Management and Prevention of Saphenous Vein Graft Failure: A Review

Intra-operative manual disruption, as well as the use of hydrostatic dilatation can promote endothelium thrombus within the graft [49]. Souza et al. in 1996 developed the “no-touch” SVG harvesting, which involved removing the pedicled SVG with the perivascular tissue intact, thus avoiding direct contact and thus manual distension of the vein. This demonstrated improved graft patency and less neointimal hyperplasia compared with the standard harvesting technique [50, 51]. More recent randomised work has suggested that compared with conventional harvesting, the use of no touch harvesting, results in less intra-operative vascular smooth muscle cell activation, suggesting less likelihood of developing neointimal hyperplasia [52]. Other studies have even suggested that the use of no touch harvesting confers a significantly higher long term (>15 years) patency than conventional technique [53].

A number of studies have compared on-pump and off-pump CABG in terms of clinical outcomes and graft patency. Off-pump CABG involves surgery without a heart–lung machine or cardioplegia. In contrast during on-pump surgery the heart is motionless and empty, and the veins are unpressurized and contracted, which may create a more favourable condition for vascular anastomoses. Although several small initial studies found that after 1 year there was no difference in graft patency or clinical outcomes [54‐57], the larger randomized on/off bypass (ROOBY) trial suggested the off-pump group had worse 1-year composite outcomes (9.9% vs. 7.4%, P = 0.04) and poorer graft patency (82.6% vs. 87.8%, P < 0.01) [58]. These results have also been reported in other randomized studies [59, 60], as well as meta-analyses [61, 62]. The poorer graft patency rates in off pump CABG could be explained by a relative hypercoaguability compared with on-pump surgery, as cardiopulmonary bypass induces platelet dysfunction and coagulopathy which may be desirable in promoting SVG patency. Mannacio et al. conducted a single-centre prospective RCT study which randomized 300 patients undergoing off-pump CABG to either aspirin 100 mg (n = 150) or aspirin 100 mg plus clopidogrel (n = 150). Graft patency was assessed by CTA. DAPT use was associated with a reduced SVG occlusion rate (7.4% vs. 13.1%; P = 0.04) [115]. Current guidelines recommend 1 year of DAPT after off pump CABG to improve SVG patency [170].

The most basic SVG configuration is a single graft, which is composed of a single distal anastomosis for every proximal anastomosis. In contrast, sequential and composite grafting involves more than one distal anastomosis for every proximal anastomosis allowing for more complete revascularisation. The sequential anastomosis was first described by both Flemma and Bartley [63, 64] which, was initially termed the “snake” operation [65] with longitudinal side-to-side “snaking” grafts between recipient arteries. The major advantage of the sequential anastomosis is the larger combined perfusion bed resulting in lower coronary vascular resistance and thus higher flow velocity compared to single grafts [65, 66]. The composite graft has either a Y- or T-end-to-side graft constructed to allow perfusion of more than one distal target using a single graft. Composite grafts were first described in arterial grafts [67], but may also be constructed with SVG. The composite graft anastomosis must be performed accurately as an error can potentially threaten both distal outflows. Furthermore, there is risk of steal from one territory to another in the case of unbalanced flows.

The use of grafts with multiple distal anastomoses allows for a more complete revascularization in patients with multi-vessel CAD by using the limited SVG material more efficiently. Initially the use of multiple distal target SVGs was met with optimism, with early data suggesting that clinical outcomes were comparable or better than single distal target SVGs [63, 65, 66]. However, more recent larger data has suggested that patients who received a composite SVG were more likely to have graft failure and had a trend towards increased death, MI, or repeat revascularization in the 5 years after surgery [68]. This is particularly true in diabetics where both the end-to-side and side-to-side anastomosis may insert into a poor-quality target vessel [69, 70].

The luminal diameter of SVG are generally much larger than the coronary artery to which they insert, potentially creating a mismatch in blood flow. This can result in stasis and abnormal flow currents within the vein, damaging the vessel and potentially leading to thrombus formation. In addition, because veins lack the muscular wall that is seen in arteries, exposure to arterial pressure damages SVG resulting in further dilation and neointimal hyperplasia. External compression of SVGs prevents dilation and promotes down-sizing, which has been shown to encourage more arterial like healing and help reduce intimal hyperplasia [71, 72]. External compression can be achieved by a support device implanted during surgery. The eSVS^® mesh (Kips Bay Medical, Inc., Minneapolis, MN, USA) is a flexible extravascular nickel-titanium mesh, with early work suggesting that it reinforces SVGs; improving healing with less endothelial injury and neointimal hyperplasia formation compared to unsupported grafts [71, 72]. Recent non-randomised studies have suggested a clinical benefit. Genoni et al. reported safe application of the device in 20 patients who received the mesh supporting the SVG to the right coronary artery only. The patency of the grafts was assessed after 5 days by computerized tomography angiography (CTA), with a 95% success rate [73]. Klima et al. reported the 7-month follow-up in 12 patients who received an on-pump non-sequential eSVS^® mesh. The CTA patency rate was 92% [74]. Inderbitzin et al. reported the 1-year follow-up in 19 of 22 surviving patients who had received the mesh with overall 1-year CTA patency rate of 21 eSVS^® meshed SVGs being 76% [75]. Larger randomised studies with longer term follow-up are needed however before more widespread clinical adoption of such devices.

Very early studies assessing the use of aspirin (acetylsalicylic acid) for SVG patency were not encouraging. Pantley et al. in 1979 assessed 50 patients who were randomized to 24 controls, 13 receiving dual antiplatelet therapy (DAPT) with aspirin and dipyridamole, and 13 receiving warfarin [85]. Treatment began on the third post-operative day. Six months after surgery, all patients underwent ICA to assess graft patency. Twenty-seven of 33 grafts (82%) with DAPT and 29 of 37 grafts (78%) with warfarin (P < 0.5) were patent. The overall conclusion was that postoperative treatment either with DAPT or with warfarin failed to improve the patency. McEnany et al. in 1982 randomized trial compared warfarin, aspirin, and placebo treatment in post-CABG patients [86]. From an initial group of 216 patients, SVG patency was determined in 111 patients (220 grafts) from 1 to 47 months postoperatively. There was a trend toward better cumulative graft patency in patients given warfarin, but the results did not achieve statistical significance. In 1984 Chesebro et al. compared the combination of aspirin and dipyridamole to placebo in 407 patients with treatment beginning as early as 7 h post-surgery [87]. ICA at 1 month showed SVG patency significantly higher in the antiplatelet therapy cohort (98% vs. 90%, aspirin and dipyridamole vs placebo; P < 0.0001). Longer term follow-up of the same study also showed a significant difference in patency (89% vs. 77%, aspirin and dipyridamole vs placebo; P < 0.0001), suggesting that DAPT prevented late SVG occlusions in those patients whose grafts had been patent at 1 month (6% vs. 14% late occlusion rate, aspirin and dipyridamole vs. placebo; P = 0.02) [32]. The Veterans Administration Cooperative Study compared the use of different aspirin regimens in 772 CABG patients [88]. They administered either (1) aspirin, 325 mg daily, (2) aspirin, 325 mg three times daily, (3) aspirin plus dipyridamole (325 mg and 75 mg, three times daily), (4) sulfinpyrazone (267 mg three times daily), or (5) placebo (three times daily). Medications were taken to for 1 year. At 60 days post-surgery, 555 patients (1781 grafts) had undergone ICA, illustrating the following graft patency rates: aspirin once daily 93.5%; aspirin three times daily 92.3%; aspirin and dipyridamole three times daily 91.9%; sulfinpyrazone 90.2%. All aspirin-containing therapeutic regimens improved (P < 0.05) graft patency compared with placebo (85.2%). Operative mortality was 2.3%, without significant differences among treatment groups. Overall conclusions were early SVG patency was improved after CABG with all aspirin-containing drug regimens.

In addition to graft patency, the use of aspirin has also been shown to reduce in-hospital mortality without an associated increase in hemorrhage-related risks [89‐91]. Consequently, its use before CABG surgery is recommended in both European and American Guidelines [92, 93].

Clopidogrel is a thienopyridine-class antiplatelet that inhibits the platelet P2Y₁₂ adenosine diphosphate receptor and has been the mainstay of DAPT therapy for over 10 years. The benefit of DAPT in acute coronary syndrome (ACS) is well established [100‐102], with National guidelines recommend their use on presentation [99, 103, 104, 107]. This has been reflected in clinical practice with the Global Registry of Acute Coronary Events (GRACE) and GRACE2 registries reporting a significant increase in early use in patients with ACS [94, 105, 106]. This is despite the fact that 7–11% of ACS patients will subsequently require CABG [94, 95] and pre-surgery use of DAPT is associated with increased risk of postoperative death, reoperations for bleeding, blood loss, and need of blood transfusions [96]. Consequently, for ACS patients who subsequently need CABG, it is recommended to stop the second antiplatelet agent 5–7 days prior to CABG if possible [97‐99]. It is recommended that DAPT should be restarted after CABG when safe [99, 104, 107]. However, the risk of bleeding remains, leading to variability in DAPT resumption post CABG [108‐110].

There is a paucity of evidence in the literature directly comparing aspirin alone to DAPT with clopidogrel to improve SVG patency. Gao et al. [111] used a weekly alternating scheme in a prospective non-randomized cohort, and assigned 102 patients to clopidogrel 75 mg daily and 95 patients to clopidogrel 75 mg plus aspirin 100 mg daily after CABG. No significant difference in SVG patency as assessed by CTA was seen at 1 month or 1 year (1 month: 98.1% vs. 98.2%, P = 0.73; 1 year: 93.5% vs. 96.3%, P = 0.25, clopidogrel vs. clopidogrel plus aspirin). Sun et al. used partial blinding to compare postoperative clopidogrel 75 mg and aspirin 81 mg daily with aspirin 81 mg alone among 100 patients undergoing on-pump CABG [112]. Graft patency was assessed by CTA, for 79 patients at 1 month. There was no difference in SVG patency either among all grafts (92.9% vs. 95%, aspirin vs aspirin and clopidogrel; P = 0.43) or SVG alone (93.2% vs. 93.5%, aspirin vs. aspirin and clopidogrel; P = 0.92). Gao et al. in a RCT randomized 249 patients to either clopidogrel 75 mg plus aspirin 100 mg daily or aspirin 100 mg alone starting within 48 h of surgery [113]. No blinding or placebo control was used in this trial. SVG patency by CTA was assessed in 90% of patients at 3 months, with patency higher in the DAPT group compared to aspirin alone (85.7% vs. 91.6%, P = 0.04). The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial was a randomized, double-blind, placebo-controlled trial comparing aspirin 162 mg alone with DAPT using aspirin 162 mg and clopidogrel 75 mg [114]. The 113 patients underwent ICA and intravascular ultrasound (IVUS) at 1 year after surgery to assess for intimal hyperplasia. The use of DAPT did not significantly reduce the development of intimal hyperplasia compared with aspirin alone. Overall graft patency (95.2% vs. 95.5%, DAPT vs. aspirin alone; P = 0.90) and SVG patency (94.3% vs. 93.2%, P = 0.69) were not significantly different. Mannacio et al. conducted a single-centre prospective RCT study which randomized 300 patients undergoing off-pump CABG to either aspirin 100 mg (n = 150) or aspirin 100 mg plus clopidogrel (n = 150). Graft patency was assessed by CTA. DAPT use was associated with a reduced SVG occlusion rate (7.4% vs. 13.1%; P = 0.04) [115]. In 2017 Rafiq et al. reported a randomized trial comparing DAPT to aspirin monotherapy in hypercoaguable patients undergoing CABG and found no difference in SVG patency rates at 3 months [116] Based on this evidence current guidelines recommend 1 year of DAPT after CABG in patients presenting with ACS or who undergo off pump surgery, however the benefits of routine DAPT after CABG have not been well established [117].

Little is known about the use of an oral anticoagulant to prevent SVG failure and improving clinical outcomes. It has been suggested that patients taking warfarin who undergo CABG have no higher rate of bleeding compared to controls, [118] and warfarin administration concomitantly with an antiplatelet agent dramatically reduces the incidence of ischemic stroke associated with postoperative atrial fibrillation [119]. Most trials assessing the use of anticoagulants to prevent SVG failure in CABG are old, have small numbers and were in direct comparison to antiplatelet therapy [85, 86, 120‐122]. However, Gohlke et al. [123] randomized 89 patients to a vitamin K antagonist, (starting on the seventh postoperative day) and 84 patients to no anticoagulation. ICA follow-up found graft patency after surgery was 90.4% in the treatment group and 84.6% in the control group (P < 0.015). The Post Coronary Artery Bypass Graft Trial was a two-by-two factorial design which assigned 1351 CABG patients to aggressive or moderate treatment to lower LDL cholesterol levels and to treatment with warfarin or placebo [124]. Angiographic follow up at 4 years showed no improvement in graft patency between the warfarin and placebo groups, although aggressive lowering of cholesterol did reduce the progression of atherosclerosis. Other trials also did not show any clinical advantage of warfarin over antiplatelets [125] and consequently the use of anticoagulants post CABG is not supported in guidelines [117] (Table 1).

The evidence supporting newer, more potent antiplatelet agents comes from two main studies, PLATO and TRITON-TIMI 38 [102, 126]. The PLATO study was a large randomized trial comparing DAPT with ticagrelor as opposed to clopidogrel, concluding that in ACS patients, ticagrelor significantly improved clinical outcomes without an increase in the rate of overall major bleeding [102]. In PLATO, 1584 patients (12%) underwent CABG. “Major Fatal/Life-Threatening” bleeding was approximately 42% in both treatment groups. Fatal CABG bleeding occurred uncommonly, six patients in each treatment group (0.8% and 0.7% of CABG patients on ticagrelor and clopidogrel, respectively). Further subgroup-analysis in the PLATO study showed that the use of ticagrelor compared to clopidogrel was associated with better clinical outcomes both in ACS patients with prior CABG and those who underwent redo CABG [102, 127, 128]. In TRITON-TIMI 38 patients that underwent CABG after presenting with ACS also had a significantly reduced all-cause mortality with prasugrel compared with clopidogrel (2.31% vs. 8.67% adjusted odds ratio: 0.26; P = 0.025) in the short term, although there was an increase in observed bleeding, platelet transfusion, and surgical re-exploration for bleeding in patients randomized to receive prasugrel [126]. A recent retrospective observational study compared the use of dual antiplatelet therapy with aspirin and ticagrelor (n = 1266) or clopidogrel (n = 978) in ACS patients who underwent CABG [129]. The incidence of CABG-related major bleeding was high when ticagrelor/clopidogrel was discontinued <24 h before surgery. Discontinuation 3 days before surgery, as opposed to 5 days, did not increase the incidence of major bleeding complications with ticagrelor, but increased the risk with clopidogrel. The overall risk of major CABG-related bleeding complications was lower with ticagrelor than with clopidogrel [12.9 vs. 17.6%, adjusted OR 0.72 (95% CI 0.56–0.92), P = 0.012]. Based on these data current guidelines support DAPT after CABG in patients presenting with ACS with either clopidogrel, prasugrel or ticagrelor (preferred over clopidogrel) [117].

As with native coronary arteries, SVG atherosclerosis correlates with serum lipid levels with the use of statins seemingly slowing disease progression. The lipid lowering aspect of the Post Coronary Artery Bypass Trial involved randomization to either aggressive or moderate cholesterol management [123]. ICA at 4 years highlighted that aggressive cholesterol treatment improved SVG patency (occlusion rates of 10% vs. 21%, P < 0.0001). Longer term follow up showed aggressive management was associated with a significant reduction in repeat revascularization and adverse cardiovascular events [130]. Makuuchi et al. randomly assigned 303 post CABG patients to either pravastatin or control. ICA were obtained at baseline and at the end of 5-year follow-up in 182 (60%) patients [131]. Although there was no significant difference in the quantitative ICA measurements between the two groups, a global change score indicated a significant pravastatin-mediated reduction in plaque progression (P < 0.01). A post hoc analysis of The CASCADE study assessed the impact of statin therapy on graft patency and neointimal hyperplasia, comparing these to different levels of LDL [132]. Twelve-month graft patency was higher for patients with LDL levels <100 mg/dL (96.5%) compared with levels >100 mg/dL (83.3%, P = 0.03). However, no improvement in graft patency was noted with further LDL reduction to less than 70 mg/dL (P = 1.00). In addition, consistent statin use throughout the trial period was independently associated with less SVG neointimal hyperplasia documented by IVUS at 12 months (P = 0.04).

A recent meta-analysis of eight studies and 6645 patients post CABG showed that aggressive statin therapy, compared to moderate statin therapy, decreased graft atherosclerotic progression by 39% with associated clinical benefits of reduced myocardial infarction [95% CI 0.66–0.95; risk ratio (RR) = 0.80; and 95% CI 0.66–0.85; RR = 0.75] and lower risk of cardiac death (95% CI 0.64–1.08; RR = 0.83) [133]. Other lipid lowering drugs have also been shown to have clinical benefits post CABG [134‐137]. However, statins have both cholesterol lowering and anti-inflammatory properties. Their anti-inflammatory effect reduces vascular oxidative stress and improves nitric oxide bioavailability, thus reducing vascular thrombosis and improving SVG patency [138‐140]. In addition, hyperlipidemia has also been identified as one of the most potent risks of increasing intimal proliferation and subsequent fibrous hyperplasia [8]. As such the early use of statins is recommended in all CABG patients unless contraindicated [141].

Gene therapy in a relatively new approach to preventing SVG failure and its use is still in the developmental stage. The aim is to inhibit the cellular proliferation that causes intimal hyperplasia thus preventing SVG failure. Bypass grafting presents an ideal opportunity for gene therapy, as SVGs can be treated ex vivo, thus maximizing gene delivery, minimizing the potential for systemic toxicity, and targeting the pathogenesis of vein graft disease at its onset [142]. Initial optimism was seen after PREVENT II, a phase IIb trial of 200 patients undergoing CABG, randomized patients to either placebo or edifoligide, a transcription factor decoy that modulates smooth muscle cell proliferation. The treatment group demonstrated a 30% relative reduction in SVG critical stenosis by ICA and a 30% reduction in total wall volume by intravascular ultrasound [143]. This was then followed by the much larger trial PREVENT IV in which 3014 patients undergoing CABG were enrolled [144]. Harvested SVG were randomly assigned to ex vivo treatment with edifoligide, or saline solution placebo before grafting. At follow-up ICA 12–18 months after the operation, there was no difference in the rate of graft occlusion (41.8% in the edifoligide group vs. 41.7% in the placebo group; P = 0.97) or the primary end-point of death and SVG occlusion, or the composite clinical end-point of death, MI or revascularization. Currently gene therapy remains an area of research, but has no role in improving SVG patency.