Mechanism of Edge Restenosis After Sirolimus-Eluting Stent Implantation

Abstract: Objectives. The present study evaluated the mechanism of edge restenosis after sirolimus-eluting stent (SES) implantation using serial (post-intervention and follow-up) intravascular ultrasound (IVUS) analysis. Background. There is little information about the mechanism of edge restenosis after SES implantation. Methods. Serial IVUS analysis was performed at 5 mm reference segments immediately proximal and distal to the SES in 25 lesions with edge restenosis. Proximal and distal reference segments were divided into 1 mm subsegments. Results. Between post-intervention and follow-up IVUS studies, a decrease in external elastic membrane area was observed at the proximal edge. There was a significant increase in plaque & media area in the subsegment closest to the proximal edge. On the other hand, there was an increase in plaque & media area at the distal edge, with no change in external elastic membrane area. Conclusions. There may be different mechanisms between proximal and distal edge restenosis after SES implantation. Negative remodeling plays a major role in proximal edge restenosis. On the other hand, intimal hyperplasia may mainly contribute to distal edge restenosis.

J INVASIVE CARDIOL 2011;24:55-57

Key words: distal edge restenosis, proximal edge restenosis, negative remodeling, intimal hyperplasia

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Stent edge restenosis has been raised as a potential limitation of drug-eluting stents.^1,2 Previous studies have demonstrated the mechanisms of edge restenosis after bare-metal stent implantation.³ However, there is little information about its mechanism after sirolimus-eluting stent (SES) implantation. The present study evaluated mechanisms of edge restenosis after SES implantation using serial (post-intervention and follow-up) intravascular ultrasound (IVUS) analysis.

Methods

At our institution, IVUS is used for every percutaneous coronary intervention. Routine angiographic follow-up is performed beyond 9 months after drug-eluting stent implantation or earlier if non-invasive evaluation or clinical presentation suggested ischemia. Between July 2005 and July 2009, routine follow-up angiography demonstrated SES (Cypher) restenosis in 55 out of 687 lesions (8.0%). In these, proximal and distal edge restenoses were observed in 19 (2.8%) and 6 lesions (0.9%), respectively. IVUS was performed in all of these lesions. Written informed consent for follow-up angiographic and IVUS examinations was obtained from all patients. This study was approved by the local council on human research.

Quantitative coronary angiography was performed using a computer-assisted automated edge-detection system (CMS; MEDIS). The minimal lumen diameter (MLD) was obtained from the single “worst” view. SES edge restenosis was defined as diameter stenosis >50% located ≤5 mm from the stent margin, but not within stent.

IVUS was performed after administration of 200 μg of intracoronary nitroglycerin through a 40 MHz IVUS catheter (Boston Scientific) with an automated pullback at 0.5 mm/s. The IVUS catheter was advanced >10 mm beyond the lesion, and an imaging run was performed back to the aorto-ostial junction. IVUS imaging was recorded only during transducer pullback onto the hard disk for off-line analysis.

Serial (post-intervention and follow-up) IVUS analysis was performed. Quantitative IVUS analysis was performed using commercially available planimetry software (echoPlaque; INDEC Systems) by an experienced cardiologist (E.I.) unaware of the clinical data, according to previously validated and published protocols.^4-6 The reference lumen and external elastic membrane (EEM) areas 5 mm proximal and distal to the stent edges were manually traced at 0.5 mm intervals. Using Simpson’s method, EEM, lumen, and plaque & media (EEM minus lumen) volumes and average area (volume/length) were calculated. Both proximal and distal reference segments were divided into 1 mm subsegments.

Statistical analysis was performed with StatView 5.0 software (SAS Institute). Data were expressed as mean ± SD or frequency (%). Continuous variables were compared using paired Student’s t-test. A value of P<.05 was considered significant.

Results

Baseline clinical, lesion, and procedural characteristics are presented in Tables 1 and 2. The average follow-up periods were 11.3 ± 6.4 months. Quantitative angiographic results are shown in Table 3.

IVUS measurements of EEM, lumen, and plaque & media area within the entire 5 mm long proximal and distal references are presented in Table 4. Average proximal reference EEM area decreased and there was no significant change in plaque & media area. On the other hand, average distal reference plaque & media area increased and there was no significant change in EEM area.

Changes in IVUS measurements at proximal and distal edges between post-intervention and follow-up at 5 consecutive 1 mm subsegments adjacent to the SES were presented in Figure 1 and 2, respectively. Between post-intervention and follow-up IVUS studies, a decrease in EEM area was observed at the proximal edge (Figure 1). There was a significant increase in plaque & media area in the subsegment closest to the proximal edge (Figure 1). On the other hand, there was an increase in plaque & media area at the distal edge, with no change in EEM area (Figure 2).

Discussion

The present study showed different mechanisms between proximal and distal edge restenosis after SES implantation. Negative remodeling played a major role in proximal edge restenosis. On the other hand, intimal hyperplasia mainly contributed to distal edge restenosis. The SIRolImUS-eluting balloon-expandable stent in the treatment of patients with de novo native coronary artery lesion study (SIRIUS) showed a lower restenosis rate within the stent (3.2% vs 35.4%; P<.001) and at distal edge (2.0% vs 7.5%; P<.001) in lesions treated with SES compared to bare-metal stents.1 On the other hand, there was no significant difference in proximal edge restenosis between SES and bare-metal stent (5.5% vs 7.8%; P=.275). In patients who developed restenosis, edge restenosis was a more frequent angiographic pattern of restenosis after implantation of SES compared to bare-metal stents (61.3% vs 14.1%; P<.001).

Possible mechanisms of edge restenosis are a decrease in EEM (negative remodeling) and an increase in plaque from disease progression or intimal hyperplasia.^3,7,8 Hoffmann et al³ showed that edge restenosis after bare-metal stent implantation was a combination of intimal hyperplasia closest to the stent edge and progressively more negative remodeling at distances remote from the stent edge. Ahmed et al⁷ demonstrated that edge restenosis after brachytherapy was the result of neointimal hyperplasia and the absence of radiation-induced positive remodeling.

Asano et al⁶ performed serial (baseline and 9-month follow-up) IVUS analysis at 5 mm reference segments immediately proximal and distal to the SES. Edge restenosis was observed in 2 of the 33 lesions. Between post-intervention and follow-up IVUS studies, there was a significant decrease in the lumen and an increase in plaque & media area in the subsegment closest to the distal edge, with no change in EEM area. There was no significant change in EEM, lumen, and plaque & media areas within the other subsegments. The present study performed serial IVUS analysis in 25 lesions with edge restenosis. A decrease in EEM area played a major role in proximal SES edge restenosis. An increase in plaque & media area may mainly contribute to distal SES edge restenosis. Previous studies demonstrated that plaque burden at SES edge was associated with negative remodeling at follow-up.^6,9 A larger plaque burden is often observed at the proximal stent edge compared to the distal stent edge.⁶ Coronary artery balloon injury due to balloon-artery mismatch may be more frequent at distal edge compared to proximal edge because of tapering of coronary arteries. An experimental study showed a higher drug concentration at the distal SES edge compared to the proximal edge.¹⁰ These might be associated with the different mechanisms of SES edge restenosis between the proximal and distal edges.

Study Limitations

There are some limitations in the present study. The sample size, especially of distal edge restenosis, is small. Thus, it might be required to evaluate the contribution of EEM change to distal edge restenosis in a larger number of lesions. There was no bare-metal stent control group. Geographic miss is one of the reasons for stent edge restenosis.¹¹ We are always careful to avoid geographic miss when postdilatation is performed. However, it could happen because the balloon might move during the cardiac cycle.

Conclusion

There may be different mechanisms between proximal and distal edge restenosis after SES implantation. Negative remodeling plays a major role in proximal edge restenosis. On the other hand, intimal hyperplasia may mainly contribute to distal edge restenosis.

References

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From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
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 July 12, 2001, provisional acceptance given August 29, 2011, final version accepted September 29, 2011.
Address for correspondence: Eiji Ichimoto, MD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Email: e.ichimoto@nifty.com