Stenting Small Coronary Arteries: The Multi-Link PIXEL‚Ñ¢ Multicenter Italian Registry

Stenting is now being used in many centers to treat coronary lesions beyond standard indications.¹ This became possible due to new and better stent designs, improvements in stent implantation techniques and effective antiplatelet therapy.² However, the remarkable reduction of restenosis obtained with stenting of vessels > 3.0 mm is still controversial in challenging situations such as small vessels or long lesions.³ Small coronary arteries represent a fair amount of the day-to-day angioplasty practice. In fact, it is estimated that the reference vessel diameter is 3 Women, diabetics and patients with peripheral vascular disease or small body surface area usually have small coronary arteries³ and their proportion is likely to further increase. Unfortunately, an inverse relationship has been found between vessel size and angiographic restenosis rate⁴ or sub-acute stent thrombosis.⁵ Although several randomized^6,7 and observational trials^8–12 have addressed the issue of small vessel stenting, their results are still controversial. In addition, it is perceived that stent hardware (stent design and strut thickness) may have important implications for outcome.¹³ Recently, a number of stents specifically designed for small vessels and characterized by an optimal radial force at a smaller diameter with a lower metal-to-vessel ratio have been developed.³ Preliminary results with these dedicated devices are encouraging. Thus, we designed a prospective, multicenter registry to test the hypothesis that routine implantation of a specifically dedicated stent (Multi-Link Pixel™; Guidant Corporation, Temecula, California) would be safe and effective in small coronary arteries with complex lesion morphology.

Methods

The Multi-Link Pixel™ study was a prospective, multicenter registry that enrolled 231 consecutive patients (243 lesions) who underwent elective, urgent or bailout implantation of a Pixel™ small vessel stent at 23 Italian centers (Appendix 1) between January 2001 and November 2001. The Institutional Ethics Committee of each participating center approved the study protocol and all patients gave informed consent. Patients were eligible for inclusion if they had acute coronary syndrome, stable angina and/or presented with objective evidence of myocardial ischemia. Angiographic inclusion criteria were the presence of a lesion with a diameter stenosis > 50% and an angiographic reference diameter 2.5 mm were allowed. Coronary procedure. Angioplasty was performed in the conventional manner by femoral or radial approach, according to standard techniques at each center. Aspirin was prescribed and intravenous heparin (either fixed or weight-adjusted doses) was given before the procedure to achieve a therapeutic anticoagulation (activated clotting time > 300 seconds or 200–250 seconds when IIb/IIIa inhibitors were used). IIb/IIIa antagonists were given according to operator judgement. Stent placement was performed after angioplasty according to standard methods. Multiple stent implantations were allowed if required. The study protocol recommended the achievement of a final diameter stenosis of Stent. The Multi-Link Pixel™ coronary stent system is a 5-crest, corrugated ring, stainless-steel stent characterized by a reduced strut thickness (0.0039´´) and a design that allows complete stent expansion in arteries with a small diameter. The stent is securely pre-mounted on a low-compliance balloon. It is characterized by a low crossing profile (0.036–0.037´´) and good flexibility. The stent is available in 3 different diameters (2.0 mm, 2.25 mm and 2.5 mm) and 5 different lengths (8 mm, 13 mm, 18 mm, 23 mm and 28 mm) Angiographic analysis. Angiography was performed using 5–8 French (Fr) guiding catheters preintervention and postintervention. Matched orthogonal views were used for quantitative analysis before and after stent deployment using contrast-filled catheters for calibration. Angiography was performed after nitroglycerine (100–200 µg) or isosorbide dinitrate (1–3 mg) intracoronary bolus. Angiograms were analyzed offline in an independent core laboratory (European Imaging Laboratory, European Hospital, Rome, Italy) with the CMS validated automated edge detection system, version 4.0 (Medis, Cardiovascular Angiography Analysis System II, Pie Medical Data, Maastricht, The Netherlands). The absolute values for the minimal lumen diameter, reference vessel diameter, lesion length and percent diameter stenosis were measured. Acute gain was calculated as postintervention stent minimal lumen diameter minus minimal lumen diameter before intervention. The modified American College of Cardiology/American Heart Association lesion classification was used.¹⁴ Flow was graded according to the standard TIMI criteria.¹⁵Study endpoints, definitions and follow-up. Follow-up was performed at 14 days and 6 months after the procedure in an outpatient clinic. Repeat angiography was undertaken only when patients developed symptoms suggestive of angina or when there was significant functional evidence of ischemia. The study endpoint was the occurrence of major adverse cardiac events (MACE), defined as a combination of death, Q-wave or non-Q wave myocardial infarction, coronary bypass surgery (CABG) or coronary angioplasty (PCI) to the target vessel. All deaths were considered cardiac unless an unequivocal noncardiac cause could be established. Myocardial infarction was defined by new Q-waves > 0.04 seconds or elevation of the serum creatinine kinase to greater than twice the upper limit of normal with an elevated MB fraction (measured at 12 and 24 hours). Target vessel revascularization required recurrent angina or signs of ischemia. Acute or sub-acute stent thrombosis required angiographic evidence of total closure at the target site. Procedural success was defined as technically successful stent deployment in the absence of any adverse cardiac event. Angiographic success was defined as achievement of a final diameter stenosis of 50% at follow-up. Statistical analysis. Continuous variables were presented as means ± standard deviations. Student’s t-test was used for comparison of continuous variables. Categorical variables were presented as counts and percentages. Statistical significance was accepted for a 2-tailed value of p Results Demographics and angiographic characteristics. The baseline characteristics of the patients are presented in Table 1. The risk profile of the study population was high (41% of cases had unstable angina, 20% diabetes and 52% had multivessel disease). A total of 252 Pixel™ stents were used in 243 lesions. In all but 21 cases, a single stent was deployed. Additional stents were used mostly to treat the target lesion, not entirely covered by the first stent or dissected (18 cases), while in 3 cases a different lesion in another vessel was treated. Additional lesions were treated with larger balloons and stents in 52 patients. Baseline angiographic characteristics are described in Table 2. Forty percent of lesions had unfavorable characteristics (type B2 or C), 10% were chronic total occlusions and 15% were bifurcation lesions. Lesion length was discrete and average vessel size was well below 2.3 mm. Procedural and in-hospital outcome. The average stent diameter implanted was 2.42 ± 0.12 mm. In fact, the 2.5 mm stent was implanted in 72% of cases, while only 2% of deployments required the 2.0 mm stent. Average stent length was 13.73 ± 3.94 mm. Again, stents of = 23 mm) were rarely used (3.2%). Successful stent deployment was achieved in all lesions. Average maximal balloon pressure was 13.21 ± 2.63 atmospheres. Angiographic results are described in Table 3. Minimal luminal diameter significantly increased from 0.71 ± 0.32 mm to 2.32 ± 0.40 mm (Figure 1) and acute lumen gain was 1.58 ± 0.25 mm. All patients received aspirin prior to the procedure, heparin at the beginning of the angioplasty, and ticlopidine or clopidogrel afterward. There were no cases of bleeding or vascular complications, or acute or subacute stent thrombosis. Follow-up outcome. Clinical follow-up was performed at 14 days and 6 months in 229 patients (99%). Most patients improved in their Canadian Cardiovascular Society class. The rate of MACE was 0.4% at 14 days and 9.6% at 6 months (Table 4). Most of these adverse cardiac events consisted of repeat revascularizations. In fact, target lesion revascularization was 0.4% at 14 days and 7.4% at 6 months. Only 1 patient experienced double MACE (Q-wave myocardial infarction first, followed by re-PTCA at the target site). Angiography was not routinely repeated at 6-month follow-up exam. Therefore, no data concerning angiographic restenosis were available. However, during the 6-month follow-up period, thirteen patients underwent angiography followed by re-PTCA for symptomatic restenosis. At univariate analysis, neither the demographic clinical and angiographic parameters nor the procedural variables had a significant effect on the MACE incidence. The same finding was confirmed with multiple logistic regression analysis.

Discussion

In this report, we show that the Multi-Link Pixel™ coronary stent can be safely and successfully implanted in small coronary arteries in patients with a variety of clinical and angiographic findings. The event-free survival rate at 6 months was > 90% and compares well with previous studies of single-vessel treatment in vessels > 3.0 mm, even though average vessel size was below 2.3 mm and 52% of the study patients had multivessel disease. Patients with lesions in vessels with small reference diameters constitute a distinct population. Their clinical characteristics are different, including more women, and more patients with diabetes, heart failure and peripheral vascular disease.³ In addition, lesions in small vessels tend to be more complex and more commonly associated with multivessel disease.³ As a result, there are a number of procedural concerns and long-term issues while performing interventions in such cases, since the risk of complications and restenosis may be higher. Retrospective and observational studies have been reported on stenting in small coronary arteries.^8–12 The initial procedural success rate ranged from 93–98%, subacute thrombosis from 0.5–3.8% and restenosis from 21–36%. Adverse clinical events ranged from 11–26%. However, the real issue of whether elective stenting is better than provisional stenting in small vessels could not be resolved from these uncontrolled studies. Thus, eight major prospective, randomized, controlled trials of elective stenting in small vessels (Table 5) involving more than 2,500 patients have been reported.^6,7,16–21 Only 2 studies (BESMART and RAP) found that elective stenting significantly reduced the angiographic restenosis rate. The average restenosis rate was 37% in the balloon angioplasty arm and 32% in the stent group. Unfortunately, clinical events at follow-up were no different in 7 of the 8 studies. We may argue that these trials were not exactly comparable (different baseline characteristics, lesion type treated, stents and antiplatelet regimen used, use of high-pressure stenting, etc.), but these results still point to provisional stenting as a better option. Whether or not these results could have been negatively influenced from the use of conventional stents instead of specially designed stents for small arteries is an issue. It is well known that stents routinely deployed in small arteries have a higher metal-to-artery ratio and this may increase the risk of subacute thrombosis or restenosis.³ In addition, it has been demonstrated that stent design²² and strut thickness23 are independent predictors of outcome in small vessels. Recently, several stents specifically designed for small vessels became commercially available. These include the BioDivYsio phosphorilcholine-coated stent (Biocompatibles International), the Ministent (Cordis Corporation, Miami, Florida), the Multi-Link Pixel coronary stent and the BeStent (Medtronic, Minneapolis, Minnesota). The Multi-Link Pixel™ stent is a third-generation, corrugated-ring stent with design and characteristics of flexibility and radial strength, which may account for the high delivery success rate and low clinical restenosis rate. The early and late incidences of adverse cardiac events in the present trial were very low (MACE, 0.4% at 14 days and 9.6% at 6 months) and compare favorably with event rates previously reported for this particular stent. In fact, a preliminary Multi-Link Pixel™ international registry²³ that enrolled 150 patients with de novo or restenotic lesions in vessels 2.0–2.5 in diameter reported a procedural success of 100% coupled with a very low rate of MACE and TVR (10.2% and 8.8%, respectively) at 6 months. The incidence of subacute stent thrombosis was 0.7%. How much these favorable outcomes could be attributed to the optimal stent design (stent/strut geometry and thickness) is an issue. However, it has been demonstrated that thinner (24 Furthermore, Rogers et al.,²⁵ using stents with a similar total surface area and strut thickness but a different geometric configuration, demonstrated that the corrugated-ring stent design in which the struts created a more complex and closed area permitted 33% less injury in the spaces bound by each strut, as compared with the stent design in which the inter-strut area was more simple and open in shape (slotted-tube design). However, whether or not these findings could be replicated in humans needs to be studied in a larger number of cases. Study limitations. First, the study was not randomized and did not include comparisons with a control group treated with balloon angioplasty or another stent. Moreover, the length of follow-up was limited to 6 months, and it is becoming evident that several clinical events following stenting occur later on, up to 9 months. However, the time frame selected is comparable to that currently used in several randomized clinical trials (Table 5). Second, the absence of systematic angiographic follow-up precludes any calculation of the angiographic restenosis rate. In fact, the very low rate of MACE and revascularization in such small vessels compared to that observed in randomized trials may raise some doubts. First, the fact that most lesions were shorter than 13 mm and stents deployed were mainly 2.5 mm in size, reflects some concern of the interventionalists involved in the study in treating long lesions and very small vessels. This preselection bias may have contributed to such a low rate of events. In any case, the low rate of revascularization has to be interpreted taking into consideration the design of the study, with a clinically oriented late follow-up. Obligatory late angiographic control has been shown to increase the occurrence of repeat target lesion revascularization considerably, with no net benefit, when compared to a clinically conducted follow-up.²⁶Conclusion. This initial experience indicates that implantation of the Multi-Link Pixel™ stent appears to be safe and effective in the treatment of complex coronary lesions in small vessels and is associated with a remarkably low target vessel revascularization rate. Acknowledgments. The authors would like to express their sincere gratitude to Mrs. Lucilla Scuto for her expert support in data acquisition. The study has been supported in part by an unrestricted grant from Guidant Italia, Milano, Italy.

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