Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans

Abstract

Background: Clinical trials have demonstrated that the second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent (PES) and is noninferior or superior to the sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from those to SES and PES because the pathology of CoCr-EES has not been described in humans.

Methods and results: A total of 204 lesions (SES=73; PES=85; CoCr-EES=46) from 149 autopsy cases with duration of implantation >30 days and ≤3 years were pathologically analyzed, and comparison of vascular responses was corrected for duration of implantation. The observed frequency of late and very late stent thrombosis was less in CoCr-EES (4%) versus SES (21%; P=0.029) and PES (26%; P=0.008). Neointimal thickness was comparable among the groups, whereas the percentage of uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%; P<0.0005) and PES (18.7%; P<0.0005). CoCr-EES showed a lower inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%; SES=35%; PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%; SES=40%; PES=19%; P=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%; SES=5.5%; PES=1.2%).

Conclusions: CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less late and very late stent thrombosis compared with SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathological events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.

Keywords: coronary restenosis; pathology; stents; thrombosis.

Figure 1

Representative images of SES, PES, and CoCr-EES implanted for stable CAD (A: a to f) and for ACS (B: g to l). (a, b) Histologic sections from a 53 year-old-man with SES implanted in the proximal LAD for 13 months. A low-power image (a) shows mild neointimal growth and underlying fibrocalcific plaque. Focal uncovered struts are highlighted in a high-power image in b. (* indicates stent strut.) (c, d) Histologic sections from a 71-year-old man with PES implanted in the RCA 11 months antemortem. A low-power image (c) shows mild to moderate neointimal proliferation and underlying fibroatheroma. Note uncovered struts with persistent peri-strut fibrin deposition shown at high power image in d. (e, f) Histologic sections from a 60-year-old man who received CoCr-EES in the mid LCX 6 months antemortem. A low-power image (e) shows mild neointimal proliferation and underlying fibrocalcific plaque. All struts are covered with proteoglycan-rich neointima with absence of fibrin, which is highlighted in a high-power image in f. (g, h) Histologic sections from a 74-year-old woman who received SES in the proximal LAD for AMI 18 months antemortem, who died of diffuse severe CAD. A low-power image (g) shows mild neointimal proliferation. Note focal uncovered struts and strut penetration into the necrotic core (NC) (h). (i, j) Histologic sections from a 64-year-old woman with PES implanted in the RCA for AMI 9 months antemortem, who died of congestive heart failure. A low-power image (i) shows patent lumen with stent struts surrounded by fibrin and an underlying NC. Note uncovered struts with fibrin deposition which overlie the NC (j). (k, l) Histologic sections from a 67-year-old man who received CoCr-EES in the proximal LAD for non-ST elevation AMI 5 months antemortem, who died of non-cardiac causes. A low-power image (k) shows mild neointimal proliferation and an underlying large NC. All struts are covered with a thin neointima overlying the NC, which is highlighted in the high-power image in l. All histologic sections are stained with Movat pentachrome. AMI=acute myocardial infarction. Other abbreviations as in Table 1.

Figure 2

Late stent thrombosis in two cases with CoCr-EES. (A and B) Histologic sections from a 55-year-old man with CoCr-EES implanted over an underlying PES in the proximal RCA 6 months antemortem, who died suddenly of stent thrombosis. A low-power image (A) shows occlusive luminal thrombus (Thr) within the stents with underlying calcified plaque (Ca=calcification). A few struts of CoCr-EES are covered with thin neointima but majority of the struts are uncovered, which is highlighted in a high-power image in B. (C and D) Histologic sections from a 72-year-old woman with CoCr-EES implanted over an underlying PES in the proximal LAD 7 months antemortem. The patient presented with AMI from stent thrombosis and underwent balloon angioplasty which resulted in rupture of LAD. A low-power image (C) shows in-stent restenosis with luminal thrombus (Thr) where neointima is focally dissected due to the balloon angioplasty with overlying non-occlusive thrombus. A high-power image (D) shows erosive neointima with overlying fibrin and platelet thrombus. (A) and (B) are Movat pentachrome staining, and (C) and (D) are stained with hematoxylin and eosin (H&E).

Figure 3

Box-and-whisker plots showing maximum neointimal thickness (A) and bar graphs showing prevalence of DES lesions with >30% uncovered struts (B) stratified by duration of implant in SES, PES, and CoCr-EES. In box-and-whisker plots, lines within boxes represent median values; the upper and lower lines of the boxes represent the 75th and 25th percentiles, respectively; and the upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. P values for CoCr-EES versus SES and for CoCr-EES versus PES are presented. Multiple-comparison threshold is used as in Table 1.

Figure 4

Sub-group analysis for the presence of >30% uncovered struts in CoCr-EES versus SES and PES. All regression analyses include duration of implant as a covariate. Multiple-comparison threshold is used as in Table 1. *Underlying stable plaques include fibroatheroma, fibrocalcific plaque, nodular calcification, pathologic intimal thickening, and restenotic lesions. OR=odds ratio; CI=confidence interval. Other abbreviations as in Table 1.

Figure 5

Hypersensitivity reaction in SES versus focal inflammation in CoCr-EES. (A) Histologic sections from a 58-year-old man with two SES and one CoCr-EES, who died suddenly one day after nasal polyp surgery. Dual antiplatelet therapy was stopped 5 days prior to the surgery. (a and b) SES implanted in distal RCA (a) and in the mid LCX (b) for 3 years. Radiographs show SES with (a-1) and without (b-1) underlying severe calcification, with no stent fracture. A low-power histology image in a-2 (Movat) shows occlusive platelet rich thrombus (Thr) with transmural inflammation and extensive malapposition of stent struts with fibrin deposition (double arrows). A low-power image in b-2 shows mild neointimal proliferation with transmural inflammation but no luminal thrombus. High-power images (a-3 to a-6 and b-3 to b-6) show extensive inflammation predominantly consisting of eosinophils (Luna stain [a-4 and b-4]) and T-lymphocytes (CD45RO [a-5 and b-5]) but rare B-lymphocytes (CD20 [a-6 and b-6]). (c) A CoCr-EES implanted in the proximal RCA of 7 months duration. A radiograph (c-1) shows a stent with underlying severe calcification and no fracture. A low-power histology image (c-2) shows a patent lumen with thin neointima. High power images (c-3 to c-6) show focal mild inflammation consisting of eosinophils (c-4) and T-lymphocytes (c-5) but no B-lymphocytes (c-6). (B) Histologic sections from a 51-year-old man who received CoCr-EES in the distal LCX 4 months antemortem. A low-power image (d) (H&E) shows a patent lumen with mild neointimal proliferation and underlying calcified plaque. High power images (e to h) show focal inflammation within the neointima consisting of eosinophils (f) and T-lymphocytes (g), but no B-lymphocytes were observed (h). (* indicates stent strut.)

Figure 6

Neoatherosclerosis in CoCr-EES. (A) Histologic sections from a 49-year-old man with CoCr-EES implanted in the mid LAD 2 years antemortem. A low-power image (a) (Movat) shows a patent lumen with moderate neointimal growth (50% cross-sectional area narrowing). (b) A high-power image of the boxed area in (a) shows foamy macrophage accumulation within the neointima close to the luminal surface, which is confirmed by imuunostaining for CD68-positive macrophages (c). (B) Histologic sections from a 73-year-old man with CoCr-EES implanted in the mid LAD for 3 years. A low-power image (d) (Movat) shows moderate luminal narrowing with moderate neointimal growth (69% stenosis) and underlying fibroatheroma. A high-power image (e) of the boxed area in (d) shows necrotic core formation within the neointima where CD68-positive macrophages are identified (f). (* indicates stent strut.)

Figure 7

Stent fracture in CoCr-EES. (A) Bar graph showing observed frequency of overall fracture, grade V fracture (acquired transection with gap in the stent body), and fracture-related thrombosis or restenosis, in CoCr-EES versus SES and PES. The analyses include duration of implant as a covariate. Multiple-comparison threshold is used as in Table 1. (B to D) A case of grade V CoCr-EES fracture showing restenosis at fracture site (Case #3 in Table 3). Radiograph of left obtuse marginal branch (B) shows a single CoCr-EES with multiple grade V fractures, which are highlighted in (C) (arrows=fracture sites). (D) Histologic sections of the fracture site (corresponding with [a] to [e] in panel C) showing focal restenosis. Note single stent struts (*) in the most severely narrowed section in b.