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MATERIAL MATTERS COLUMN

Intravascular stents

Intravascular stents constitute one of the most significant and important implantable medical devices at the present time. However, notwithstanding the immense contribution they make to saving lives and improving the quality of life of so many patients with arterial disease, they remain controversial. The current status of these devices and the arguments that continue to surround their safety, provide a powerful example of the complexities of balancing risk and benefit in medical technology.

The story so far

Stents are used in the treatment of certain patients with atherosclerotic disease and have been under development and in clinical use for approximately fifty years. Their use arose from the significant clinical developments in angioplasty techniques and the associated methods of tackling the restenosis that often follows angioplasty. Angioplasty was initially found to be effective in the treatment of atherosclerosis in the early 1960s and first used clinically in 1964. The technique was developed over the next decade and the first clinical cases of coronary angioplasty were reported in 1977. Although successful in re-canalising vessels, there were many problems and long-term success was by no means guaranteed. The concept of leaving a synthetic material, for example, a plastic or stainless steel tube, within the vessel to maintain its patency, was already being suggested in the late 1960s and early 1970s. Stents were used in experimental animals during the 1970s and early 1980s, although there were significant problems with stent migration and stability. The first clinical use of intravascular stents in coronary arteries was reported in 1987. During the period between 1987 and approximately 1994, there were many developments in the general area of intervention within coronary arteries to treat atherosclerosis, including atherectomy, intravascular ultrasound and brachytherapy.

Many of the developments that took place during that time were centred around the parallel needs to improve the techniques of stent insertion and deployment, and to minimise the process of restenosis, in which the lumen of the vessel gradually narrowed after stent placement. This was caused by the irritation caused to the endothelial surface of the vessels and to the underlying smooth muscle cells within the vessel, and resulted in tissue proliferation, or hyperplasia. This was not surprising, and we can see an interesting paradox in relation to biocompatibility. The whole purpose of angioplasty is to open up a vessel that has become occluded by atherosclerotic plaque, and the proliferative response of the endothelial cells and smooth muscle cells to this plaque. Although usually of immediate success, the process of opening up the vessel further irritates the endothelium, hence the vessel usually quickly becomes blocked again. The purpose of the stent is to maintain the vessel patent after angioplasty, literally by applying mechanical force radially outwards onto the vessel, and keeping it open by its physical presence. Again not surprisingly, this forceful approach to patency usually results in even more mechanical irritation to the endothelium. The classical “bare-metal” stent, usually made of stainless steel, a nickel-titanium shape memory alloy or a cobalt-based alloy, was often seen to be affected by so-called in-stent restenosis. This may occur several years after stent placement, resulting in the need for a new procedure, albeit after a few successful years of keeping the patient alive. It is important to note that with appropriate medical follow-up, this process of restenosis is manageable and not normally life threatening, although it would be of enormous benefit, both clinically and economically, if the need for revision was obviated.

The drug-eluting stent

This is where the drug-eluting stent comes in. The cause of the restenosis lies in the process whereby the stent struts activate the cytokines and growth factors of the cells of the vessels, which stimulate their proliferation and that of circulating platelets and macrophages. On the basis of this rather general mechanism, it was considered that the process of proliferation could be interrupted through the use of a drug that interfered with the cell cycle in some way, and a series of drugs with anti-proliferative, anti-inflammatory or immunosuppressive characteristics were evaluated. Although there have been many drugs considered and evaluated over the past decade, two have been at the forefront: paclitaxel and sirolimus. Paclitaxel is a drug used in chemotherapy, which inhibits certain enzymes involved in the cell cycle and it has been shown to reduce vascular cell proliferation, migration and signal transduction. Sirolimus is a potent immunosuppressive agent that is an effective inhibitor of smooth muscle cell proliferation. The two drug-eluting stents approved by the United States (US) Food and Drug Administration (FDA) involve these two drugs; they are the sirolimus stent, Cypher, manufactured by Cordis; and the paclitaxel stent, Taxus, produced by Boston Scientific. Several early studies such as the one conducted by J. Orford et al.¹ showed clinical effectiveness in relation to reduced restenosis, but suggestions began to emerge that there was an increase in the risk of thrombosis in these patients.

Late thrombosis risk

In a major study of the pathology of the response to drug-eluting stents, Joner et al.,² have evaluated the histological appearance of the affected arteries of 23 patients, who died at times greater than 30 days after placement of a drug-eluting stent. They found 14 of these had significant delayed healing, characterised by fibrin deposition and poorer endothelialisation than in patients with bare-metal stents, and concluded that this situation disposes towards a greater risk of thrombosis. The FDA has now decided to take some action by referring this matter to its Circulatory Systems Devices Advisory Panel, largely on the basis of two studies that report higher thrombosis related complications of drug-eluting stents. It is clear that the data is confusing. Both of these studies showed an increase in death or myocardial infarction in patients with drug-eluting stents compared with those with bare-metal stents, but these were small increases and, because of the small numbers of patients, not necessarily of any significance. Another major study³ has not been able to show any similar increase and points to the fact that the overall effect of drug-eluting stents is extremely beneficial. A major factor here is that if a patient suffers from late thrombosis, the results are likely to be severe, with a reported incidence of death of 45% for those drug-eluting stent patients that suffer an infarction.⁴ This is clearly an important issue compared with the generally nonfatal consequences of restenosis, as mentioned earlier. Also of major significance is the fact that the risk of late thrombosis may well be related to the anti-platelet regime that the patient is given. There is a suggestion that the best way to minimise late thrombosis is to retain the patient on systemic anti-platelet drugs for much longer than the usual one month or so.

David Williams Clinical Engineering Department, Royal Liverpool University Hospital, Liverpool L69 3BX, UK, tel. +44 151 706 5606 fax +44 151 706 5803, e-mail: dfw.ce@liverpool.ac.uk

The dilemma

Because the consequences of late thrombosis in patients with drug-eluting stents are significant, it is obviously sensible to re-evaluate the overall effectiveness of these products, bearing in mind that some of these products have been through the regulatory process in the US and Europe. However, the numbers of patients that appear to be affected is small: most studies would suggest an incidence of less than 1%. There is no doubt that the use of potent drugs such as those mentioned here, even if in extremely low amounts, has the potential for adverse effects on the tissues within the blood vessels as well as the proven effect on reducing restenosis. Clearly, a careful investigation is required, where all benefits and risks of drug-eluting stents are compared with bare-metal stents. The need to balance risk and innovation, as discussed many times previously in this column, is highlighted once again.  

Professor David Williams DSc, FREng is Professor of Tissue Engineering at the University of Liverpool and Director of the UK Centre for Tissue Engineering located in the Universities of Liverpool and Manchester. He is Editor-in-Chief of Biomaterials, the leading journal in the biomaterials field. He is Scientific Director of STEPS, the European Commission Framework VI Programme on a Systems Approach to Tissue Engineering Products and Processes. Professor Williams is also a Managing Partner of Morgan & Masterson LLC, a consulting partnership that focusses on global health-care issues.