Drug-eluting stents and diseased saphenous vein grafts: Long-term risk in RRISC

Progressive disease in saphenous vein grafts remains a major short-term and long-term clinical challenge after surgical revascularization. Compared with native coronary arteries, saphenous veins can rapidly develop progressive graft disease. This may be due to increased local inflammatory cellular response with exuberant intimal hyperplasia and a diffuse, friable atherosclerosis with a poorly developed or absent fibrous cap and minimal calcium components. Compounding this pathophysiology is slow flow hemodynamics when a large vein is anastomosed to a smaller caliber native coronary vessel, which can lead to stasis and thrombosis.

Clinically significant saphenous vein graft disease has traditionally been treated surgically, but reoperation in patients with diseased saphenous vein grafts is associated with higher morbidity and mortality than an initial coronary artery bypass graft surgery. When possible, it has been preferable to repair saphenous veins percutaneously. Percutaneous balloon angioplasty alone, however, although technically feasible, is limited by a high incidence of restenosis and concern for procedural-related distal embolization. Six-month restenosis rates after balloon angioplasty have been reported to be between 46% and 66%.^1,2 With the introduction of bare-metal stents (BMS), graft restenosis has been reduced but remains high, with restenosis at 6 months ranging from 24% to 37%.¹ The advent of drug-eluting stents has offered hope of a more durable strategy to treat diseased saphenous vein grafts. Five small registry studies with sirolimus-eluting stents (SES) and paclitaxel-eluting stents were encouraging, with 6- to 9-month restenosis rates of ≤10%.^3-7 The Reduction of Restenosis in Saphenous Vein Grafts with Cypher Stent (RRISC) trial⁸ was the first prospective randomized drug-eluting stent trial. The 6-month restenosis rate was 11.4% for SES vs 30.6% for BMS (P = .02).

Despite the low restenosis rate with drug-eluting stents, multiple reports over the past year have raised concern regarding the long-term safety and the risk of late stent thrombosis of drug-eluting stents in native coronaries. This safety concern was not addressed in the initial saphenous vein drug-eluting stent studies. The first RRISC report was limited to a mean follow-up period of 6 months, with all patients receiving a minimum of 2 months' treatment with aspirin and clopidogrel (Plavix). The

report in this issue

of Cardiology Review summarizes the post-hoc analysis of long-term safety in the RRISC cohort after a mean follow-up period of 32 months. Eleven of 38 subjects (29%) died in the SES group compared with none of 37 subjects (0) in the BMS group (P <.001). Late stent thrombosis was deemed definite in 5% of drug-eluting stent subjects and probable in 13% of subjects. Unexpectedly, there were 6 deaths judged to be unrelated to the SES procedure, whereas there were no deaths in the BMS group over the 3-year follow-up period.

Several mechanisms may be responsible for an unusually high rate of complications with SES placed in saphenous vein conduits. Saphenous veins have increased endothelial cell loss and medial damage. These vessels have a prothrombotic milieu with increased tissue factor exposure; decreased thrombomodulin, heparin sulfate, nitric oxide, and tissue plasminogen activator; and increased fibrinogen. Sirolimus in particular may increase tissue factor expression.⁹ An intravascular ultrasound substudy from the RRISC trial showed decreased neointimal hyperplasia in SES compared with BMS.¹⁰ This reduced cellular response may be a "double-edged sword" reducing restenosis but simultaneously impairing protective stent endothelialization.

It should be recognized that the long-term RRISC study is based on a small patient sample with a post-hoc analysis. Yet, although drug-eluting stents are the best strategy for providing long-term patency of diseased saphenous vein grafts, the follow-up results from the RRISC study are concerning. Until further data are available, possible approaches to diseased saphenous vein bypass grafts would be to: (1) use a drug-eluting stent and continue aspirin and clopidogrel indefinitely, (2) consider a BMS as the initial stent and place a drug-eluting stent if there is clinical restenosis, or (3) use a drug-eluting stent along with high-dose clopidogrel, which may reduce the risk of late stent thrombosis.¹¹