Incomplete Stent Apposition and Very Late Stent Thrombosis After Drug-Eluting Stent Implantation
Background— Stent thrombosis may occur late after drug-eluting stent (DES) implantation, and its cause remains unknown. The present study investigated differences of the stented segment between patients with and without very late stent thrombosis with the use of intravascular ultrasound.
Methods and Results— Since January 2004, patients presenting with very late stent thrombosis (>1 year) after DES implantation underwent intravascular ultrasound. Findings in patients with very late stent thrombosis were compared with intravascular ultrasound routinely obtained 8 months after DES implantation in 144 control patients, who did not experience stent thrombosis for ≥2 years. Very late stent thrombosis was encountered in 13 patients at a mean of 630±166 days after DES implantation. Compared with DES controls, patients with very late stent thrombosis had longer lesions (23.9±16.0 versus 13.3±7.9 mm; P<0.001) and stents (34.6±22.4 versus 18.6±9.5 mm; P<0.001), more stents per lesion (1.6±0.9 versus 1.1±0.4; P<0.001), and stent overlap (39% versus 8%; P<0.001). Vessel cross-sectional area was similar for the reference segment (cross-sectional area of the external elastic membrane: 18.9±6.9 versus 20.4±7.2 mm2; P=0.46) but significantly larger for the in-stent segment (28.6±11.9 versus 20.1±6.7 mm2; P=0.03) in very late stent thrombosis patients compared with DES controls. Incomplete stent apposition was more frequent (77% versus 12%; P<0.001) and maximal incomplete stent apposition area was larger (8.3±7.5 versus 4.0±3.8 mm2; P=0.03) in patients with very late stent thrombosis compared with controls.
Conclusions— Incomplete stent apposition is highly prevalent in patients with very late stent thrombosis after DES implantation, suggesting a role in the pathogenesis of this adverse event.
Received August 14, 2006; accepted February 20, 2007.
Stent thrombosis (ST) has complicated coronary artery stent implantation since its inception and is associated with considerable morbidity and mortality due to abrupt vessel closure.1,2 Several case reports and observational studies suggest that ST may occur unusually late in patients treated with drug-eluting stents (DES), a phenomenon referred to as very late ST.3,4 Recent investigations have reported variables consistently associated with ST after DES implantation, such as discontinuation of antiplatelet therapy, brachytherapy, bifurcation stenting, acute coronary syndromes, renal insufficiency, and diabetes.2,5 Furthermore, hypersensitivity reactions and localized inflammation have been identified in autopsy-proven ST cases.6,7 However, the cause of very late ST and the underlying changes in arterial structure are largely unknown.
Intravascular ultrasound (IVUS) identifies mechanisms of stent failure by providing complementary information regarding the extent and distribution of neointima, arterial remodeling, stent underexpansion, and incomplete stent apposition (ISA).8 IVUS studies in patients suffering from early (≤30 days) ST after bare metal stent (BMS)9 and DES implantation10 found stent underexpansion and residual stenoses as predisposing factors. However, no study examined structural differences in stented vessel segments in patients with very late ST (>1 year) after DES implantation. We therefore performed IVUS imaging before emergency percutaneous coronary intervention (PCI) in patients presenting with very late ST after DES implantation. These findings were compared with IVUS routinely obtained 8 months after DES implantation in 144 control patients, who did not experience ST within 2 years of follow-up, in an attempt to identify structural changes in the stented vessel segment associated with very late ST.
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Nineteen patients presented with very late ST (>1 year) after DES implantation at our institution (Figure 1). Since January 2004, a protocol was implemented to perform IVUS before emergency PCI in patients presenting with very late ST. Thus far, 13 patients were investigated and represent the study population of this report. Control patients constituted a subpopulation of the SIRTAX (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization) trial,11 in which IVUS was performed routinely at the time of follow-up angiography (8 months after DES implantation) in the first 236 enrolled subjects. After exclusion of patients who underwent IVUS at another institution, those who had suffered from ST during the 2-year follow-up period, and segments with failed acquisition, volumetric analysis was possible in 144 patients with 175 stented segments. IVUS control patients were monitored prospectively for ≥2 years with documentation of the absence of any clinical adverse event during this observation period. The study complied with the Declaration of Helsinki regarding investigation in humans and was approved by the ethics committee at the University Hospital Bern in Switzerland. All patients provided written informed consent.
DES availability at our institution is summarized in Figure 1. Sirolimus-eluting stents (SES) (Cypher, Cordis, a Johnson & Johnson Company, Miami Lakes, Fla) became available in April 2002, followed by paclitaxel-eluting stents (PES) (Taxus, Boston Scientific) in March 2003. From April 2003 to May 2004, both DES were used in a randomized clinical trial.11 This was followed by use of both DES on an alternating basis until April 2005, at which time the use of PES was abandoned.
Definition of ST
Timing of ST was categorized as very late when occurring >1 year after DES implantation. Only patients presenting with very late ST were included in the present study. ST was defined as the association of clinical symptoms with angiographic confirmation of thrombotic stent occlusion. Clinical signs and symptoms were considered to be present if at least 1 of the following criteria was met: (1) sudden onset of typical chest pain with duration >20 minutes; (2) ischemic ECG changes; (3) typical rise and fall of cardiac biomarkers.
Angiographic criteria for ST were fulfilled when the Thrombolysis in Myocardial Infarction flow was (1) grade 0 with occlusion originating in the persistent region or (2) grade 1, 2, or 3 in the presence of a thrombus originating in the persistent region.
Quantitative Coronary Angiographic Analysis
Coronary angiograms were recorded digitally at baseline, after the procedure, and at follow-up and were assessed at the angiographic core laboratory of the University Hospital Bern. Angiograms were analyzed by personnel unaware of patient group or type of stent implanted. Digital angiograms were analyzed with the use of an automated edge-detection system (CAAS II, Pie Medical Imaging, Maastricht, the Netherlands). Quantitative measurements included diameter of the reference vessel, minimal luminal diameter, and extent of stenosis (defined as diameter of the reference vessel minus minimal luminal diameter, divided by reference diameter, and multiplied by 100).
IVUS Image Acquisition and Analysis
The protocol sequence to obtain IVUS is depicted in Figure 2A. In very late ST patients, IVUS was obtained in the affected stent segment before emergency PCI. First, intracoronary nitroglycerin was administered, and an angiogram with the use of a 6F guiding catheter was performed to define the site of thrombotic stent occlusion. Then a 0.014-inch coronary guidewire was passed through the affected stent, followed by advancement of the IVUS catheter (EagleEye, Volcano Therapeutics, Inc, Cordova, Calif) >10 mm beyond the distal edge of the affected stent. The IVUS catheter was withdrawn with the use of motorized pullback (0.5 mm/s), and images were recorded continuously throughout the stent and at least 10 mm distal and proximal to the stent. Then the imaging catheter was withdrawn, and PCI with the use of standard techniques was begun. IVUS was repeated at the end of the procedure. All IVUS procedures were recorded digitally on CD-ROM.
Quantitative IVUS analyses were performed offline with computerized planimetry (In-VisionView 1.0, Medimatic Inc) (Figure 2B). Quantitative measures included the external elastic membrane (EEM) (mm2), lumen cross-sectional area (CSA) (mm2), and stent CSA (mm2) at stented and reference segments. The image slice with the smallest stent CSA and lumen CSA and the image slice with the greatest EEM were also analyzed. Minimal stent CSA (mm2) was measured at the site of the smallest stent diameter through the center point of the stent. The proximal and distal reference segments selected for analysis were the most normal-looking cross sections within 10 mm proximal or distal to the lesion but before any side branch. ISA was defined as lack of contact between at least 1 strut and the underlying arterial wall intima that did not overlap a side branch with evidence of blood flow behind the strut (Figure 2C).12,13 Stent expansion index was defined as the ratio of minimal stent CSA divided by the mean proximal and distal reference lumen areas. Stent underexpansion was defined as stent expansion <80% (stent expansion index <0.80).9 Neointima was calculated as stent minus lumen CSA measures. Coronary aneurysm was defined as a maximum lumen area >50% larger than the proximal reference lumen area.
Continuous data are expressed as mean±SD. Continuous data were compared with the use of an unpaired t test if the data were normally distributed; otherwise, a Mann-Whitney U test was used. Categorical data are presented as frequencies and were compared by χ2 statistics. A 2-tailed probability value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS software 12.0.1.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline Clinical and Angiographic Characteristics
Baseline clinical characteristics were similar in patients with very late ST and DES controls (Table 1). The indication for the PCI at the time of the index procedure was an acute ST-segment elevation myocardial infarction in 46% of very late ST patients and in 26% of DES controls (P=0.17).
Baseline angiographic characteristics showed significant differences between very late ST patients and DES controls with respect to lesion length (23.9±16.0 versus 13.3±7.9; P<0.001), stent length (34.6±22.4 versus 18.6±9.5 mm; P<0.001), number of stents per lesion (1.6±0.9 versus 1.1±0.4; P<0.001), and rate of overlapping stents (39% versus 8%; P<0.001) (Table 2). In contrast, lesion site, DES type, reference vessel diameter, stent diameter, and angiographic results at the end of the procedure were comparable for both groups.
Very Late ST
A total of 13 patients suffered very late ST (8 patients with SES, 5 with PES), with detailed information of individual patients regarding time, DES type, antiplatelet therapy, and IVUS findings provided in Table 3. Very late ST occurred at a mean of 630±166 days after the index procedure (Figure 1). All very late ST patients underwent IVUS before emergency PCI. The DES control patient population were all free of adverse events at a mean follow-up of 732±35 days (P=0.05 versus mean follow-up of very late ST patients).
Quantitative IVUS analysis was possible in all segments (n=13 for very late ST patients; n=175 segment in 144 DES control patients), and data are summarized in Table 4. Vessel CSA was comparable for the reference segment (EEM CSA: 18.9±6.9 versus 20.4±7.2 mm2; P=0.46) but significantly larger for the in-stent segment (EEM CSA: 28.6±11.9 versus 20.1±6.7 mm2; P=0.03) in patients with very late ST compared with DES controls (Figure 3). Incomplete stent apposition was present in 10 very late ST patients (77%) compared with 21 DES controls (12%) (P<0.001), and maximal ISA area was larger in very late ST patients compared with DES controls (8.3±7.5 versus 4.0±3.8 mm2; P=0.03) (Figure 4A and 4B). ISA foci were located at the proximal stent segment in 36%, at the stent body in 45%, and at the distal stent segment in 18% of cases. Although stent CSA (7.7±2.0 versus 7.5±2.0 mm2; P=0.83) and minimal stent CSA were similar (6.6±2.0 versus 6.6±1.8 mm2; P=0.90), 2 of 13 very late ST lesions (15%) had a minimal stent CSA <4.0 mm2 compared with 9 of 175 control lesions (5%) (P=0.13). Stent expansion index was reduced in very late ST patients compared with DES controls (0.68±0.19 versus 0.81±0.18; P=0.04). In 4 of 13 very late ST patients (31%), stent underexpansion was related to a circumferential calcium ring (arc 360°) (Figure 4C). Stent expansion was inversely related to stent length (R2=0.10, P<0.001), and overlapping stents were less well expanded than nonoverlapping stents (very late ST group, 0.61±0.23 versus 0.72±0.21; P=0.42; control group, 0.67±0.18 versus 0.81±0.18; P=0.02).
The present study demonstrates that patients with very late ST show evidence of positive arterial remodeling with a high incidence of ISA. This is especially apparent when these patients are compared with DES controls.
Incomplete Stent Apposition
ISA is defined as separation of stent struts from the arterial wall with evidence of blood flow behind the strut in the absence of a bifurcation.12,14 Late acquired ISA has been observed in 2% to 5% of patients treated with BMS.15,16 Most IVUS studies of DES thus far have investigated SES and PES, the 2 DES stent types also employed in the present study, and ISA has been reported in 7% to 21% of these patients.17,18
Several mechanisms of ISA have been proposed and are depicted schematically in Figure 5, as follows: (1) positive arterial remodeling with an increase of EEM out of proportion to the increase in persistent plaque and media; (2) a decrease in plaque and media due to dissolution of jailed thrombus or plaque debris, ie, patients undergoing stent implantation during acute myocardial infarction; (3) ISA not recognized at implantation and detected at follow-up (persistent ISA); this may be mediated in part by severely calcified lesions not allowing for homogeneous stent expansion and resulting in stent underexpansion (lever principle); and (4) chronic stent recoil without any change in arterial dimensions (not illustrated).
To differentiate late acquired from persistent ISA, IVUS imaging is required both at the end of the index procedure and at follow-up. The omission of postprocedural IVUS imaging is an important limitation of the present study, in which IVUS was performed only at the time of very late ST or 8 months after DES implantation in the control group. Therefore, it was not possible to discern chronic stent recoil and persistent ISA from the other mechanisms responsible for late ISA. However, previous studies with tubular slotted stents have shown the absence of any significant stent recoil, rendering this mechanism of ISA unlikely in this study.19 In addition, the incidence of ISA in the DES control group (12%) was similar to the rates reported by other investigators in recent IVUS studies with DES,17,20,21 in which regional remodeling was identified as the prevailing mechanism of late ISA. Accordingly, ISA due to positive arterial remodeling with an increase of the EEM out of proportion to changes in plaque and media appears to be the most likely mechanism of ISA in the present study. Because a considerable portion of patients presented with an acute coronary syndrome at the time of the index procedure, the decrease of plaque with dissolution of jailed thrombus may have been another important mechanism of ISA in our patient population. The proportion of patients with ST-segment elevation myocardial infarction was (nonsignificantly) higher in the very late ST group than in controls, and long-term follow-up from prospective randomized trials comparing DES with BMS in the setting of acute myocardial infarction will determine whether the use of DES is associated with an increased risk of very late ST in this patient population.
Recently, Feres and colleagues22 described 2 patients with very late ST after DES implantation in whom serial angiographic and IVUS imaging were available for detailed analysis. These investigators observed late acquired ISA with pronounced positive arterial remodeling within the stented segment, suggesting a causal link between the vascular response to DES implantation and very late ST in certain patients. Virmani et al6 described a local hypersensitivity reaction with extensive vasculitis of the intima, media, and adventitia consisting predominantly of lymphocytes and eosinophils in a patient suffering from very late ST (18 months) after DES implantation. Histopathological analysis revealed an aneurysmal dilatation of the vessel wall within the stented segment with evidence of stent malapposition and thick fibrin thrombus between the stent and the arterial wall. Chronic inflammation with outward remodeling of the arterial wall in response to DES implantation has been confirmed as one of the mechanisms of ST in a larger pathological series from the same laboratory,7 and clinical evidence of hypersensitivity reactions stems from the Research on Adverse Drug Events and Reports project (RADAR) registry,23 in which 17 of 5783 cases were probably or certainly related to DES.
In the retrospective Predictors and Outcomes of Stent Thrombosis (POST) registry,9 ISA was observed in 49% of 53 patients with early ST (<30 days) after BMS implantation. Subsequent IVUS studies with BMS24 and DES17,20,21 failed to identify late ISA as a predictor of clinical adverse events. However, the predictive accuracy of these studies may have been limited by the small number of patients with late ISA (13 to 90 patients), the limited follow-up period of only 12 months in patients after DES implantation, and the infrequent occurrence of very late ST in stent patients. The approach in the present study was different in that we focused on the rare patient presenting with very late ST (13 of 4140 DES patients) and performed IVUS before emergency PCI. The finding of ISA in more than three quarters of patients (77%) with very late ST contrasts with an incidence of only 12% in the DES control group, suggesting a role in the pathogenesis of this adverse event. In addition, the extent of ISA, in terms of both length and depth, was more pronounced in very late ST patients than in controls. This finding suggests that small areas of ISA may be clinically silent, whereas large areas of ISA may increase the risk of ST. Interestingly, 2 patients with very late ST had a BMS implanted in addition to a DES in the same vessel during the index procedure. In both patients, EEM CSA was considerably enlarged in the vicinity of the DES but not in the BMS (Figure 4), and ST was limited to the DES segment with no thrombus present in the BMS.
The mechanism by which ISA may contribute to ST remains speculative. It has been postulated that ISA may serve as a local nidus for thrombus formation by allowing for fibrin and platelet deposition.25 Thus, ISA may be the consequence of chronic inflammation and delayed healing, resulting in tissue necrosis and erosion around the stent.7 In addition, the positive remodeling of the arterial wall reduces blood flow between the aneurysmatic wall and the stent struts. Finally, ISA may be only a marker for other mechanisms primarily causing ST such as delayed reendothelialization, impaired vasomotion, and chronic inflammation, which allow for platelet adhesion, initiation of the coagulation cascade, and subsequent thrombotic stent occlusion.
Other Ultrasonic Predictors of ST
Ultrasonic predictors of early ST after BMS implantation were stent underexpansion, residual dissections, and thrombus.9,13 In a recent study of 21 patients with documented SES thrombosis occurring an average of 14 days after the index procedure, Fujii and colleagues10 identified stent underexpansion and a residual reference segment stenosis as predictors of early ST. In the present study, 4 very late ST patients also had evidence of stent underexpansion, which was related to severely calcified lesions with a calcium arc of 360°. Although stent CSA and minimal stent CSA were similar between very late ST patients and DES controls in the present study, stent expansion was reduced in the former, reflecting the somewhat larger reference lumen CSA in this group. Stent expansion may have been related to inappropriate stent deployment at the time of the index procedure. Alternatively, positive remodeling of the reference segments caused by the drug-polymer combination may have led to the false impression of stent underexpansion, whereas the vessel only outgrew the originally appropriately sized stent.
Two patient populations emerged from the present study. The majority of patients with very late ST showed evidence of vessel remodeling with or without aneurysm formation associated with predominantly large areas of ISA covering a long segment of the stent length, suggesting a dynamic biological process possibly related to chronic inflammation within the arterial wall. In contrast, another group was characterized predominantly by stent underexpansion with or without only small areas of ISA and/or restenosis, suggesting rather mechanical factors and inadequate stent implantation as factors contributing to ST.
Several limitations require consideration when the results of the present study are interpreted. The most important limitation is the lack of a reference IVUS examination at the end of the index procedure and therefore the inability to differentiate between persistent and late acquired ISA. The control group underwent routine IVUS imaging at 8 months, and subsequent clinical follow-up was uneventful up to 2 years after DES implantation. However, it cannot be excluded that IVUS results might have changed during extended follow-up. Given the size of the control group and the extent of differences between both patient populations, it is unlikely that results would have changed considerably.
Moreover, IVUS results of the very late ST group were acquired at the time of stent thrombosis and may have been different if IVUS had been performed at an earlier time point. Accordingly, the predictive value of the presence or absence of ISA during follow-up IVUS examinations remains unknown. Furthermore, the results of the present study apply only to patients with very late ST after DES implantation, whereas early ST may be associated with other or additional factors. Finally, the number of patients with very late ST was small, and therefore it was not the purpose of this study to address other clinical predictors of ST.
ISA is highly prevalent in patients with very late ST after DES implantation, suggesting a role in the pathogenesis of this adverse event. Positive arterial remodeling appears as the most likely mechanism of ISA in the present study.
Sources of Funding
The present study was supported by a research grant from the University Hospital Bern, Bern, Switzerland. There was no industry involvement in the design, conduct, or analysis of the study.
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Stent thrombosis is an infrequent but severe complication resulting in abrupt coronary artery closure, which may lead to myocardial infarction or sudden cardiac death. It may occur unusually late after drug-eluting stent implantation, and its cause is largely unknown. The present study sought to identify structural differences of the stented segment between patients with and without very late stent thrombosis (>1 year) with the use of intravascular ultrasound. Findings in 13 patients with very late stent thrombosis were compared with intravascular ultrasound routinely obtained 8 months after drug-eluting stent implantation in 144 control patients, who did not experience stent thrombosis for ≥2 years. We observed a high prevalence of incomplete stent apposition in patients with very late stent thrombosis (77%) compared with drug-eluting stent controls (12%; P<0.001), suggesting a role in the pathogenesis of this adverse event. Several mechanisms of incomplete stent apposition have been proposed, including positive arterial remodeling, a decrease in plaque and media due to dissolution of jailed thrombus, persistent incomplete stent apposition, and chronic stent recoil. The first 2 mechanisms are most likely responsible for late acquired incomplete stent apposition complicating the use of drug-eluting stents.