Comparison of Drug-Eluting Stents With Bare-Metal Stents for PCI of Saphenous Vein Graft Lesions: Systematic Review and Meta-Analysis

Abstract: Background. The superiority of drug-eluting stent (DES) implantation over bare-metal stent (BMS) implantation in saphenous vein graft (SVG) lesions is controversial, with significant heterogeneity demonstrated in the literature. Methods. A study search was conducted from January 2003 to October 2015, and identified four randomized controlled trials (RCTs) and 35 observational studies comparing DES vs BMS in SVG interventions. Clinical endpoint data were abstracted and analyzed by combining the odds ratios (ORs) of individual studies into a pooled OR using a random-effects model. Results. The meta-analysis included 39,213 patients in the DES group and 26,461 patients in the BMS group. Patients who underwent percutaneous coronary intervention with DES had lower major adverse cardiovascular event (MACE) rate (OR, 0.63; 95% confidence interval [CI], 0.54-0.74; P<.001), lower all-cause mortality rate (OR, 0.76; 95% CI, 0.69-0.84; P<.001), lower target-vessel revascularization (TVR) rate (OR, 0.70; 95% CI, 0.57-0.86; P<.001), and lower target-lesion revascularization (TLR) rate (OR, 0.64; 95% CI, 0.50-0.84; P<.01), with no difference in stent thrombosis (OR, 0.90; 95% CI, 0.61-1.32; P=.58). There was no significant reduction in myocardial infarction (MI) in the DES group compared with the BMS group (OR, 0.87; 95% CI, 0.73-1.04; P=.13). Benefits were sustained at long-term follow-up of 36 months without an increased risk of early and/or late stent thrombosis. The observed benefit for MACE was only seen in observational studies (OR, 0.63; 95% CI, 0.53-0.75; P<.001) with no benefit in RCTs (OR, 0.53; 95% CI, 0.20-1.40; P=.20). Conclusions. The results suggest that patients with DES in comparison with BMS implantation for PCI to SVG lesions had lower MACE, all-cause mortality, and TVR rates, without a significant reduction in MI and TLR.

J INVASIVE CARDIOL 2016;28(12):E139-E169. Epub 2016 November 15.

Key words: stenting, drug-eluting stent, DES, bare-metal stent, BMS

Percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) lesions comprises up to 15% of all coronary artery interventions.^1,2 Approximately 50% of all vein grafts develop significant stenosis or complete occlusion within 10 years of implantation.^1,3 Given the high-risk nature of repeat coronary artery bypass graft (CABG) surgery in these patients, PCI is preferred to restore vessel patency and improve symptoms.^4,5 Drug-eluting stent (DES) implantation has demonstrated superiority to conventional balloon angioplasty and bare-metal stent (BMS) implantation for the treatment of de novo in-stent restenosis in native coronary artery lesions.⁶ Despite the wealth of evidence, the superiority of DES to BMS implantation in SVG lesions has shown significant heterogeneity in clinical outcomes. 

The DELAYED-RRISC (Death and Events at Long-term follow-up Analysis: Extended Duration of the Reduction of Restenosis In Saphenous vein grafts with Cypher stent) randomized trial of 75 patients with sirolimus DES vs BMS showed a trend toward increased repeat revascularization and increased mortality in the DES group at 6 months.⁷ In contrast, the SOS (Stenting of Saphenous Vein Grafts) randomized trial of 80 patients demonstrated that patients receiving pac-litaxel DES had less myocardial infarction (MI), target-lesion revascularization (TLR), and target-vessel revascularization (TVR), and a trend toward decreased stent thrombosis (ST) compared with those receiving BMS.⁸ Since these trials, observational studies and registry data have been published with a focus on long-term clinical endpoints.⁹ Therefore, we performed an updated meta-analysis of randomized controlled trials (RCTs) and observational studies to compare the efficacy and safety of DES vs BMS to treat SVG lesions.

Methods

Study selection. A systematic search was conducted to retrieve RCTs and observational studies that investigated the efficacy and safety of DES vs BMS for the treatment of SVG lesions. The study search was conducted through PubMed and EMBASE for studies from January 2003 (the advent of DES) to October 2015. The following keywords were used: “saphenous vein graft,” “drug-eluting stent,” and “bare-metal stent.” The related articles and reference lists of studies were also reviewed to identify additional relevant publications by manual search. An electronic search of abstracts available online was also reviewed from the annual congresses of the Canadian Cardiovascular Congress, European Society of Cardiology, American College of Cardiology, and the American Heart Association.

Inclusion criteria for the studies included the following: (1) RCTs and observational studies; (2) patients with de novo SVG lesions amenable to PCI; (3) patients eligible for both DES and BMS implantation; and (4) studies published in the English language. Eligibility assessment and data extraction were carried out independently by two investigators (WM and ME) with discrepancies resolved by a third investigator (SG). 

Study outcomes. The primary outcome was major adverse cardiovascular event (MACE) rate. Secondary outcomes of interest included all-cause mortality, MI, TVR, TLR, and ST. The definitions of the primary outcome of MACE and the secondary outcomes of MI, TLR, TVR, and stent thrombosis according to each study are included in Table 1. When MACE rate was not specifically reported, individual study endpoints were combined for a pooled estimate. We also performed a stratified analysis of endpoints according to follow-up duration post PCI (≤12 months, between 12 to 36 months, and ≥36 months). We performed a separate threshold analysis to assess the use of embolic protection devices (EPDs) and the relationship with MACE.

Data extraction and study quality. The included studies were independently reviewed for eligibility and quality assessment, and abstracted by two evaluators (WM and ME). The quality assessment was done using a modified Newcastle-Ottawa Quality Assessment Scale for observational studies, and the Jadad score for randomized studies (Supplementary Table 2; see .Pdf). Any discrepancies in data abstraction and study inclusion were resolved by consultation with a third author (SG). 

Statistical analysis. The meta-analysis was conducted by combining the odds ratios (ORs) of individual studies into a pooled OR using a random-effects model. Summary ORs were calculated and reported with 95% confidence intervals (CIs). A P-value <.05 was deemed indicative of a statistically significant difference. We tested for heterogeneity using the Chi² test and the I² test. Funnel plots were constructed to assess for publication bias. The analyses were performed with RevMan 5.1 software (Review Manager [RevMan] version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2011).

Results

Study selection. Figure 1 outlines the search strategy, which yielded 429 results. Of these, 63 studies were duplicate studies, which were removed. A total of 366 studies were screened, 281 were excluded upon review of the title and abstract, with 46 studies excluded after careful review of the full text. Of these studies, 28 did not include the outcome of interest, 5 were missing a cohort arm for comparison,^10-14 3 included arterial grafts in the study population,^15-17 2 were post hoc analyses,^18,19 2 were abstracts,^20,21 and 3 included the same study population as prior studies.^22-24 Three papers were published for the Stenting of Saphenous Vein Grafts (SOS) trial;^8,25,26 only the study with the longest post-PCI follow-up was included in the analysis.²⁶ Thus, 39 studies with 65,674 patients were eligible for inclusion in the systematic review. 

Characteristics of included studies. Four randomized trials^7,26-28 and 35 observational studies^9,13,29-61 were included, with patients enrolled from 2005 to 2015. There was no evidence of publication bias (Figure 2). As detailed in Table 1, all studies included patients with first-generation DES; 5 studies included patients with exclusively paclitaxel-eluting stents,^{8,25,26,32,35} 4 studies included exclusively sirolimus-eluting stents,^7,31,33,34 7 studies did not specify the type of DES,^{9,51,52,57,58,61} and 26 studies included patients with both paclitaxel-eluting and sirolimus-eluting stents. Five studies included patients with second-generation DESs (everolimus-eluting and zotarolimus-eluting)^{45,54,55,59,60} as well as first-generation DESs. All patients were treated with lifelong aspirin (81 to 325 mg). Clopidogrel was prescribed for a minimum of 1 month after BMS implantation in all studies, and a minimum of 3-6 months after DES implantation, except in the DELAYED-RISCC study,⁷ where clopidogrel was administered for at least 2 months in all patients.

Patient and procedure characteristics. Characteristics of eligible studies, patient demographics, and procedural features are outlined in Table 1 and Table 2. Patients had a mean age of 70 years, were less likely to be female (24%), and had multiple cardiovascular risk factors including hypertension (75%), hyperlipidemia (75%), diabetes (38%), and a history of smoking (22%). The mean SVG age was 10.7 years, with an average of 1.5 stents placed per patient. Approximately 60% of all patients underwent PCI for acute coronary syndrome (ACS). 

Outcomes. Table 3 summarizes the results for all outcomes. For the primary outcome, patients who underwent PCI with a DES had fewer MACE than patients in the BMS group (Figure 3) (OR, 0.63; 95% CI, 0.54-0.74; P<.001). Patients who underwent PCI with DES had less all-cause mortality (Figure 4) (OR, 0.76; 95% CI, 0.69-0.84; P<.001), TLR (Figure 5) (OR, 0.64; 95% CI, 0.50-0.84; P<.01), and TVR (Figure 6) (OR, 0.70; 95% CI, 0.57-0.86; P<.001), without a significant difference in MI (Figure 7) (OR, 0.87; 95% CI, 0.73-1.04; P=.13) or stent thrombosis (Figure 8) (OR, 0.90; 95% CI, 0.61-1.32; P=.58). A sensitivity analysis was performed with the exclusion of the largest study by Brennan et al,⁶¹ and the results remained consistent for MACE (OR, 0.61; 95% CI, 0.52-0.73; P<.001), all-cause mortality (OR, 0.76; 95% CI, 0.67-0.86; P<.001), TLR (OR, 0.64; 95% CI, 0.50-0.84; P<.01), TVR (OR, 0.69; 95% CI, 0.58-0.82; P<.001), MI (OR, 0.86; 95% CI, 0.70-1.05; P=.13), and stent thrombosis (OR, 0.90; 95% CI, 0.61-1.32; P=.58). 

When analyzed according to the type of study, the benefit for MACE was only seen in observational studies (OR, 0.63; 95% CI, 0.53-0.75; P<.001), with no benefit in RCTs (OR, 0.53; 95% CI, 0.20-1.40; P=.20). Similarly, a benefit for all-cause mortality was only seen in observational studies (OR, 0.75; 95% CI, 0.72-0.78; P<.001), with no benefit in RCTs (OR, 1.45; 95% CI, 0.44-4.84; P=.54). A sensitivity analysis was performed with the exclusion of the DELAYED-RRISC trial,⁷ showing a significant reduction of MACE in the DES group for the remaining RCTs (OR, 0.34; 95% CI, 0.13-0.90; P=.03).

A stratified analysis of events according to the duration of follow-up post PCI showed that at 36 months of follow-up in those with DES, there were lower MACE (OR, 0.79; 95% CI, 0.64-0.97; P=.03), and all-cause mortality rates (OR, 0.76; 95% CI, 0.73-0.79; P<.001). The initial reduction of MI observed <12 months post PCI in the DES group (OR, 0.72; 95% CI, 0.57-0.92; P<.01) was not consistent over time, without a significant benefit observed in studies reporting outcomes ≥36 months (OR, 0.82; 95% CI, 0.59-1.12; P=.21). This was similar for TVR (OR, 0.71; 95% CI, 0.49-1.02; P=.07) and TLR (OR, 0.77; 95% CI, 0.27-2.22; P=.63), without an observed benefit at ≥36 months. There was no significant increase in ST in the DES group for all time points of follow-up post PCI (<12 months post PCI: OR, 0.89; 95% CI, 0.45-1.74 [P=.11]; 12-36 months post PCI: OR, 0.58, 95% CI, 0.30-1.13 [P=.11]; ≥36 months post PCI: OR, 0.75; 95% CI, 0.35-1.61 [P=.46]).

To address the role of EPD use, we performed a threshold analysis to compare MACE based on the percentage of EPD use in each group. This was performed with the exclusion of the largest study by Brennan et al.⁶¹ Patients in the DES group had lower MACE rate regardless of EPD use (<20%: OR, 0.47 [P<.001]; <30%: OR, 0.72 [P<.001]; <40%: OR, 0.69 [P<.001]). Further specific details for each study included in the meta-analysis are available in Supplementary Tables 1-4 and Figures 1-6, in .Pdf. 

Discussion 

The results of this meta-analysis show that in patients who underwent PCI to SVG lesions, DES implantation in comparison with BMS had lower MACE, all-cause mortality, TLR, and TVR rates. Patients who underwent implantation with DES did not have an increased risk of early and/or late ST compared with BMS. The benefit for MACE and mortality appears to be driven by observational studies, without benefit seen in RCTs. There was no reduction in MI and TLR at long-term follow-up in patients who underwent DES implantation. 

There are several strengths to this updated meta-analysis. Our study is the largest reported meta-analysis with the addition of recent long-term data from the original trials that compared DES vs BMS stent implantation for SVG lesions. We provide the first pooled analysis of long-term efficacy and safety of DES vs BMS, which allows us to assess the sustained benefit of reduction in events. Our analysis is the first to demonstrate the benefit of DES implantation in SVG-PCI regardless of the percentage of EPD use. 

Several discrepancies were noted between RCTs and observational studies — most notably, the increased all-cause mortality seen in RCTs in patients who underwent DES implantation. The largest increase in all-cause mortality was seen in the DELAYED-RRISC trial, a small trial of 75 patients with a 30-fold increase in all-cause mortality. There are several reasons why such a large discrepancy may have been seen in this RCT. This trial did not have adequate power to identify true effects on mortality, and the results were not replicated in any other RCT or observational study. The observed increase in mortality in this trial was due to non-cardiac deaths. Based upon this evidence, we do not suggest that patients who underwent DES implantation had an increased risk of cardiovascular mortality. Furthermore, the recommended duration of dual-antiplatelet therapy (DAPT) in both groups in this study was a minimum of 2 months, with additional therapy left to the treating physician. At 6 months, there was no significant difference between the two groups, with half of patients in both groups still taking DAPT. The probability of death due to a premature termination of DAPT, while possible, remains unclear. 

The reduction in MACE seen only in observational studies may also be attributed to selection bias in cohort studies. In the large studies that showed a mortality benefit with DES,^46,54,55,58 BMS implantation was utilized more in acute settings such as ST-elevation MI, which may overestimate the benefit of DES use. Patients in the DES group also received DAPT for a longer duration, which may have also offered additional long-term benefit. To further assess this heterogeneity, the DELAYED-RRISC trial was excluded through sensitivity analysis. The results of this sensitivity analysis were reassuring, as RCTs still showed a significant reduction in MACE in the DES group, thus supporting the results of observational studies.

Several studies have attempted to address the late catch-up phenomenon, which describes an early benefit of DES implantation that becomes insignificant over time due to delayed and progressive lumen loss resulting in long-term events.^7,46 Our analysis of study endpoints according to the duration of follow-up post PCI (<12 months post PCI, 12-36 months post PCI, and ≥36 months post PCI) showed that the early benefit of DES implantation for MACE and all-cause mortality remained consistent even at ≥36 months follow-up post PCI. However, there was no long-term benefit for MI, TVR, and TLR. Therefore, this late catch-up phenomenon may exist for these outcomes, which weakens the suggested benefit of DES implantation in the long-term.

The mechanism of in-stent restenosis in SVG differs from that of native coronary arteries as there is prolonged intimal hyperplasia, accelerated atherosclerosis, delayed endothelialization, and thrombotic tendency.^61,62 For these reasons, DES implantation is thought to reduce high rates of repeat revascularization. First-generation DES implantation has been shown to increase late ST in PCI to native coronary artery vessels with increased mortality.^62,63 In our stratified analysis of events, we did not observe an increased risk of early and/or late ST, MI, or TLR in DES patients. Our analysis suggests first-generation DES use in PCI to SVG lesions is safe at early and long-term follow-up.

Study limitations. There was an inconsistency among the studies’ definitions of MACE, because some studies did not include TLR or TVR in the reported composite outcome. In addition, only 4 studies^9,26,51,54 reported follow-up durations of ≥36 months for TLR with a total of 1131 patients, which is a significantly smaller group of patients in comparison with other endpoints assessed for the same follow-up duration. This may result in a selection bias and underestimation of the overall treatment effect. The benefit of first-generation DES implantation is obsolete, as current practice utilizes almost exclusively second-generation DES implantation. In our analysis, patients included in observational studies and RCTs had first-generation DESs; the results of this meta-analysis may not be generalizable to the newer generation of DESs. The study by Aggarwal and colleagues⁶⁰ is the only RCT that included patients who underwent PCI with second-generation DES implantation. In this study, patients receiving second-generation DESs had lower mortality than those with first-generation DESs; both had significant mortality benefit over BMS. A recent study also concluded that first-generation and second-generation DESs had similar long-term outcomes in vein grafts.⁶⁴

Conclusion

The results of our meta-analysis suggest that patients with DES for PCI to SVG lesions had lower MACE, all-cause mortality, and TVR rates, without a significant reduction in MI and TLR rates vs BMS implantation. Despite the use of first-generation DESs with a higher risk profile than current second-generation DESs, these benefits are sustained at long-term follow-up with no increased risk of early and/or late ST, independent of EPD use. These results suggest that DES use in SVG-PCI patients is safe, effective, and consistent.

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From the ¹University at Buffalo, Department of Medicine, Buffalo, New York; ²McMaster University, Department of Medicine (Division of Cardiology), Hamilton, Ontario; ³University of Dublin, Trinity College, Dublin, Ireland; and ⁴Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario. 

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

Manuscript submitted May 18, 2016, provisional acceptance given June 20, 2016, final version accepted July 26, 2016.

Address for correspondence: Michael E. Farkouh, MD, MSc, FRCPC, FACC, FAHA, 585 University Avenue, 4N474, Toronto, Ontario M5G 2N2. Email: michael.farkouh@uhn.ca