a difference in patency.6,8 There are also numerous other factors including, but not limited to, runoff from the graft, age, diabetes, coronary artery size, ejection fraction, and vein quality, which impact early graft patency, and these were not controlled for in this study.4,5,20 Equivalency of treated and untreated vein graft is thus appropriate as vein graft disease may take years to develop.

This study has several limitations. First, this was a feasibility study to primarily determine safety and thus was not powered to gain statistical significance in patency. Vein harvesting and surgical techniques varied among centers. While vessels bypassed were required to have at least a 70% stenosis, there was variance with obstructive lesions versus total occlusion between left and right systems, which could have impacted outcomes. The angiographic follow-up at 2 years was only 80% of the total enrollment. At one center, results were poor for a variety of possible reasons, and lastly, there was variability in experience with the device (Tables 5 and 6).

With this experience in hand, stricter criteria made for vein qualification elimination of the 3.0 mm size and use of recommended operative technique and improvement in use of the device made and further studies are ongoing. Longer term evaluation is warranted.

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vein graft patency; external graft support

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