Self-Expanding Versus Balloon Expanding Coronary Stents in Intervention of the Degenerated Saphenous Vein Graft: Memmingen Coronary Artery Bypass Stenosis Trial (MECAST)

Objectives The aim of this retrospective analysis was to compare the patient outcome after interventional therapy of saphenous vein graft (SVG) stenoses in an all-comers population receiving either self-expanding drug-eluting stents (SExS) or balloon expanding drug-eluting stents (BExS). Background The interventional therapy of degenerated SVGs remains challenging. Diameter variations of stenotic segments and friable plaques can lead to malapposition and distal embolization with increased major adverse cardiac event (MACE) rates. Methods 107 patients with a total of 130 SVG interventions were separated into two groups according to either SExS (n = 51) or BExS (n = 56) treatment. Primary endpoint was the MACE rate, which is defined as the composite of cardiac death, myocardial infarction (MI), target vessel (TVR), and target lesion revascularization (TLR) at 30 days and at one-year follow-up. Results Both patient groups did not differ significantly regarding patient characteristics. The patient outcome was significantly better in the SExS patient group: the MACE rate at 30 days was 1/51 (2.0%) in group SExS vs. 7/56 (12.5%) in group BExS; p < 0.05. At one-year follow-up, the MACE rate remained significantly lower in the SExS group 8/51(15.7%) vs. 20/56 (35.7%) in the BExS group, p < 0.02. Additionally, cardiac death occurred significantly later within the SExS patient group compared to the BExS group (p < 0.05). A better overall outcome of patients with de novo SVG-stenosis compared to patients with previous CABG (coronary artery bypass graft) intervention was noted in both groups. Conclusion Our findings demonstrate that SVG treatment with SExS is safe and provides clinical benefits by comparatively improving short and especially long-term patient outcomes.


Introduction
Coronary artery bypass graft (CABG) surgery, whilst declining, is still a frequent procedure used worldwide for the treatment of coronary artery diseases. Although guidelines recommend a full arterial revascularization, most patients still receive at least one or more saphenous vein grafts in daily routine practice [1,2]. In patients undergoing CABG, the rate of venous graft failure by graft occlusion is around 50% after 10 years follow-up [3]. Tis venous graft disease difers from classical arteriosclerosis in coronary artery disease: saphenous vein grafts (SVGs) typically degenerate and form stenotic segments over years developing difuse intima hyperplasia with minor calcifcation and more friable plaques [4]. In consequence, these stenoses in older SVGs are often located close to ecstatic venous segments, making it difcult to choose the adequate stent diameter during interventional treatment. Another issue is the risk of distal embolization during the procedure due to the high debris burden in friable plaques. Tis can lead to slow or no refow phenomenon with the risk of periprocedural MI. Te use of an embolic protection device has been recommended based on the data of the SAFER trial [5]. However, it was downgraded (class IIa) in current ESC/EACTS guidelines on myocardial revascularization due to conficting results in recent observational trials [2,6,7] and has never been used frequently in daily practice [8]. Overall, the interventional therapy of degenerated SVGs remains challenging and major cardiac adverse event (MACE) rates in bypass interventions are higher, compared to interventions in native coronaries [8]. Terefore, interventional treatment of the bypassed native coronary artery should be favored if possible [2]. However, bypassed native coronary arteries are often calcifed, or chronically totally occluded which results in other challenges especially in the acute coronary syndrome [9].
Another important aspect is the difculty in selecting the adequate coronary device. Until now, it is still unclear whether drug-eluting stents (DES), which proved superior compared to bare metal stents (BMS) for native coronary interventions, have the same advantages in the treatment of SVG stenoses. Although DES performed better compared to BMS in the ISAR-CABG trial at one-year follow-up, after a longer period of observation (5 years), MACE rates in both groups did not difer anymore [10,11]. In the DIVA trial, where patients received either DES or BMS, the outcome in both groups remained equal [12]. In a recent trial comparing DES versus BMS in patients undergoing SVG intervention, the long-term follow-up after 5 years revealed a signifcantly lower MACE rate within the DES patient group. However, the list of exclusion criteria was extensive (previous stent implantation in the target SVG, need for concomitant intervention in a native coronary artery, SVG <6 months old, need for oral anticoagulation, etc.) [9].
Self-expanding drug-eluting stents (SExS) may have some advantages over conventional balloon expandable drug-eluting stents (BExS) due to their unique design (tight stent struts, active outward force, soft expansion, full stent apposition) [13]. Its soft expansion might reduce the risk of SVG perforation due to oversize ballooning or oversized stent implantation [9]. Furthermore, SExS have shown a full stent apposition rate without signifcant malapposition [14,15]. Malapposition itself is an independent risk factor for stent thrombosis, leading to worse outcome [16]. In SVG interventions malapposition can occur in up to 50% of all cases [17] Terefore, SExS might be especially useful in SVG interventions with its varying diameter and friable plaques. In its current generation, the SExS is mounted on a balloon with a splittable sheath. Its delivery works similarly to a BExS; however, the balloon infation serves for splitting the sheath only. While retrieving the splitted sheath, a slight or moderate resistance due to friction must be overcome. To prevent a distal coronary perforation, especially in SVG interventions, the modifed foating wire technique facilitating its delivery process has been recommended [18].
A single center observation of 42 patients treated with SExS in degenerated SVG stenoses demonstrated a low restenosis rate of 4.8% after a median follow up of 13.4 months, proving the feasibility of SExS use in daily routine practice, however no peer group was evaluated [19].
Terefore, the Memmingen Coronary Artery bypass Stenosis Trial (MECAST) was initiated to analyze the potential clinical beneft of SExS in comparison to BExS regarding patient outcome for intervention of degenerated SVGs in daily routine practice. (Figure 1). From Jan 2012 to Jan 2018, we performed 131 SVG interventions with DES stents in 108 patients at our institution. One patient receiving one procedure was lost to follow-up within the BExS group. An all-comers retrospective analysis was performed dividing these patients into two groups according to treatment (operator dependent): Group SExS mainly received (91.8%) second generation SExS (STEN-TYS-SES ® ; Xposition S ® , nitinol alloy, sirolimus coated, cell area of 0.95 mm 2 , diameter range 2.5-4.5 mm, length 17-37 mm) (23) (patients: N � 51; SVG procedures: N � 61), while group BExS all received second generation BExS (diameter range 2.25-5.0 mm, length 8-32 mm) (patients: N � 56; SVG procedures: N � 69). Te SExS stents were delivered through balloon infation (12 atm) with a splittable sheath (Figure 2(a)) Due to higher resistance (splittable sheath) while retrieving the SExS delivery system, we modifed the foating wire technique: an additional wire was inserted through the guiding catheter foating free in the ascending aorta and thereby preventing the guiding catheter from deep intubation and possible subsequent distal wire perforation (Figure 2(b)) [18][19][20]. Post-interventional treatment and antiplatelet therapy was performed according to current guidelines. All patients were followed up to a period of one-year either angiographically or by a phone call.

Patients and SVG-Intervention Procedure
Patients who had received BMS, drug eluting balloon, or plain old balloon angioplasty (POBA) for SVG treatment were not included in the trial.
To analyze and quantify the plaque burden of the degenerated SVG, we used the SVG degeneration score analysis according to a predictive model [13].
All participants provided informed written consent.

Outcomes and Defnitions.
Technical success was defned as residual restenosis <20% of the target lesion and thrombolysis in myocardial infarction (TIMI) II-III fow at the end of the procedure. Primary endpoints were the MACE rate within 30 days and at one-year follow-up. MACE was defned as a composite of target vessel revascularization (TVR), target lesion revascularization (TLR), myocardial infarction (MI) (according to current ESC guidelines [14]), and cardiac death. Additionally, stent thrombosis rate, defned according to the recommendations of the Academic Research Consortium, was analyzed [15].

Statistical Analysis.
For all statistical analyses, the computer programs Excel (Microsoft, Redmond, USA), SPSS (Version 24, IBM, Armonk, USA) and MedCalc (Version 19.2, MedCalc Software, Ostend, Belgium) were used. Continuous data were summarized as mean ± standard deviation (normally distributed data) or median and interquartile range and compared using t-test or Mann-Whitney U test, as appropriate. Categorical variables were expressed as frequencies or percentages and were compared by using Fisher's exact test. Clinical event rate during follow up was calculated using the Kaplan-Meier curve and compared using the log-rank test. Hazard ratios were evaluated using Cox regression analysis. Results were considered signifcant with a p value of <0.05.

Patients and Lesion
Characteristics. Patient recruitment details are depicted in Figure 3. Baseline characteristics are shown in Table 1 All patient and lesion characteristics were not normally distributed according to the Kolmogorov-Smirnov test. Terefore, a Mann-Whitney U test was applied which revealed no signifcant diference between both patient groups regarding baseline characteristics rendering them comparable. Table 2 depicts procedural characteristics. In most patients, the SVGs were minor or moderately degenerated (≤50% of total SVG length), leading to a degeneration score of either 0 or 1, with no signifcant diferences between both groups (group SExS: 77.0%; group BExS 63.8%, p � 0.30).
No periprocedural complications occurred within the BExS group. Of note, one patient died due to pericardial tamponade related to wire perforation of a distal coronary artery within the SExS group. Tis complication was related to retrieval of the SExS stent delivery system. To prevent further SExS-related perforations, we applied the modifed foating wire technique [18,19]. No similar additional complications occurred.
Patient outcomes including the MACE rate are demonstrated in Table 3 and Figures 4(a) and 4(b). MACE at 30 days was lower in group SExS (2.0% vs. 12.5%, p < 0.05). At one-year follow-up, the MACE rate remained signifcantly Additionally, one stent thrombosis was noted within the SExS group in comparison to 7 stent thromboses in the BExS group (2.0% vs. 12.5%, p < 0.05).
Te Kaplan-Meier curve analysis regarding MACE rate after 30 days and at one-year follow up demonstrated the superiority of SExS treatment compared to BExS. MACEfree survival was signifcantly better in the SExS patient   ). Furthermore, patients who sufered cardiac death within one-year follow-up died signifcantly earlier when treated by BExS as compared to SExS (Log rank: p < 0.05; Figure 5(c)). Cox regression analysis revealed several risk factor covariates with protective or negative efect on patient outcome ( Figure 6). Of note, treatment of de novo SVG stenoses resulted in a signifcantly lower MACE rate in both patient groups (p < 0.01).

Discussion
In our trial, we performed a retrospective analysis of an allcomers patient population in the clinic of Memmingen over a period of six years who received an SVG intervention either by SExS (n � 51) or BExS (n � 56) and compared patient outcome specifcally regarding MACE rate and cumulative survival.
Both patient groups (SExS and BExS) did not difer signifcantly regarding baseline characteristics and were therefore comparable. Of note, patients treated by SExS had slightly more comorbidities (Table 1). For procedural characteristics, the only signifcant diference between patient groups concerned lesion preparation (pre-dilatation SExS: 100% vs. BExS: 73.9%, p < 0.0001; post-dilatation SExS: 75.4% vs. BExS: 29.0%, p < 0.0001). User guidelines for SExS utilization strongly recommend pre-and post-dilatation, which explains the higher dilatation rate in the SExS group. It is highly unlikely that the lower pre-and post-dilatation rate had a negative impact on the outcome of the BExS group. In order to prevent distal embolization even direct stenting has been proposed, which in contrast led to a better short and long-term outcome after a one-year follow up compared to conventional BExS intervention [16], and as shown in a post hoc analysis of the DIVA trial, was associated with a lower stent thrombosis rate and lower target vessel MI-rate [17].
MACE rates in our BExS group were higher than in previous studies such as the ISAR-CABG or BASKET-SAVAGE trial. However, patients presenting with a cardiogenic shock or previous stent implantation or patients under oral anticoagulation were excluded in these trials. In contrast, in our study, we performed an all-comers analysis with no patient exclusions. Tis may explain the higher MACE-rates regarding the BExS patient group [9,10].
On the other hand, we were able to demonstrate that patients treated by SExS had a signifcantly lower MACE rate after 30 days follow up than patients treated by BExS (2.0% vs. 12.5%, p < 0.05). Tis was mainly driven by a lower incidence of MI, TLR and TVR. Te use of an embolic  Journal of Interventional Cardiology protection device was relatively low (SExS: 9.8% vs. BExS: 11.6%, p � 0.43). Our results are comparable to the ADEPT trial [21], analyzing the previous generations of STENTYS stents (STENTYS bare-metal vs. STENTYS paclitaxel-eluting) in SVG interventions. In this trial, a low MACE rate at 30 days follow-up could be demonstrated in both groups (3.7% vs. 6.7%), with a low incidence of EPD use (<20%) [21]. Te early beneft of SExS use in our trial might be due to soft expansion and full stent apposition with less distal embolization as mentioned above.
Another major fnding of our study was the following: Although the number of cardiac deaths was similarly low in both groups (SExS: n � 5; BExS: n � 7, p � 0.66), cardiac death occurred signifcantly earlier within the BExS patient group indicating a longer survival rate after SExS intervention (p < 0.05). Tis could impact the patient outcome and needs to be further investigated in larger trials.
Cox regression analysis of risk factor covariates revealed several risk factors with hazard ratios >1, as well as protective factors (hazard ratio <1), however only one was signifcant: history of previous CABG treatment resulted in a higher one-year MACE rate in both patient groups as compared to de-novo SVG intervention (p < 0.01). Tis fnding is highly interesting and suggests that within this patient subgroup treatment of the bypassed native coronary artery should be preferred, if possible.
In summary, our results suggest a potential beneft of SExS treatment in SVG stenoses. SExS may have a positive impact on the patient outcome, in particular by increasing cumulative survival and lowering incidence of the MACE rate.
Several limitations need to be mentioned. Our trial was a retrospective analysis of a single center only. Te number of patients included in both groups was relatively small, due to the low incidence of patients in need of SVG intervention. Te pre-and post-dilatation rates were overall higher within the SExS patient group. We only performed the analysis over a period of one-year follow-up. Post-procedural cardiac markers were not regularly acquired. Of note, the SExS tested in our study is currently no longer available (STENTYS-SES ® ).

Conclusion
In conclusion, we could demonstrate that the interventional therapy of degenerated SVGs by SExS is safe, even in patients with ACS. Te SExS showed a clinical beneft over BExS regarding MACE rate at 30-days as well as at one-year follow-up, in particular concerning the rate of MI, TLR, and TVR. Furthermore, cardiac death occurred signifcantly later after treatment with SExS. Te history of previous SVG intervention was an independent risk factor in both groups.  Figure 6: Forest plot depicting hazard ratios of several covariates. Statistical signifcance (p < 0.01) marked with a star. A hazard ratio <1 illustrates a protective efect on patient outcome, whereas a hazard ratio >1 represents a negative efect. ACS � acute coronary syndrome; EF � ejection fraction; PAOD � peripheral artery occlusive disease, EPD � embolic protection device; CABG � coronary artery bypass graft; TIMI � thrombolysis in myocardial infarction; and SVG � saphenous vein graft.
Our fndings should be further investigated in larger multicentric randomized trials and might enable an alternative interventional strategy in the treatment of SVG stenoses.

Data Availability
Te data used to support the fndings of this study are available upon request from the corresponding author.

Conflicts of Interest
Te authors declare that they have no conficts of interest.