Drug-Eluting Stents: Did We "Over-Stent" Our Bounds?

Dr Myerson is Director of Preventive Cardiology, St. Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY.

Coronary angioplasty was introduced in the late 1970s and represented a major breakthrough in the treatment of coronary artery disease. The procedure used a balloon mounted on a catheter that was inflated at the site of a lesion to open an occluded vessel. Looking back, this now seems rather crude and was limited in how well operators could get vessels open and remain patent. In the late 1980s, Julio C. Palmaz, MD, and colleagues developed a balloon-mounted stent inserted in conjunction with angioplasty to keep the artery open. Comparison trials in the early 1990s found that stents were superior to simple balloon dilatation, and these devices quickly became the standard of care.

The stents gave a clear advantage but were not without problems. In particular, there was subacute thrombosis and vessel closure despite aggressive anticoagulation. Restenosis presented a problem in the months after implantation. Once again, investigators looked for a better way. And why not? The advances so far in percutaneous intervention each represented an improvement, with no major drawbacks. Industry was also glad to support development of a new device with billions of dollars in sales.

The next generation of stents, known as drug-eluting stents, delivered either antiproliferative or immunomodulatory materials to the area covered by the stent. The materials, for example, sirolimus (Rapamune) and paclitaxel (Taxus), inhibit the proliferative process that may foster restenosis. In 2003, the FDA gave approval to the use of drug-eluting stents. The FDA approved them for use in specific vessels, but off-label use spread, with drug-eluting stents being placed in longer, larger, and more complex lesions.

The initial studies showed good results, and there was little concern for the widespread off-label use. The first randomized trial, Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL), included 238 patients with single lesions. The restenosis rate at 6 months was 0% in the drug-eluting stent group compared with 26% in the bare-metal stent group.¹

Looking back, this total embrace of a new device may not have been so wise, according to Drs Campbell Rogers, of Brigham and Women’s Hospital, Boston, and Elazer Edelman, of Harvard-MIT Division of Health Sciences and Technology, Cambridge. “Contemporaneously, widespread adoption of drug-eluting stents has emboldened clinicians and provided greater security in the use of these devices in lesions or patients previously thought to be destined for device failure. For this reason, as well as many others, clinically testing stents beyond the limits of ‘safe and effective’ has become the norm.”²

The Bad News

The unbridled enthusiasm was tempered when studies revealed that there might be a problem with late events. While early stent thrombosis (within the first 30 days of implantation) was less frequent with drug-eluting stents, late thrombosis (after 30 days) seemed to occur more often. In March of 2006, investigators from the Basel Stent Kosten Effektivitäts Trial—Late Thrombotic Events Trial (BASKET-LATE) showed that during 7 to 18 months, the rate of cardiac death and nonfatal myocardial infarction (MI) was greater in the drug-eluting stent group than the bare-metal stent group. Follow-up of the RAVEL participants showed a similar pattern. A total of 19% of the patients who had received sirolimus-eluting stents died or had an MI compared with 11% of the bare-metal stent group. This difference did not reach significance but was seen as a red flag.

Meanwhile, the FDA had required manufacturers to follow patients in their stent trials for 5 years. Boston Scientific, makers of the paclitaxel-eluting Taxus stent, had 4-year follow-up data on nearly 3500 patients who received either a drug-eluting stent or a bare-metal stent. The group with the drug-eluting stent had higher rates of thrombus formation after 6 months than the bare-metal stent group. At 3 years the drug-eluting stent group had a 0.5% greater risk for thrombosis than the bare-metal stent group.

Despite the initial promise of drug-eluting stents, perhaps the interventional cardiology community had moved too fast in adopting the large-scale use of drug-eluting stents. Some feel they should now retreat, give up on these devices, and even go back to the use of bare-metal stents.

The Good News

Cardiology

The October issue of the American College of Cardiology bulletin devoted its cover story to this question.³ Spencer B. King III, MD, of Emory University, and Fuqua Chair of Interventional Cardiology, Piedmont Hospital, Atlanta, and past president of the American College of Cardiology, states that the evidence for increased risk of late thrombosis in drug-eluting stents is not yet definitive. David R. Holmes, Jr, MD, Scripps Professor of Medicine, Mayo Clinic, Rochester, adds that the overall incidence of late thrombosis is relatively low—approximately 0.5% to 0.8% in the early trials. He points out that as these stents were being used in more complex lesions, more complications should be expected. Also important, there are other factors that may be responsible for thrombosis, such as premature discontinuation of dual antiplatelet therapy.

Very recent data support those who want drug-eluting stents to stay. Two drug-eluting stent manufacturers, Boston Scientific and Johnson & Johnson, recently combined their databases and presented the results of their analysis at the October 2006 Trans-catheter Cardiovascular Therapeutics Symposium in Washington, DC. The data confirmed that after >1 year, drug-eluting stents had a greater incidence of stent thrombosis than bare-metal stents, although the numbers were small: 5 patients in the sirolimus stent group had stent thrombosis compared with none in the bare-metal stent group, and 9 patients in the paclitaxel group compared with 2 in the bare-metal stent group. The absolute risk, therefore, was quite small. Furthermore, the data did not show that drug-eluting stents resulted in greater risk for death or MI.

Journal of the American College of Cardiology

This month (December 2006), the will publish results of BASKET-LATE that looked at patients randomly assigned 2:1 to drug-eluting stents versus bare-metal stents. After 18 months, the rates of cardiac death and MI were not different between the drug-eluting and bare-metal stent groups. When the investigators looked at those who stopped clopidogrel, the drug-eluting stent group had more thrombosis-related events, mostly MI or death. The small number of events overall did not allow them to conclude that the use of drug-eluting stents was responsible for this.

Prescription for Caution

At the recent American Heart Association meeting in Chicago, Alfred A. Bove, MD, PhD, chief of cardiology, Temple University School of Medicine and Temple University Hospital, Philadelphia, quoted the FDA as saying that drug-eluting stents remain safe and effective when used in patients who are similar to the participants in trials that led to approval of the stents. Because much drug-eluting stent use is off label, Dr Bove feels that we should not stop using drug-eluting stents, but should realize the situations where we can safely use them.

Mun Hong, MD, director of interventional cardiology at St. Luke’s-Roosevelt Hospital, New York City, also feels that drug-eluting stents have a role. “They were not designed to solve all the potential problems of stents. We have to utilize all available data, including information on the benefit of prolonged dual antiplatelet therapy, to make the best decision for our patients.”

Our knowledge on how to use drug-eluting stents, and the stents themselves, will continue to evolve. Ongoing research should help guide us on where and how to safely use drug-eluting stents and under what circumstances. We may also find out how to improve antithrombotic therapy. Going back to bare-metal stents may be a step—but in the wrong direction.

References

1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002; 346: 1773-1780.

2. Rogers C, Edelman FR. Pushing drug-eluting stents into uncharted territory: simpler than you think—more complex than you imagine. Circulation. 2006; 113:2262-2265.

3. Holmes D, King S. Clarifying the DES issue. Cardiology. 2006; 10:4-5.