Stenting for Small Coronary Vessels<br />

Smaller vessels constitute a large group in daily practice of percutaneous coronary interventions. Depending on definition, prevalence ranges from 35–67%.^1–6 Patients who underwent treatment of smaller vessels had a significantly increased risk of major adverse clinical events (MACE) both after percutaneous transluminal coronary angioplasty (PTCA) and stenting of native coronary arteries.^1–4,7–10 Small vessel size is a well-known potent predictor of restenosis after PTCA, as well as after stent placement.^{1,2,5,6,9–12} Though several randomized studies^13–19 comparing stenting and PTCA for small coronary vessels show divergent results, common findings in most trials are that stenting is associated with a significantly greater minimum lumen diameter (MLD) at the end of the procedure and that provisional stenting is needed in about 20% of patients initially assigned to PTCA. Recently, a meta-analysis of stent versus PTCA trials in small coronary arteries²⁰ demonstrated a strong relationship between the residual stenosis grade after PTCA and restenosis reduction after stenting. This means that it is certainly better to stent than to be satisfied with a suboptimal post-PTCA result. It is well known that routine stents, deployed in small arteries, have a higher metal-to-artery ratio; this may increase the risk of sub-acute thrombosis or restenosis.²¹ Dedicated stents for small vessels with less amount of metal, appropriate expansion to the vessel size with correct radial force and cells morphology, and less pro-thrombotic properties might further improve the results of stenting in this setting (fewer thinner struts, fewer cells, or loops per circumference). Various studies have shown that stent design,^22,23 stent coating²⁴ and stent strut thickness^25,26 may determine event-free survival. Addressing this issue in this Journal, Dr. Gianni Casella and colleagues²⁷ report the results of the multi-link Pixel multicenter Italian registry using the dedicated small vessel stent, called PIXEL. The Multi-Link Pixel stent is a 5-crest corrugated ring, stainless-steel stent characterized by a reduced strut thickness (0.0039´´). This study was a prospective, multicenter registry that enrolled 231 patients (243 lesions) who underwent implantation of a Pixel small vessel stent at 23 Italian centers. Angiographic inclusion criteria were the presence of a lesion with a diameter stenosis >50% with an angiographic reference diameter = 23 mm) were used rarely (3.2%). MLD significantly increased from 0.71 ± 0.32 mm to 2.32 ± 0.40, and acute lumen gain was 1.58 ± 0.25 mm. Clinical follow-up performed at 14 days and 6 months showed improvement in their CCS class. The rate of MACE was 0.4% at 14 days and 9.6% at 6 months; target lesion revascularization was 0.4% at 14 days and 7.4% at 6 months. Relevant limitations should be accounted for before trying to draw conclusions. This was not a randomized study and did not compare with a control group treated with balloon angioplasty or another stent. Angiographic indexes are sensitive markers of restenosis and carry a low risk of bias, particularly when re-angiography is routinely done. The strategy of clinically driven re-angiography adopted in this study may not be appropriate especially for patients who undergo interventions in small vessels, because restenosis-induced symptoms may be less severe for small vessels as compared to larger vessels. Summarizing the registry results, the Pixel stent appears to be highly effective in the treatment of complex coronary lesions in small vessels; Casella et al. are to be commended for the very low MACE and target vessel revascularization rate. These results are enviable even for interventions in larger vessels. Other studies with dedicated small vessel stents. Several stents specifically designed for small vessels are becoming commercially available. These include, among others, BioDivYsio phosporilcholine-coated stent (Biocompatibles International), Ministent (Cordis Corporation, Miami Lakes, Florida), Multi-Link Pixel coronary stent (Guidant Corporation) and BeStent (Medtronic). Hausleiter et al.²⁸ used eight different stent designs in small coronary arteries of various slotted-tube and interconnected ring designs and identified stent design as a strong independent predictor of angiographic restenosis. The incidence of restenosis varied from 29.6–55.8% (overall rate of 38.4%), depending on the stent design and stented segment length used and the Multi-Link stent was associated with the lowest restenosis rate in their study.²⁸ In a recent study using the multilink Pixel stent²⁹ presented at EuroPCR 2003, Drs. Garcia et al. showed that the overall 6-month MACE rate was only 7.7%, and the binary in-stent restenosis rate was 19.3%. In the Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries (ISAR-SMART) trial,¹⁴ using the multi-link stent, the restenosis rate was 35.7% among stent patients and 37.4% among PTCA patients (p = NS). In the BeStent in Small Arteries (BESMART) trial,15 the binary restenosis rate was 21% after stenting and 47% after PTCA (p 16 using the BeStent, showed a trend toward fewer in-hospital events in the stent group (3% versus 7.1% in angioplasty group); binary restenosis rate was 28% after stenting and 32.9% after PTCA (p = NS). In the Restenosis en Arterias Pequeñas study (RAP),17 with BeStent, the binary restenosis rate was 27% among stent and 37% among PTCA patients (p 19 intended to enroll 200 patients, but was terminated by the sponsor after inclusion of 145 patients. The primary endpoint of the trial, MLD, was slightly better in the stent group but without achieving statistical significance (1.69 mm in the stent arm vs. 1.57 mm in the PTCA arm; p = 0.1), but showed a trend to less angiographic restenosis for stenting as compared to PTCA (9.7% versus 18.8%; p = 0.15). Coated and drug-eluting stents. Coated and drug-eluting stents are promising new technologies that could turn stents into highly attractive devices for treating lesions in small coronary arteries. Sirolimus-eluting stents dramatically inhibit neointimal hyperplasia, subsequently reducing in-stent and in-segment restenosis and target vessel failure.³⁰ In the RAVEL trial,³¹ patients were randomized to receive either an 18-mm bare metal Bx Velocity (n = 118), or a sirolimus-eluting Bx Velocity stent (n = 120). Approximately 40% of the vessels were small (32 Subgroups were stratified according to their reference diameter (RD) stratum I, RD 2.84 mm). At 6-month follow-up, the restenosis rate in the sirolimus stent group was 0% in all strata versus 35%, 26%, and 20%, respectively, in the bare stent group. In-stent late loss was 0.01 ± 0.25 versus 0.80 ± 0.43 mm in stratum I, 0.01 ± 0.38 versus 0.88 ± 0.57 mm in stratum II, and -0.06 ± 0.35 versus 0.74 ± 0.57 mm in stratum III (sirolimus stent versus bare stent). In the sirolimus stent group, the minimal lumen diameter (MLD) remained unchanged in 97% of the lesions and increased in 3% of the lesions. The classic inverse relationship between vessel diameter and restenosis rate was seen in the bare stent group but not in the sirolimus-eluting stent group.³² The SIRIUS trial³³ was specifically oriented towards a high-risk lesion subset, larger vessels were excluded and the vessels had to be between 2.5–3.5 mm. A total of 556 patients were randomized to receive the sirolimus-coated stent and 545 to receive a bare metal stent. In-segment restenosis (defined as restenosis within the margins of the stent but extending about 5 mm proximal and distal to the stent) occurred in 8.9% of the study group and in 36.3% of the control group (p 33 Another coated stent using an antiproliferative agent, paclitaxel, showed similar results in the small vessels. The Taxus 2 study³⁴ randomized 536 patients into 2 cohorts: 267 in the slow-release component, and 269 in the moderate-release component. Results showed that paclitaxel coated stents met their primary endpoint, improving 6-month in-stent net volume obstruction by more than 60%. The restenosis rate in the analysed segment including the stent margins were 13.5% (2.5 mm vessel) versus 0% (vessels more than 3 mm) and restenosis rate within stent were 2.7% (2.5 mm vessel) versus 0% (vessels more than 3 mm).³⁴ Thus, the restenosis rate was higher at the stent margins and was disproportionately greater as the reference vessel diameter decreased. Though drug-eluting stents prevent neointimal proliferation and late lumen loss irrespective of the vessel diameter, in the small vessel subset, it has only attenuated, and not completely eliminated the restenosis. The reason for this high persistence of restenosis in small versus large vessels is the higher frequency of edge restenosis. An arguement has been made that the higher frequency of edge restenosis in smaller vessels may be secondary to inappropriate lesion coverage, but it remains to be seen whether longer stents will attenuate the frequency of this phenomenon. Which is the best option in small coronary arteries? The randomized trials do not discourage the routine use of stenting for lesions in small coronary arteries. The improvement potential of PTCA in small vessels seems to be exhausted with the achievement of an optimal acute result. All the trials in which a dedicated small vessel stent was used — whether it was the BeStent,^15–17,19 Biodivysio stent³⁵ or Multilink,^28,29 and including the multicenter Italian registry data by Casella et al.,²⁷ showed the advantage of stenting; therefore, focal lesions in small vessels should probably be treated with these particular stents. There is a great enthusiasm as to the value of drug-eluting stents in treating small vessel disease. Further studies in small vessels should be planned randomizing dedicated small-vessel and drug-eluting stents. Dedicated small vessel stents coated with sirolimus or paclitaxel may be available in the future and will revolutionize the management of small vessel disease.

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