Percutaneous coronary revascularization has revolutionized modern cardiovascular care. It has become one of the most well-studied and frequently performed procedures in modern medicine and is currently performed in more than 900,000 patients per year, exceeding the rate of coronary bypass surgery. It is used in an increasingly large number of patient subsets and used to treat an increasingly large number of complex lesions.
Initially described in 1977, the procedure involved placement of a balloon-tipped catheter across a subtotal stenosis followed by balloon inflation and deflation to improve coronary flow. Although the initial patient treated was fortunate to have an early and long-lasting excellent result, many early patients did not - with initial success rates of only 60%, and a relatively high rate of acute occlusion from the arterial trauma of balloon inflation that resulted in myocardial infarction and need for emergency coronary bypass surgery and culminated in increased mortality rates. In those patients fortunate enough to have a good initial angiographic result, restenosis with recurrent blockage of the segment initially treated occurred in up to 40% to 50% of patients within six or seven months of the initial index procedure.
Having recognized these problems, investigators and industry developed, tested, and implemented a variety of devices to make the procedure safer, more effective, and able to be applied in an ever-broadening group of patients and coronary lesions. Although some of the new technology never reached a sustaining application, other specific devices did - the foremost of these was the application of intracoronary stenting. This approach was initially tested and then approved for treatment of acute closure occurring as a result of percutaneous coronary intervention. By acting as a mechanical scaffold, stenting was very effective in preventing and treating coronary dissection and occlusion. Early problems with stenting, however, included the requirement for intense anticoagulation and antiplatelet therapy, which led to long hospitalization times and high bleeding rates. Newer approaches substantially ameliorated these problems and led to widespread use. By the late 1990s, stents had become the dominant revascularization strategy and had been found to improve early as well as late outcomes compared with conventional percutaneous transluminal coronary angioplasty (PTCA). Although restenosis rates were improved and reduced by approximately 30% compared with conventional PTCA, the problem was not eliminated. In the setting of stent placement, restenosis was found to be related to excessive neointimal hyperplasia. Stents worked by preventing recoil of the arterial segment compared with conventional PTCA, which showed that neointimal hyperplasia was even increased.
Grading schemes for in-stent restenosis were developed. In some patients, this in-stent restenosis was very resistant to therapy and many patients eventually required surgery for the treatment of it. Given the magnitude of the problem, new approaches were developed to treat the in-stent restenosis, including the development of the entire field of vascular brachy therapy.
Recognizing that in-stent restenosis was the result of neointimal hyperplasia, research focused on means to prevent it. These efforts culminated in the current generation of devices which have now become predicate devices - namely, drug-eluting stents.
Current drug-eluting stents have three components:
- The bare metal backbone, which serves as the mechanical scaffold - this element affects deliverability, access to side branch and surface area over which the drug is delivered.
- A polymer or combination of polymers - this is a critical component. It varies from manufacturer to manufacturer. Concerns have been expressed over the eventual degradation of the polymer and whether that will lead to inflammation. The specific polymer affects distribution kinetics of drug delivery.
- The specific drug - at the present time, there are two approved drugs - Sirolimus and paclitaxel. The release kinetics depend upon the specific drug chosen and the polymer. Both fast- and slow-release formulations have been tested. Multiple other drugs and drugs classes are being tested.
The majority of data on the currently approved two drug-eluting stents comes from either randomized controlled trials comparing a drug-eluting stent with a bare metal stent or registry studies of the use of the drug-eluting stent in specific patient or angiographic groups. The majority of data that has been published, relates to the Sirolimus-eluting stent (SES), although there is an increasing amount on the paclitaxel-eluting stent (PES). A single randomized study, which has completed enrollment, compares SES versus PES (REALITY Trial). Approximately 1,400 patients have been randomized. No end-point data is as yet available. This trial will be of seminal importance in comparing the two currently available drug-eluting stents, both acutely and over the longer-term.
The end-points of the registries and the randomized clinical trials have varied. Some of the early studies, e.g. First In Man, were safety and also some measure of efficacy. Once safety was documented, the larger studies have used efficacy as the primary end-point - looking at target lesion revascularization or target vessel failure - the latter a composite of death, myocardial infarction, and repeat revascularization of the target vessel.
The larger multicenter randomized trials have usually included an angiographic substudy so that angiographic restenosis can be assessed. Relatively new terms have been developed for angiographic assessment: 'in-stent analysis' - an analysis confined to within the borders of the stent and 'in-segment analysis' - in which a 5mm segment proximal and distal to the stent is analyzed in addition to the stented length. Follow-up duration varies, although with SES there is now follow-up of up to four years. In the pivotal US SIRIUS trial, at two years, there was a dramatic reduction in target lesion revascularization - 5.8% in the SES versus 21.3% in the bare metal stent arm (p <0.0001). Stent thrombosis was similar in both arms at 0.6% and 0.8% respectively. Angiographic restenosis in the stent at nine months was reduced from 35.4% to 3.2%, and angiographic restenosis in the analysis segment was reduced from 36.3% to 8.9%. In all patient subsets studied, there was concordance with a reduction in target lesion revascularization (TLR) by 70% to 80%.
With the Paclitaxel drug-eluting stent, there is less data, but it is also concordant; in TAXUS IV, there was a reduction in target vessel failure (death, myocardial infarction, target vessel revascularization (TVR)) from 14.4% in the bare metal stent to 7.6% with the PES. Target lesion revascularization at nine months was reduced from 11.3% to 3.0%.There was also a marked improvement in TLR and target vessel failure (TVF) in TAXUS VI, a higher risk group of patients and lesions. In all of these studies, there was also general concordance across patient subsets. There was no difference in stent thrombosis. These studies among others have documented several findings:
- drug-eluting stents are safe - early, 30-day, and out to four years;
- clinical outcome is dramatically improved mainly by a reduction in clinical restenosis;
- there is little difference in longer-term mortality or myocardial infarction between bare metal and drug-eluting stents, i.e. the drug-eluting stents will not, in general, decrease mortality at least in the patients studied to date. In higher risk patients, e.g. left main coronary artery (LMCA) or diffuse three-vessel disease, there may be a different answer. However, there is only limited data to date. Multiple studies are targeting these higher risk groups; and
- there are differences in late loss between the two different drug-eluting stents with more late loss with PES compared with SES. Whether that will result in clinical events in more diverse patient and lesion subsets is unclear.
At the present time, market penetrance of drug-eluting stents varies between countries and between institutions.
Much of this variability relates to the substantial increased cost of the stents, although with the introduction of the second device, competitive market pressures have brought down the costs somewhat. In those centers where there is unrestricted availability, the drug-eluting stents are used in the majority of cases - the exception being when the optimal device size is not available, e.g. treatment of a 5.5mm vessel as no 5mm or 5.5mm drug-eluting stent is available, or in some patient subsets where there is very limited data, e.g. treatment of saphenous vein graft disease.
In centers where there is restricted use, higher risk patients and lesions are treated preferentially with drug-eluting stents, e.g. diabetics and patients with more diffuse disease, in whom the predicted restenosis rates with bare metal stents are very high.
Drug-eluting stents have revolutionized the practice of interventional cardiology. They are safe and effective in dramatically improving patient outcome and have become state-of-the-art as well as state-of-the-science predicate devices.