Characteristics of Late-Acquired Incomplete Stent Apposition: A Comparison With First-Generation and Second-Generation Drug-Eluting Stents

Abstract: Objective. This study aim was to investigate the morphometric parameters of late-acquired incomplete stent apposition (ISA) following use of Cypher sirolimus-eluting stent (SES; Cordis), Taxus paclitaxel-eluting stent (PES; Boston Scientific), and Resolute zotarolimus-eluting stent (ZES; Medtronic). Background. Characteristics of late-acquired ISA between first-generation and second-generation drug-eluting stents (DESs) have not been systematically examined. Methods. Late-acquired ISA was defined as separation of at least 1 stent strut from the vessel wall with evidence of blood speckle behind the strut, where poststent implantation intravascular ultrasound (IVUS) revealed complete apposition. A total of 30 late-acquired ISA cases (12 SES, 10 PES, 8 ZES) were included in this IVUS analysis. Corresponding cross-sections at post procedure were selected for comparison. Vessel, lumen, peristent tissue, and stent area were measured in the late-acquired ISA arc as referenced to stent center. Results. Late-acquired ISA area was 2.4 ± 1.5 mm² in SES, 2.2 ± 2.7 mm² in PES, and 0.9 ± 0.6 mm² in ZES (P=.02 for SES vs ZES). Vessel area increased from post procedure to follow-up in SES (4.6 ± 1.7 mm² to 7.0 ± 2.5 mm²; P<.01) and PES (3.6 ± 1.7 mm² to 5.7 ± 3.8 mm²; P=.06), but not in ZES. Vessel expansion was the main mechanism in SES and PES groups; however, tissue regression and stent recoil, as well as vessel expansion, also contributed to late-acquired ISA in ZES. Per-patient analyses demonstrated that vessel expansion was the predominant mechanism of late-acquired ISA in 83% of SES, 60% in PES, and 50% of ZES cases. Conclusion. The magnitude and mechanism of late-acquired ISA appear to be different between first-generation and second-generation DESs, possibly due to varying vessel response to different stent component types.

J INVASIVE CARDIOL 2016;28(8):323-329. Epub 2015 December 15.

Key words: late stent malapposition, intravascular ultrasound, drug-eluting stent, coronary intervention

Recent studies have shown that late-acquired incomplete stent apposition (ISA) develops following drug-eluting stent (DES) implantation,^1-4 and several reports have suggested that late-acquired ISA may be associated with adverse cardiac events, including stent thrombosis, especially in first-generation DESs.^2,5,6 However, the clinical relevance of late-acquired ISA remains somewhat controversial. Intravascular ultrasound (IVUS) studies have demonstrated that morphological features of late-acquired ISA range from subtle incomplete strut apposition from the vessel wall to prominent aneurysmal changes at the stented segment. In the present study, the morphometric features of late-acquired ISA following use of the first-generation Cordis Cypher sirolimus-eluting stent (SES) and Boston Scientific Taxus paclitaxel-eluting stent (PES) and the second-generation Medtronic Resolute zotarolimus-eluting stent (ZES) were compared using serial IVUS examination. The aim of this study was to investigate the underlying mechanisms of late-acquired ISA that develop with different DES types.

Methods

Patient population. Data were derived from the IVUS database of the Cardiovascular Core Analysis Laboratory at Stanford University: the SIRIUS, DDD, and SVELTE trials for SES;^4,7,8 the control arm of the ZoMaxx I, ZoMaxx II and ENDEAVOR IV trials for PES;^9,10 and the RESOLUTE FIM and RESOLUTE US trials for ZES.^11,12 Patients who met the following criteria were selected: (1) implantation of either SES, PES, or ZES; (2) native coronary artery lesion; (3) availability of high-quality serial IVUS images at post procedure and follow-up (mandated 6-9 months after procedure); and (4) confirmation of late-acquired ISA through comparative serial IVUS interrogation. In all patients, IVUS follow-up was prospectively scheduled at 6-9 months regardless of symptoms as part of the clinical research protocols. Lesions with acute coronary syndromes (ACS) requiring emergent percutaneous coronary intervention (PCI), bifurcation, chronic total occlusion, and thrombus were excluded from this study.

The study protocol for each clinical trial was approved by the institutional review board at each participating site and written, informed consent was obtained from all patients prior to the procedure.

IVUS analysis. All IVUS images were acquired using a dedicated software (echoPlaque; Indec Medical Systems) as previously described.⁶ISA was defined as separation of at least 1 stent strut from the intimal surface, with evidence of blood flow behind the stent strut(s). Late-acquired ISA was defined as ISA identified at follow-up, but not at post procedure.¹³ To specify late-acquired ISA location, the IVUS image of the stent was longitudinally divided into three segments: proximal edge (within 5 mm from proximal edge); body; and distal edge (within 5 mm from distal edge). 

Follow-up image at the site of greatest stent-lumen gap was selected and a matched corresponding still image at post procedure was selected for comparison based on the length from stent edge(s) or perivascular landmarks. “Late-acquired ISA arc” and “apposed arc” were identified in the follow-up image, and postprocedural image was matched circumferentially based on perivascular landmarks (Figure 1). Both postprocedure and follow-up still images were then exported to commercial software (Tapemeasure; Indec Medical Systems). At post procedure, tissue thickness beneath the stent at the middle of each arc was measured. Vessel, lumen, and stent area were measured in the entire cross-section and late-acquired ISA arc. Peristent tissue (plaque) area was calculated as vessel area minus stent area. Late-acquired ISA area was calculated as lumen area minus stent area in the late-acquired ISA arc at follow-up. Vessel area change (defined as vessel area at follow-up minus vessel area at baseline), tissue area change (defined as tissue area at follow up minus tissue area at baseline), and stent area change (defined as stent area at follow-up minus stent area at baseline) were calculated. Contribution of vessel, tissue, and stent area change to ISA area were obtained as Dvessel, Dtissue, or Dstent area divided by ISA area, and most impact of contribution factor was determined as the predominant mechanism.

Statistical analysis. Statistical analysis was performed using Statview 5.0 (SAS Institute, Inc). Continuous variables are expressed as mean ± standard deviation. For continuous variables, comparisons of either SES, PES, or ZES were performed with ANOVA, and comparisons between postprocedure and follow-up results were done by two-tailed, paired t-test. In addition, comparison between first-generation and second-generation DESs were done by unpaired t-test. Categorical data were compared using chi-square test. A P-value <.05 was considered statistically significant.

Results

Incidence of late-acquired ISA and baseline lesion characteristics. A total of 1078 cases were reviewed and 466 cases (159 SES cases, 181 PES cases, and 125 ZES cases) were available for serial volumetric analysis. Late-acquired ISA was identified in 30 cases (12 SES cases, 10 PES cases, and 8 ZES cases). The incidence of late-acquired ISA was 7.5% in SES, 5.5% in PES, and 6.4% in ZES cases (P=.75). Late-acquired ISA was mainly observed at the stent body rather than stent edges regardless of DES type.

Baseline patient and lesion characteristics are summarized in Table 1. There were no significant differences among the 3 DES types, except for age, male gender, and lesion location. The ZES cases included patients that were significantly older, fewer males, and more right coronary artery (RCA) lesions compared with SES and PES cases.

Quantitative IVUS analysis. Regarding tissue thickness at post procedure, SES showed significantly thinner late-acquired ISA arc than apposed arc (1.0 ± 0.4 mm vs 0.4 ± 0.2 mm, respectively; P<.001). However, PES and ZES showed no significant difference between late-acquired ISA arc and apposed arc (PES: 0.7 ± 0.4 mm vs 0.7 ± 0.4 mm,  respectively [P=.83]; ZES: 0.8 ± 0.4 mm vs 0.7 ± 0.4 mm, respectively [P=.65]) (Figure 2). Serial (postprocedure and follow-up) IVUS analyses are summarized in Table 2. Vessel area was significantly increased in SES from baseline to follow-up in both entire cross-section and late-acquired ISA arc. PES showed vessel area was significantly increased at the entire cross-section and tends to be increased at the late-acquired ISA arc. However, ZES showed no significant change from baseline to follow-up in both entire cross-section and late-acquired ISA arc. The Dvessel areas for both entire cross-section and late-acquired ISA arc were significantly larger in SES vs ZES. PES showed numerically larger Dvessel area than ZES, but it did not reach statistical significance. ISA area was significantly larger in SES and numerically larger in PES compared with ZES (P=.02 and P=.20, respectively) (Table 3). 

Mechanism of late-acquired ISA. A representative image of late-acquired ISA for each stent is shown in Figure 3, and the magnitude and mechanism of late-acquired ISA are summarized in Figures 4 and 5. For the development of late-acquired ISA, vessel expansion was the main mechanism in SES and PES. In contrast, tissue regression and stent recoil also contributed to late-acquired ISA in ZES as well as vessel expansion (Figure 4). In per-patient analyses, the predominant mechanism was identified in each case. Vessel expansion was the predominant mechanism in 83% of SES cases, 60% of PES cases, and 50% of ZES cases. Tissue regression was the predominant mechanism in 17% of SES cases, 40% of PES cases, and 37.5% of ZES cases. Stent recoil was observed in 1 ZES case (Figure 5).

Clinical implications. Although target-lesion revascularization (TLR) was observed in 2 cases (1 SES and 1 ZES) up to 3 years, no SES and ZES cases had stent thrombosis up to 3 years. There was no report of TLR and stent thrombosis in patients with PES up to 3 years.

Discussion

The main findings in this study are as follows: (1) late-acquired ISA was mainly observed at the stent body rather than stent edges, regardless of stent type; (2) late-acquired ISA of SES was observed on the thinner plaque side at baseline; (3) late-acquired ISA area was larger in SES vs ZES; and (4) patient-level analysis showed different predominant mechanisms. 

Mechanism of late-acquired ISA. It has been reported that late-acquired ISA is relatively common following first-generation DES implantation, and was found in ~10% of patients receiving DES at IVUS follow-up in the pivotal initial trial.^14-16 In the present study, the incidence of late-acquired ISA was similar among SES, PES, and ZES. However, the magnitude and mechanism of late-acquired ISA appeared to be different among the stents, especially between first-generation and second-generation DESs. Although vessel expansion was identified as the predominant late-acquired ISA mechanism in SES and PES, vessel expansion, tissue regression, and stent recoil were identified as late-acquired ISA mechanisms in ZES. In addition, late-acquired ISA area was smaller in ZES vs SES and PES. These findings indicate that different DES components may cause different vascular response for the development of late-acquired ISA.

Vessel expansion was the main mechanism in both SES and PES late-acquired ISA cases. However, the cause of vessel expansion might be different between SES and PES. Previous IVUS studies have shown that SES did not induce vessel expansion (positive remodeling) and caused even negative vessel remodeling through modification of plaque components behind the struts.^17-19 On the other hand, vessel expansion in the stented segment was consistently reported after PES implantation.^9,10,16 Virmani et al reported an autopsy case that had shown aneurysmal dilatation of the SES implanted arterial segments with a severe localized hypersensitivity reaction to the polymer consisting predominantly of T-lymphocytes and eosinophils.² For PES, vessel expansion was observed with a dose-dependent manner.^20,21 In a porcine model, exposure to a high dose of paclitaxel eliminated direct contact between the strut sites and medial wall by medial wall cell necrosis, implying that the vessel wall had undergone dilatation relative to the stent.²² These data suggest that a patient-specific sensitivity to sirolimus and/or polymer might be proposed as the cause of vessel expansion for the underlying mechanism of late-acquired ISA in SES; however, paclitaxel itself may play a key role via vessel expansion in the mechanism of late-acquired ISA after PES implantation. 

In the present study, not only vessel expansion but also tissue regression and stent recoil were identified as late-acquired ISA mechanisms in ZES. Tissue regression might be caused by dissolution of plaque or resolution of jailed thrombus. Effects of medication or plaque rupture behind the stent strut might cause dissolution of plaque.^23-27 Although comparison in medications among the three stent groups could not be performed, pathological vascular response after ZES implantation seems to be different from SES and PES. In addition, one chronic stent recoil case as the cause of late-acquired ISA was observed in the ZES group. The ZES is based on a thin-strut, cobalt-alloy material, and previous IVUS study did not reveal significant chronic stent recoil in the Endeavor stent, which uses the same stent platform.²⁸ This study may still have insufficient power to reveal the exact mechanism of late-acquired ISA. However, some kinds of metal, design, and strut thickness may affect the mechanism of late-acquired ISA due to insufficient radial strength.

For better understanding of the underlying late-acquired ISA mechanism, IVUS evaluation prior to stenting may be needed. Unfortunately, our study could not evaluate plaque characteristics before stenting, since IVUS recording before the procedure was not mandated according to the protocol of each clinical study. However, late-acquired ISA in the SES group was observed on the thinner plaque side at post procedural IVUS. A previous report suggested baseline plaque morphology may affect the vascular response after stent implantation.²⁹ Further studies are needed to evaluate plaque morphology before stent implantation by using other imaging modalities, such as radiofrequency reconstructed IVUS or optical coherence tomography.

Clinical relevance of late-acquired ISA. The relationship between late-acquired ISA and subsequent clinical events including late stent thrombosis remains unclear. Previous studies, with short- to middle-term follow-up, suggested that late-acquired ISA was not associated with adverse clinical events after SES and PES implantation.^{3,4,14,15,30,31} However, Cook et al reported that ISA was highly prevalent in patients with very late stent thrombosis after DES implantation vs controls.⁵ Hassan et al performed a meta-analysis including five studies with follow-up <12 months, suggesting the risk of very late stent thrombosis in patients with late-acquired ISA was higher vs those without.³² One major issue in identifying the clinical relevance of late-acquired ISA is the relatively low incidence of late-acquired ISA and stent thrombosis. In addition, late-acquired ISA was multifactorial, as our study and others have shown. Nonetheless, the definition of late-acquired ISA included any type of late-acquired ISA; ie, not only vessel expansion but also tissue regression and/or stent recoil. Even some stent fractures will be diagnosed as ISA by current IVUS definitions. Previous case reports of stent thrombosis showed aneurysmal change and/or late-acquired ISA;^1,33,34 however, current published data did not differentiate from multiple mechanisms. As shown in our study, even the incidence of late-acquired ISA was similar among the DESs, and the potential risk of late-acquired ISA for each DES type might be different due to different magnitude and predominant mechanism of late-acquired ISA. Thus, the definition of late-acquired ISA may need to be modified to “blood speckle was observed behind the stent strut with positive remodeling or without positive remodeling.”¹³ Since the threshold to identify blood speckle might differ among analysts, semiquantitative analysis is needed to minimize interobserver variability. 

The incidence of late-acquired ISA might be affected by many factors, as discussed. Although the influence by diversity of mechanism of late-acquired ISA between first-generation and second-generation DESs on clinical course is still unclear, different magnitude and mechanism of late-acquired ISA between two generations of DES might affect the long-term clinical course. Evaluation of the clinical impact of late-acquired ISA derived from different stent types will be necessary.

Study limitations. First, this is a retrospective study derived from a pooled analysis of randomized control trials or registries. However, since the incidence of late-acquired ISA was relatively low, pooled analysis was needed to perform detailed systematic analysis of late-acquired ISA. Second, our study population was limited. Therefore, some parameters may not reach statistical significance. Third, IVUS images before intervention could not be evaluated in this study, since preintervention IVUS was not mandated by the original study protocol. Therefore, morphometric and morphologic features before PCI could not be fully evaluated. Finally, frequency of ISA may be affected by the type of imaging modality used for assessment.

Conclusion

The magnitude and mechanism of late-acquired ISA appear to be different among three DES types, possibly due to varying vessel response to different stent components. 

Acknowledgment. The authors thank the principal investigators of the SIRIUS trial (Dr Leon, Columbia University, New York, NY; Dr Moses, Columbia University, New York, NY), the DDD trial (Dr Sousa, Institute the Dante Pazzanese of Cardiology, San Paulo, Brazil), the SVELTE trial (Dr Meier, Swiss Cardiovascular Center Bern, University Hospital, Bern, Switzerland), the ZoMaxx I (Dr Chevalier, Centre Cardiologique du Nord, Saint-Denis, France), the ZoMaxx II (Dr Yeung, Stanford University, Stanford, CA; Dr Gray, Columbia University, New York, NY), the ENDEAVOR IV (Dr Leon, Columbia University, New York, NY; Dr Kandzari, Piedmont Heart Institute, Atlanta, GA), RESOLUTE FIM (Dr Meredith, Monash Heart Center, Clayton, Australia) and the RESOLUTE US (Dr Leon, Columbia University, New York, NY; Dr Mauri, Harvard Clinical Research Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA; Dr Yeung, Stanford University, Stanford, CA). The authors also thank Heidi N. Bonneau, RN, MS, CCA, for her review of this manuscript.

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From Stanford University, Division of Cardiovascular Medicine, Stanford, California.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein. 

Manuscript submitted January 13, 2015, provisional acceptance given March 30, 2015, final version accepted July 16, 2015.

Address for correspondence: Yasuhiro Honda, MD, Stanford University, Division of Cardiovascular Medicine, 300 Pasteur Drive, Room H3554, Stanford, CA 94305-5637. Email: crci-cvmed@stanford.edu