Drug-eluting stents (DES) are the standard percutaneous treatment strategy in patients with coronary artery disease (CAD). Their use has further reduced the incidence of restenosis and repeatrevascularisation in single vessel de novo disease. These stents have bioactive coatings that, through a complex mechanism, allow the release of various antiinflammatory and anti-proliferative drugs at high concentrations in the wall of the treated vessel without significant release into the bloodstream, to prevent restenosis of the vessel without systemic side effects.
Despite recent reports suggesting that the use of DES in US hospitals is declining, Dr Gregg W Stone, Professor of Medicine and Director of Cardiovascular Research and Education, Columbia University Medical Center, and Chairman, Cardiovascular Research Foundation, New York City, and one of the world’s leading interventional cardiologists, firmly advocates their use and comments, “there is no firm data to confirm whether the use of DES in hospitals is declining or not.” However, he does concede that recently there has been an increase in concern about stent thrombosis issues associated with their use. “Late stent thrombosis appears to be a specific concern with DES, whereas the rate of early stent thrombosis is similar to that found with bare-metal stents (BMS). There appears to be a small, but real excess of late stent thrombosis after approximately six to 12 months; with the exact percentage varying depending on the study.” These studies, presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2005 Conference, suggest that both the Cypher and Taxus stents show an approximate 0.5% increase in late stent thrombosis over their bare-metal counterparts between approximately nine to 12 months and three years post insertion. Although this is a small absolute number, the data comes from more than 5,000 patients partaking in eight prospective, randomised, double-blind trials. “These patients remain blinded and follow-up will continue for the next five years so understanding of whether the phenomenon stops after three years or continues through five years can be gained. Early indications suggest that there may still be a few continuing episodes of thrombosis even after three years,” comments Dr Stone.
He goes on to reiterate, “on the whole there is little doubt that DES are the best devices for advanced treatment of coronary artery disease. If you look specifically at the 5,000 randomised patients reported at TCT, although there is a modest excess in late stent thrombosis this does not seem to translate to an overall late excess death or myocardial infarction.” One explanation for this may be that DES have other benefits over BMS; restenosis, while often a benign event, in as many one in three patients may present with death, myocardial infarction (MI) or unstable angina “Thus, by preventing restenosis compared to BMS, DES are preventing many of these episodes.”
Some small studies, including the Basel Stent Costeffectiveness Trial-Late Thrombotic Events (BASKET-LATE), conclude the hazard of DES could be even greater than 0.5% and may translate into an increased rate of death from myocardial infarction. However, Dr Stone is keen to emphasise “that this was a small trial, with only 743 patients, and the data need to be replicated in a larger cohort.”
There are also a number of current trials that have five-year follow-up planned. In Dr Stone’s opinion, one of the most important ones is the Horizons AMI trial. Consisting of more than 3,000 high-risk patients with acute myocardial infarction (AMI), this randomised trial of the Taxus stent versus BMS will follow patients for five years. “As this trial will be four times larger than BASKETLATE and the procedure is being performed in a very high-risk population, it should provide a true sense of the ‘outer bound’ of the risk of late stent thrombosis,” says Stone.
Cypher vs Taxus
Despite several clinical trials, “there are no convincing studies which have demonstrated significant differences between the Cypher and Taxus stents, either in terms of safety or efficacy,” stresses Dr Stone. He continues, “all trials that have been performed to date have been markedly underpowered and too small to be definitive. Some trials, including the largest trial to date, show no significant clinical differences between Cypher and Taxus, although, other smaller or single-centre trials have shown clinical differences between the two. What is needed is a definitive, large, head to head, randomised trial.”
“Given this lack of definitive information, physicians are choosing stents based on softer, subtler differentiators between the stents, such as stent deliverability, price or brand loyalty,” comments Dr Stone. He continues, “some physicians are very much influenced by randomised trial data, some consider the large, registry studies and the fact that there are no differences between the two stents, and then rely on more subtle differences. Others look at the smaller trials and meta-analysis, and base their decision on a small but real difference, favouring a specific stent. Other physicians rely on their own anecdotal experience. If they have been experiencing noticeably better results with one stent versus the other or been using the same product exclusively for years and getting great results this will lead them in one direction (despite the fallacy of this reasoning). Others will use more subtle factors in their decision-making such as deliverability, quality of scaffolding, price or bundling.”
Adverse Responses to the Placement of DES
As with any new bioactive device, DES have a unique set of potential adverse effects in patients. These include reactions of the polymer, hypersensitivity reactions to the drug, actual aneurysm formation or late stent malapposition because of the marked potency of the drug and the issue of late stent thrombosis. In order to maintain successful results, Dr Stone emphasises “DES require prolonged courses of a dual anti-platelet regimen with aspirin and clopidogrel which can be problematic for some patients to take. If, because of clots or the need for surgery, their platelet agents need to be discontinued, this leads to an increased risk of stent thrombosis.”
Safety of DES
An unintended consequence of the market success of drug-eluting stents has been a growing concern about their safety. Dr Stone is quick to point out “in simple to complex lesions there is no difference in rates of death and MI” – the two most reliable safety measures. “Although there does seem to be a modest increase in late stent thrombosis compared with that seen with bare-metal stents this is probably counter-balanced by the favourable effects of DES on preventing these complications by reducing restenosis. However, more data in real world patients, where DES are used in more complex situations that in the randomised trials already performed, is needed,” informs Dr Stone.
Stone is confident that “over the next five years, safer and more effective drug-eluting stents will be developed.” Similar to first-generation stents, secondgeneration stents have been designed to show increased deliverability and safety. The question of safety is also being addressed, “with increased use of bioabsorbable polymers or stents that will be absorbed over time, possibly solving the late stent thrombosis issue,” Dr Stone reassures. In addition, he is keen to highlight, “stents that will release drugs without using any sort of polymer are currently being researched. Some of the adverse safety consequences of DES with regard to stent thrombosis are linked, in some people’s minds to the polymer, rather than the drug.”
Studies are also in progress looking into aspirin and clopidogrel hyporesponsiveness found in different patients and how these vary. “Some patients’ haematologic systems may not respond equally to aspirin and clopidogrel. There is a tremendous amount of research and investigation being carried out into newer, more potent agents that could be used in such patients to further improve the safety of drug-eluting stents,” says Dr Stone. He summarises, “although there are still safety issues with drug-eluting stents, these devices have markedly improved the quality of life for patients with coronary artery disease, and the future still looks bright!”