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J Am Coll Cardiol, 2006; 48:193-202, doi:10.1016/j.jacc.2006.03.042
(Published online 4 May 2006). © 2006 by the American College of Cardiology Foundation |
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,1
* CVPath, International Registry of Pathology, Gaithersburg, Maryland
Cardiac Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
Miami Dade County Medical Examiner Department, Heart Radiology, Miami, Florida
Interventional Cardiology Devices Branch, U.S. Food and Drug Administration, Rockville, Maryland
Manuscript received January 26, 2006; revised manuscript received March 10, 2006, accepted March 16, 2006.
* Reprint requests and correspondence: Dr. Renu Virmani, CVPath, International Registry of Pathology, 19 Firstfield Road, Gaithersburg, Maryland 20878 (Email: rvirmani{at}cvpath.org).
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Abstract |
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BACKGROUND: Although DES reduce the need for repeat revascularization compared with bare-metal stents (BMS), data suggest the window of thrombotic risk for Cypher (Cordis Corp., Miami Lakes, Florida) and Taxus (Boston Scientific Corp., Natick, Massachusetts) DES extends far beyond that for BMS.
METHODS: From a registry of 40 autopsies of DES (68 stents), 23 DES cases of >30 days duration were compared with 25 matched autopsies of BMS implantation. Late stent thrombosis was defined as an acute thrombus within a stent >30 days old.
RESULTS: Of 23 patients with DES >30 days old, 14 had evidence of LST. Cypher and Taxus DES showed greater delayed healing characterized by persistent fibrin deposition (fibrin score 2.3 ± 1.1 vs. 0.9 ± 0.8, p = 0.0001) and poorer endothelialization (55.8 ± 26.5%) compared with BMS (89.8 ± 20.9, p = 0.0001). Moreover, DES with LST showed more delayed healing compared with patent DES. In 5 of 14 patients suffering LST, antiplatelet therapy had been withdrawn. Additional procedural and pathologic risk factors for LST were: 1) local hypersensitivity reaction; 2) ostial and/or bifurcation stenting; 3) malapposition/incomplete apposition; 4) restenosis; and 5) strut penetration into a necrotic core.
CONCLUSIONS: The Cypher and Taxus DES result in delayed arterial healing when compared with BMS of similar implant duration. The cause of DES LST is multifactorial with delayed healing in combination with other clinical and procedural risk factors playing a role.
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Current polymer-based sirolimus-eluting (Cypher, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting (Taxus, Boston Scientific Corp., Natick, Massachusetts) stents are the only DES approved by the U.S. Food and Drug Administration (FDA) for human use. Some published studies of animal models with similar DES implanted in normal arteries show a substantial impairment of arterial healing relative to BMS (9–13). To date, there has been no systematic published analysis of the long-term effects of DES on arterial healing in humans. We examined 40 consecutive autopsies of patients who died subsequent to DES implantation to determine the long-term effects of DES placement on coronary arterial healing and to identify pathologic mechanisms underlying LST.
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Materials and methods |
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Stented arteries had been fixed in 10% buffered formalin, dissected off the heart, examined via radiography, and submitted for plastic embedding. Arteries were sectioned 2 to 3 mm apart and stained with hematoxylin and eosin and Movat pentachrome as previously described (17). Cases with histologic evidence of an acute occlusive or nonocclusive mural thrombus within a coronary artery stent in place >30 days were defined as LST. Stented arteries with severe narrowing, defined as in-stent luminal cross-sectional area narrowing of 
75% by neointimal growth, were defined as restenosis; and those <75% area narrowing were designated as patent stents.
Morphologic and morphometric measurements. Computer-guided morphometric measurements were performed using IPLab Spectrum software (Scanalytics Inc., Vienna, Virginia) on sections from stents implanted for >30 days. Digital images were captured (4x magnification), and area measurements included the internal elastic lamina, plaque burden, stent area, and lumen area; stent lengths were measured from radiographs. For calculation of in-stent neointimal growth, fibrin deposition, and surface endothelialization, stents with occlusive thrombi were excluded to overcome biased measurements. Ordinal data for fibrin were collected on each stent section using a scale of 0 to 3+ as previously reported (18). Inflammation was scored at each stent strut using a scale from 0 to 5 (with 0 for 0 to 25 surrounding inflammatory cells, 1 for 25 to 50, 2 for 50 to 100, 3 for 100 to 150, 4 for 150 to 200, and 5 for >200 surrounding inflammatory cells). The percentage of struts with surrounding fibrin and luminal surface endothelium was also recorded. Delayed arterial healing was defined as persistence of fibrin beyond 30 days. Total eosinophils were evaluated by counting the four most severely inflamed struts per section and reported as eosinophils per strut.
Statistical analysis.
Continuous variables are presented as the mean ± SD and categorical variables either as mean ± SD or frequency (%). Continuous variables were first checked for normal distribution using Shapiro-Wilk goodness-of-fit test and compared by Student t test for normally distributed or a Wilcoxon rank-sum test for non-normally distributed variables. For comparison of rates of LST between the DES group and the control BMS group, a Fisher exact test was used. A p value 
0.05 was considered significant. The percentage of struts covered by endothelial cells was plotted against the duration of implant to derive a slope, intercept, and correlation coefficient to determine relationships.
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Results |
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Procedural outcome. At the time of coronary intervention, all patients had angiographically successful stent deployment with one DES placed in 15 patients, two DES in 7 patients, and three DES in 1 patient. Mean stent length for DES was 32.1 ± 17.3 mm (range 8 to 76 mm; median 25 mm, 75% <35 mm). Ostial/bifurcation stenting was performed in three cases (left circumflex/obtuse marginal bifurcation stenting, crush technique; left anterior descending/diagonal ostial stenting; and left anterior descending at the take-off of left circumflex [ostial stenting]), and all three cases showed occlusive thrombi.
Thirty-six BMS were examined from 25 individuals (mean age 61 ± 9 years) with one BMS placed in 18 patients, two BMS in 4 patients, three BMS in 2 patients, and four BMS in 1 patient. Mean stent length for BMS was 20.2 ± 11.9 mm (range 8 to 42 mm; median 18 mm, 75% <33 mm). Ostial/bifurcation stenting was performed in two cases (left anterior descending/diagonal bifurcation stenting, V-stenting technique; and left circumflex/obtuse marginal ostial stenting), and both died secondary to restenosis without evidence of thrombosis.
Antiplatelet therapy. During catheterization procedures, aspirin and clopidogrel were administered to all patients; 17 of 23 patients were being continued on an antiplatelet regimen at the time of death. In five cases, it was confirmed that patients were not receiving clopidogrel or aspirin at the time of death. In one case the antiplatelet therapy was unknown at the time of death. Of the 17 patients who could be confirmed to be on antiplatelet therapy, 14 were maintained on dual antiplatelet therapy with aspirin and clopidogrel. An additional two patients were receiving clopidogrel monotherapy, and one patient was on aspirin only.
Causes of death. Thirteen of the 14 DES cases of LST died of cardiac causes (Fig. 1). The cause of death was either total thrombotic occlusion of the stent or subtotal occlusion with distal embolization leading to acute myocardial infarction or sudden cardiac death. Seven DES cases had patent stents, and none died of stent-related complications. Two DES cases had in-stent restenosis and died of acute myocardial infarction or sudden cardiac death. Two of the 25 BMS patients died of LST. Eighteen BMS cases had patent stents, and no patients died of stent-related complications (15 patients had a cardiac cause of death and 3 had a noncardiac cause of death). Five patients with BMS implants had in-stent restenosis and died secondary to stent related acute myocardial infarction (three cases) or sudden cardiac death (two cases).
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30 days).
Of 23 DES cases, 14 (61%) had stent thrombosis, and of the 25 cases of BMS included as controls, 2 (8%) had LST (p = 0.0001). Both cases of BMS LST also had evidence of in-stent restenosis. The rate of LST in the control BMS group is similar to that previously reported from our registry of BMS (19). Comparison of DES and BMS implants. Stent length in DES was greater than in BMS (32.1 ± 17.3 vs. 20.2 ± 11.9, p = 0.01) (Table 1). The DES had significantly less in-stent neointimal growth compared with BMS (neointimal area 2.9 ± 1.1 mm2 vs. 4.9 ± 3.0 mm2, p = 0.005; % stenosis 54.4 ± 23.6% vs. 66.5 ± 22.0%, p = 0.05). Although the extent of overall inflammation was not significantly different in the two groups, eosinophils surrounding struts were more frequent in DES compared with BMS (5.6 ± 11.1 vs. 0.6 ± 2.3 per strut, p = 0.01). The DES also showed significantly higher fibrin scores (2.3 ± 1.1 vs. 0.9 ± 0.8, p = 0.0001) and percentage of struts surrounded by fibrin (49.3 ± 30.8% vs. 22.3 ± 17.8%, p = 0.0005). The percentage of endothelialized stent struts was significantly higher in BMS compared with DES (89.8 ± 20.9% vs. 55.8 ± 26.5%, p = 0.0001). Regardless of implant duration, BMS stents showed significantly greater endothelialization than DES (Fig. 2).
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Pathologic mechanisms of DES LST. In all 14 patients with LST delayed arterial healing was found as a cardinal risk factor and was the only pathologic risk factor in 3 (21%) patients. Additional pathologic risk factors for LST were found in 11 of the 14 patients (Table 3). They were grouped into five major categories: 1) chronic inflammation characterized by lymphocytes, macrophages, and extensive eosinophilic infiltration of the intima and media (hypersensitivity) (n = 3); 2) stenting along major side branches using the crush technique and/or stenting over major branch points (n = 3) (Fig. 3); 3) malapposition refers to arterial wall expansion (positive remodeling) late after stent deployment (>6 months) or incomplete apposition caused by suboptimal stent deployment (n = 2) (Fig. 4); 4) in-stent restenosis (n = 2) with superimposed thrombosis; and 5) struts penetration of necrotic core (n = 1). In comparison, in the 2 patients with BMS the cause of LST was in-stent restenosis.
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The Cypher stents showed greater inflammatory reaction including eosinophils and giant cells at 60 days, whereas Taxus stents predominantly showed greater fibrin deposition and fewer inflammatory cells at a similar time point. At 120 days there was focal fibrin deposition and giant cell reaction around Cypher stents, whereas Taxus stents showed greater inflammation consisting of lymphocytes, eosinophils, and macrophages at this time point. Fibrin deposition persisted in both Taxus and Cypher stents. In comparison, at 60 days BMS did not show fibrin deposition, but relatively greater neointimal coverage of stent struts was seen. Giant cell reaction and inflammation was substantially less in the BMS examined. The 120-day BMS showed circumferential neointimal growth with complete coverage of stent struts. Chronic inflammatory cells (mostly lymphocytes, macrophages, and giant cells) are commonly seen in BMS at this time point but without evidence of eosinophilic infiltrate.
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Discussion |
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Histologic findings 30 days.
In patients suffering from LST after DES placement, the major pathologic finding distinguishing thrombosed from patent DES was evidence of significantly greater delay in arterial healing as manifested by persistent peristrut fibrin deposition and poor endothelialization. In contrast, the control group of BMS implants showed greater neointimal healing with very little peristrut fibrin and near complete endothelialization consistent with earlier pathologic studies of BMS, which have suggested near-complete endothelialization by 3 to 4 months (19,20). Throughout a wide range of time points examined, BMS consistently showed evidence of greater healing when compared with DES.
Mechanisms of delayed arterial healing. The mechanisms by which DES cause a prolongation of arterial healing in humans are poorly understood. Although sirolimus or paclitaxel reduce neointimal formation by impeding smooth muscle cell proliferation and migration, these drugs also impair the normal healing processes of the injured arterial wall (21–23). Animal studies using healthy pigs have shown persistence of fibrin at 28 days, however, endothelialization was similar between DES and BMS (9). Also, it is well known that in pig coronary arteries endothelialization after BMS implantation may be >80% by 7 days and that healing takes longer in humans as compared with normal animal coronary arteries (24). Moreover, rates of endothelialization after stent implantation seem to vary among currently used animal models. Although experience from porcine coronary implants suggests complete endothelialization 28 days after stent deployment (11), our own data of rabbit iliac implants indicate a clear delay of endothelialization in sirolimus- and paclitaxel-eluting stents (13).
Because of the small number of stents examined, it is impossible to make definitive comparative conclusions about the selective effects of each type of drug/stent combination on arterial wall healing in humans. Coronary segments implanted with either type of DES showed delayed healing when compared with BMS.
Both the Cypher and Taxus stents allow the selective release and binding of drug that significantly influences arterial wall concentration and distribution responsible for local pharmacologic effects (25). For example, Cypher stents elute nearly all of the loaded sirolimus by 30 days from a polyethylene-co-vinyl acetate and poly n-butyl methacrylate non-erodable polymer (10,26). In contrast, Taxus stents release paclitaxel as a initial burst from poly(styrene-b-isobutylene-b-styrene) polymer followed by a constant slow release up to 90 days (R. Virmani, unpublished data, April 2005).
The thrombus as well as lipid within the stented atherosclerotic plaque may also influence drug distribution and retention (27). Previous data regarding drug levels of sirolimus and paclitaxel delivered on stents have been generated in normal animals (10,26), and given the hydrophobic nature of both compounds it is unclear whether atherosclerosis prolongs tissue retention leading to long-term biological effects.
Pathologic correlates: late thrombosis is likely multifactorial in causality. Although the degree of arterial healing was significantly less in thrombosed DES sections, stent length was significantly greater. A governing principle in the deployment of DES has been to effectively treat the entire lesion (28,29). This dictum has led to the use of longer stents.
The findings of this study support prior clinical observations that the risk of stent thrombosis after DES placements is related to stent length (29,30). As stent length increases, it may be more difficult to ensure complete deployment (30,31), causing a predispositon toward thrombosis by creating abnormal shear stress (32,33) at malapposed or incompletely apposed stent struts. Malapposition/incomplete apposition was observed in 2 of 14 cases and thus represents an additional risk factor for LST. This is consistent with intravascular ultrasound studies that have shown that stent malapposition and underexpansion are significantly associated with stent thrombosis (34).
Other additional risk factors that predispose toward late thrombosis include local arterial hypersensitivity reactions as evidenced by eosinophils, which may be secondary to polymer (15). Further, penetration of a necrotic core by stent struts, crossing branch points, or bifurcation stenting are additional risk factors for late DES thrombosis as occurs with BMS (19,35). Breaching a necrotic core may lead to the exposure of thrombogenic lipid content to flowing blood. Arterial branch points may also predispose towards thrombosis by inducing flow disturbances and changes in shear stress (35,36). Withdrawal of aspirin and/or clopidogrel therapy has previously been reported to be a very significant risk factor for LST with DES. It is not surprising that poorly healed sites of DES placement pose a significant risk for complete thrombosis when antiplatelet therapy is abruptly discontinued.
Late thrombosis: clinical correlates. The true incidence of DES LST is unknown. The reported rates of LST vary from 0.23% to 0.7% (7,29,37). Complicating the interpretation of these data are the differing definitions of LST (clinical vs. angiographic), the differing duration of antiplatelet therapy, the types of lesions stented, and duration of follow-up. The increasing use of DES for a wide variety of clinical and anatomic situations such as bifurcation stenting, overlapping stent deployment, or acute myocardial infarction, most of which have not been evaluated in randomized studies, means that the reported incidence of DES LST in these trials may not reflect the real-world incidence.
It is difficult to compare the incidence of DES LST with that from the BMS era because of the complicating issues of restenosis with superimposed thrombosis, prior brachytherapy treatment, and differing duration and type of antiplatelet therapy used. The reported incidence of late thrombosis for BMS varies from 0.6% to 0.8% (19,38,39). However, BMS do not cause the same degree of delay in arterial healing seen with the two currently FDA-approved DES.
Regardless of the true incidence, the consequences of DES LST are dire. Iakovou et al. (7) reported a 45% rate of death for patients suffering DES LST, with the majority of others suffering nonfatal myocardial infarction. This lethality is substantially higher than the reported 16.7% to 20.8% fatality rate for BMS LST, and in part may reflect the tendency to perform more complex multiterritory revascularization in the DES era (30,38). This study shows that even 6 to 7 months after implantation of Cypher and Taxus DES, these sites are not completely endothelialized in the patients studied in this report. Therefore, it remains uncertain at what time point after stenting the patients can safely be taken off of antiplatelet therapy.
Study limitations. Because this is an autopsy study, the results presented may not be representative of persons who receive DES and survive. Also, a large number of patients in this study received DES stents for non–FDA-approved indications such as acute myocardial infarction, and so may not reflect the arterial pathologic changes that occur when these stents are placed only for approved uses. In the present study, however, a large number of stents were analyzed in individuals who did and did not suffer stent-associated morbidity, and it is likely that the results reported here are applicable to patients receiving DES.
Conclusions. This is the first published study to examine systematically the effects of the two currently FDA-approved DES on human coronary pathology. Both DES caused a significant delay in arterial healing characterized by persistent fibrin deposition and delayed re-endothelialization when compared with sites of BMS implantation. The cause of DES LST is likely multifactorial, with delayed healing in combination with other clinical and/or procedural risk factors such as withdrawal of antiplatelet therapy, malapposition/incomplete apposition, and bifurcation stenting playing an important role. Because the time course of arterial healing after Cypher or Taxus DES placement may vary from patient to patient, all patients at high risk for late thrombosis should receive dual antiplatelet therapy with aspirin and clopidogrel for prolonged periods of time.
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Acknowledgments |
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Footnotes |
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1 Drs. Joner and Finn contributed equally to this work. 
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References |
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