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J Am Coll Cardiol, 2007; 49:539-546, doi:10.1016/j.jacc.2006.09.042
(Published online 19 January 2007). © 2007 by the American College of Cardiology Foundation |
Cardiology Unit, Cardiothoracic Department, University of Pisa, Pisa, Italy.
Manuscript received July 5, 2006; revised manuscript received September 22, 2006, accepted September 27, 2006.
* Reprint requests and correspondence: Dr. Anna S. Petronio, Dipartimento Cardiotoracico, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy. (Email: a.petronio{at}ao-pisa.toscana.it).
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BACKGROUND: Both the SES (Cypher, Cordis, Miami Lakes, Florida) and the paclitaxel-eluting stent (PES) (Taxus, Boston Scientific, Natick, Massachusetts) have shown a marked reduction in neointimal hyperplasia compared with bare-metal stents. Intravascular ultrasound (IVUS) is the best method to assess arterial response to stent deployment, but few IVUS data are available comparing complex lesions treated with SES or PES.
METHODS: We prospectively randomized patients with complex lesions to SES or PES implantation. Intravascular ultrasound and quantitative angiography were performed post-procedure and at 9 months. Mean neointimal hyperplasia area (NIHA), percent of NIHA (NIHA%), mean peristent plaque area (PSPA), and percent of PSPA (PSPA%) were calculated. The primary end point was NIHA% at follow-up. Secondary end points included change in PSPA% and angiographic late luminal loss at follow-up.
RESULTS: Of the 100 patients enrolled, 42 receiving the SES and 43 receiving the PES had adequate IVUS assessment. Vessel, plaque, and lumen areas were comparable at follow-up, but NIHA% was significantly lower with SES than PES (7.4 ± 4.2% vs. 15.4 ± 8.1%; p < 0.001). A significant reduction in PSPA% was observed with SES (–4 ± 10% vs. 0 ± 8%; p = 0.01). Late loss was significantly lower with SES (0.16 ± 0.19 mm vs. 0.32 ± 0.33 mm; p = 0.003).
CONCLUSIONS: The SES shows a significantly higher inhibition of neointimal hyperplasia compared with PES in complex lesions. However, both stents have excellent IVUS and angiographic results at 9 months. A significant reduction in peri-stent plaque is observed only with SES.
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16 mm in length; 3) vessel reference diameter between 2.5 and 3.7 mm at lesion site; and 4) consent to undergo a follow-up angiography at 9 months. Exclusion criteria were: 1) ST-segment elevation acute myocardial infarction; 2) intolerance to aspirin or clopidogrel; 3) severe comorbidity; and 4) participation in another clinical study. The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients gave written informed consent. Randomization and treatment. Randomization was performed after diagnostic angiography and before angioplasty. Sequentially numbered, sealed randomization envelopes were used, with a computer-generated random allocation sequence. Patients were randomized on a 1:1 basis to treatment with an SES (Cypher) or a PES (Taxus). Stent diameter ranged from 2.75 to 3.50 mm; minimum stent length was 18 mm for the SES and 16 mm for the PES. Shorter stents could be used as a second stent for complete lesion coverage, or to treat edge dissection. In case of inability to deliver a single stent to cover the whole length of the lesion, the use of 2 shorter stents with overlapping edges was allowed. If a mixture of drug-eluting stents could not be avoided, the patient was excluded from the study.
Before percutaneous coronary intervention (PCI), all patients received 100 mg of aspirin, and a 300-mg loading dose of clopidogrel was administered before or at the time of PCI. Percutaneous coronary intervention was performed using a standard technique with unfractionated heparin (70 U/kg of body weight). Use of glycoprotein IIb/IIIa inhibitors was at the physician’s discretion. Successful intervention was defined as a patent vessel with antegrade Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 and angiographic residual stenosis <50%. Patients were discharged on aspirin 100 mg daily indefinitely, and clopidogrel 75 mg daily for 6 months after PCI. In addition, all patients were discharged on simvastatin indefinitely, at a daily dose of 20 or 40 mg, as necessary to obtain low-density lipoprotein cholesterol levels of <110 mg/dl.
IVUS analysis. A commercially available IVUS system (Boston Scientific) was used. All IVUS studies were performed at the end of the procedure, after the intracoronary administration of nitroglycerin 200 µg. The IVUS catheter was advanced at least 10 mm distal to the stent, and imaging was performed to at least 10 mm proximal to the stent, with a motorized transducer pullback speed of 0.5 mm/s. Intravascular ultrasound images were recorded onto S-VHS tape and analyzed by 2 expert readers blinded to the treatment arm, with intraobserver and interobserver agreements of r = 0.96 and r = 0.91, respectively. The interobserver variability was assessed comparing the measurement of lumen volume in 15 recordings. Intraobserver variability was assessed by reanalyzing 15 recordings 1 month after the initial analysis. Intravascular ultrasound characteristics were identified according to the criteria of the American College of Cardiology Clinical Expert Consensus document on IVUS (11), using computerized planimetry (Tapemeasure, Indec Inc., Mountain View, California).
The external elastic membrane, stent, and lumen contours were identified, both at baseline and follow-up, every millimeter within the stented segment by semiautomatic detection contour mode. When the external elastic membrane could not be identified (due to acoustic shadowing) over a >90° arc, it was not measured. If the external elastic membrane could not be measured in >75% of the stent length, the patient was excluded from the study. The total vessel volume, stent volume, and lumen volume were measured, and the mean vessel area, mean stent area, and mean lumen area were calculated as the ratio of the corresponding volume to the analyzed length. The minimal lumen area (MLA) was also measured. The length of each stent that was free of IVUS-detectable neointimal hyperplasia was determined. The following parameters were calculated: mean peristent plaque area (PSPA) (defined as [vessel area] – [stent area], PSPA% (defined as PSPA/[vessel area] x 100), mean neointimal hyperplasia area (NIHA) (defined as [stent area] – [lumen area] at follow-up), and NIHA% (defined as NIHA/[stent area] x 100). Minimal in-stent lumen area after implantation was considered optimal when >6 mm2 (12).
Incomplete stent apposition was defined as a separation of at least 1 stent strut from the intimal surface of the arterial wall. Incomplete apposition at 9 months was considered "persistent" if already present post-procedure, and "late-acquired" if it was not present after implantation (13).
Quantitative coronary angiography. Coronary angiograms at baseline, immediately after PCI, and at follow-up were performed in at least 2 orthogonal views after intracoronary administration of nitroglycerin 0.2 mg. Care was taken to avoid vessel overlapping and to obtain the same views at baseline and follow-up. Angiograms were analyzed by 2 experienced readers, unaware of treatment allocation, with the use of an automated edge-detection system (Quantcor Siemens System, Siemens AG, Erlangen, Germany). The intraobserver and interobserver agreements were r = 0.95 and r = 0.88, respectively. The interobserver variability was assessed comparing the measurement of minimal lumen diameter in 15 angiograms. Intraobserver variability was assessed by reanalyzing 15 angiograms 1 month after the initial analysis. Parameters measured were the reference vessel diameter (RVD), the minimal luminal diameter (MLD), the percent stenosis (defined as [RVD – MLD]/RVD x 100), and the late luminal loss (LL) (defined as [MLD after PCI] – [MLD at follow-up]). All angiographic measurements of the target lesion were obtained within the stent and within its proximal and distal 5-mm margins.
Study end points. The primary prespecified end point was the comparison of NIHA% at follow-up between SES and PES use. Secondary end points included the comparison of: 1) change in PSPA% from baseline to follow-up; and 2) angiographic LL at follow-up.
Major adverse cardiac events were assessed at 9 months, but were not an end point. They included death from cardiac causes, myocardial infarction, and target-lesion revascularization. Myocardial infarction was defined as an increase in creatine kinase to more than twice the upper limit of the normal range, with elevation of troponin I. Target-lesion revascularization was defined as revascularization for a stenosis within the stent or its 5-mm borders.
Statistical analysis. At the time of study design, IVUS data on the SES and the PES in the literature involved short coronary lesions in small populations, with a NIHA% of 6.6 ± 5.5% for the SES (5), and of 7.8 ± 9.9% (0.7 ± 0.9 mm2) for the PES (3). Since total stented length increases the risk of in-stent restenosis also for drug-eluting stents (14), we anticipated a 60% increase in NIHA% in long, complex lesions. Thus, a NIHA% of 9 ± 5% and of 13 ± 7% with the SES and the PES, respectively, was anticipated. Consequently, a total of 74 patients provided 81% power to detect a 4% absolute difference in NIHA%, with a significance level of 0.05. Allowing for 25% attrition due to lack of follow-up angiography and insufficient IVUS quality, we calculated that 100 patients would need to be enrolled.
Data are presented as frequencies or mean ± SD. Comparisons between the SES and the PES were performed with the 2-tailed, unpaired t test or the Mann-Whitney test for continuous parameters, the paired t test for change from post-procedure to follow-up, and the Fisher exact test for categorical variables. Correlations between NIHA and PSPA% post-procedure and between angiographic LL and NIHA% were performed by linear regression analysis. Significance was set at an alpha of 0.05.
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The degree of coronary atherosclerosis was indicated by the high prevalence of multivessel disease (75.3%), previous myocardial infarction (30.6%), and diabetes mellitus (24.7%), and by lesion length (mean 20.6 ± 9.4 mm, range 12 to 49 mm). A trend toward a larger RVD in the PES group was found (p = 0.09).
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IVUS results. Mean vessel, stent, and lumen areas were similar in the SES and PES groups, both after stent implantation and at 9-month follow-up (Table 3). The changes in mean vessel, plaque, and lumen areas at follow-up are represented in Figure 2. Mean lumen area showed a significant reduction in both groups (p = 0.004 and p < 0.001, for the SES and PES groups, respectively), related to the development of neointimal hyperplasia. The reduction in lumen area at follow-up was significantly higher in the PES group (p = 0.002). Conversely, NIHA and NIHA%, the primary end point of the study, were significantly smaller in the SES group (p < 0.001). The stent length free of IVUS-detectable neointimal hyperplasia was significantly shorter in the PES group (p < 0.001). More than 75% of stent length was neointimal hyperplasia-free in 59.5% of SES versus 25.6% of PES (p = 0.002), while less than 25% of stent length was neointimal hyperplasia-free in 9.5% of SES versus 41.9% of PES (p = 0.001). Neointimal hyperplasia-free stent length was inversely correlated with NIHA% in both SES and PES (p < 0.001) (Fig. 3).
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An in-stent MLA of >6 mm2 after implantation (72.6% vs. 74.4%, in SES and PES groups, respectively; p > 0.2) was associated with no target-lesion revascularization during follow-up (0% vs. 9.2%; p = 0.06), and with minimal binary in-stent restenosis (1.6% vs. 13.6%; p = 0.05), compared with an in-stent MLA 
6 mm2.
Incomplete stent apposition was comparable in the SES and PES groups, both after implantation (7.1% vs. 9.3%, respectively; p > 0.2) and at 9 months (14.3% vs. 11.7%; p > 0.2), being persistent in 4.8% versus 4.7% of patients in the SES and PES groups, respectively (p > 0.2), and late-acquired in 9.5% versus 7.0% (p > 0.2). Incomplete apposition was never associated with a major adverse cardiac event.
Angiographic results. The mean in-stent LL at follow-up was 0.16 ± 0.19 mm in the SES group and 0.32 ± 0.33 mm in the PES group (p = 0.003) (Table 4). The mean percent stenosis was quite low in both groups (10.7% vs. 16.8% for the SES and PES groups, respectively; p = 0.04), with a rate of in-stent binary restenosis of only 2.4% versus 7.0% (p > 0.2). With 5-mm proximal and distal stent margins, the rate of in-segment restenosis was 2.4% versus 9.3%, for the SES and PES groups, respectively (p > 0.2). A highly significant linear correlation between angiographic LL and NIHA% was observed in the entire population (r = 0.567, p < 0.001).
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In particular, in our SES population, with a mean lesion length 21.2 mm, the NIHA% was 7.4%, which is higher than that reported with SESs for shorter lesions at 8 to 12 months follow-up: 2.3% was reported in the first series from São Paulo, Brazil (mean lesion length 12.9 mm) (4), 1% in the RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial (mean lesion length of 14.4 mm) (7), 1.2% in the E-SIRIUS (European Sirolimus-Eluting Stent in Coronary Lesions) trial (mean lesion length of 15.5 mm) (18), and 3.1% in the SIRIUS (Sirolimus-Eluting Stent in Coronary Lesions) trial (mean lesion length of 14.4 mm) (2). Interestingly, in the first series by São Paulo, NIHA% appeared to increase to 6.6% at 2 years follow-up (5), and to 7.9% at 4 years (6).
Regarding the PES, in our population with mean lesion length 20.1 mm, the NIHA% (15.4%) was higher than the 7.8% reported in the TAXUS-II trial with a mean lesion length 10.6 mm (3), but similar to the 12.2% of the TAXUS-IV trial (mean lesion length 12.5 mm) (10), and the 13.1% of the TAXUS-V trial (mean lesion length 17.3 mm) (17).
The present study describes, for the first time in the literature, a direct comparison of IVUS results after SES and PES implantation for long lesions. Most published IVUS reports involve short lesions treated with a single SES (4–8) or PES (3,9,10). Fewer IVUS data involve more complex lesions, with use of multiple SESs (2,18) or PESs (17). The only randomized comparison of the SES and the PES in complex lesions, the CORPAL (Drug-Eluting Stent for Complex Lesions) trial, has only been presented orally (19).
The length of stent free of IVUS-evident neointimal hyperplasia has been reported to be greater in a non-polymeric PES than in the corresponding bare-metal stent, and to correlate inversely with NIHA% (20). In the present study, the inverse correlation with NIHA% was confirmed both for Cypher and Taxus stents (p < 0.001). Interestingly, the mean neointimal hyperplasia-free stent length in SES was almost double than in PES (p < 0.001), and IVUS-detectable neointimal hyperplasia was observed in over 75% of stent length in 41.9% of PES versus only 9.5% of SES (p = 0.001). Thus, neointimal hyperplasia inside PES is often represented along the entire stent length, while SES appear neointimal hyperplasia-free for most of their length. However, since the assessment of stent endothelization is below the resolution of IVUS (20), the absence of IVUS-detectable hyperplasia does not imply the absence of re-endothelization.
There was no correlation between neointimal hyperplasia and post-procedural peri-stent plaque burden in our study. This finding is in agreement with previous reports showing that suppression of neointimal proliferation occurs irrespective of residual plaque burden after procedures with both the SES (21) and the PES (9). Late-acquired incomplete stent apposition was infrequent in both the SES and PES groups (9.5% vs. 7.0%, p > 0.2) in the current study, which is consistent with a recent large, retrospective study by Hong et al. (22), indicating a prevalence of 13.2% with the SES and 8.4% with the PES in a real-world population. The number of patients with late-acquired incomplete stent apposition in our study was too small to draw any conclusions about its possible mechanism or clinical relevance.
Although the absolute changes in vessel and plaque area from baseline to follow-up in the current study were small and did not reach statistical significance, the reduction in PSPA% in the SES group was significant. This finding is in contrast with previous reports showing no such variations at 6-month follow-up (7,8). However, at 4-year follow-up after SES implantation, a significant negative vessel remodeling behind the stent struts has been described (23). With regard to PES, we did not observe significant changes in PSPA%, which is in agreement with the TAXUS-IV trial (10). On the contrary, an IVUS subanalysis of the TAXUS-II trial showed a significant increase in PSPA at 6 months (9), although this increase regressed at 2-year follow-up (16).
In our opinion, factors other than the stent-eluted drug may play a major role in peri-stent plaque changes. We recently demonstrated that treatment with simvastatin 20 mg/day in normocholesterolemic patients undergoing bare-metal stent implantation significantly reduces PSPA% compared with placebo (–14% vs. +6%) (15). This observation, together with the apparent clinical benefits of statin treatment, underlies the aggressive lipid-lowering approach (aiming for an low-density lipoprotein cholesterol level <110 mg/dl) we routinely use with all patients undergoing coronary interventions. At follow-up, 93% of SES patients and 95% of PES patients were on statins. Statin treatment may play a role in the observed reduction in PSPA% in the SES group in our study, and may mask the positive remodeling tendency described with the PES in the TAXUS II trial (3).
An MLA >6 mm2 has been reported to reduce the risk of target-lesion revascularization and qualifies as an "optimal IVUS result" (12). In our SES and PES populations, an MLA >6 mm2 post-procedure was associated with a very low rate of angiographic binary in-stent restenosis (1.6% vs. 13.6%; p = 0.05), and with no need for target-lesion revascularization during follow-up.
In agreement with the IVUS findings, quantitative angiography in our study showed a significantly lower LL with the SES than the PES (0.16 ± 0.19 mm vs. 0.32 ± 0.33 mm). In fact, a tight linear correlation between NIHA% and LL was observed (p < 0.001). In-stent LL values are comparable to those reported in other randomized trials comparing the SES and the PES, such as the SIRTAX (Sirolimus-Eluting Stent Compared With Paclitaxel-Eluting Stent for Coronary Revascularization) trial (0.12 ± 0.36 mm vs. 0.25 ± 0.49 mm with the SES and the PES, respectively; p < 0.001) (24), the ISAR-DIABETES (Paclitaxel-Eluting Stent Versus Sirolimus-Eluting Stent for the Prevention of Restenosis in Diabetic Patients With Coronary Artery Disease) trial (0.19 ± 0.44 mm vs. 0.46 ± 0.64 mm; p < 0.001) (25), and the REALITY (Prospective Randomized Multi-Center Head-to-Head Comparison of the Sirolimus-Eluting Stent [Cypher] and the Paclitaxel-Eluting Stent [Taxus]) trial (0.09 ± 0.43 mm vs. 0.31 ± 0.44 mm; p < 0.001) (26). Angiographic restenosis rates in the present study were also similar to those reported in the literature, but the population size was too small to allow meaningful considerations.
The present study was not powered to detect differences in clinical end points; however, the rate of major adverse cardiac events was low and comparable between the 2 groups. Our data confirm the results of subgroup analyses of patients with a stenosis in the left anterior descending artery in the SIRIUS (27) and TAXUS-IV (28) trials, showing a 1-year binary in-stent restenosis rate of 2.0% and 8.7%, respectively, and a target-lesion revascularization rate of 6.0% and 5.8%, respectively. In a recent meta-analysis of 6 randomized trials comparing the clinical and angiographic outcome of SES and PES implantation, Kastrati et al. (29) concluded that patients receiving the SES have a significantly lower risk of restenosis and target-vessel revascularization. However, until results of a multicenter study with an adequately powered clinical end point are available, the SES and the PES should be considered clinically equivalent.
This study is limited by the absence of an IVUS core lab. However, we perform an average of 150 IVUS examinations per year, thus providing reliable expertise in the evaluation of IVUS images. Secondly, the identification of the external elastic membrane beyond the stent struts can be difficult or even impossible due to acoustic shadowing and presence of side branches, making the measurement of vessel volumes unreliable. In order to improve the quality of our data, we excluded those patients in whom the external elastic membrane could not be identified in >75% of stent length, and calculated the mean vessel area as the ratio of vessel volume to the actually analyzed length. We also acknowledge that the inclusion of patients with acute coronary syndromes and the discretional administration of glycoprotein IIb/IIIa inhibitors may have had confounding effects on neointimal proliferation. Finally, the sample size was too small to compare the clinical outcome, which was not an end point of the study, but it was adequate for the prespecified comparison of neointimal hyperplasia.
Whether or not the use of the SES (with the lower neointimal hyperplasia formation) provides superior clinical outcomes in the prognostically important left anterior descending artery cannot be answered in this study but is certainly an area deserving further investigation in future studies.
Conclusions. The present study demonstrates that both the SES and the PES cause limited neointimal hyperplasia in complex lesions, with a significant difference in favor of the SES. Comparison with IVUS data obtained in previous studies involving shorter lesions shows a higher neointimal net volume obstruction for both the SES and PES in more complex lesions, and this was particularly evident for the PES. The difference in neointimal hyperplasia observed between the SES and the PES in the present study, however, does not translate into higher rates of angiographic in-stent and in-segment restenosis.
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