Abstract: Background. The presence of intermediate “non-obstructive” saphenous vein graft (SVG) lesions is a strong predictor of cardiac events. We wanted to assess the efficacy of sealing these SVG lesions with drug-eluting stent (DES) implantation for reducing major adverse cardiac event (MACE) rate. Methods. The present analysis is based on the pooled data from the VELETI and VELETI II randomized trials. Patients with at least 1 intermediate SVG lesion (30%-60% diameter stenosis) were randomized to DES implantation (SVG-DES) or medical treatment (SVG-MT). The primary outcome was the first occurrence of MACE, defined as the composite of cardiac death, myocardial infarction, or coronary revascularization related to the target SVG. Results. A total of 182 patients were included (mean age, 70 ± 9 years), with 90 and 92 patients allocated to the SVG-DES and SVG-MT groups, respectively. After a mean follow-up of 4 ± 1 years, patients in the SVG-MT group exhibited a higher rate of MACE related to the target SVG (23.9% vs 17.8% in the SVG-DES group; P=.04) and MACE related to the target SVG lesion (21.7% vs 12.2% in the SVG-DES group; P<.01). In the multivariable analysis, a higher total cholesterol value at baseline (P=.04) was the only independent predictor of SVG disease progression leading to clinical events. Conclusions. In patients with prior coronary artery bypass grafting and intermediate non-obstructive SVG lesions, plaque sealing with DES reduced the incidence of MACE related to SVG disease progression. A higher cholesterol level was the main predictor of SVG disease progression leading to clinical events in these patients.
J INVASIVE CARDIOL 2019;31(11):E308-E315.
Key words: drug-eluting stents, long-term follow-up, meta-analysis, myocardial infarction, percutaneous coronary intervention, saphenous vein graft
Saphenous vein grafts (SVGs) are the most common conduits used in coronary artery bypass graft (CABG) surgery. However, the rates of graft failure secondary to SVG occlusion are as high as 10% and 50% at 1 and 10 years after CABG, respectively.1-3 Furthermore, SVG obstruction frequently leads to an acute coronary syndrome with high mortality and complication rates.3,4 Several studies have identified the presence of intermediate “non-obstructive” SVG lesions as a strong predictor of cardiac events at mid-term follow-up.5-11 The VELETI and VELETI II trials were both randomized prospective studies assessing the efficacy of sealing intermediate SVG non-obstructive lesions with drug-eluting stent (DES) implantation in post-CABG patients.11-13 VELETI was a pilot trial that showed the association of SVG plaque sealing with a reduction of disease progression and a tendency toward a lower rate of cardiac events at 1-year and 5-year follow-up.12,13 The VELETI II trial was designed to demonstrate the efficacy of SVG plaque sealing in reducing the rate of major adverse cardiac event (MACE) related to the target SVG.14 However, the trial was prematurely stopped due to slow recruitment rate, preventing the investigators from drawing any definite conclusions regarding the potential benefits of the SVG plaque-sealing strategy. The purpose of this pooled analysis including the VELETI and VELETI II trials was to determine the impact of plaque sealing in patients with intermediate SVG lesions on clinical events over the duration of follow-up (minimum of 2 years).
The present analysis is based on the pooled individual data from the VELETI and VELETI II trials.12-14 Both studies were approved by the local ethics committee of each participating center and patients provided written informed consent to participate in the trials. We were granted access to anonymized patient-level data from these two investigations. Data on baseline patient characteristics, procedure information, and clinical events were cross-checked against previous publications and then pooled and analyzed in a single dataset. The design details of these studies have been previously published.12-14 Briefly, patients ≥18 years old with at least 1 intermediate SVG lesion (30%-60% diameter stenosis by visual estimation) that was not the culprit lesion responsible for the clinical syndrome of the patient were eligible. Patients were randomized (1:1) to either DES implantation of the moderate SVG lesion or medical treatment alone. The SVG target-lesion angioplasty was performed using standard techniques with either paclitaxel-eluting stents (Taxus Element, Express, or Ion stents [Boston Scientific]) or everolimus-eluting stents (Promus Element [Boston Scientific]). The use of a FilterWire EX (Boston Scientific) distal to the target lesion during the angioplasty procedure was recommended if technically feasible. Patients were followed by telephone or clinic visit at 30 days, 180 days, and 1 year, as well as yearly thereafter up to 5 years. The occurrence of adverse events, cardiac symptoms, and medication compliance was assessed at each follow-up visit. The events were adjudicated by an independent event-adjudication committee.
Study outcomes. The primary outcome was the first occurrence of MACE, defined as the composite of cardiac death, myocardial infarction (MI), or coronary revascularization related to the target SVG over the duration of follow-up. The secondary outcomes were MACE related to the target SVG lesion and overall (related or not to the SVG) MACE. Any death was considered cardiac related unless proved otherwise. All randomized patients were included in the main analyses. Patients were included in the treatment group to which they were originally allocated by an interactive voice response system (intent-to-treat analysis).
Statistical analysis. The databases from the two trials were combined for an overall pooled analysis. Continuous variables were compared using the Student’s t-test or Wilcoxon’s rank-sum test depending on variable distribution. Categorical variables were compared using the Chi-squared test or Fischer’s exact test, as appropriate. Differences in clinical events between groups were evaluated using the Cox proportional hazard model. Univariable and multivariable Cox proportional hazard models were used to determine the predictive factors of MACE at follow-up. The variables exhibiting a P-value <.10 in the univariable analysis were included in the multivariable model. Kaplan-Meier curves were used to present the cumulative incidence of MACE over time according to the treatment allocation. All tests were two-sided and a P-value of <.05 was considered statistically significant. All analyses were performed using the statistical package SAS, version 9.1.3 (SAS Institute).
A total of 182 patients with previous CABG including at least 1 SVG with a clinical indication for coronary angiography were included. Of these, ninety were randomized to SVG-DES and 92 patients to SVG-MT. Five patients in the SVG-DES group did not finally receive the allocated treatment, and all patients in the SVG-MT group received the allocated treatment. Patient flow through the VELETI + VELETI II trials is shown in Figure 1. The baseline clinical and angiographic characteristics of the study population according to the allocated treatment are shown in Table 1. Mean patient age was 70 ± 9 years and 160 (88.0%) were men. Median time from CABG was 12 years (range, 8-16 years), and the vast majority of patients (92.0%) were receiving statin therapy, with mean total cholesterol and low-density lipoprotein (LDL) levels of 136.5 ± 36.3 mg/dL and 67.9 ± 29.5 mg/dL, respectively. All patients had at least 1 intermediate SVG lesion, with a mean diameter stenosis (as determined by quantitative coronary angiography) of 41 ± 11%. There were no differences between groups in baseline clinical and angiographic characteristics. In the SVG-DES group, most patients (86.4%) received a paclitaxel-eluting stent, and a FilterWire during SVG-PCI in 37.7% of patients.
The outcomes data classified according to the randomization group are shown in Table 2. There were no early (30-day) events in the SVG-MT group and 1 patient in the SVG-DES group had a periprocedural MI following SVG angioplasty. After a mean follow-up of 4 ± 1 years, a total of 38 patients (20.9%) had at least 1 MACE related to the target SVG. There was a higher rate of target SVG events in the SVG-MT group compared with the SVG-DES group (23.9% vs 17.8%, respectively; hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.02-2.36; P=.04). The differences between groups remained significant when considering only MACE related to the target SVG lesion (21.7% in the SVG-MT group vs 12.2% in the SVG-DES group; HR, 1.99; 95% CI, 1.23-3.23; P<.01), and this was mainly driven by a higher target-lesion revascularization rate in the SVG-MT group (19.6% vs 11.1% in the SVG-DES group; HR, 1.99; 95% CI, 1.09-3.63; P=.03). There was only 1 cardiac death related to the target SVG, which occurred in a patient with unstable angina caused by in-stent restenosis. The patient had successful revascularization with implantation of a second DES, but died suddenly 3 weeks after this intervention. Among the 9 MI events related to the target SVG in the SVG-DES group, one was periprocedural, four were due to stent restenosis, one was related to late stent thrombosis, and 3 were not related to the target SVG lesion (SVG disease progression in unstented segments). In the SVG-MT group, the 8 MI events related to the target SVG were due to the progression of the target SVG lesion. Among the 16 target SVG revascularization events in the SVG-DES group, ten were related to stent restenosis and 6 were related to SVG disease progression of unstented segments. Among the 20 target SVG revascularization events in the SVG-MT group, eighteen were related to disease progression at the level of the target SVG lesion, and 2 were related to disease progression in other SVG segments. The Kaplan-Meier curves for clinical events up to 5-year follow-up related to the target SVG and target SVG lesion are shown in Figures 2 and 3, respectively. The rates of global MACE (related or not to the target SVG) were similar between groups (45.7% in the SVG-MT group vs 38.9% in the SVG-DES group; HR, 1.27; 95% CI, 0.80-2.0; P=.31), as well as global death, MI, and revascularization, evaluated individually (Table 2 and Figure 4).
The factors associated with clinical events over the follow-up period are shown Table 3. In the multivariable analysis, a higher total cholesterol level was the only factor associated with an increased risk of clinical events related to the target SVG (1.10 for each increase of 10 mg/dL; 95% CI, 1.01-1.20; P=.04), whereas a higher cholesterol level, a younger age, and the absence of stenting at the level of the intermediate SVG lesion were associated with an increased risk of events related to the SVG target lesion. Higher cholesterol levels and a younger age also determined a higher risk of global events over the follow-up period.
This study showed that in patients with intermediate non-obstructive SVG lesions at a median of 12 years post CABG, sealing the intermediate SVG lesion with a DES was associated with a reduction in clinical events after a mean follow-up of 4 years. The vast majority of events in the SVG-MT group were related to the progression of the intermediate SVG lesion. Higher baseline cholesterol values determined an increased risk of SVG disease progression leading to clinical events over the follow-up period.
The results of this study are in agreement with those of prior studies showing the rapid progression of intermediate SVG lesions leading to a high rate of cardiovascular events.5-11 Thus, about one-fourth of the patients in the SVG-MT group had a MACE related to target SVG failure, and the events were due to the progression of the intermediate SVG lesion in 91% of cases, confirming the major impact of such lesions on the high burden of cardiovascular events in these patients. Also in accordance with previous studies, SVG disease progression led to an acute coronary syndrome in most patients, and MI accounted for more than one-third of the events. Importantly, this rapid progression occurred despite appropriate statin therapy in most patients, with mean total cholesterol and LDL levels below 140 mg/dL and 70 mg/dL, respectively.
The accelerated process of atherosclerosis progression observed in intermediate SVG lesions may represent a good model for evaluating a mechanical plaque-sealing strategy. However, SVG stenting has been associated with a high rate of periprocedural events,15 generating concerns about the safety of implementing mechanical plaque sealing in SVGs. Importantly, previous studies showed that most periprocedural events during SVG-PCI occurred in those lesions with the highest plaque burden or with complex features such as thrombus or ulceration.16-18 In contrast, the results of this meta-analysis showed a very low rate of periprocedural events associated with stenting intermediate SVG lesions without complex features, with a periprocedural event rate as low as 1% related to angioplasty with DES implantation of the intermediate SVG lesion.
The present study showed that sealing intermediate SVG lesions of old SVGs (median, 12 years old) with a DES reduced the risk of major cardiovascular events by 35.0% at a mean follow-up of 4 years. This was mainly related to a significant (up to 50%) reduction in those events related to the intermediate SVG lesion, particularly SVG revascularization over the follow-up period. Interestingly, the reduction of SVG-related events was maximal during the initial 2 years (see Figure 2), and subsequently attenuated after this period up to 5-year follow-up. This was partially due to the 11% SVG repeat revascularization rate secondary to DES clinical restenosis (mainly >2-year follow-up) in most cases, partially reducing the initial clinical benefit that had been observed with the SVG stenting strategy. First- and second-generation DESs have been shown to be superior to bare-metal stents with respect to angiographic and clinical restenosis following SVG-PCI.19-21 However, the late restenosis phenomenon following SVG stenting has been described with the use of first-generation DESs and it is unclear at this time whether or not this may also occur with the use of newer-generation DESs.22-24 Reducing late stent restenosis appears to be a key factor for maintaining the clinical benefits of intermediate SVG lesion plaque sealing over time, and future studies should evaluate the potential benefits of newer-generation DESs in this setting.
In addition to late restenosis, the progression of SVG disease in unstented segments was responsible for the clinical events in about one-third of the patients in the SVG-DES group. In fact, higher baseline cholesterol levels were the main factor determining SVG disease progression leading to clinical events in the global population including SVG-DES and SVG-MT patients. These results are in line with previous studies showing that cholesterol level is a strong predictor of SVG atherosclerosis progression despite mean LDL levels <90 mg/dL.5-7 Lipid-lowering therapy has been proven to be the most effective medical therapy to retard SVG disease progression, and the vast majority of patients included in the VELETI trials were receiving statin therapy, leading to mean LDL levels <70 mg/dL.25,26 Thus, further reductions in cholesterol levels may be embraced as a further step in trying to prevent SVG atherosclerosis progression in old SVGs with intermediate lesions. These data may inform future studies with the use of newer-generation lipid-lowering drugs, such as lipoprotein convertase subtilisin/kexin type-9 inhibitors in the high-risk subset of patients with old SVGs and intermediate SVG lesions.
Study limitations. Although this analysis includes the 2 currently available prospective randomized trials assessing the efficacy of stenting intermediate non-obstructive SVG lesions with DES options, the overall study size remains relatively small, and is likely under-powered for the efficacy endpoint (prevention of MACE). The results of this pooled analysis should therefore be interpreted as exploratory. Also, as there was no systematic coronary angiography during follow-up, some cases of late silent SVG obstruction may have been missed, and the rate of SVG failure may have been under-estimated.
Patients with intermediate non-obstructive lesions in old SVGs are at very high risk of SVG disease progression leading to cardiovascular events at mid-term follow-up. Sealing such lesions with DES implantation (mainly paclitaxel-eluting stents) was safe and reduced the risk of SVG-related events after a mean follow-up of 4 years. These results should stimulate further studies in the field, particularly with the use of newer-generation DES options. Also, more aggressive lipid-lowering therapies need to be evaluated to reduce SVG atherosclerosis progression and cardiovascular events in this high-risk population.
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From 1Quebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada; 2Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada; 3Vancouver General hospital, Vancouver, British Columbia, Canada; and 4Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jolly reports institutional research grants from Boston Scientific. Dr Maes reports grant support from the Fondation Saint-Luc (Brussels, Belgium). Dr Rodés-Cabau reports grant support from the Cannectin Network and an unrestricted grant from Boston Scientific Corporation; research chair of the “Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 11, 2019, provisional acceptance given April 22, 2019, final version accepted May 14, 2019.
Address for correspondence: Josep Rodés-Cabau, MD, Quebec Heart & Lung Institute, Laval University, 2725 Chemin Ste-Foy, G1V 4G5, Quebec City, Quebec, Canada. Email: email@example.com