Abizaid lacerations of the arterial wall. Injury stimulates smooth muscle cells to both proliferate excessively and migrate from the underlying vessel wall (Scott 2006). Despite the scaffolding effect of the stent, the smooth muscle cells accumulate gradually, impinging upon the lumen. Tissue growth continues to be a problem because stents do not stop smooth muscle cell proliferation (Spier et al 1995). Cur- rently, drug-eluting stents have emerged as the most promising approach in the ﬁght against restenosis. What is sirolimus? Sirolimus was ﬁrst isolated from a soil micro-organism, Streptomyces hygroscopius, found on Easter Island, as reported by in 1975 (Vezina et al 1975). Rapa Nui is the local name for Easter Island, inspiring the compound’s well- known common name of rapamycin. Crystalline sirolimus was puriﬁed from fermentation media and found to be active against several strains of yeast and ﬁlamentous fungi. The produced streptomycyte was also active against some bacteria (Sehgal et al 1975; Vezina et al 1975), leading to the original classiﬁcation of sirolimus as an antifungal antibiotic (Singh et al 1979; Chakraborty et al 1995). Since sirolimus is very lipid soluble (ie, lipophilic), almost no drug is released into the bloodstream during stent placement at the lesion site, and after stent implantation, the diffusion gradient favors elution into tissue, again limiting the amounts of circulating free sirolimus. In addition to its antibiotic activity, it became apparent that sirolimus also possessed powerful anti-proliferative and immunosuppressant properties (Chang et al 1991). Sirolimus was shown to be a novel inhibitor of cellular proliferation, distinct from cyclosporin A in a variety of in vitro and in vivo models (Chang et al 1991; Stepkowski et al 1991; Groth et al 1999). The smooth muscle anti-proliferative properties have been characterized in numerous vascular models (Marx et al 1995; Poon et al 1996; Pham et al 1998; Poston et al 1999). In vivo studies in allograft and angioplasty models demonstrated the effectiveness of sirolimus in preventing tissue hyperplasia following vascular injury and led to is consideration as an agent for the prevention of restenosis (Gregory et al 1995; Gallo et al 1999). Clinical studies The First-in-Man feasibility study, conducted in Sao Paulo, Brazil and Rotterdam, the Netherlands showed the CYPHER® sirolimus-eluting stent (Cordis Corporation, Johnson & Johnson, Warren, NJ, USA) to be remarkably effective in eliminating the occurrence of restenosis (Sousa et al 2001). These early results were followed by the unprecedented ﬁndings from the RAVEL trial, the ﬁrst double blind, ran- domized, controlled trial of a drug-eluting stent (Morice et al 2002). These exceptional results are well known and have been replicated in three additional randomized, con- trolled trials – SIRIUS, E-SIRIUS, and C-SIRIUS (Moses et al 2003; Schofer et al 2003; Schampaert et al 2004). Subsequently, the ﬁndings from the First-in-Man study study show that the efﬁcacy and safety of sirolimus have been sustained out to 4 years (Sousa et al 2005). Since the preliminary results from the First-in-Man feasibility study were presented, the CYPHER stent is currently available in more than 80 countries and has been used by doctors to treat more than 2 million patients world- wide (Cordis Corporation, Warren, New Jersey, USA, press release 26 April 2006). The sirolimus-eluting coronary stent (SES) is the most studied drug-eluting stent today with the largest body of clinical evidence demonstrating long-term safety and efﬁcacy of its drug and polymer (Fig. 1). In addition, the SES was shown to yield the same strong patient outcomes with or without balloon pre-dilation, according to the comparison of intravascular ultrasound results from the multicenter, randomized E-SIRIUS and SIRIUS trials (Hoffmann et al 2005). However, the main criticism of any controlled clinical program is that by its very nature, patient entry is limited by the strict inclusion and exclusion criteria. It is against this background that several prospective registry studies have begun, in order to collect a large series of data in more challenging lesions (such as small vessels, long lesions, bifurcations, chronic total occlusions and left main disease) and patient populations (acute coronary syndromes and multi-vessel disease). Management of complex lesions and “high-risk” patients As operator experience with SES grows, and the clinical evidence base is enhanced following the outcomes from a series of independent, “head-to-head” comparative trials, so SES are being used to treat increasingly complex lesions and patients considered to be “high risk”. Among the factors associated with this changing face of interventional cardiol- ogy three stand out: 192 Vascular Health and Risk Management 2007:3(2)