Coronary interventions have revolutionized the treatment of coronary artery disease (CAD). Stents, which were used initially for the complications arising from coronary angiography gradually, came to occupy a more prominent role in coronary interventions. However, restenosis remained a limiting factor from a therapeutic point of view. Recent development of drug-eluting stents is a step toward overcoming this problem. This development has elicited a great interest in both physician as well as patient communities. We have reviewed the available medical evidence regarding drug-eluting stents.
In affluent parts of the world, CAD is the leading cause of morbidity and mortality. Percutaneous transluminal coronary angioplasty (PTCA) has revolutionized the treatment of ischemic heart disease during the past 2 decades. It is estimated that over 1 million PTCA procedures are performed in the United States each year. 1 PTCA is often performed in conjunction with stent placement. Coronary stenting was introduced in 1989 to treat the acute complications of PTCA. 2 However, it is now routinely used for most angioplasties. The elective stent era began in 1994 with 2 randomized trials showing reduced rates of restenosis as compared with PTCA alone. 3,4 According to one estimate, the number of stenting procedures has grown from approximately 177,000 procedures per year in the United States in 1996 to approximately 456,000 procedures per year in 2000. 5
The true potential of these techniques remains to be fully realized because of the phenomenon of restenosis. This could lead to recurrent symptoms within 6 months of the procedure. Numerous causes for restenosis exist, including elastic recoil after the stretching of the artery, platelet-mediated thrombosis formation, neointimal hyperplasia resulting in both new tissue growth and migration and proliferation of smooth muscle cells to the lumen, and remodeling and contraction of the artery. 6
Neointimal hyperplasia begins soon after coronary intervention as a result of platelet activation, inflammation, and proliferation of smooth muscle cells. Pharmacologic inhibition of these processes by using drugs administered systemically has had little success in preventing restenosis. A platelet IIb/IIIa receptor antagonist, abciximab, has shown modest benefit for patients with diabetes mellitus undergoing stent implantation, 7 but trials of other drugs have often failed spectacularly despite promising preliminary work in animal models.
Although the use of coronary stents is associated with lower rates of restenosis than balloon angioplasty alone, 3 rates of up to 40% have been reported in some series, and treatment options are often unsatisfactory with high recurrence rates after further intervention. 8
Stents resist elastic recoil and cover dissections. Stents were initially shown to reduce the rate of restenosis in relatively simple, straightforward lesions in large-diameter coronary vessels, 3,4 although their use has been adopted in a wide spectrum of complex lesion types.
Despite improvement in vessel patency with stenting as compared with PTCA alone, the occurrence of in-stent restenosis (ISR) often poses a difficult management dilemma. ISR results primarily from neointimal hyperplasia distributed focally within the stent at the proximal and/or distal margins or diffusely over the entire length of the stent, occasionally extending beyond the stent margins (commonly known as “edge restenosis”). 9
Conventional percutaneous coronary interventions (PCI), such as PTCA, rotational atherectomy, excimer laser ablation, as well as repeat stenting, have been used in treating ISR. Focal ISR often responds well to such conventional PCI techniques, whereas diffuse ISR has a high rate of recurrence despite utilization of these techniques. Intravascular radiation (brachytherapy) using sources emitting gamma rays or beta rays is an effective way of treating established restenosis, 8,10 although its use for the prevention of restenosis has been disappointing. Furthermore, several important safety issues are associated with brachytherapy and, owing to strict regulation the procedure, is currently restricted.
Despite these treatments, recurrent ISR still occurs, necessitating further PCI procedures (which are associated with even higher rates of recurrent ISR) or coronary artery bypass surgery. 1,11
Previous pharmacologic trials focused on giving a systemic drug to prevent restenosis and could have failed in part because adequate local concentrations of the drug were not achievable without systemic toxicity.
A novel solution to this problem has been the recent development of drug-eluting stents, allowing controlled release of a drug directly to the injured endothelium.
Coronary artery stents coated with a variety of pharmacologic agents are beginning to be marketed as a potential solution to the restenosis problem. Unlike earlier pharmacologic trials in which systemic agents were administered during/after PCI to prevent restenosis, drug-eluting stents allow controlled local release of a drug directly to the injured endothelium, avoiding systemic side effects. The stents are coated with a polymer that acts as a drug reservoir and allows for the gradual elution of the drug over time. Two pharmacologic agents used in drug-eluting stents are paclitaxel, a toxoid drug that prevents cell replication by binding to microtubules during cell division, and sirolimus, a macrocyclic lactone that blocks cytokine-proliferation of T-lymphocytes, which are important for cell-cycle progression. 1
The Food and Drug Administration (FDA) approved the first drug-eluting stent (sirolimus; CYPHER, Cordis/Johnson & Johnson) in April 2003. Another company (Boston Scientific Corp.; paclitaxel) anticipates having its drug-eluting stent approved by the end of 2003. 5 Drug-eluting stents are only approved for the prevention of restenosis in native coronary arteries.
We review the evidence available regarding the use of drug-eluting stents.