For personal use. Only reproduce with permission from The Lancet Publishing Group. RAPID REVIEW Lancet 2003; 361: 247–49 Department of Radiology, Cardiovascular Unit, University Hospital S Orsola, 40138 Bologna, Italy (R Fattori MD, T Piva MD) Correspondence to: Dr Rossella Fattori, Istituto di Cardiologia (padiglione 21), Policlinico S Orsola, Via Massarenti 9, 40138 Bologna, Italy (e-mail: ross@med.unibo.it) Percutaneous transluminal coronary angioplasty (PTCA) has become the main method of coronary revascularisation, accounting for more than 1 500 000 procedures worldwide every year. 1 Despite technical advancements, of which coronary stenting has been the most significant, restenosis remains the major problem that hampers the procedure’s efficacy. Compared with balloon angioplasty alone, coronary stenting coupled with aggressive antithrombotic and antiplatelet therapy improved acute outcome and long-term negative arterial remodelling. 2–7 However, in practice stenting can lead to in-stent restenosis, a particular refractory form of neointimal proliferation. Stent restenosis rates are reported to be 15–20% in ideal coronary lesions, but may occur in over 30–60% of patients with complex lesions (eg, small vessel, diffuse atheromasia, and bifurcation lesion). Moreover recurrent restenosis is more common after percutaneous treatment of in-stent restenosis, with clinical and economic impacts on health-care systems. The evolution of stent design, which has produced increasingly safer and easier-to-use devices, extended the use of PTCA, allowing approach to multivessels disease as an alternative to coronary bypass surgery. However, the increasing volume of cardiac surgery in the past few years 1 suggests that the widespread use of coronary interventions has been extended more to medical than surgical patients Therefore in-stent restenosis can be expected to increase as coronary stenting becomes more frequent, being used in a wider spectrum of patients and types of coronary lesions. Mechanisms of restenosis Restenosis is the reduction of the luminal size due to loss of gain in lumen size after intravascular interventional procedure. Several cellular and molecular events occur sequentially after a vascular injury. 2,8 The initial response of the elastic fibres of the vascular wall to overstretching by balloon catheter is elastic recoil, responsible for the loss of gain, which characterises the early phase of restenosis. The endothelial denudation and the exposure of subintimal components cause platelet adherence and aggregation, fibrinogen binding, and thrombus formation. Thrombus formation can also act as a scaffold into which vascular smooth-muscle cells can migrate, synthesise matrix and collagen, and reorganise the thrombus, providing the substrate for neointimal formation. Activated platelets release several mitogens and chemotactic factors, which stimulate smooth-muscle-cell migration and proliferation into the injury site. Inflammatory mediators and cellular elements contribute to trigger a complex array of events that modulate matrix production and cellular proliferation. Finally, remodelling, a gradual dynamic process mediated by adventitial myofibroblasts that leads to a change in vessel size by constrictive remodelling without an overall change in tissue volume, contributes to the loss of lumen at later times. Stenting reduces elastic recoil and negative remodelling, the mechanical component of restenosis, but also stimulates the cellular mechanisms yielding to in-stent restenosis. By contrast with balloon angioplasty, restenosis after stenting is due mostly to neointimal formation. The bulk of in-stent restenosis consists of extracellular matrix, proteoglycans, and collagen, with only 11% cells. Greater Drug-eluting stents in vascular intervention Rossella Fattori, Tommaso Piva Rapid review THE LANCET • Vol 361 • January 18, 2003 • www.thelancet.com 247 Context Restenosis is the most important long-term limitation of stent implantation for coronary artery disease, occurring in 15–60% of patients. In-stent restenosis, a refractory coronary lesion resulting from neointimal hyperplasia, challenges both vascular biologist and interventional cardiologist. Various drugs and devices have been used tried to overcome restenosis but are not particularly successful. Over 1 500 000 percutaneous coronary interventions are done annually. Restenosis is not only important clinically but also for its impact on health- care costs. Starting point Growth and migration of vascular smooth- muscle cells result in neointimal proliferation after vascular injury and are the key mechanism of in-stent restenosis. The rationale of the most recent approaches to restenosis (eg, brachytherapy and immunosuppressive agents) arises from the similarity between tumour-cell growth and the benign tissue proliferation which characterises intimal hyperplasia. Several immunosuppressants have been tested for their potential to inhibit restenosis, with the novel strategy of administering the drug via a coated stent platform. Local drug delivery achieves higher tissue concentrations of drug without systemic effects, at a precise site and time. The first multicentre trial with stents coated with sirolimus was by Marie-Claude Morice and colleagues (N Engl J Med 2002; 346: 1773–80). In a trial of 238 patients, restenosis of 50% or more at 6 months was 0% and 27% with sirolimus or normal stents (p<0·001), respectively, after percutaneous revascular- isation. Muzaffer Degertekin and colleagues (Circulation 2002; 106: 1610–13) present data on 2-year follow-up of 15 patients who had been implanted with the sirolimus stent in another study, and confirm persistent inhibition of restenosis and an absence of unexpected adverse events. Where next? Local application of antiproliferative agents is a promising technique and research is developing. Other agents with potential benefits (eg, statins, local gene-therapy, adenovirus-mediated arterial gene-transfer, L-arginine, abciximab, angiopeptin, recombinant pegylated hirudin, and hiloprost) as well as improvements in polymer technology (biodegradable smart polymers, coatings for multiple-drug release) are under evaluation. The clinical impact of the elimination of restenosis may influence the approach to coronary artery disease, the future of cardiac surgery, and health-care economics in cardiology.