The potential role of external venous supports in coronary artery bypass graft surgery

The potential role of external venous supports in coronary artery bypass graft surgery Abstract Despite the apparent superiority of arterial conduits for coronary artery bypass grafting (CABG), the long saphenous vein remains the most commonly used graft. The high failure rate of long saphenous vein grafts (SVGs) over time is therefore an important limiting factor for the long-term outcomes of CABG. Various methods to improve SVG patency have been proposed, although few have had a significant impact on clinical practice. External SVG supports have been a focus of research over the past 50 years, with their use intended to minimize well-documented pathophysiological changes that occur in the SVG following implantation into the coronary circulation. These devices have been trialled extensively in animal models to assess their impact on both the morphology and the function of vascular conduits. Recently, a number of studies have been conducted in patients, leading to a substantial development in their design and the accumulation of a large body of evidence attesting to their potential benefit in CABG. In this review, we briefly discuss the proposed mechanism of action of external SVG supports and then evaluate the results from animal studies and more recent research assessing their use in CABG patients. Finally, we conclude that newer models of external stents have the potential to improve long-term outcomes in SVG. Coronary artery bypass grafting, Cardiac, Saphenous vein, External stent, Revascularization INTRODUCTION Since its inception over 50 years ago [1], coronary artery bypass grafting (CABG) has been shown to have both symptomatic and prognostic benefits for coronary artery disease, and it remains the gold standard therapy for patients with multivessel and/or left main stem disease [2, 3]. In recent years, although there has been substantial evidence indicating that the use of arterial bypass grafts is associated with better clinical outcomes [4–9], autologous saphenous vein grafts (SVGs) remain the most frequently used conduit in CABG [5, 10]. In contemporary practice, approximately 80% of all grafts for CABG are venous. This is likely to be due to a number of factors, including abundance, ease of harvest and less susceptibility to competitive flow [11]. However, the high failure rate of SVGs over time is a limiting factor for the long-term outcomes of CABG [12, 13], and this correlates with an increase in major adverse cardiac events [14]. Although a significant number of studies have been conducted to identify the techniques that improve long-term patency, currently, only statins and aspirin are routinely administered to reduce vein graft failure [13, 15]. One particular concept that has been repeatedly explored over the last half century is the use of an external support for venous grafts [16]. Such supports have been shown to have a number of important effects and may decrease SVG failure rates; until recently, only few clinical trials of external stenting had been published [17]. This review will briefly consider the pathophysiology of SVG failure and evidence from animal models, before focusing on the recent clinical data from patients. Pathophysiology of saphenous vein graft failure The pathophysiology of SVG failure has been extensively described in the literature [12, 13] and is not the primary subject of this review. Early graft failure (a few hours postoperatively) is largely due to endothelial damage, thrombus formation and technical errors that can be modified by surgical technique [18–23]. The main cause of mid-term graft failure (occurring from 1 month to 1 year postoperatively) is intimal hyperplasia [12, 13, 24], first described in 1906 by the Nobel prize-winning surgeon Alexis Carrel [25]. The change in the haemodynamic forces upon implantation into the coronary circulation alters the shear stress along the vessel wall and causes the migration of vascular smooth muscle cells from the media into the intima, resulting in hyperplasia [12, 24, 26–31]. Late graft failure is due to degenerative changes resulting in atherosclerotic-like lesions developing from the hyperplastic intima [27]. Although structural non-uniformity (including intimal hyperplasia) is a feature of failed grafts, even long-term patent grafts demonstrate pathological abnormalities, with 81% of patent grafts displaying some degree of disease 15 years postoperatively [32]. Origin of external venous supports The use of external supports was first proposed by Parsonnet et al. [16] in 1963. It was hypothesized that this would reduce the diameter mismatch between the vein graft and the target vessel and minimize the extent to which the vein dilates on implantation into the higher pressure arterial system, possibly protecting against intimal damage and thrombosis. In their landmark study, the authors used a monofilament-knitted tube consisting of polyethylene, polypropylene and Teflon to cover a segment of the excised external jugular used to replace the common carotid artery of dogs. They demonstrated that the external stents were capable of limiting the dilatation of the vein graft, and after 63 days, 96% of the grafts supported with a stent were patent compared to all of the control grafts. Comparable results were reported in a later study by Karayannacos et al. [33] in 1978, who used a Dacron mesh prosthesis in a similar experimental model. The external stent was reported both to reduce the intimal hyperplasia and to increase the number of vasa vasorum in the graft wall, which are 2 important and interlinked pathological processes that occur post-SVG implantation. This is one of the first studies to link the use of an external support device with a structural change in the conduit. A limited human trial was then performed by Barra et al. [34] in 1987, with 4 SVGs supported by the stent being shown to be patent on angiography after 2 months. These findings served as ‘proof of principle’, preceding more robust studies. MATERIALS AND METHODS In June 2016, the PubMed database was searched using the terms ‘external stent’, ‘CABG’ and ‘saphenous vein graft’. Results were searched for further articles, and any other incidental articles discovered were also included in the analysis. RESULTS Mechanism of action and research in animal models Given that early graft failure is thought to be mainly due to the surgical preparation of the SVGs and technical errors during implantation, the main benefit of external supports is likely to be on the mid-term and the long-term graft failures. The mechanisms associated with improved graft success have been identified in a variety of animal models. These include changing the biomechanical properties of the graft and the biological interactions that result in venous wall remodelling, such as changing the pattern of vascular smooth muscle cell proliferation and migration and promoting the neovascularization of the adventitia [17]. It has also been demonstrated that the use of external stents can have a measurable impact on a number of different signalling pathways and, to some extent, restore normal signalling function in the grafted tissue [35, 36]. Furthermore, there is also evidence from ApoE*Leiden transgenic mouse and cholesterol-fed pig models that external stents may reduce late (atherosclerosis-mediated) graft failure [37, 38]. One of the most important postulated effects of external stents is the modulation of haemodynamic changes within the graft. In a series of reports by Zilla et al. [39–42], it was demonstrated that not only does the use of external venous supports reduce the degree of dilatation that SVGs undergo when transplanted but also their use is associated with a significant reduction in the intimal hyperplasia in a baboon model. Progressive constriction of the SVG lumen up to a >90% reduction significantly reduced graft intimal hyperplasia, with no effect on patency was shown [40]. These studies also highlighted a potential role for knitted rather than braided external devices, although this was not demonstrated in vivo [41]. Similar studies have been performed by Angelini et al. [43, 44]; however, in contrast to Zilla et al., this group found that less constrictive stents (6 and 8 mm) were associated with a reduction in intimal hyperplasia and constrictive stents (5 mm) resulted in an increase in intimal hyperplasia. However, such animal studies are unlikely to faithfully translate to CABG, with many using carotid or femoral artery interposition techniques. In response to this, Ben-Gal et al. [45] performed a small, proof-of-principle study in 2013, with the aim of accurately reproducing CABG in a sheep model. They performed coronary revascularization in 14 sheep, each receiving grafts to the left anterior descending artery and obtuse marginal artery. Each sheep received 1 VEST-supported graft with the other vein graft used as a control. They found that not only there was a significantly lower level of graft non-uniformity at 12 weeks (P < 0.002) but also the intimal layer of the supported grafts was smaller in the intervention group than the control (P < 0.02). Additionally, none of the stented grafts was thrombosed at the end of the study, but 3 of the non-stented grafts were thrombosed. Animal studies have also indicated a potential role for biodegradable external supports [46, 47]. However, unlike non-absorbable stents, these have yet to make the transition into human trials, and despite this promising early research, it remains to be seen whether they will have a substantial clinical impact. Clinical studies of external saphenous vein graft stenting Despite the relative wealth of animal data indicating a potential role for external supports in improving SVG patency, until recently, only limited numbers of good quality clinical data exist, assessing their potential benefit in patients. As discussed above, probably the earliest assessment into the use of an external stent in humans was performed in 1986 by Barra et al. [34]. However, the small number of patients and lack of properly randomized controls mean that early clinical results are difficult to generalize [48]. A number of larger studies have now been published, the results of which are summarized in Table 1. In 2007, a randomized trail of the Extent device (a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs) produced poor results [49]. In this study, 20 patients received an Extent-supported graft to either the right or the left coronary system. However, in all of the 17 patients returning for follow-up, the Extent-supported grafts were found to be thrombosed on angiographic assessment (6 and 19 months postoperatively), while all of the left internal mammary artery grafts and non-stented vein grafts remained patent. The authors attributed this to a combination of stent rigidity, oversizing and incomplete tube design leading to graft kinking either at the anastomoses or within the middle of the graft. Table 1: Summary of use of external stents for CABG in human trials Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory a Probability not stated in the original article. CABG: coronary artery bypass graft; N/A: not applicable; SVG: saphenous vein graft. Table 1: Summary of use of external stents for CABG in human trials Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory a Probability not stated in the original article. CABG: coronary artery bypass graft; N/A: not applicable; SVG: saphenous vein graft. Despite the disappointing results, these findings were used to improve the design of subsequent external stenting devices, leading to the development of the eSVS mesh (Kipsbay Medical Inc., MN, USA) and then the VEST device (Vascular Graft Solutions LD, Tel Aviv, Israel). The eSVS mesh is an elastic nitinol knit designed to accommodate veins between 3.5 mm to 7.0 mm in diameter when distended and aims to reduce the diameter of the graft by up to 20%, attempting to more realistically match the size of a normal coronary artery [58]. The first data on patients were published in 2011 by Schoettler et al. [50]. Patients (n = 25) were randomly assigned to receive an eSVS-supported SVG to either the right coronary artery (RCA) or to the circumflex artery, with an untreated SVG acting as a control. This, therefore, allowed each patient to be effectively used as their own control for intrinsic characteristics that may influence graft survival such as blood pressure, lipid profile and glucose-handling profile. All patients also received an in situ left internal mammary artery graft to the left anterior descending artery. Angiographic patency of the grafted vessels in the 18 subjects who attended postoperative follow-up after 9 months was 28% for eSVS-supported vessels and 86% for the non-stented vein grafts, while the patency of the left internal mammary artery grafts was 100%. Subsequently, a number of other studies assessing the immediate and early patency of eSVS-supported vein grafts were published. In 2013, a study from Genoni et al. [51] found that early (5 days postoperatively) computed tomography (CT) angiographic patency was 95% in a population of 20 eSVS-supported grafts, with only 1 occluded venous anastomosis. Rescigno et al. [53] assessed the patency of 25 eSVS-supported SVGs grafted to the RCA, posterior descending artery or the obtuse marginal artery. It was found that cumulative patency of the grafts, as assessed by multidetector CT, was 87% after 1 month, 43% at 6 months and 34% at 12 months. Furthermore, this study found that graft occlusion rate was especially high for vessels that received the 3.5-mm mesh rather than the larger 4-mm mesh. A similar study in 2015 found that, in a total of 19 patients at an average of 12 ± 0.1 months after surgery, all arterial grafts and unmeshed SVGs were patent compared to just 76% of the stented SVGs [56]. A series of studies using the eSVS mesh have also been published by Klima et al. [52, 54] working at Kips Bay Medical. In 2014, they performed CT angiography on 11 patients with 23 stented SVGs at an average of 7.2 months postoperatively and reported a 92% patency rate. In 2015, they reported the results of their First-in-Man eSVS Mesh External Saphenous Vein Support Feasibility Trial, despite the trial having been initiated over 6 years previously [54]. This study compared graft patency at 9–12 months in stented and non-stented grafts in 90 patients at multiple operative centres. Stent sizes of 3.0, 3.5, 4.0 and 4.5 mm were used. Here, it was found that stenting reduced graft patency, with 49% (36 of 73) patency in the stented group and 81% (59 of 73) patency in the control group (P < 0.001). In further analysis, multiple data were excluded leading to their reporting of the final stented patency as 73% (24 of 33; statistically non-significant from the control group data). Both pre- and post-exclusion data are included in Table 1 for completeness. Despite the poor performance of the eSVS Mesh in clinical trials, a number of important lessons were learnt that contributed significantly to the development of second-generation devices. Firstly, it was found that aggressive overconstriction to 3 mm and 3.5 mm leads to high failure rates, despite success in the large stents [54]. As such, the minimum diameter should be larger than 4 mm. Secondly, a number of problems were identified with the fixation of the external stent to the conduit. The use of fibrin glue and the incorporation of the external stent to the anastomoses were required by the eSVS mesh to prevent device fraying and migration and to optimize the dimensional match with the SVG. However, the use of fibrin glue led to tissue damage, fibrosis and intimal hyperplasia and therefore should be avoided. Additionally, incorporating the external stent to the anastomoses required significant change in the grafting technique and was found to be associated with higher acute failure rates. A few years after the clinical trials for eSVS began, the VEST external stent was investigated in the clinical setting. VEST (Vascular Graft Solutions) consists of a cobalt-chrome braid with axial plasticity (allowing elongation) and radial elasticity (making the stent kink and crush resistant). Technical specifications of the Extent device, eSVS Mesh and VEST External Stent are compared in Fig. 1. Following the initial favourable results of the VEST device described by Ben-Gal et al. [45] in 2013, the first in-human trial was performed earlier this decade by Taggart et al. [10]. In the VEST trial, patients received 1 SVG supported by an external stenting device to either the right or the circumflex coronary territory, with 1 or more SVGs being left unstented for use as a control. The results demonstrated (in a total of 21 stented SVG and 23 non-stented) that there was a significant decrease in the mean intimal–medial area between the stented and the unstented groups (P = 0.04), with a small decrease in intimal thickness (P = 0.06). There was no change in the lumen diameter between the 2 groups (P = 0.60). The effects of different external stents on SVG diameter are summarized in Fig. 2. Figure 1: View largeDownload slide Photographs of the external stent devices. (A) The Extent device, a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs and featuring a flange to guide placement (image taken from The Extent Study). (B) The eSVS Mesh, made of highly flexible and kink resistant knitted nitinol wires and mounted on colour-coded fluorinated ethylene propylene (FEP) tubes. (C) The VEST External Stent, a braided kink-resistant stent made of plastically deformable (red arrow) and elastic (blue arrow) cobalt-chrome wires. The combination of wires provides VEST with axial plasticity and radial elasticity. Figure 1: View largeDownload slide Photographs of the external stent devices. (A) The Extent device, a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs and featuring a flange to guide placement (image taken from The Extent Study). (B) The eSVS Mesh, made of highly flexible and kink resistant knitted nitinol wires and mounted on colour-coded fluorinated ethylene propylene (FEP) tubes. (C) The VEST External Stent, a braided kink-resistant stent made of plastically deformable (red arrow) and elastic (blue arrow) cobalt-chrome wires. The combination of wires provides VEST with axial plasticity and radial elasticity. Figure 2: View largeDownload slide Schematic representation of the degree of size reduction of 3 different stents on 2 different sizes of vein graft. V1 represents an average vein graft of 4.5 mm in diameter and a wall thickness of 0.5 mm, while V2 represents a larger vein graft of 5.5 mm in diameter and 0.8 mm in thickness. (A) The Extent device. Models of stent were 6 mm and 8 mm in diameter, meaning that vein graft size was unaffected [V1 outer diameter (OD)  = 4.5 mm and inner diameter (ID)  = 3.5; V2 OD = 5.5, ID = 4]. (B) The eSVS Mesh. Large degree of constriction achieved with 3.5 mm and 4.5 mm stents leading to smaller lumens and folds forming (V1 OD = 3.5, ID = 2.5; V2 OD = 4.5, ID = 2.8). (C) The VEST Externa Stent. Milder constriction of vein grafts compared with the eSVS Mesh (V1 OD = 4.2, ID = 3.2; V2 OD = 5, ID = 3.5). Figure 2: View largeDownload slide Schematic representation of the degree of size reduction of 3 different stents on 2 different sizes of vein graft. V1 represents an average vein graft of 4.5 mm in diameter and a wall thickness of 0.5 mm, while V2 represents a larger vein graft of 5.5 mm in diameter and 0.8 mm in thickness. (A) The Extent device. Models of stent were 6 mm and 8 mm in diameter, meaning that vein graft size was unaffected [V1 outer diameter (OD)  = 4.5 mm and inner diameter (ID)  = 3.5; V2 OD = 5.5, ID = 4]. (B) The eSVS Mesh. Large degree of constriction achieved with 3.5 mm and 4.5 mm stents leading to smaller lumens and folds forming (V1 OD = 3.5, ID = 2.5; V2 OD = 4.5, ID = 2.8). (C) The VEST Externa Stent. Milder constriction of vein grafts compared with the eSVS Mesh (V1 OD = 4.2, ID = 3.2; V2 OD = 5, ID = 3.5). The overall patency was 70% for the stented grafts and 71.8% for the control grafts. Interestingly, although there was no difference between the graft failure rates overall, there was a significant decrease in graft failure with stenting in the grafts to the circumflex territory (18% in the stented group vs 28% in the unstented group, P = 0.01), yet an increase in graft failure to the right coronary territory (46% vs. 13%, P = 0.01). As transit time flow measurements had been satisfactory in all grafts prior to sternal closure, the authors postulated that graft failure may have been due to fixation of the device to the anastomoses whose geometry then altered with chest closure, particularly those on the right side because of the acute margin of the heart. A higher occlusion rate was also observed when metallic clips rather than suture ligature was used to occlude vein graft side branches. These metallic clips may have deformed the vessel within the stent particularly around the acute margin of the heart on the right side. In the same study, intravascular ultrasonography data demonstrated a benefit from the use of sutures over the metal clips with stented vessels for side branch ligation, with improvements being shown for plaque thickness (P = 0.04, suture ligation stented vs. non-stented) and a trend towards the same effect on plaque area (P = 0.05) [10]. In grafts in which sutures were used for ligation, a significantly greater proportion were classed as Fitzgibbon Type I (i.e. perfect graft patency) and having a greater degree of lumen uniformity. Additionally, 2 subsequent studies also assessed the population of patients included in the VEST study [59, 60]. These found, using optical coherence tomography, that mean lumen cross-sectional area was greater in the unstented grafts than in the stented grafts (P = 0.005) and that there was greater uniformity in the stented grafts. Furthermore, post hoc computational fluid dynamic analysis found that mean oscillatory shear index was significantly reduced compared with the non-stented group and that this correlated with the development of diffuse intimal hyperplasia (P = 0.01, n = 43). Taken together, these results suggest that altering the haemodynamic forces that the graft is subjected to can result in a significant reduction in SVG structural change. The promising results of the VEST trial led to the establishment of the VEST II study, in which the use of clip ligation and fixation of the external stent to the anastomoses were avoided [57]. In this study, it has been found that at 3–6 months postoperatively the patency rate of supported SVGs to the RCA was 86%, comparable with published historical data for unstented SVGs to the same territory [61]. This suggests that the use of external stents on the RCA is safe and that the previous reduction in patency was most likely due to surgical technique. Overall, these results appear to demonstrate that the external support with VEST is safe and that improved haemodynamics within the graft reduce intimal hyperplasia over the short term. Whether this will translate into improved graft patency over the long term is the subject of ongoing studies. Ongoing studies The results of previous studies involving the VEST device have led to the establishment of 2 further trials: VEST III and VEST IV. VEST III (NCT02511834) is a multicentre study that has recently completed recruitment of 180 patients. Patients received a stented SVG randomly assigned to either the right or the left coronary territory and a non-stented graft, acting as a control as well as an internal mammary graft. Major cardiovascular and cerebral events will serve as the study end-point, alongside graft patency as assessed by CT angiography at 6 months and 2 years. The final results are expected in the early 2019. On the other hand, VEST IV will examine the long-term outcomes of the VEST I study, assessing major cardiovascular and cerebral event and graft patency 5 years postoperatively. Two angiographic images of the same stented SVG at 2 different time points in the VEST studies are shown in Fig. 3. Figure 3: View largeDownload slide Images from the VEST studies. (A) Externally stented saphenous vein graft to the right territory 12 months after coronary artery bypass grafting. (B) The same graft 53 months after coronary artery bypass grafting. Figure 3: View largeDownload slide Images from the VEST studies. (A) Externally stented saphenous vein graft to the right territory 12 months after coronary artery bypass grafting. (B) The same graft 53 months after coronary artery bypass grafting. Further benefits of external stenting In addition to improving the failure rates of SVG in CABG, other research studies have demonstrated that external stents may allow the use of conduits that would have previously been deemed to be unsuitable for surgery. In a series of reports, Zurbrügg et al. [62, 63] investigated the use of an external ultrafine constrictive metal mesh to generate ‘biocompound’ grafts with varicose vein tissue. They demonstrated that such grafts had favourable patency rates after hospital discharge (41 of 43) and had similar patency rates to non-stented SVG after 3 years, thus potentially increasing the number of conduits the surgeon may utilize in CABG. DISCUSSION Vein graft failure is a major obstacle to the long-term benefit of CABG. However, momentum has been building behind the use of external venous support devices for SVGs. So far, a large body of preclinical data has demonstrated a favourable role for these devices in improving the morphological characteristics of vein graft failure and subverting some of the mechanisms by which pathophysiological remodelling processes occur. Although most of the animal models used are unlikely to be fully representative of CABG (especially those using carotid or femoral interposition models), these preclinical studies have paved the way for more recent trials in humans. Furthermore, they have also identified some of the key structural requirements of the external stent, such as porous stents that promote the adventitial revascularization of the vessel [47]. Recently, a number of clinical trials have been published assessing the benefit of external vein graft stenting in patients, with a satisfactory evidence of data demonstrating that this can minimize some of the pathophysiological changes seen in SVGs after use as a conduit for CABG, including a reduction in intimal hyperplasia [10, 45]. As would be expected with any new surgical technique, the method and materials of graft used have developed considerably over time. Despite poor results from early studies, it has been demonstrated that the newest generation of these devices are capable of providing equivalent patency rates to non-stented vessels, at least in the short to mid-term, and techniques are still being improved to ensure good patency results in all regions of the heart [10, 57]. The key question is the long-term outcome of stented vein grafts that remain perfectly patent at 1 year. Furthermore, for the use of external stents to become universally accepted, it will be necessary to conduct future long-term studies to demonstrate superior graft patency compared with non-stented controls, rather than just non-inferiority. One of the most important aspects of external venous supports is the size of the stent that would be appropriate for the grafted vessels. Previous work by Zilla et al. [64] found that an average diameter constriction of 27% would be sufficient to eliminate diameter irregularities in the vast majority of vein grafts, although this study only analysed human vein graft tissue prior to implantation. Studies on animals have yielded contradictory data on the most appropriate diameter of stent [40, 44], and this, therefore, makes it difficult to apply these results in clinical practice. However, inappropriately high levels of graft constriction have been an important reason behind the failure of early external stents such as the eSVS [54]. Presumably, the truth lies somewhere in between the 2 extremes described by Angelini and Zilla and that both over- and under-constriction of the SVG lead to poorer outcomes. This has been an important point of development leading to the production of the second-generation devices such as the VEST support. It is also worth considering the measures by which patency is assessed. The majority of articles assessing the patency of CABG conduits angiographically assign an arbitrary cut-off value to denote stenosed or occluded grafts. Although this practice is widespread, it may not adequately take into account the structural variation existing within different grafts. Other studies have used different assessment systems. In a recent study investigating radial artery graft patency, a 4-point grading system was used, labelling grafts as either: perfectly patent, patent with irregularities, stringed or occluded [65]. Perfectly patent in this context refers to grafts that are completely uniform in nature. This is important when considering the pathophysiology of vein graft failure and the progression to non-uniformity that has been observed previously [32]. This may be one of the major processes behind eventual graft failure. Therefore, mechanisms that improve the uniformity of grafts may have a great impact on long-term outcomes. The positive effect of external stenting on graft non-uniformity has already been demonstrated at 1 year postoperatively [10], but it remains to be seen whether this effect is preserved in the long-term. Previous studies have also demonstrated a potential role for external stenting in grafts which would be otherwise deemed to be unsuitable for surgery; although with the lack of clinical trials directly comparing the same type of vessels stented and unstented, such studies are difficult to interpret [62, 63]. However, it is possible that external stents may have a role in increasing the acceptance of such conduits in the uncommon scenario where they are the only available option. CONCLUSION Despite clear preclinical evidence of the benefits of external stents, early studies in patients have so far yielded conflicting results of their potential benefit. Newer models of stents have been associated with comparable patency to non-stented grafts but with significant improvements in haemodynamic flow within the stents and reduced intimal hyperplasia. Ongoing studies will determine whether this translates into superior graft patency over the longer term. ACKNOWLEDGEMENTS We would like to acknowledge Eyal Orion, CEO of Vascular Graft Solutions (VGS), for general and financial support in conducting the VEST studies and for general and technical advice regarding this article. 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The potential role of external venous supports in coronary artery bypass graft surgery

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© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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Abstract

Abstract Despite the apparent superiority of arterial conduits for coronary artery bypass grafting (CABG), the long saphenous vein remains the most commonly used graft. The high failure rate of long saphenous vein grafts (SVGs) over time is therefore an important limiting factor for the long-term outcomes of CABG. Various methods to improve SVG patency have been proposed, although few have had a significant impact on clinical practice. External SVG supports have been a focus of research over the past 50 years, with their use intended to minimize well-documented pathophysiological changes that occur in the SVG following implantation into the coronary circulation. These devices have been trialled extensively in animal models to assess their impact on both the morphology and the function of vascular conduits. Recently, a number of studies have been conducted in patients, leading to a substantial development in their design and the accumulation of a large body of evidence attesting to their potential benefit in CABG. In this review, we briefly discuss the proposed mechanism of action of external SVG supports and then evaluate the results from animal studies and more recent research assessing their use in CABG patients. Finally, we conclude that newer models of external stents have the potential to improve long-term outcomes in SVG. Coronary artery bypass grafting, Cardiac, Saphenous vein, External stent, Revascularization INTRODUCTION Since its inception over 50 years ago [1], coronary artery bypass grafting (CABG) has been shown to have both symptomatic and prognostic benefits for coronary artery disease, and it remains the gold standard therapy for patients with multivessel and/or left main stem disease [2, 3]. In recent years, although there has been substantial evidence indicating that the use of arterial bypass grafts is associated with better clinical outcomes [4–9], autologous saphenous vein grafts (SVGs) remain the most frequently used conduit in CABG [5, 10]. In contemporary practice, approximately 80% of all grafts for CABG are venous. This is likely to be due to a number of factors, including abundance, ease of harvest and less susceptibility to competitive flow [11]. However, the high failure rate of SVGs over time is a limiting factor for the long-term outcomes of CABG [12, 13], and this correlates with an increase in major adverse cardiac events [14]. Although a significant number of studies have been conducted to identify the techniques that improve long-term patency, currently, only statins and aspirin are routinely administered to reduce vein graft failure [13, 15]. One particular concept that has been repeatedly explored over the last half century is the use of an external support for venous grafts [16]. Such supports have been shown to have a number of important effects and may decrease SVG failure rates; until recently, only few clinical trials of external stenting had been published [17]. This review will briefly consider the pathophysiology of SVG failure and evidence from animal models, before focusing on the recent clinical data from patients. Pathophysiology of saphenous vein graft failure The pathophysiology of SVG failure has been extensively described in the literature [12, 13] and is not the primary subject of this review. Early graft failure (a few hours postoperatively) is largely due to endothelial damage, thrombus formation and technical errors that can be modified by surgical technique [18–23]. The main cause of mid-term graft failure (occurring from 1 month to 1 year postoperatively) is intimal hyperplasia [12, 13, 24], first described in 1906 by the Nobel prize-winning surgeon Alexis Carrel [25]. The change in the haemodynamic forces upon implantation into the coronary circulation alters the shear stress along the vessel wall and causes the migration of vascular smooth muscle cells from the media into the intima, resulting in hyperplasia [12, 24, 26–31]. Late graft failure is due to degenerative changes resulting in atherosclerotic-like lesions developing from the hyperplastic intima [27]. Although structural non-uniformity (including intimal hyperplasia) is a feature of failed grafts, even long-term patent grafts demonstrate pathological abnormalities, with 81% of patent grafts displaying some degree of disease 15 years postoperatively [32]. Origin of external venous supports The use of external supports was first proposed by Parsonnet et al. [16] in 1963. It was hypothesized that this would reduce the diameter mismatch between the vein graft and the target vessel and minimize the extent to which the vein dilates on implantation into the higher pressure arterial system, possibly protecting against intimal damage and thrombosis. In their landmark study, the authors used a monofilament-knitted tube consisting of polyethylene, polypropylene and Teflon to cover a segment of the excised external jugular used to replace the common carotid artery of dogs. They demonstrated that the external stents were capable of limiting the dilatation of the vein graft, and after 63 days, 96% of the grafts supported with a stent were patent compared to all of the control grafts. Comparable results were reported in a later study by Karayannacos et al. [33] in 1978, who used a Dacron mesh prosthesis in a similar experimental model. The external stent was reported both to reduce the intimal hyperplasia and to increase the number of vasa vasorum in the graft wall, which are 2 important and interlinked pathological processes that occur post-SVG implantation. This is one of the first studies to link the use of an external support device with a structural change in the conduit. A limited human trial was then performed by Barra et al. [34] in 1987, with 4 SVGs supported by the stent being shown to be patent on angiography after 2 months. These findings served as ‘proof of principle’, preceding more robust studies. MATERIALS AND METHODS In June 2016, the PubMed database was searched using the terms ‘external stent’, ‘CABG’ and ‘saphenous vein graft’. Results were searched for further articles, and any other incidental articles discovered were also included in the analysis. RESULTS Mechanism of action and research in animal models Given that early graft failure is thought to be mainly due to the surgical preparation of the SVGs and technical errors during implantation, the main benefit of external supports is likely to be on the mid-term and the long-term graft failures. The mechanisms associated with improved graft success have been identified in a variety of animal models. These include changing the biomechanical properties of the graft and the biological interactions that result in venous wall remodelling, such as changing the pattern of vascular smooth muscle cell proliferation and migration and promoting the neovascularization of the adventitia [17]. It has also been demonstrated that the use of external stents can have a measurable impact on a number of different signalling pathways and, to some extent, restore normal signalling function in the grafted tissue [35, 36]. Furthermore, there is also evidence from ApoE*Leiden transgenic mouse and cholesterol-fed pig models that external stents may reduce late (atherosclerosis-mediated) graft failure [37, 38]. One of the most important postulated effects of external stents is the modulation of haemodynamic changes within the graft. In a series of reports by Zilla et al. [39–42], it was demonstrated that not only does the use of external venous supports reduce the degree of dilatation that SVGs undergo when transplanted but also their use is associated with a significant reduction in the intimal hyperplasia in a baboon model. Progressive constriction of the SVG lumen up to a >90% reduction significantly reduced graft intimal hyperplasia, with no effect on patency was shown [40]. These studies also highlighted a potential role for knitted rather than braided external devices, although this was not demonstrated in vivo [41]. Similar studies have been performed by Angelini et al. [43, 44]; however, in contrast to Zilla et al., this group found that less constrictive stents (6 and 8 mm) were associated with a reduction in intimal hyperplasia and constrictive stents (5 mm) resulted in an increase in intimal hyperplasia. However, such animal studies are unlikely to faithfully translate to CABG, with many using carotid or femoral artery interposition techniques. In response to this, Ben-Gal et al. [45] performed a small, proof-of-principle study in 2013, with the aim of accurately reproducing CABG in a sheep model. They performed coronary revascularization in 14 sheep, each receiving grafts to the left anterior descending artery and obtuse marginal artery. Each sheep received 1 VEST-supported graft with the other vein graft used as a control. They found that not only there was a significantly lower level of graft non-uniformity at 12 weeks (P < 0.002) but also the intimal layer of the supported grafts was smaller in the intervention group than the control (P < 0.02). Additionally, none of the stented grafts was thrombosed at the end of the study, but 3 of the non-stented grafts were thrombosed. Animal studies have also indicated a potential role for biodegradable external supports [46, 47]. However, unlike non-absorbable stents, these have yet to make the transition into human trials, and despite this promising early research, it remains to be seen whether they will have a substantial clinical impact. Clinical studies of external saphenous vein graft stenting Despite the relative wealth of animal data indicating a potential role for external supports in improving SVG patency, until recently, only limited numbers of good quality clinical data exist, assessing their potential benefit in patients. As discussed above, probably the earliest assessment into the use of an external stent in humans was performed in 1986 by Barra et al. [34]. However, the small number of patients and lack of properly randomized controls mean that early clinical results are difficult to generalize [48]. A number of larger studies have now been published, the results of which are summarized in Table 1. In 2007, a randomized trail of the Extent device (a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs) produced poor results [49]. In this study, 20 patients received an Extent-supported graft to either the right or the left coronary system. However, in all of the 17 patients returning for follow-up, the Extent-supported grafts were found to be thrombosed on angiographic assessment (6 and 19 months postoperatively), while all of the left internal mammary artery grafts and non-stented vein grafts remained patent. The authors attributed this to a combination of stent rigidity, oversizing and incomplete tube design leading to graft kinking either at the anastomoses or within the middle of the graft. Table 1: Summary of use of external stents for CABG in human trials Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory a Probability not stated in the original article. CABG: coronary artery bypass graft; N/A: not applicable; SVG: saphenous vein graft. Table 1: Summary of use of external stents for CABG in human trials Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory Study Device type Average follow-up Patency of stented SVGs, % (n) Patency of control SVGs, % (n) Comment Murphy et al. [49] Extent 6–19 months 0 (17) 100 (25) Rescigno et al. [48] ProVena 10 days 100 (1) N/A Schoettler et al. [50] eSVS mesh 9 months 27.8 (18) 85.7 (18) Genoni et al. [51] eSVS mesh 5 days 95 (20) N/A Klima et al. [52] eSVS mesh 7.2 ± 3.7 months 92 (23) N/A Rescigno et al. [53] eSVS mesh 1 month 87.5 (25) N/A Cumulative patency calculated from the initial number of patients having received a stented graft 6 months 42.7 12 months 34.1 Emery et al. [54] eSVS mesh 9–12 months 49 (73) 81 (73), P < 0.001 In the analysis of results, data were removed from one CABG site and from one size of stent 73 (33) 81 (73), P = NSa Taggart et al. [10] VEST 12 months Overall: 70 (30) 71.8 (39), P = 0.55 Left: 82.4 (17) 72.5 (24), P = 0.02 Right: 53.8 (13) 86.6 (15), P = 0.01 Suwalski et al. [55] eSVS mesh 4 weeks 100 (2) N/A Inderbitzin et al. [56] eSVS mesh 12 ± 0.1 months 76 (21) 100 (7) Taggart et al. [57] VEST 3–6 months 86.2 (29) 100 (14) All supported SVGs came from the right territory and all unsupported from the left territory a Probability not stated in the original article. CABG: coronary artery bypass graft; N/A: not applicable; SVG: saphenous vein graft. Despite the disappointing results, these findings were used to improve the design of subsequent external stenting devices, leading to the development of the eSVS mesh (Kipsbay Medical Inc., MN, USA) and then the VEST device (Vascular Graft Solutions LD, Tel Aviv, Israel). The eSVS mesh is an elastic nitinol knit designed to accommodate veins between 3.5 mm to 7.0 mm in diameter when distended and aims to reduce the diameter of the graft by up to 20%, attempting to more realistically match the size of a normal coronary artery [58]. The first data on patients were published in 2011 by Schoettler et al. [50]. Patients (n = 25) were randomly assigned to receive an eSVS-supported SVG to either the right coronary artery (RCA) or to the circumflex artery, with an untreated SVG acting as a control. This, therefore, allowed each patient to be effectively used as their own control for intrinsic characteristics that may influence graft survival such as blood pressure, lipid profile and glucose-handling profile. All patients also received an in situ left internal mammary artery graft to the left anterior descending artery. Angiographic patency of the grafted vessels in the 18 subjects who attended postoperative follow-up after 9 months was 28% for eSVS-supported vessels and 86% for the non-stented vein grafts, while the patency of the left internal mammary artery grafts was 100%. Subsequently, a number of other studies assessing the immediate and early patency of eSVS-supported vein grafts were published. In 2013, a study from Genoni et al. [51] found that early (5 days postoperatively) computed tomography (CT) angiographic patency was 95% in a population of 20 eSVS-supported grafts, with only 1 occluded venous anastomosis. Rescigno et al. [53] assessed the patency of 25 eSVS-supported SVGs grafted to the RCA, posterior descending artery or the obtuse marginal artery. It was found that cumulative patency of the grafts, as assessed by multidetector CT, was 87% after 1 month, 43% at 6 months and 34% at 12 months. Furthermore, this study found that graft occlusion rate was especially high for vessels that received the 3.5-mm mesh rather than the larger 4-mm mesh. A similar study in 2015 found that, in a total of 19 patients at an average of 12 ± 0.1 months after surgery, all arterial grafts and unmeshed SVGs were patent compared to just 76% of the stented SVGs [56]. A series of studies using the eSVS mesh have also been published by Klima et al. [52, 54] working at Kips Bay Medical. In 2014, they performed CT angiography on 11 patients with 23 stented SVGs at an average of 7.2 months postoperatively and reported a 92% patency rate. In 2015, they reported the results of their First-in-Man eSVS Mesh External Saphenous Vein Support Feasibility Trial, despite the trial having been initiated over 6 years previously [54]. This study compared graft patency at 9–12 months in stented and non-stented grafts in 90 patients at multiple operative centres. Stent sizes of 3.0, 3.5, 4.0 and 4.5 mm were used. Here, it was found that stenting reduced graft patency, with 49% (36 of 73) patency in the stented group and 81% (59 of 73) patency in the control group (P < 0.001). In further analysis, multiple data were excluded leading to their reporting of the final stented patency as 73% (24 of 33; statistically non-significant from the control group data). Both pre- and post-exclusion data are included in Table 1 for completeness. Despite the poor performance of the eSVS Mesh in clinical trials, a number of important lessons were learnt that contributed significantly to the development of second-generation devices. Firstly, it was found that aggressive overconstriction to 3 mm and 3.5 mm leads to high failure rates, despite success in the large stents [54]. As such, the minimum diameter should be larger than 4 mm. Secondly, a number of problems were identified with the fixation of the external stent to the conduit. The use of fibrin glue and the incorporation of the external stent to the anastomoses were required by the eSVS mesh to prevent device fraying and migration and to optimize the dimensional match with the SVG. However, the use of fibrin glue led to tissue damage, fibrosis and intimal hyperplasia and therefore should be avoided. Additionally, incorporating the external stent to the anastomoses required significant change in the grafting technique and was found to be associated with higher acute failure rates. A few years after the clinical trials for eSVS began, the VEST external stent was investigated in the clinical setting. VEST (Vascular Graft Solutions) consists of a cobalt-chrome braid with axial plasticity (allowing elongation) and radial elasticity (making the stent kink and crush resistant). Technical specifications of the Extent device, eSVS Mesh and VEST External Stent are compared in Fig. 1. Following the initial favourable results of the VEST device described by Ben-Gal et al. [45] in 2013, the first in-human trial was performed earlier this decade by Taggart et al. [10]. In the VEST trial, patients received 1 SVG supported by an external stenting device to either the right or the circumflex coronary territory, with 1 or more SVGs being left unstented for use as a control. The results demonstrated (in a total of 21 stented SVG and 23 non-stented) that there was a significant decrease in the mean intimal–medial area between the stented and the unstented groups (P = 0.04), with a small decrease in intimal thickness (P = 0.06). There was no change in the lumen diameter between the 2 groups (P = 0.60). The effects of different external stents on SVG diameter are summarized in Fig. 2. Figure 1: View largeDownload slide Photographs of the external stent devices. (A) The Extent device, a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs and featuring a flange to guide placement (image taken from The Extent Study). (B) The eSVS Mesh, made of highly flexible and kink resistant knitted nitinol wires and mounted on colour-coded fluorinated ethylene propylene (FEP) tubes. (C) The VEST External Stent, a braided kink-resistant stent made of plastically deformable (red arrow) and elastic (blue arrow) cobalt-chrome wires. The combination of wires provides VEST with axial plasticity and radial elasticity. Figure 1: View largeDownload slide Photographs of the external stent devices. (A) The Extent device, a macroporous Dacron sheath reinforced with polytetrafluoroethylene ribs and featuring a flange to guide placement (image taken from The Extent Study). (B) The eSVS Mesh, made of highly flexible and kink resistant knitted nitinol wires and mounted on colour-coded fluorinated ethylene propylene (FEP) tubes. (C) The VEST External Stent, a braided kink-resistant stent made of plastically deformable (red arrow) and elastic (blue arrow) cobalt-chrome wires. The combination of wires provides VEST with axial plasticity and radial elasticity. Figure 2: View largeDownload slide Schematic representation of the degree of size reduction of 3 different stents on 2 different sizes of vein graft. V1 represents an average vein graft of 4.5 mm in diameter and a wall thickness of 0.5 mm, while V2 represents a larger vein graft of 5.5 mm in diameter and 0.8 mm in thickness. (A) The Extent device. Models of stent were 6 mm and 8 mm in diameter, meaning that vein graft size was unaffected [V1 outer diameter (OD)  = 4.5 mm and inner diameter (ID)  = 3.5; V2 OD = 5.5, ID = 4]. (B) The eSVS Mesh. Large degree of constriction achieved with 3.5 mm and 4.5 mm stents leading to smaller lumens and folds forming (V1 OD = 3.5, ID = 2.5; V2 OD = 4.5, ID = 2.8). (C) The VEST Externa Stent. Milder constriction of vein grafts compared with the eSVS Mesh (V1 OD = 4.2, ID = 3.2; V2 OD = 5, ID = 3.5). Figure 2: View largeDownload slide Schematic representation of the degree of size reduction of 3 different stents on 2 different sizes of vein graft. V1 represents an average vein graft of 4.5 mm in diameter and a wall thickness of 0.5 mm, while V2 represents a larger vein graft of 5.5 mm in diameter and 0.8 mm in thickness. (A) The Extent device. Models of stent were 6 mm and 8 mm in diameter, meaning that vein graft size was unaffected [V1 outer diameter (OD)  = 4.5 mm and inner diameter (ID)  = 3.5; V2 OD = 5.5, ID = 4]. (B) The eSVS Mesh. Large degree of constriction achieved with 3.5 mm and 4.5 mm stents leading to smaller lumens and folds forming (V1 OD = 3.5, ID = 2.5; V2 OD = 4.5, ID = 2.8). (C) The VEST Externa Stent. Milder constriction of vein grafts compared with the eSVS Mesh (V1 OD = 4.2, ID = 3.2; V2 OD = 5, ID = 3.5). The overall patency was 70% for the stented grafts and 71.8% for the control grafts. Interestingly, although there was no difference between the graft failure rates overall, there was a significant decrease in graft failure with stenting in the grafts to the circumflex territory (18% in the stented group vs 28% in the unstented group, P = 0.01), yet an increase in graft failure to the right coronary territory (46% vs. 13%, P = 0.01). As transit time flow measurements had been satisfactory in all grafts prior to sternal closure, the authors postulated that graft failure may have been due to fixation of the device to the anastomoses whose geometry then altered with chest closure, particularly those on the right side because of the acute margin of the heart. A higher occlusion rate was also observed when metallic clips rather than suture ligature was used to occlude vein graft side branches. These metallic clips may have deformed the vessel within the stent particularly around the acute margin of the heart on the right side. In the same study, intravascular ultrasonography data demonstrated a benefit from the use of sutures over the metal clips with stented vessels for side branch ligation, with improvements being shown for plaque thickness (P = 0.04, suture ligation stented vs. non-stented) and a trend towards the same effect on plaque area (P = 0.05) [10]. In grafts in which sutures were used for ligation, a significantly greater proportion were classed as Fitzgibbon Type I (i.e. perfect graft patency) and having a greater degree of lumen uniformity. Additionally, 2 subsequent studies also assessed the population of patients included in the VEST study [59, 60]. These found, using optical coherence tomography, that mean lumen cross-sectional area was greater in the unstented grafts than in the stented grafts (P = 0.005) and that there was greater uniformity in the stented grafts. Furthermore, post hoc computational fluid dynamic analysis found that mean oscillatory shear index was significantly reduced compared with the non-stented group and that this correlated with the development of diffuse intimal hyperplasia (P = 0.01, n = 43). Taken together, these results suggest that altering the haemodynamic forces that the graft is subjected to can result in a significant reduction in SVG structural change. The promising results of the VEST trial led to the establishment of the VEST II study, in which the use of clip ligation and fixation of the external stent to the anastomoses were avoided [57]. In this study, it has been found that at 3–6 months postoperatively the patency rate of supported SVGs to the RCA was 86%, comparable with published historical data for unstented SVGs to the same territory [61]. This suggests that the use of external stents on the RCA is safe and that the previous reduction in patency was most likely due to surgical technique. Overall, these results appear to demonstrate that the external support with VEST is safe and that improved haemodynamics within the graft reduce intimal hyperplasia over the short term. Whether this will translate into improved graft patency over the long term is the subject of ongoing studies. Ongoing studies The results of previous studies involving the VEST device have led to the establishment of 2 further trials: VEST III and VEST IV. VEST III (NCT02511834) is a multicentre study that has recently completed recruitment of 180 patients. Patients received a stented SVG randomly assigned to either the right or the left coronary territory and a non-stented graft, acting as a control as well as an internal mammary graft. Major cardiovascular and cerebral events will serve as the study end-point, alongside graft patency as assessed by CT angiography at 6 months and 2 years. The final results are expected in the early 2019. On the other hand, VEST IV will examine the long-term outcomes of the VEST I study, assessing major cardiovascular and cerebral event and graft patency 5 years postoperatively. Two angiographic images of the same stented SVG at 2 different time points in the VEST studies are shown in Fig. 3. Figure 3: View largeDownload slide Images from the VEST studies. (A) Externally stented saphenous vein graft to the right territory 12 months after coronary artery bypass grafting. (B) The same graft 53 months after coronary artery bypass grafting. Figure 3: View largeDownload slide Images from the VEST studies. (A) Externally stented saphenous vein graft to the right territory 12 months after coronary artery bypass grafting. (B) The same graft 53 months after coronary artery bypass grafting. Further benefits of external stenting In addition to improving the failure rates of SVG in CABG, other research studies have demonstrated that external stents may allow the use of conduits that would have previously been deemed to be unsuitable for surgery. In a series of reports, Zurbrügg et al. [62, 63] investigated the use of an external ultrafine constrictive metal mesh to generate ‘biocompound’ grafts with varicose vein tissue. They demonstrated that such grafts had favourable patency rates after hospital discharge (41 of 43) and had similar patency rates to non-stented SVG after 3 years, thus potentially increasing the number of conduits the surgeon may utilize in CABG. DISCUSSION Vein graft failure is a major obstacle to the long-term benefit of CABG. However, momentum has been building behind the use of external venous support devices for SVGs. So far, a large body of preclinical data has demonstrated a favourable role for these devices in improving the morphological characteristics of vein graft failure and subverting some of the mechanisms by which pathophysiological remodelling processes occur. Although most of the animal models used are unlikely to be fully representative of CABG (especially those using carotid or femoral interposition models), these preclinical studies have paved the way for more recent trials in humans. Furthermore, they have also identified some of the key structural requirements of the external stent, such as porous stents that promote the adventitial revascularization of the vessel [47]. Recently, a number of clinical trials have been published assessing the benefit of external vein graft stenting in patients, with a satisfactory evidence of data demonstrating that this can minimize some of the pathophysiological changes seen in SVGs after use as a conduit for CABG, including a reduction in intimal hyperplasia [10, 45]. As would be expected with any new surgical technique, the method and materials of graft used have developed considerably over time. Despite poor results from early studies, it has been demonstrated that the newest generation of these devices are capable of providing equivalent patency rates to non-stented vessels, at least in the short to mid-term, and techniques are still being improved to ensure good patency results in all regions of the heart [10, 57]. The key question is the long-term outcome of stented vein grafts that remain perfectly patent at 1 year. Furthermore, for the use of external stents to become universally accepted, it will be necessary to conduct future long-term studies to demonstrate superior graft patency compared with non-stented controls, rather than just non-inferiority. One of the most important aspects of external venous supports is the size of the stent that would be appropriate for the grafted vessels. Previous work by Zilla et al. [64] found that an average diameter constriction of 27% would be sufficient to eliminate diameter irregularities in the vast majority of vein grafts, although this study only analysed human vein graft tissue prior to implantation. Studies on animals have yielded contradictory data on the most appropriate diameter of stent [40, 44], and this, therefore, makes it difficult to apply these results in clinical practice. However, inappropriately high levels of graft constriction have been an important reason behind the failure of early external stents such as the eSVS [54]. Presumably, the truth lies somewhere in between the 2 extremes described by Angelini and Zilla and that both over- and under-constriction of the SVG lead to poorer outcomes. This has been an important point of development leading to the production of the second-generation devices such as the VEST support. It is also worth considering the measures by which patency is assessed. The majority of articles assessing the patency of CABG conduits angiographically assign an arbitrary cut-off value to denote stenosed or occluded grafts. Although this practice is widespread, it may not adequately take into account the structural variation existing within different grafts. Other studies have used different assessment systems. In a recent study investigating radial artery graft patency, a 4-point grading system was used, labelling grafts as either: perfectly patent, patent with irregularities, stringed or occluded [65]. Perfectly patent in this context refers to grafts that are completely uniform in nature. This is important when considering the pathophysiology of vein graft failure and the progression to non-uniformity that has been observed previously [32]. This may be one of the major processes behind eventual graft failure. Therefore, mechanisms that improve the uniformity of grafts may have a great impact on long-term outcomes. The positive effect of external stenting on graft non-uniformity has already been demonstrated at 1 year postoperatively [10], but it remains to be seen whether this effect is preserved in the long-term. Previous studies have also demonstrated a potential role for external stenting in grafts which would be otherwise deemed to be unsuitable for surgery; although with the lack of clinical trials directly comparing the same type of vessels stented and unstented, such studies are difficult to interpret [62, 63]. However, it is possible that external stents may have a role in increasing the acceptance of such conduits in the uncommon scenario where they are the only available option. CONCLUSION Despite clear preclinical evidence of the benefits of external stents, early studies in patients have so far yielded conflicting results of their potential benefit. Newer models of stents have been associated with comparable patency to non-stented grafts but with significant improvements in haemodynamic flow within the stents and reduced intimal hyperplasia. Ongoing studies will determine whether this translates into superior graft patency over the longer term. ACKNOWLEDGEMENTS We would like to acknowledge Eyal Orion, CEO of Vascular Graft Solutions (VGS), for general and financial support in conducting the VEST studies and for general and technical advice regarding this article. 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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Dec 8, 2017

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