The problem plagued angioplasty since its beginnings: reclosure of the vessel. The discovery that elastic recoil or contracture was sometimes responsible led to the development of stents to prop the vessel open. These devices did indeed help: the reclosure rate fell from about 50% to 20% to 30%.1  Unfortunately, intimal hyperplasia resulting from the vessel injury, inflammation, and thrombus caused by angioplasty balloons are worse in vessels that have been stented,2 so the vessel may occlude through restenosis. The consequences range from asymptomatic angiographic narrowing to angina or myocardial infarction. Every year, 150,000 Americans who have undergone coronary angioplasty require another treatment because of restenosis.3 The smaller the treated vessel, the higher the risk.

The first attempts to stop restenosis employed radiation. A gamma or beta source is either applied to a ribbon that is left in the lesion temporarily after stenting or incorporated into stent material.4 Such irradiation does indeed inhibit neointima formation,3,5 but intravascular brachytherapy has two undesirable consequences: an increase in the risk of thrombosis and stimulation of hyperplasia at the ends of the stent (the candy wrapper effect). The Food and Drug Administration (FDA) therefore has approved such devices only for the treatment of in-stent restenosis, not for primary stenting.

Attention has now turned to antiproliferative drugs delivered on stents, which have the advantage of requiring no special storage facilities (although there are shelf-life limitations). One design, approved by the FDA in April 2003 and previously approved in Europe, is a balloon-expandable stainless-steel stent carrying sirolimus in a two-polymer coating. In the RAVEL trial of this stent, carried out in Europe and Latin America, there was significantly less intimal hyperplasia at 6 months in patients randomized to receive the drug-eluting stents.6 No restenosis exceeding 50% was seen in patients having the test stents, whereas it developed in 27% of the control patients. The rates of major adverse cardiac events (MACE), particularly target-vessel revascularization, at 1 year were 6% and 29%, respectively. The inhibition of neointimal hyperplasia continued up to 2 years,7 and there were no instances of thrombosis or cardiac death.8 Patients getting the test stent did not show an increase in stenosis in the side branches of stented arteries,9 nor was there any difference in the likelihood of restenosis according to vessel size.10 A trial in patients with lesions at arterial bifurcations also yielded good results.11 In a trial at Erasmus University in 16 “very challenging” patients, the late lumen loss averaged only 0.25 mm. The sirolimus-delivering stent also performed well in a much larger US trial. The late restenosis rate was 9% in the patients treated de novo for coronary lesions with the drug-eluting stent and 36% in the control patients, and the target-lesion revascularization rates in the first 9 months were 4% and 17%, respectively.12

Since this stent received regulatory approval, there have been some reports of postdeployment thrombosis. The manufacturer has begun a registry and has cautioned that the stent must be deployed firmly against the vessel wall, that overexpansion to fit larger vessels should be avoided, and that antiplatelet drugs must be given in appropriate doses. Failure to adhere to these recommendations was associated with several of the instances of thrombosis.

The other polymer-coated stent in late development contains paclitaxel in a slow-release polymer coating. In TAXUS I, which enrolled 61 patients, the rate of MACE at 12 months was 3% in patients receiving the test stent versus 10% in patients having the same stent without the drug. Intravascular ultrasonography showed an average intimal hyperplasia burden of 14.8 mm3 and 21.6 mm3, respectively, in the two groups.13 TAXUS II compared a slow-release with a moderate-speed-release stent. TAXUS III enrolled 28 patients with in-stent restenosis, who received one or two stents. At 6 months and 10 months, the rates of re-restenosis were 4% and 16%, respectively. There was one non-Q-wave myocardial infarction, one coronary artery bypass operation, and six target lesion revascularizations, two necessitated by gaps between or misplacement of the stents.14 TAXUS IV, the US pivotal trial, began in April of last year and has enrolled 1,326 patients for de novo treatment. At the 2003 Transcatheter Cardiovascular Therapeutics (TCT) Symposium, a target lesion revascularization rate of 3.0% at 9 months was reported for patients from TAXUS IV who received this stent versus 11.3% in the patients who received the same stent without paclitaxel. The symptom-driven repeat revascularization rates were 4.7% and 12.0%, respectively, and in-stent restenosis was found in 5.5% versus 24.4% of patients. Similarly good results were seen in diabetic patients. Four days before these results were released, the paclitaxel-coated stent received marketing clearance from the Therapeutic Products Directorate of Health Canada.

Other drug-eluting stents have the compound applied directly to the modified surface. ASPECT compared stents having one of two doses of paclitaxel, the outcomes being assessed clinically and with intravascular ultrasonography. In the 28 patients receiving stents with the lower drug dose (1.28 µg/mm2), the average amount of intimal hyperplasia was 18 mm3, and in the 28 patients receiving stents with a higher dose (3.10 µg/mm2), the average amount was 13 mm3. In the 25 control patients, who received the same stent without any drug, it was 31 mm3. The corresponding restenosis rates were 12%, 4%, and 27%.15

Commenting on the results of the various clinical trials, Gregg W. Stone, MD, director of cardiovascular research and education at the Lenox Hill Heart and Vascular Institute in New York City and principal investigator for TAXUS IV, said, “Drug-eluting stents may be the biggest breakthrough in interventional cardiology since the stent itself. I think they will revolutionize the way we take care of patients with symptomatic atherosclerosis. At TCT 2002, some speakers joked that cardiovascular surgeons need to look for other day jobs.”

Other observers are more cautious.  Renu Virmani, MD, and her colleagues at the Armed Forces Institute of Pathology have noted delayed vascular healing in rabbit and pig arteries after placement of irradiating and drug-eluting stents, with no benefit apparent at 3 and 6 months.16 During a debate on the future of drug-eluting stents, she argued that there may be serious biological consequences, with the stents producing toxic vasculitis and rebound intimal hyperplasia. Although the clinical results to date have not shown such problems, only longer follow-up will reveal whether the animal data are applicable to humans.


Several investigators have examined whether these stentswhich cost almost $3,000will be affordable. Crucial to this analysis is knowledge of the financial impact of restenosis, which was studied by David J. Cohen, MD, MSc, director of interventional cardiology research at Beth Israel Deaconess Medical Center in Boston.17 The costs can be classified as direct, indirect, and noneconomic (eg, repeat revascularization procedures, caregiver time, and poorer quality of life, respectively). His research suggested a direct cost of $1,000 to $8,000 per patient for restenosis and indicated that a treatment that prevents restenosis will be cost neutral if the stent price is no more than $1,600 per patient. However, even if the treatment modestly increases the financial costs, it still may be worthwhile if it improves the quality of life. Simulations indicate that drug-eluting stents will be cost-effective for the majority of patients and cost-saving for high-risk patients.  Additional savings may be obtainable if the stents permit more patients to be treated by angioplasty rather than bypass surgery.

William W. O’Neill, MD, director of interventional cardiology at the William Beaumont Hospital in Royal Oak, Mich, projected the impact of drug-eluting stents on coronary disease.18 Even with the reduction in redo cases, use of the stents would convert a net income of $1,475 per case to -$153 per case. A similar analysis was carried out by the Health Alliance of Greater Cincinnati.19 These investigators assumed that all stents placed would be of the drug-eluting type, that 10% of bypass operations would be replaced by insertion of the new type of stents, that 15% of straightforward angioplasty procedures will change to stenting, and that use of the stents would reduce readmissions by 25%. According to their results, unless incremental reimbursement is provided, costs would increase 25%, and revenue would decline 5%, with a resulting net loss of nearly $11 million in the first year the new stents are used.

As a means of reducing the financial impact of drug-eluting stents, Issam Moussa, MD, of Lenox Hill Heart and Vascular Institute argued for selective use.20 A similar position was taken by A. Morton and colleagues of Sheffield Teaching Hospitals in the United Kingdom,21 where analysis suggested that the maximum benefit at the lowest cost could be provided by restricting the use of drug-eluting stents to patients such as diabetics. “There is a law of diminishing returns in terms of the level of restenosis reduction achieved as costs mount,” those authors said. Not addressed in these studies were the medicolegal implications of not using the new stent in a patient who suffered restenosis.

One encouraging development is the recent announcement by the Centers for Medicare & Medicaid Services that incremental reimbursement will be provided for use of drug-eluting stents both in elective procedures and in acute myocardial infarction. Typically, the increment will cover 1.3 to 1.5 drug-eluting stents. Commenting on this practice,   Stone observed that “if you put two stents in every patient, you are going to lose money, and if you put three stents in every patient, you are going to lose a lot of money.”


An inkling of the place of drug-eluting stents in practice was provided by a recent survey of an international group of interventional cardiologists by the TCTMD. Slightly more than half of the respondents said that at present, they use such stents in fewer than 25% of their patients, although 19% use the stents in 50% to 80% of their cases. Most (88%) expect to use more such stents in the future, and no one foresaw a decrease in use. The respondents, particularly those located outside the United States, think that cost will be the principal determinant of future stent usage, although availability and greater choices of stent diameter and length will also play a role.

NOTE: Space constraints preclude mention of many clinical trials that are in progress or have been completed. A summary is available at .

Judith Gunn Bronson, MS, is a contributing writer for Decisions in Axis Imaging News.


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