Failure of the Symbiot PTFE-Covered Stent to Reduce Distal Embolization During Percutaneous Coronary Intervention in Saphenous V

Within a decade of coronary artery bypass graft surgery, 50% of saphenous vein grafts fail, causing recurrent angina and acute coronary syndromes.¹ Because of the substantial risk associated with re-operation, percutaneous intervention is often preferred to further surgery in this population. However, percutaneous revascularization is hampered by a high incidence of acute complications, specifically, distal embolization and periprocedural myocardial infarction (MI).^2,3 Significant elevation in cardiac enzymes resulting from distal embolization is an independent predictor of late mortality.³ The advent of distal protection devices to capture embolic material has improved outcomes substantially by reducing the incidence of periprocedural MI.⁴ However, even with distal protection, non-Q-wave MI still occurs in approximately 10% of patients.^4,5 Membrane-covered stents were designed to trap friable degenerated plaque against the graft wall, and hence reduce the probability of distal embolization. Unfortunately, randomized, controlled trials of different covered stents have consistently failed to demonstrate any reduction in periprocedural MI.^6–9 The reasons for this lack of benefit are unclear. We performed a randomized, controlled trial of the Symbiot™ Covered Stent System (Boston Scientific, Natick, Mass.), a distal-to-proximal, self-expanding, polytetrafluoroethylene (PTFE)-covered stent, to specifically examine its effect on distal embolization, and to explore the mechanism for the apparent failure of covered stents to reduce periprocedural MI. Materials and Methods The study was a prospective, randomized trial conducted in a single center. Approval was obtained from the local research and ethics committee, and all patients provided written, informed consent. Patients were eligible if they presented with stable or unstable angina, with a greater than or equal to 50% de novo stenosis in the body of a saphenous vein graft suitable for a FilterWire™ Distal Protection Device (Boston Scientific) (reference 3.0–5.5mm; greater than or equal to 30 mm “landing zone” distal to the lesion and before the graft insertion). Exclusion criteria were age less than or equal to 18 years, women of child-bearing age, contraindication to aspirin or clopidogrel, primary or rescue angioplasty for acute ST-elevation MI, and a target lesion which was aorto-ostial, Protocol. Patients were randomly assigned before the start of the procedure to treatment with either a Symbiot covered stent or a conventional bare metal stent, using sealed envelopes. All patients were treated with aspirin, clopidogrel (300 mg greater than or equal to 6 hours preprocedure) and heparin (5,000 U). Abciximab (bolus and infusion over 12 hours) was recommended. Transfemoral access was used, with 8 French (Fr) catheters for Symbiot patients, and 6 Fr catheters for the control group. Prior to intervention, a FilterWire™ EX or EZ (Boston Scientific) distal protection device was deployed distal to the target lesion. If difficulty traversing the target lesion with the FilterWire was anticipated or encountered, the use of a “buddy” conventional angioplasty guidewire and, if necessary, low-pressure predilatation with a small diameter balloon, were permitted. Direct stenting was recommended if technically possible. Postdilatation was performed in all Symbiot patients as recommended by the manufacturer and according to operator preference in the control group. End Points and Definitions. The primary end point was the quantity of embolic debris captured in the FilterWire. Secondary end points were: “Filter no-reflow,” no-reflow, angiographic evidence of distal embolization, and final Thrombolysis in Myocardial Infarction (TIMI) flow grade. Filter no-reflow was defined as a reduction of greater than or equal to 1 TIMI flow grade to TIMI grade 2 with the FilterWire in situ. No-reflow was defined as a reduction of greater than or equal to 1 TIMI flow grade to TIMI grade 2 which persisted after removal of the FilterWire and with no other mechanical cause of obstruction. Angiographic evidence of distal embolization was defined as the occurrence of no-reflow, Filter no-reflow, or the appearance of a new angiographic filling defect in the FilterWire. Quantification of embolic debris. At the end of the procedure, the FilterWire was removed. The Filter was detached from the wire, irrigated with saline, taking care not to displace any solid embolic debris, and was then fixed in 10% buffered paraformaldehyde. Subsequently, the Filter was immersed in saline and photographed using a Nikon Coolpix digital camera mounted on a Nikon dissecting microscope. Digital images were transferred to ImagePro Plus (Media Cybernetics, Silver Spring, Maryland), and embolic debris area was measured by semi-automated edge detection analysis (Figure 1). Each case was calibrated to the length of the guidewire from rim to tip (1.5 cm), and the debris area was expressed in mm². Statistical analysis. The data are presented as numbers and percentages, or mean ± SD. Categorical variables were compared with the Fisher’s exact test. Continuous variables were compared with the Student’s t-test. A two-tailed p-value of less than or equal to 0.05 was considered significant. Results Thirty patients, ages 71 ± 8 years, 83% men, were randomized to the Symbiot stent (n = 14), or to a conventional stent (n = 16). Baseline clinical characteristics did not differ significantly between the two groups (Table 1). A high percentage of patients presented with unstable angina (63%). The age of the treated grafts was 14 ± 3 years in the conventional group, and 13 ± 6 years in the Symbiot group. Angiographic and procedural variables are shown in Table 2. Lesion characteristics were comparable between the two groups. In 1 patient in the Symbiot group, the landing zone was insufficient to accommodate both the FilterWire and the deployment sheath of the Symbiot, which extends some way beyond the distal margin of the stent itself. The Symbiot was deployed without distal protection in this patient. Direct stenting was possible in only 1 patient in the Symbiot group, compared to 8 of 16 in the conventional stent group (p = 0.01). Postdilatation was performed in all Symbiot patients, compared to 6 of 16 conventional stent patients (p p p = 0.07). High-pressure inflation was employed in both groups (16 ± 3 versus 17 ± 3 atm; p = NS). Glycoprotein IIb/IIIa inhibitors were administered in the majority of cases (11 of 14 versus 14 of 16; p = NS). Distal embolization. Embolic debris was identified in 100% of patients in both the Symbiot and conventional stent groups. There was no significant difference in the quantity of embolic material liberated (Figure 2, Table 3), although there was a trend toward increased embolic debris area in the Symbiot group (10.5 ± 6.8 versus 6.6 ± 7.8 mm²; p = 0.18). Filter no-reflow occurred in about 50% of patients in each group (7/14 versus 7/16; p = NS). However, true no-reflow, which persisted after removal of the FilterWire, occurred only in the Symbiot group (3/15 versus 0/16; p = 0.09), and final TIMI flow grade was lower with the Symbiot stent (2.7 ± 0.5 versus 3.0 ± 0.5; p = 0.01). Any angiographic evidence of distal embolization was seen in 9 of 14 patients with the Symbiot versus 8 of 16 patients in the conventional stent group (p = NS). Distal embolization in the Symbiot group was seen in only 2 patients after initial stent deployment; in the remaining 7 patients, it occurred only after postdilatation (p = 0.05). Discussion The principal finding of this study is that the Symbiot PTFE-covered stent did not reduce distal embolization when compared to a conventional bare metal stent during percutaneous coronary intervention (PCI) in degenerate saphenous vein grafts. Distal embolization with the Symbiot covered stent occurred almost exclusively after mandatory postdilatation. Distal embolization of friable atherosclerotic material is the principal cause of acute complications during PCI in saphenous vein grafts. Early evaluation of distal protection devices revealed almost universal liberation of embolic debris during SVG PCI.^10,11 The use of these devices has substantially reduced adverse events, in particular, the incidence of periprocedural non-Q-wave MI (NQMI).⁴ However, NQMI still occurs in around 10% of patients despite distal protection.^4,5 Covered stents were designed to trap friable debris against the wall of the vein graft, preventing distal embolization. The first widely used device was the Jostent^® Stent Graft (Abbott Vascular Devices, Redwood City, California), which has a sandwich-like design with a PTFE membrane between two stainless steel stents. However, in two large, randomized, controlled trials, STING and RECOVERS, the Jostent failed to reduce distal embolization and periprocedural major adverse cardiac events (MACE), and in RECOVERS, it was associated with a significant increase in NQMI compared to a conventional stent.^6,7 A third trial, BARRICADE, was stopped early because of a lack of benefit.⁸ In contrast to the Jostent, the Symbiot consists of a single nitinol stent with an inner and outer PTFE membrane designed to achieve a lower profile, and hence to enhance deliverability and reduce embolization while crossing the lesion. The Symbiot is a self-expanding stent and expands from distal-to-proximal on deployment so that atherosclerotic debris can be squeezed back, and subsequently trapped, behind the stent. The results of the 400-patient randomized, controlled Symbiot III trial, comparing the Symbiot with a bare metal control stent, were recently presented.⁹ There was no difference in periprocedural MACE, including non-Q-wave MI, between the Symbiot and control groups. Why do covered stents fail to improve acute outcomes during vein graft PCI? One theory is that the high-profile stents cause significant distal embolization when crossing the target lesion. Furthermore, predilatation is more often required to allow delivery of the bulky device and may also liberate embolic debris. In our study direct stenting was only possible in 1/14 Symbiot patients compared to 8/16 in the conventional stent group because of actual or expected difficulty in traversing the target lesion with the covered stent, although angiographic evidence of distal embolization was not observed after predilatation. The STING investigators suggested that the high pressure necessary to fully expand the Jostent (mean = 16.4 atm) may have contributed to distal embolization and periprocedural MI. Postdilatation is mandatory to achieve satisfactory expansion of the Symbiot stent. In Symbiot III, the mean pressure employed was also 16 atm. Our findings indicate that the failure of the Symbiot to reduce periprocedural MI is explained by a failure to reduce distal embolization. Furthermore, distal embolization seems to occur almost exclusively after mandatory postdilatation. Angiographic evidence of distal embolization in this study was not seen at all after predilatation or passage of the stent across the lesion, and in only two cases, it was identified after initial stent deployment. It appears that the pressures required to achieve adequate deployment of the Symbiot stent may also cause distal embolization by axial displacement of debris either proximally or distally from behind the stent. This is a limitation that may well apply to all designs of covered stents. Study limitations. The primary limitation of this study is its size, and the conclusion that the Symbiot fails to reduce distal embolization is hampered by the small numbers included. No judgement can be made from this study on the effects of the Symbiot on clinical outcomes, which the study was not powered to assess. Cardiac markers were not routinely measured postprocedure, further precluding evaluation of the effects of the Symbiot on non-Q-wave MI. Finally, we cannot be certain that the quantification of embolic debris captured in the distal protection device would correlate with the clinical end points that have been attributed to distal embolization, such as periprocedural MI. Conclusions The Symbiot PTFE-covered self-expanding stent does not reduce distal embolization compared to a conventional bare metal stent. Distal embolization with the Symbiot appears to occur almost exclusively after mandatory postdilatation. These findings may explain the failure of the Symbiot, and of covered stents in general, to improve clinical outcomes during vein graft PCI.

1. Fitzgibbon GM, Kafka HP, Leach AJ, et al. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616–626. 2. Hong MK, Mehran R, Dangas G, et al. Are we making progress with percutaneous saphenous vein graft treatment? A comparison of 1990 to 1994 and 1995 to 1998 results. J Am Coll Cardiol 2001;38:150–154. 3. Hong MK, Mehran R, Dangas G, et al. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation 1999;100:2400–2405. 4. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002;105:13–18. 5. Stone GW, Rogers C, Hermiller J, et al. Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration system during percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts. Circulation 2003;108:548–553. 6. Stankovic G, Colombo A, Presbitero P, et al. Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous vein grafts: The Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts (RECOVERS) Trial. Circulation 2003;108:37–42. 7. Schachinger V, Hamm CW, Munzel T, et al. A randomized trial of polytetrafluoroethylene-membrane-covered stents compared with conventional stents in aortocoronary saphenous vein grafts. J Am Coll Cardiol 2003;42:1360–1369. 8. Stone GW, Goldberg S, Mehran R, et al. A prospective, randomized U.S. trial of the PTFE covered JOSTENT for the treatment of diseased saphenous vein grafts: the BARRICADE trial (Abstr). J Am Coll Cardiol 2005;45:27A. 9. Buchbinder M, Turco M, on behalf of the SYMBIOT III investigators. 8 months results from the Symbiot III randomized SVG trial. Presented at Transcatheter Cardiovascular Therapeutics 2004, Washington DC. 10. Grube E, Schofer J, Webb J, et al. Evaluation of a balloon occlusion and aspiration system for protection from distal embolization during stenting in saphenous vein grafts. Am J Cardiol 2002;89:941–945. 11. Popma JJ, Cox N, Hauptmann KE, et al. Initial clinical experience with distal protection using the FilterWire in patients undergoing coronary artery and saphenous vein graft percutaneous intervention. Catheter Cardiovasc Interv 2002;57:125–134.