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Drug-Eluting Stent Thrombosis: Weighing the Evidence

Four studies add to the evidence base that experts must consider as they assess potential risks.

Reports of late thrombosis after drug-eluting stent (DES) implantation have sparked numerous mainstream-press reports. An FDA advisory panel was recently convened to study the issue; an official FDA response is pending. Data from four recent studies are among the evidence for the FDA to consider in assessing the risks and benefits of widely used DES technology.

One research group synthesized data from 14 randomized trials, involving 6675 patients, in which DES (47% sirolimus-eluting; 53% paclitaxel-eluting) was compared with bare-metal stents (BMS). Thrombosis incidence, per 1000 patients treated, was similar between DES and BMS within 30 days after implantation (4.4 and 5.0 events, respectively), but incidence was significantly greater with DES than with BMS more than 6 months after implantation (4.4 vs. 0.6 events) and more than 1 year after implantation (5.0 vs. 0.0 events). When stent thromboses occurred more than 30 days after implantation, they tended to appear much later with DES than with BMS (median, 15.5 months vs. 4.0 months after implant). Differences between sirolimus- and paclitaxel-eluting stents did not appear to be substantial, but direct comparisons were not made.

Using prospective data from a large, 140-center registry, another group of investigators studied 6906 consecutive patients who each received a single stent (56% sirolimus-eluting; 38% paclitaxel-eluting; 6% BMS). BMS recipients were older and sicker than DES recipients. DES and BMS recipients had a similar adjusted 1-year rate of death or MI combined, but the target-vessel revascularization (TVR) rate at 1 year was significantly lower with DES (6.0% vs. 9.5%; adjusted hazard ratio, 0.58). The 1-year incidence of stent thrombosis was similar between BMS recipients (0.8%) and DES recipients (0.6%) and by DES type (sirolimus-eluting, 0.5%; paclitaxel-eluting, 0.8%, P=0.06). Notably, follow-up was less than 90% complete at 1 year.

In a single-center observational study, 746 patients who had received 6 months of clopidogrel maintenance therapy during a 6-month randomized DES-versus-BMS trial were followed for an additional 12 months after clopidogrel discontinuation. The 18-month combined incidence of cardiac death or MI was similar with DES and BMS, but event rates in the first 30 days were higher with BMS due to baseline patient characteristics. After discontinuation of clopidogrel (7–18 months post-implant), the incidence of cardiac death or MI was significantly higher with DES than with BMS (4.9% vs. 1.3%), even after adjustment for potential confounders (HR, 2.2; P=0.03). Thrombosis-related events occurred a median of 116 days (range, 15–362) after discontinuation of clopidogrel, accounted for 25% of late events, and (consistent with the late-outcomes data) tended to occur more often with DES than with BMS.

Cleveland Clinic researchers retrospectively identified 984 patients who presented to their center over a 4.3-year period with clinical evidence of BMS in-stent restenosis (ISR; 1186 total cases); 64.1% had exertional angina, 26.4% had unstable angina requiring hospitalization before coronary angiography, and 9.5% had acute MI (STEMI, 7.3%; NSTEMI, 2.2%). Multivariate predictors of an acute presentation with BMS ISR included prior bypass surgery, current renal insufficiency, female sex, lower LV ejection fraction, and lack of beta-blocker use.

Comment: Previous evidence has shown clearly that drug-eluting stents reduce the risk for restenosis and the need for subsequent TVR by up to 70%, compared with bare-metal stents. However, randomized and observational studies have documented a consistent and disturbing small increase in the absolute risk for late stent-related thrombotic events with the drug-eluting devices (an excess of 1 event per 200 patients in randomized trials; greater in real-world patients). Nonetheless, DES and BMS are associated with similar rates of cardiac and all-cause mortality, likely due to the greater risk for restenosis-associated events with BMS. Whether long-term use of clopidogrel can reduce the risk for late DES thrombosis is not known, although recent observational findings suggest that the stent recipients who fare best are those who receive both DES and long-term clopidogrel maintenance therapy (Journal Watch Cardiology Dec 5 2006). For now, I continue to recommend DES for patients at increased risk for restenosis, and to have them maintain clopidogrel therapy for at least 1 year after implantation.

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology December 20, 2006

Citation(s):

Bavry AA et al. Late thrombosis of drug-eluting stents: A meta-analysis of randomized clinical trials. Am J Med 2006 Dec; 119:1056-61.

• Medline abstract (Free)

Williams DO et al. Outcomes of 6906 patients undergoing percutaneous coronary intervention in the era of drug-eluting stents: Report of the DEScover registry. Circulation 2006 Nov 14; 114:2154-62.

Pfisterer M et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: An observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006 Dec 19; 48:2584-91.

• Original article (Subscription may be required)
• Medline abstract (Free)

Chen MS et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006 Jun; 151:1260-4.

• Medline abstract (Free)