Treatment of Restenotic Drug-Eluting Stents: An Intravascular
Ultrasound Analysis

Sirolimus-eluting and paclitaxel-eluting stents decrease neointimal hyperplasia leading to a reduction, but not elimination, of in-stent restenosis.^1–4 Because sirolimus and paclitaxel decrease neointimal hyperplasia, restenosis is dependent on final drug-eluting stent (DES) dimensions; an optimally expanded stent area assessed by intravascular ultrasound (IVUS) is a strong predictor of freedom from clinical, angiographic and IVUS restenosis after DES implantation.^5–9 However, it is not possible to obtain an optimum stent area in all lesions, and it is not clear how underexpanded stent dimensions impact the outcome of a repeat intervention (i.e., an intervention to treat DES restenosis). Because there are only limited data on the treatment of DES restenosis,^10,11 we evaluated the IVUS findings during repeat interventions for the treatment of DES restenosis.

Methods

Patient and lesion population. Between August 2004 and July 2006, we identified 181 DES restenosis lesions (> 50% angiographic diameter stenosis) within the Cypher^™ sirolimus-eluting stent (Cordis Corp., Miami Lakes, Florida) or the Taxus^® paclitaxel-eluting stents (Boston Scientific Corp., Natick, Massachusetts) in 136 patients who underwent repeat percutaneous intervention. Excluding edge restenoses, in which the minimum lumen area was outside of the stent, both pre- and postintervention IVUS were performed in 62 lesions in 55 patients; this represents the cohort for the current study. Clinical and procedural variables were recorded and entered prospectively into a database by a dedicated data coordinating center that was unaware of the IVUS findings. This study was approved by the Institutional Review Board, and written informed consent was obtained from all patients.
IVUS imaging and analysis. IVUS was obtained after intracoronary administration of 0.1–0.2 mg nitroglycerin using commercially available ultrasound catheters and motorized transducer pullback. The ultrasound catheter was advanced > 10 mm beyond the stent and withdrawn at a pullback speed of 0.5 mm/second to a point > 10 mm proximal to the stent. IVUS studies were recorded during pullback for offline analysis.
Quantitative IVUS analysis was performed using computerized planimetry (Echo Plaque, Indec Systems, Mountain View, California) according to published standards.¹² Measurements were performed at the pre- and postintervention minimal lumen area (MLA) and the minimal stent area (MSA) sites and at the proximal and distal reference sites. Measurements included: (1) stent, lumen, intimal hyperplasia (stent minus lumen) areas and percentage of intimal hyperplasia at the stented cross-sections; and (2) the external elastic membrane (EEM) and lumen areas at the reference cross-sections.
Quantitative coronary angiography. Quantitative coronary angiography (QCA) was obtained pre- and postintervention using a computer-assisted, automated, edge-detection algorithm (CMS, MEDIS, Leiden, The Netherlands). Thepattern of angiographic in-stent restenosis was classified as suggested by Mehran et al.¹³
Statistical analysis. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were expressed as mean ± 1 standard deviation (SD) and categorical variables were expressed as frequencies. Continuous variables were compared with the student’s paired or unpaired t-test. Multivariate predictors of a larger postintervention MLA and MSA were identified using stepwise selection with entry/stay criteria 0.2/0.1. A p-value < 0.05 was considered statistically significant.

Results

Baseline patient, angiographic and IVUS data. Patient and baseline lesion characteristics are presented in Tables 1 and 2. There were 45 (73%) sirolimus-eluting stent and 17 (27%) paclitaxel-eluting stent restenoses. Repeat stent implantation was performed in 55 lesions (89%); the rest were treated with balloon angioplasty alone.
QCA and IVUS data are presented in Table 3. When preintervention lumen, stent and intimal hyperplasia area at the MLA site are compared to those at the MSA site, they measured 2.3 ± 0.7 mm² versus 3.2 ± 1.2 mm² (p < 0.001), 5.1 ± 1.9 mm² versus 4.3 ± 1.7 mm² (p < 0.001) and 2.8 ± 1.7 mm² versus 1.2 ± 1.5 mm² (p < 0.001), respectively.
Acute angiographic and IVUS results. The minimal lumen diameter (MLD) by QCA significantly improved from 1.0 ± 0.4 mm preintervention to 2.7 ± 0.5 mm postintervention (p < 0.001), and the diameter stenosis improved from 64 ± 15% to 11 ± 8% (p < 0.001). Similarly, the MLA by IVUS increased from 2.3 ± 0.7 mm² to 4.4 ± 1.6 mm² (p < 0.001). Although the number of lesions treated with balloon angioplasty was small, when angiographic and IVUS outcomes after repeat stent implantation and balloon angioplasty were compared, repeat stent implantation achieved a larger MLD and smaller diameter stenosis by QCA (Table 3).

Assuming that preintervention stent dimensions at the time of restenosis reflected lumen dimensions achieved immediately after the initial stent implantation procedure (serial IVUS studies have shown that stent dimensions do not change over time¹⁴), then postintervention MLA and preintervention MSA were well correlated (r = 0.79; p < 0.001; Figure 2) and both were almost identical (4.4 ± 1.6 mm² and 4.3 ± 1.7mm²; p = 0.7). This finding was seen both after repeat stent implantation (r = 0.79; p < 0.001 and 4.4 ± 1.6 mm² versus 4.4 ± 1.7mm²; p = 0.7) and after balloon angioplasty (r = 0.90; p = 0.007 and 4.1 ± 0.9 mm² versus 4.2 ± 1.3 mm²; p = 0.8). The same finding was seen in both the sirolimus-eluting stent (r = 0.84; p < 0.001 and 4.5 ± 1.6 mm² vs 4.4 ± 1.7 mm²; p = 0.5) and paclitaxel-eluting stent (r = 0.63; p = 0.007 and 4.0 ± 1.4 mm² versus 4.1 ± 1.5 mm²; p = 0.8) restenosis lesions.
Mechanism of lumen enlargement during treatment of DES restenosis. Overall at the MLA site, the lumen area increased from 2.3 ± 0.7 mm² to 5.1 ± 1.9 mm² (p < 0.001), with no change in the stent area (5.1 ± 1.9 mm² versus 5.3 ± 2.0 mm²; p = 0.4). Conversely, at the MSA site there was an overall increase in both lumen area (3.2 ± 1.2 mm² to 4.7 ± 1.8 mm²; p < 0.001) and stent area (4.3 ± 1.7 mm² to 5.0 ± 2.0 mm²; p < 0.001). Additionally, at the MSA site, preintervention MSA < 5.0 mm² was seen in 43 (69.4%) lesions. However, the postintervention MSA increased to > 5.0 mm² in only 14 (33%) among them.
When restented and balloon angioplasty lesions were analyzed separately, there was an increase in stent and lumen areas at both the MSA and MLA sites in patients treated with balloon angioplasty; however, in patients treated with repeat stent implantation, there was an increase in lumen area, but not stent area at the MLA site, and an increase in both lumen and stent areas at the MSA site (Figure 1).

Location of the MLA. We compared the locations of preintervention MLAs to those of preintervention MSAs (Table 4). The MLA was seen at exactly the MSA in 26 lesions (42%), proximal from the MSA in 26 lesions (42%) and distal in 10 lesions (18%). When MLA and MSA locations were divided into 3 locations (proximal, mid and distal), preintervention IVUS MLA was located more proximal to the MSA.
Postintervention, the MLA migrated to a different location in 31 lesions (50%). The postintervention MLA was more often located at the preintervention MSA site (45 lesions, 73%) than at the preintervention MLA site (31 lesions, 50%).
Predictors of the postintervention MSA. Multivariate analysis using stepwise selection identified MSA by IVUS and average reference EEM area by IVUS as the independent predictors of larger final MLA and a larger final MSA. Other predictors of larger final MLA were the number of strut layers and percent intimal hyperplasia at the MLA (Table 5).

Discussion

The major findings of this study are the following: (1) nearly 75% of postintervention MLAs were located at the preintervention MSA site; (2) there was a strong correlation between the postintervention MLA and the preintervention MSA; (3) preintervention MSA was the strongest independent predictor of both the postintervention MLA and MSA. The preintervention MSA at the time of DES restenosis is a measure of stent and lumen dimension achieved immediately after the initial stent implantation procedure because serial IVUS studies have shown that stent dimensions do not change over time.¹⁴ Therefore, the MSA of the original stent implantation procedure continues to have an important impact on subsequent interventions to treat DES restenosis. This retrospective IVUS study during repeat interventions for the treatment of DES restenoses demonstrated the ongoing importance of achieving adequate expansion during the initial DES implantation procedure.
Final MSA at the time of initial DES implantation. Stent area after initial DES implantation has been shown as a strong predictor of freedom from clinical, angiographic and IVUS restenosis.^5–9 In the current study, stent area significantly increased during the repeat intervention, suggesting that these restenotic DES could have been better expanded at initial implantation. We speculate, but cannot prove, that better initial expansion might have eliminated some of the restenoses.
Restenting or balloon angioplasty for the treatment of DES restenosis. Previous bare-metal stent restenosis studiesshowed that a larger lumen area was achievable after repeat stenting compared to balloon angioplasty alone during the treatment of bare-metal stent restenosis.^15,16 However, DES restenosis is associated with less intimal hyperplasia and more stent underexpansion than bare-metal stent restenosis because the eluted drugs reduce intimal hyperplasia.^5–8,17 This may explain why there was less of a beneficial effect of re-stenting on acute lumen dimensions. Mehran et al reported that balloon angioplasty alone did not recover the original lumen dimensions of the initial bare-metal stent implantation procedure; the MLA after balloon angioplasty alone was smaller than the preintervention MSA.¹³ Additional stent implantation was the only percutaneous technique that allowed recovery of all the lumen area of the original implantation procedure.18 However, in our current DES restenosis study, postintervention MLA after balloon angioplasty was identical to the preintervention MSA, indicating that repeat intervention in patients with DES restenosis recovered theoriginal lumen dimensions, again because of the smaller amount of neointimal hyperplasia in DES restenosis.

Study Limitations

This study has several limitations. First, this study was a retrospective analysis of lesions treated with balloon angioplasty or stent implantation. The two treatment strategies, restenting or balloon angioplasty alone, were not randomly assigned. Second, we did not analyze long-term patient outcomes. The current study mainly focuses on the mechanisms of redilating an in-stent restenotic lesion and the acute results. Third, patients with occluded stents and very diffuse in-stent restenosis were not included because IVUS was not performed for these lesions. Fourth, postintervention IVUS was performed immediately after completion of the intervention, therefore, the impact of time-dependent effects of tissue reintrusion was not investigated.¹⁹

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