Drug eluting stents

Last week an expert panel of the US Food and Drug Administration (FDA) recommended that the FDA should issue warnings to doctors and patients about drug eluting coronary stents. The safety of such stents is unclear except in low risk patients. Furthermore, patients with drug eluting stents should take antiplatelet therapy for at least one year after insertion.

Percutaneous coronary intervention is the dominant treatment for patients with coronary artery disease; 73 000 procedures were performed in the United Kingdom in 2005, compared with 25 000 coronary artery bypass operations. Drug eluting stents have been part of the procedure since 2002 as they reduce the risk of in-stent restenosis.

In-stent restenosis, caused by injury induced cell proliferation and scar tissue formation, requires repeat intervention in 12-20% of patients receiving a bare metal (non-drug eluting) stent.1 Randomised trials have shown that drug eluting stents, which are coated with agents such as sirolimus or paclitaxel that inhibit such local smooth muscle proliferation, reduce the need for repeat procedures to about 5%.2 3

Do drug eluting stents have disadvantages? During percutaneous coronary intervention, balloon inflation and stent deployment injures the endothelial layer of the vessel wall. Endothelial recovery takes about four weeks with bare metal stents, but it can take several months with drug eluting stents because of bystander eluted drug inhibition. The risk of stent thrombosis may therefore increase because of prolonged exposure to the stent strut. Stent thrombosis may occur later with drug eluting stents than with bare metal stents, potentially many months after the procedure.4 Though this happens in only about 2% of patients, up to half of these may die or have acute myocardial infarction.5

To reduce the risk of stent thrombosis, patients are given dual antiplatelet therapy with aspirin and clopidogrel.6 7 With bare metal stents patients take aspirin for life, while clopidogrel is needed to cover the one month period of endothelial regrowth only. The duration of clopidogrel therapy is difficult to determine for drug eluting stents, however, as it is unclear how long endothelial healing takes, and the manufacturers of each drug eluting stent have in the past recommended different lengths of treatment (two to six months). Anecdotal cases8 of late thrombosis—more than one year after the procedure—with drug eluting stents have raised many unanswered questions. Is stent thrombosis, particularly late thrombosis, more common with drug eluting stents? How long is the period of risk? Does antiplatelet therapy need to be continued for longer with drug eluting stents and if so, for how long?

Because the incidence of stent thrombosis and late thrombosis is small, large trials are needed for accurate measurement of excess risk. Meta-analyses of randomised studies and registries have shown either no significant difference in thrombosis rates with drug eluting stents compared with bare metal stents,9 10 or non-significant trends towards excess rates of thrombosis with drug eluting stents (0.29%, 95% confidence interval −0.08% to 0.66%; P=0.13).11 A recently presented but as yet unpublished meta-analysis by the European Society of Cardiology found significantly more stent thrombosis at three years with drug eluting stents (3.9% for bare metal stents v 6.3% for drug eluting stents; P=0.03), raising the possibility of ongoing cumulative risk and the need for long term dual antiplatelet therapy. However, independent clinical event committees who tried to reproduce the findings from patient level data found no excess adverse clinical events (acute myocardial infarction or death) associated with drug eluting stents at four years. Although this is reassuring, concern remains regarding the risk of excess stent thrombosis in the longer term.

Despite the paucity of current data, the British Cardiovascular Interventional Society has recently recommended that dual antiplatelet therapy should be continued for one year in all patients having drug eluting stents inserted. Thus, in the UK about 30 000 people who have drug eluting stents inserted each year will also need dual antiplatelet therapy for at least one year afterwards. This can be a problem if clopidogrel needs to be stopped within this time, either because of side effects or the need for non-cardiac surgical procedures. It is particularly important as the greatest risk factor for stent thrombosis at any time is premature discontinuation of clopidogrel (hazard ratio 89.8; 29.9 to 269.6; P<0.001).12

Interventional cardiologists can assess the risk of stent thrombosis associated with stopping the drug by taking into account the nature of the lesion, timing of the procedure, angiographic results, and other factors such as presence of renal failure and diabetes. Increasingly, patients treated with drug eluting stents are asked to carry an information or warning card that indicates the recommended length of clopidogrel therapy.13 Antiplatelet therapy should not be discontinued at any time, but especially within the first six to 12 months after inserting a drug eluting stent, without discussion with an interventional cardiologist. If possible, non-cardiac procedures should be undertaken without stopping clopidogrel.

Ultimately, continued research into developing drug eluting stents that allow more rapid endothelial regrowth will reduce the need for prolonged dual antiplatelet therapy.14 15 In the meantime, we recommend that the excess risk of stent thrombosis (up to 0.3% each year) balanced against a 60-70% reduction in the need for a repeat procedure with drug eluting stents compared with bare metal stents should be used as the basis for informed consent.