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Neoatherosclerosis frequently develops in drug-eluting stents (DES) within 2 years after implantation, according to a pathology study published online March 2, 2011, ahead of print in the Journal of the American College of Cardiology. The diseased tissue is also found in bare-metal stents (BMS) but less often and much longer after implantation.

To investigate the incidence, characteristics, and temporal development of atherosclerosis within stents, researchers led by Renu Virmani, MD, of CVPath Institute (Gaithersburg, MD), looked at 299 consecutive autopsy cases from the CVPath stent registry in which the implanted device had been in place for more than 30 days at the time of death. Of 406 lesions, 197 had been treated with BMS, while 209 had received DES (103 SES and 106 PES).

Neoatherosclerosis was defined as clusters of lipid-laden foamy macrophages within the neointima with or without a necrotic core.

The median duration of DES implantation was about half that of BMS (361 days; range 172-540 vs. 721 days; range 271-1,801; P < 0.001). Notably, 85% of DES had been placed within 2 years, while 55% of BMS had been in place for longer periods, with 17% extending beyond 6 years.

DES More Susceptible Than BMS

Neoatherosclerosis was found nearly twice as often in DES as in BMS, with DES disease almost evenly divided between peristrut foamy macrophage clusters and fibroatheromas. Moreover, the temporal pattern of disease onset differed markedly between the stent types. Atherosclerotic changes occurred within a median of 420 days (range 361-683) in DES vs. 2,160 days (range 1,800-2,880) in BMS (P < 0.001).

On the other hand, the incidence of unstable lesions characterized by thin-cap fibroatheroma or plaque rupture was similar for the 2 stent types, although these more advanced lesions tended to occur much earlier in DES than in BMS, after an average 1.5 years vs. 6.1 years (table 1).

Table 1. Incidence and Type of Neoatherosclerosis Stratified by Implant Duration

Abbreviation: TCFA, thin-cap fibroatheroma.

Moreover, within the DES category, neoatherosclerotic changes were more common with sirolimus-eluting than with paclitaxel-eluting stents for implants of 2 years or less (37% vs. 21%; P = 0.021) but not for longer durations.

With regard to the location of neoatherosclerosis within the stent, atherosclerotic changes in BMS were more likely to be seen in proximal lesions than in mid/distal lesions (27% vs. 12%; P = 0.014), while in DES atherosclerosis was more evenly distributed among those sites (33% vs. 30%; P = 0.611).

Interestingly, among patients who suffered stent-related death, the incidence of neoatherosclerosis was similar in BMS (18%) and DES (27%; P = 0.339). In patients with non-stent-related death, however, DES were more likely than BMS to exhibit neoatherosclerosis (42% vs. 20%; P < 0.001).

Multiple logistic modeling identified 5 independent predictors of neoatherosclerosis:

• Younger age (OR 0.963; P < 0.001)
• Longer implant duration (OR 1.028; P < 0.001)
• SES use (OR 6.534; P < 0.001)
• PES use (OR 3.200; P = 0.001)
• Underlying unstable plaque (OR 2.387; P = 0.004)

“These observations raise the question whether neoatherosclerosis seen within DES as well as BMS at follow-up may in part be responsible for some late thrombotic events,” the authors say.

Dysfunctional Stent ‘Healing’

Dr. Virmani and colleagues hypothesize that the neoatherosclerotic process involves a dysfunctional endothelialized stent covering that cannot effectively prevent uptake of circulating lipids. But the mechanisms appear to differ between the stent types, with disease more related to incomplete endothelialization in DES and to shear stress in BMS. The relatively faster development of neoatherosclerosis in DES is likely due to the effect of the stent drug, the investigators add.

In an accompanying editorial, L. Maximilian Buja, MD, of St. Luke’s Episcopal Hospital (Houston, TX), writes that the strength of pathological studies lies in identifying the underlying mechanisms that contribute to the vascular response to stents, noting that previous findings “have pointed to the importance of complete and effective endothelialization.”

However, he observes, simply determining number and percent of covered and uncovered struts is not a definitive approach to evaluating the extent and quality of endothelial covering. It should be supplemented by other techniques such as immunocytochemistry and functional assessment.

The Dead Tell Tales—But Mostly About Themselves

The most important caveat about this and any autopsy study is that the characteristics of a cohort consisting entirely of patients who have died may not be comparable to those of patients in general, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said in a telephone interview with TCTMD.

“It’s interesting that there is a lower incidence of neoatherosclerosis in BMS than DES,” he observed. “It reemphasizes what we kind of already knew: that at least the first generation of DES are not vessel friendly, possibly because of the polymer that releases the drug or chronic inflammation due to the presence of uncovered metal.”

However, “there is good evidence that the second-generation DES are better, certainly at the clinical level,” Dr. Brener said. “And some data, particularly for Endeavor, [with regard to] the biology of the stent itself.”  Furthermore, these findings whet clinicians’ appetite for bioabsorbable stents, he added.

“The study observations are important because they provide an alternative explanation of why events occur, particularly late after stent implantation,” Dr. Brener concluded. “We shouldn’t assume that it’s always because of stent thrombosis.”

Good News/Bad News

“I see this as a sort of good news/bad news story,” Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), told TCTMD in a telephone interview. “The bad news is that 31% of DES patients who are examined after dying a little more than a year after their implant have some evidence of atherosclerosis. The good news is that it’s rarely advanced disease. There’s only a 3.1% incidence of ruptured plaque or thin-cap fibroatheroma.”

Noting that neoatherosclerosis is a fairly recently recognized entity, Dr. Ellis said, “This is probably the best report we have on it so far.” However, he underlined that “the follow-up on the DES side is relatively short. You have to wonder what’s going on later. To me the take-home message is that we need to do a better job of following patients up in the major randomized trials beyond 5 years. We really have a paucity of [such long-term] data.”

Drs. Brener and Ellis agreed that given the current imaging technology, monitoring DES patients for evidence of unstable plaque is not feasible. But Dr. Ellis said that a study “where you use IVUS, maybe OCT, or infrared spectroscopy on a consecutive cohort of patients that have been implanted with DES between, say, 2 and 10 years ago would be really interesting and perhaps more meaningful than an autopsy study.”

2. Buja ML. Vascular responses to percutaneous coronary intervention with bare-metal stents and drug-eluting stents: A perspective based on insights from pathological and clinical studies. J Am Coll Cardiol. 2011;Epub ahead of print.

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