Comparison of Inflammatory Response After Implantation of Sirolimus- and Paclitaxel-Eluting Stents in Porcine Coronary Arteries

Abstract

Background-Although both sirolimus (CYPHER) and paclitaxel (TAXUS) drug-eluting stents have demonstrated efficacy and safety in clinical trials, human autopsy data have raised concerns about long-term healing and the potential for local inflammatory reactions. Methods and Results-Overlapping stents (CYPHER drug-eluting stents, Bx SONIC bare metal stents, TAXUS drug-eluting stents, and Liberté bare metal stents) were implanted in noninjured coronary arteries of 58 domestic swine. Histopathological evaluation of proximal, overlapped, and distal stented segments was determined with emphasis on inflammation at 30, 90, and 180 days. Circumferential granulomatous inflammation in all stented segments was defined as inflammation consisting of macrophages, multinucleated giant cells, lymphocytes, and granulocytes, including many eosinophils, adjacent to almost all struts. Circumferential granulomatous inflammation was more prevalent in CYPHER (9 of 23, 39%) compared with TAXUS (1 of 21, 5%; Pϭ0.01) and control bare metal stents (0 of 44) in the combined 90-and 180-day cohorts. Only CYPHER specimens showed marked adventitial inflammation (Pϭ0.0025) and fibrosis (Pϭ0.0055) accompanied by extensive remodeling. Fibrin deposition within neointima and medial smooth muscle cell death were greater (both PϽ0.001) in TAXUS than CYPHER at 30 days, with more fibrin in TAXUS than CYPHER through 90 days (PϽ0.05). Conclusions-Although these data cannot be directly extrapolated to humans, the high prevalence in this porcine model of diffuse granulomatous inflammation seen with CYPHER stents, persisting at 180 days and associated with extensive remodeling of the artery, and persistent para-strut fibrin deposition with TAXUS stents emphasize the need for further investigation of biocompatibility with these and other novel combination drug/polymer drug-eluting stents. (Circulation.

Downstream coronary effects of drug-eluting stents

“…Although these results demonstrate protection from lesion formation, toxicity of antiproliferative drugs still remains a concern, particularly in tissues affected by infarction because of the potential for inducing a thrombogenic state through platelet dysfunction as well as neoatherosclerosis. 18,31,39 Despite these uncertainties, our findings should encourage a clinical trial with advanced coronary imaging tools to further investigate the effects that DES have on atherosclerosis in downstream vessels.…”

“…29,30 In addition, paclitaxel is a well-known immunomodulatory agent and has also been associated with atherosclerotic regression in animal models, as well as reduced inflammation in stented porcine arteries. 23,31 Furthermore, given that the product labeling and pharmacokinetic studies in sirolimus-eluting stents describe serum detectability of antiproliferative agents for over 2.5 weeks and an estimated 3 month elution period after implantation (depending on stent type), one would expect these drugs to have long-term effects on the downstream vascular bed. [32][33][34] As confirmation of prolonged biologic effect, neointimalization, the process by which the stent is covered by new endothelium postdeployment, appears to be delayed up to 12 months in sirolimus-eluting stents.…”

Nobori Biolimus-Eluting Stent vs. Permanent Polymer Drug-Eluting Stents in Patients Undergoing Percutaneous Coronary Intervention

“…9 SES and PES have been associated with diffuse granulomatous inflammation and para-strut fibrin deposition, respectively. 26 On the other hand, persistent inflammation induced by permanent polymer DES may act as a primary driver of late restenosis via the vehicle of neointimal proliferation, leading to a "catchup phenomenon". Contrariwise, the absence of a permanent polymer from the DES platform seems to mitigate this late reduction in anti-restenotic efficacy.…”

Clinical outcomes in patients with ST-segment elevation myocardial infarction treated with everolimus-eluting stents versus bare-metal stents (EXAMINATION): 5-year results of a randomised trial

“…[3][4][5][6][7] Conversely, these benefi ts were counterbalanced by an increased risk of very late stent thrombosis, [8][9][10][11] safety concerns that were confi rmed on autopsy, and intravascular imaging studies showing evidence of incomplete endothelialisation, delayed arterial healing, and vessel remodelling because of chronic infl ammation. [12][13][14][15] The development of neotherosclerosis, 16 which might occur earlier after DES than after BMS, 17 has also been identifi ed as a potential cause.…”