Graft disease remains a therapeutic challenge. Procedural complications and unsatisfactory patency rates are realized with both percutaneous intervention and repeat coronary artery bypass graft (CABG) surgery. The efficacy of sirolimus-eluting stents (SES) for the treatment of de novo coronary artery disease has been established, but the use of this technology to treat bypass graft disease remains undefined. The aim of this study was to evaluate the safety and feasibility of SES to treat patients with high-risk bypass graft disease. Methods. The compassionate use of SES (SECURE) study included patients with recurrent coronary disease and no acceptable alternative available treatment, including brachytherapy or CABG. Outcomes from 76 patients (n = 94 lesions) with graft lesions treated with SES in the U.S. were compared with the outcomes of 176 patients (n = 311 lesions) with only native vessels. IVUS follow-up was performed at 8 months in 14 patients with graft SES treatment. Results. In-hospital outcomes were similar between both groups, with 99% of patients discharged without adverse events. The incidence of target vessel failure including death, MI, and TVR at 12 months in the bypass graft group (55.3%) was similar to that observed in the native vessel group (45.5%, p = 0.17). Intimal hyperplasia (IH) measured by IVUS was 11.8 ± 16.5%; 50% of patients with graft SES had < 1% IH at 8 months. Conclusion. Implantation of SES in high-risk patients with recurrent bypass graft disease is feasible. SES represents a future.

Treatment options for bypass graft disease, such as repeat CABG and percutaneous revascularization, are limited and provide disappointing outcomes.^1-4 Patients undergoing repeat CABG have over a four times greater rate of mortality compared to patients undergoing their first surgery.¹ The benefits of percutaneous revascularization with stent implantation, though superior to balloon angioplasty, are limited by a high incidence of procedural complications such as thrombosis and distal embolization, and unsatisfactory long-term reocclusion rates.^2-4

Large randomized trials have confirmed the long-term safety and efficacy of SES implanted in native coronary arteries.^5,6 However, SES have not been evaluated for the treatment of bypass graft disease. The aims of this study are to determine the feasibility and safety of using SES to treat high-risk patients with bypass graft disease.

Methods
The compassionate-use SES (SECURE) registry enrolled 252 patients and included the first series of patients with bypass graft disease treated with SES in the United States. This was a multicenter (5 U.S. sites) study involving the deployment of SES in patients with ischemic cardiac disease who had no acceptable revascularization alternatives available, as agreed upon by both cardiologist and surgeon.

Six- and 12-month outcomes of patients with at least one graft treated with SES were compared with those of patients who had only native vessels treated. Target vessel failure (TVF) was defined as a composite of death, MI and TVR. Q-wave myocardial infarction (MI) was defined as the development of new, pathological Q-waves in e2 leads, with CK twice the upper limit of normal (< 190 U/L). Non-Q-wave MI was defined as an elevation of CK levels twice the upper limit of normal and abnormal CK-MB levels. Major adverse cardiac events (MACE) included death, MI, emergency CABG and TLR. Clopidogrel (75 mg/day) was maintained for at least 6 months; brachytherapy failure patients received clopidogrel indefinitely. Angiographic and IVUS follow-up was recommended, but not mandatory, at 8 months for brachytherapy failure patients. Events were adjudicated by an independent clinical event committee. The protocol was approved by the Medical Ethical Committees and informed consent was obtained from all patients.

Angiographic and IVUS data were analyzed at independent core laboratories (Borgess Heart Institute, Kalamazoo, Michigan and Cardiovascular Imaging Core Laboratories, Jacksonville, Florida, respectively) as previously reported.⁷

Statistical analysis. Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as percentages. Continuous variables were compared by means of an unpaired Student’s t-test. Categorical variables were compared by means of the chi-square test. A two-tailed value of p < 0.05 was considered statistically significant.

Results
Baseline demographics are described in Table 1. Bypass graft disease was present in 76 patients, with a total of 94 lesions treated (71 vein and 23 arterial grafts); 90.4% were ISR and 67.1% had previous brachytherapy. A total of 176 patients (n = 311 lesions) were treated with SES exclusively in native vessels. Of these, 83.0% were in-stent restenosis (ISR) and 72.2% had undergone previous brachytherapy.

Angiographic data are provided in Table 2. Procedural success was achieved in all but 8 lesions (5 native and 3 graft lesions).

Follow-up data. There were 3 in-hospital deaths (2 in the native vessel group and 1 in the graft group). In the native vessel group, one death was secondary to stent thrombosis. Stent thrombosis was not documented in the other 2 patients who died of sudden cardiac death. All other patients were discharged without any complications.

At 6 months, TVR rates were 18.1% in the native vessel population versus 16.7% in the graft population (p = 0.82), and the incidence of MI was 3.8% versus 3.3%, respectively. The cumulative 12-month outcomes are described in Table 3. The incidence of target vessel failure (primary endpoint) including death, MI, and TVR at 12 months in the bypass graft group (55.3%) was similar to that observed in the native vessel group (45.5%, p = 0.17).

There were no differences comparing outcomes of patients with arterial or venous grafts treated with SES. Furthermore, clinical outcomes of patients with bypass grafts were not influenced by previous intravascular radiation therapy. However, TVR rates were higher in the native vessel brachytherapy treated population as compared with patients without previous brachytherapy (46.5% versus 25%, respectively; p = 0.023).
IVUS data were available in 14 bypass grafts treated with SES. The volume of IH was 19.9 ± 25.5 mm3 in a total length of 26.4 ± 9.8 mm. Percent IH was 11.8 ± 16.5% and was virtually absent (< 1%) in 50% of lesions.

Discussion
This study suggests the feasibility of using SES to treat high-risk patients with bypass graft disease. At one year, patients with bypass graft treatment had similar outcomes compared to patients treated for native vessel disease.

The treatment of diseased bypass grafts has been a challenge for both interventional cardiologists and cardiac surgeons. Unfortunately, up to 20% of vein grafts are occluded within the first year following CABG and many more develop significant disease within 10 years.⁸ Repeat operations are technically more difficult and are associated with high surgical morbidity and mortality rates.¹ Similarly, percutaneous revascularization strategies have provided unsatisfactory outcomes, with a high incidence of restenosis.^2–4

The high-risk profile of the present population limits comparison with previous studies involving less complex patients with bypass graft disease. Radiation therapy studies in patients treated for ISR in bypass grafts reported a 48% incidence of MACE at 12-month follow-up.9 In the SVG-WRIST trial (Washington Radiation for In-Stent restenosis Trial), TVR rates were 28% and 62% in patients with vein grafts treated with gamma radiation versus placebo, respectively.¹⁰ These findings compare favorably with the long-term results observed in the present study, which included patients who were refractory to other treatment modalities, including radiation therapy. It is nevertheless important to note that conventional percutaneous revascularization of patients with failed radiation therapy has been associated with 6% mortality and 32% TVR rates 6 months after the procedure.¹¹

The limited inventory available in this early study handcuffed operators when selecting appropriate stent sizes. Mean reference vessel diameter (Table 2) was relatively small as measured by QCA, which reflects the diffuse characteristics of the lesions and the lack of a “normal” reference vessel segment. Further, the initial concerns with the use of multiple DES in a single target vessel may have limited adequate lesion coverage. These factors may explain the < 1.0 stent length/lesion length ratio (Table 2), and may have influenced clinical outcomes. The ongoing STLLR multi-center study is evaluating procedural data from 1,500 patients treated with SES and will provide important insights on the impact of complete lesion coverage when using DES.

Nevertheless, both venous and arterial grafts showed little intimal hyperplasia as assessed by IVUS. The small amount of intimal hyperplasia detected by IVUS compares favorably with previous reports on native ISR lesions treated with SES.¹² Fifty percent of the segments had virtually no intimal proliferation along the entire stented segment. These encouraging findings in this high-risk group warrant further randomized investigations to confirm whether percutaneous revascularization using SES is an effective treatment for patients with bypass graft disease.

Study limitations. The study sample may not be representative of the general population, given their high-risk status. In addition, the comparison group may not be ideal, as it is composed of patients with native vessel disease. Nevertheless, the outcomes of this first series of patients with bypass graft disease treated with SES in the U.S. are extremely relevant for an increasing number of high-risk patients treated percutaneously in everyday practice. Therapeutic decisions for these patients cannot be supported by classic randomized studies. The ongoing Cypher™ Stent Post-Market Surveillance registry, which had no exclusionary criteria and represents routine clinical practice in the U.S., features 69% of patients who had previous stenting, 32.7% CABG and 7.5% brachytherapy — all common features of the present population. The favorable results observed in the present report provide important information regarding the feasibility of SES in bypass graft disease. Certainly, such findings require confirmation in well-designed prospective randomized trials which have not yet been developed.


Email: dominick.angiolillo@jax.ufl.edu

1. Shroyer AL, Plomondon ME, Grover FL, Edwards FH. The 1996 coronary artery bypass risk model: The Society of Thoracic Surgeons Adult Cardiac National Database. Ann Thorac Surg 1999;67:1205–1208.
2. de Feyter PJ. Percutaneous treatment of saphenous vein bypass graft obstructions: A continuing obstinate problem. Circulation 2003;107:2284–2286.
3. Savage MP, Douglas JS Jr, Fischman DL, et al. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators. N Engl J Med 1997;337:740–747.
4. Roffi M, Mukherjee D, Chew DP, et al. Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials. Circulation 2002;106:3063–3067.
5. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
6. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
7. Abizaid A, Albertal M, Costa MA, et al. First human experience with the 17-beta-estradiol-eluting stent: The Estrogen And Stents To Eliminate Restenosis (EASTER) trial. J Am Coll Cardiol 2004;43:1118–1121.
8. 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.
9. Stone GW, Mehran R, Midei M, et al. Usefulness of beta radiation for de novo and in-stent restenotic lesions in saphenous vein grafts. Am J Cardiol 2003;92:312–314.
10. Waksman R, Ajani AE, White RL, et al. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med 2002;346:1194–1199.
11. Ajani AE, Waksman R, Cheneau E, et al. The outcome of percutaneous coronary intervention in patients with in-stent restenosis who failed intracoronary radiation therapy. J Am Coll Cardiol 2003;41:551–556.
12. Sousa JE, Costa MA, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24–27.