Intravascular Ultrasound Comparison of Small Coronary Lesions Between Novel Guidewire-Based Sirolimus-Eluting Stents and Conventional Sirolimus-Eluting Stents

Abstract: Background. The Sparrow stent system (Biosensors International) consists of a self-expanding, ultra-thin nitinol stent mounted within a 0.014˝ guidewire designed for small or tortuous coronary lesions. We compared the intravascular ultrasound (IVUS) findings between the novel self-expanding sirolimus-eluting stent (Sparrow-SES) and a conventional balloon-expandable sirolimus-eluting stent (Cypher-SES) in patients with small coronary disease. Methods. We examined 14 lesions treated with the Sparrow-SES from CARE II, compared with 22 small vessel lesions treated with Cypher-SES. IVUS examination was performed post-procedure and 8 months later. Volumetric data were standardized by length as volume index (VI; mm³/mm). Results. While baseline stent VI trended smaller in Sparrow-SES, follow-up stent VI became similar between the 2 groups due to a significant increase of stent VI in self-expanding Sparrow-SES during the follow-up period. At 8 months, Sparrow-SES showed greater neointima than Cypher-SES (0.8 ± 0.6 mm³/mm vs 0.2 ± 0.2 mm³/mm; P<.001). However, the decrease in lumen VI was only 0.3 ± 0.7 mm3/mm in Sparrow-SES, as compared to 0.1 ± 0.3 mm³/mm in Cypher-SES (P=.259), since the late loss due to neointimal hyperplasia was partly counterbalanced by the chronic stent expansion in Sparrow-SES. Conclusion. While 8-month follow-up of Sparrow-SES revealed greater amounts of neointimal hyperplasia compared with conventional Cypher-SES, chronic stent expansion preserved the lumen by increasing stent volume. This novel, guidewire-based, self-expanding stent system designed to be delivered through complex anatomies may be useful to treat patients with small-caliber coronary lesions by offering sufficient lumen preservation at follow-up. 

J INVASIVE CARDIOL 2012;24(10):489-493

Key words: coronary, small-vessel disease, percutaneous coronary intervention, drug-eluting stent

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Percutaneous coronary intervention (PCI) targeting small coronary arteries comprises up to 35% of all catheter-based procedures in daily practice.¹ In the bare-metal stent (BMS)era, smaller vessel diameter was a recognized determinant of restenosis after PCI.^2,3 The drug-eluting stent (DES) has significantly reduced stent restenosis rates, yet PCI in small coronary arteries remains a challenging lesion subset in the DES era.⁴ In addition, failure to cross the tight lesion (with the undeployed stent) due to vessel tortuosity represents another challenge of PCI in the treatment of small coronary artery disease, having design implications for small-vessel stent delivery systems with drug elution and crossing profile.

Previously, a feasibility study of a guidewire-based, self-expanding stent delivery system, the Sparrow stent system (CardioMind; purchased by Biosensors International), was reported.^5,6 These encouraging preliminary clinical results of the use of the Sparrow stent have led to the development of a drug-eluting version for this platform.^7,8 Coupled with guidewire-based crossing profile and sirolimus, a well-established anti-proliferative drug,⁹ this DES iteration of the Sparrow stent may be more useful to treat small vessel coronary disease than conventional catheter based DES platforms. Thus, this study was performed as an initial investigation to compare the intravascular ultrasound (IVUS) findings between the novel Sparrow sirolimus-eluting stent (Sparrow-SES, Biosensors International) with those of conventional balloon-expandable sirolimus-eluting stents (Cypher-SES, Cordis) in patients with small vessel coronary artery disease. 

Methods

Patient selection. The study population for the analysis of the Sparrow-SES consisted of patients with IVUS analysis from the CARE II trial implanted with the Sparrow-SES. The CARE II trial was a 3 arm prospective, randomized, multicenter single-blind trial evaluating the safety and efficacy of the Sparrow-SES compared to the Sparrow bare-metal stent and a commercial bare-metal stent in the treatment of single de novo small native coronary artery lesions.^7,8 Conventional balloon-expandable Cypher-SES data were derived from the SVELTE trial, a prospective, multicenter trial of Cypher-SES in the treatment of single de novo small coronary disease, and the ENDEAVOR III trial (Cypher-SES arm), a multicenter, single-blind, parallel, 2-arm, randomized control study comparing the efficacy of zotarolimus-eluting stents and Cypher-SES for the treatment of de novo coronary artery lesions.^10,11 From these trials, patients who met the following criteria were enrolled into this IVUS analysis: (1) a single de novo >50% stenosis, in a native epicardial coronary vessel between 2.0 and 2.5 mm in diameter; and (2) availability of high-quality, serial (baseline and follow-up) IVUS images with volumetric analysis.

Device description. The Sparrow-SES delivery system is comprised of the self-expanding nitinol stent, which is loaded into a 0.014˝″guidewire platform. This self-expanding stent was able to be delivered to the target lesion after balloon angioplasty and released from the wire under the guidance of two radiopaque markers at both edges of the stent by electrolysis. In the CARE II trial, the stent deployment was followed by mandated postdilation per protocol to ensure optimal stent expansion and complete stent apposition to the vessel wall. A detailed description of the stent deployment procedure was provided in a previous case report.⁵ This stent employs a closed-cell design with metal-to-artery ratio of 8%-12% and incorporates sirolimus in a biodegradable PLA/PGLA block copolymer matrix. Comparisons of the Sparrow-SES and Cypher-SES device characteristics are shown in Table 1 and representative IVUS images of both stent are shown in Figure 1.

IVUS analysis. IVUS examination was performed at post-procedure and 8 months later. The IVUS procedure was performed in a standard fashion using automated motorized pullback (0.5 mm/s) with commercially available imaging systems (40 MHz IVUS catheter, Boston Scientific Corporation, or 20 MHz IVUS catheter, Volcano Corporation). IVUS analysis was performed at an independent core laboratory by clinicians blinded to the treatment arm. Volumetric measurements were performed using a PC based software (echoPlaque; Indec Systems Inc) as previously described.^12,13 Peristent plaque volume was calculated as vessel minus stent volume. Neointimal volume was calculated as stent minus lumen volume, and neointimal obstruction (%) was defined as neointimal volume divided by stent volume. Each volume was divided by the measurement of stent length to adjust for different stent lengths (volume index: VI, mm³/mm). Cross-sectional narrowing (%) was defined as neointima area divided by stent area.

Tissue prolapse, stent edge dissection, and incomplete stent apposition (ISA) were assessed by qualitative IVUS analysis. ISA was defined as 1 or more struts clearly separated from the vessel wall with evidence of blood speckles behind the strut. ISA was classified as ‘persistent,’ ‘resolved,’ or ‘late-acquired’ as previously described.^13,14 All images were reviewed by two independent observers and adjudication of opinion was based on the consensus of these observers.

Statistical analysis. Statistical analysis was performed with SPSS version 18.0 for Windows (SPSS Inc). Categorical variables were presented as counts and percentages, and compared with the Fisher exact test or the chi-square test. Continuous variables were presented as mean value ± standard deviation (SD) after testing the normality of the data with the Kolmogorov-Smirnov test or Saphiro-Wilks test. For continuous variables, Student’s t-test was used to differentiate between two sets of data (paired and unpaired according to the compared data). A P-value of <.05 indicated statistical significance.

Results

Serial IVUS images were analyzed in 14 small coronary lesions treated with the Sparrow-SES and 22 with the Cypher-SES. There were no significant differences in baseline demographic, clinical, and procedural characteristics between the Sparrow-SES and Cypher-SES (Table 2), and thus, no propensity score matching was performed. While baseline stent VI trended smaller in the Sparrow-SES, follow-up stent VI became similar between the 2 groups due to a significant increase in stent VI of the self-expanding Sparrow-SES during the follow-up period (Table 3). Individual changes of stent VI are shown in Figure 2 with change in the Sparrow-SES significantly greater than in the Cypher-SES (14.6% vs 1.8%). At 8-month follow-up, the Sparrow-SES showed greater neointima VI and percent neointimal obstruction than those of the Cypher-SES group (Table 3). However, the decrease in lumen VI was only 0.3 ± 0.7 mm³/mm in the Sparrow-SES group, as compared to 0.1 ± 0.3 mm³/mm in the Cypher-SES (P=.259), since the late loss due to neointimal hyperplasia was partly counterbalanced by the chronic stent expansion in the Sparrow-SES (Figure 3). Table 4 presents the quantitative IVUS results for the reference segments, showing that vessel, plaque, and lumen VI did not change significantly in either group. Regarding the results of qualitative analyses, no significant differences between the Sparrow-SES and Cypher-SES in either tissue prolapse or stent edge dissection were observed (Table 5). However, there was a trend toward more ISA at baseline in the Sparrow-SES than in the Cypher-SES (8 cases in the Sparrow-SES, 5 cases in the Cypher-SES; P=.073). Resolved ISA was observed in 7 of 8 cases (87.5%) in the Sparrow-SES group and 2 of 5 cases (40.0%) in the Cypher-SES group.

Discussion

This study is the first report of the clinical use of the self-expanding Sparrow-SES in comparison with a conventional balloon-expandable Cypher-SES. The major findings of this IVUS analysis were: (1) the Sparrow-SES showed greater neointima hyperplasia than the Cypher-SES; (2) stent VI in the Sparrow-SES group increased significantly during the follow-up period; and (3) the decrease in lumen VI was not significantly different between the 2 groups, since late loss due to neointimal hyperplasia was partly offset by the chronic stent expansion of the Sparrow-SES.

The current analysis enrolled the patients treated with the Sparrow-SES from the CARE II trial, the main results of which were presented elsewhere. Briefly, the angiographic in-stent late loss was significantly less in the Sparrow SES (0.29 mm) compared with the Sparrow BMS (0.86 mm; P=.0001), as well as the MicroDriver (Medtronic, 0.99 mm; P<.0001). Cumulative major adverse cardiac events (MACE) through 12 months showed favorable safety profiles for the Sparrow SES (6.3%) and the Sparrow BMS (14.3%), while the MicroDriver exhibited a MACE rate of 26.7% (Sparrow SES vs MicroDriver; P=.040).⁷

The two types of DES tested in the present study deliver the same antiproliferative drug with similar elution kinetics (sirolimus release at 28 days: Sparrow-SES 98%, Cypher-SES 85%),⁷ but utilizing different stent material (nitinol vs stainless-steel) and polymer coating (biodegradable vs durable). In addition, there are several differences in stent properties that may account for the results of the present study. While self-expanding stents can facilitate gentler stent deployment through a reduction in balloon barotrauma, the chronic outward force may possibly be associated with a sustained stimulus to the arterial wall. Of note, the theoretical advantage of the reduced barotrauma at stent deployment may have been diminished in the present study due to the use of postdilatation mandated by the CARE II study protocol. Another potentially important difference is that the Sparrow-SES has a relatively smaller total surface area of stent struts compared with Cypher-SES (metal-to-artery ratio: 8%-12% in Sparrow-SES, 12%-15% in Cypher-SES). In fact, the number of stent struts visualized on cross-sectional IVUS images was significantly less in the Sparrow-SES than in the Cypher-SES (Figure 1). The smaller metal-to-artery ratio can represent a theoretical advantage of less vessel injury, thereby reducing unfavorable arterial response such as neointimal hyperplasia. On the other hand, this property may be disadvantageous as a drug carrier platform with respect to the maximum drug load capacity on the struts and the uniform drug delivery to the vessel wall. The vessel response and long-term outcomes can theoretically be affected by the balance of multiple aspects described above.

The clinical impact of neointima excepting in-stent restenosis is still unclear. In some cases, neointimal rupture several years after BMS implantation has been reported, suggesting that large neointimal volume might be associated with further incidence of atherosclerosis.^15,16 In contrast, stent coverage by neointima was associated with a reduced likelihood of stent thrombosis after Cypher-SES implantation.¹⁷ The long-term implications of neointimal hyperplasia differences remain unclear. Further long-term follow-up studies with larger patient populations are needed to clarify the clinical impact of neointimal volume after Sparrow-SES implantation.

In this study, the Sparrow-SES had greater neointimal hyperplasia than conventional Cypher-SES, suggesting reduced lumen volume in Sparrow-SES. However, the Sparrow-SES, incorporating a self-expanding nitinol stent, expanded by about 15% during the follow-up period, comparable to a previous report of the Sparrow, which is the bare-metal version of this stent system.⁶ As a result, these factors appear to have offset one another. Lumen VI in the Sparrow-SES was not significantly different between baseline and follow-up, and the change in lumen VI was not significantly different between the Sparrow-SES and Cypher-SES in this study. In fact, clinical efficacy of the Sparrow-SES and Cypher-SES in the treatment of small-vessel coronary artery disease was similar in previous reports (target lesion revascularization rate at 8 months: 0% for both Sparrow-SES in the CARE II trial and Cypher-SES in the SVELTE study).^7,10

The design of the Sparrow-SES incorporates a self-expanding nitinol stent, with ultra-thin strut thickness, mounted in a shapeable, steerable guidewire-type delivery platform, maintaining its 0.014˝ (356 µm) profile along the entire stent system.^5,6,18 Considering the ultra-low profile and enhanced flexibility, this novel stent system may greatly facilitate deliverability and provide sufficient lumen preservation in the treatment of smaller-vessel atherosclerotic disease.

Study limitations. There are several limitations in this IVUS study. First, this is a retrospective, non-randomized study based on a limited sample size, raising the possibility of selection bias and limited generalizability. Therefore, large-scale prospective randomized studies are warranted for the definitive evaluation of this new device. In addition, the limited number of patients may have resulted in underpowered comparisons in some IVUS parameters, although the sample size of this study was sufficient (0.05 two-sided; 80% power) for primary results (neointima, lumen, and stent change). Second, follow-up IVUS analysis was limited to a mid-term period of 8 months. The ultimate effectiveness and safety of this novel DES technology should be addressed in further studies with longer-term follow-up. Third, IVUS assessment might not be performed in cases with severe stenosis because of inherent limitations in catheter-based imaging.

Conclusion

Despite greater amounts of neointimal hyperplasia observed at 8-month follow-up, the Sparrow nitinol stents with sirolimus presented chronic stent expansion to compensate for neointimal obstruction and thus preserved the lumen by increasing stent volume. This novel, guidewire based, self-expanding stent system designed to be delivered through complex anatomies may be useful to treat patients with small-caliber coronary lesions by offering sufficient lumen preservation at follow-up.

Acknowledgment. The authors thank Heidi N. Bonneau, RN, MS, CCA, for her review of this manuscript.

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From the ¹Stanford University Medical Center, Stanford, California, ²Instituto do Coração do Triângulo Mineiro, Uberlândia, Brazil, ³Antwerp Cardiovascular Institute Middelheim, Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium, ⁴St. Vincent’s Hospital, Melbourne, Australia, ⁵Monash Medical Center, Melbourne, Australia, ⁶Royal Adelaide Hospital, Adelaide, Australia, ⁷National Heart Centre, Mistri Wing, Singapore, and ⁸Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Yock and Abizaid received a research grant from Cordis. Dr Fitzgerald received a research grant from Cordis and worked as advisory board member of Cordis/CardioMind.  The other authors reported no disclosures.
Manuscript submitted December 28, 2011, provisional acceptance given February 7, 2012, final version accepted May 8, 2012.
Address for correspondence: Yasuhiro Honda, MD, Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Drive, Room H3554, Stanford, CA 94305-5637. Email: crci-cvmed@stanford.edu