Author + information
- Received January 9, 2001
- Revision received June 5, 2001
- Accepted August 13, 2001
- Published online November 15, 2001.
- Rasmus Moer, MD*,* (, )
- Yngvar Myreng, MD, PhD*,
- Per Mølstad, MD, PhD*,
- Per Albertsson, MD, PhD†,
- Pål Gunnes, MD, PhD‡,
- Bo Lindvall, MD§,
- Rune Wiseth, MD, PhD∥,
- Kjetil Ytre-Arne, MD*,
- John Kjekshus, MD, PhD¶ and
- Svein Golf, MD, PhD*
- ↵*Reprint requests and correspondence:
Dr. Rasmus Moer, Department of Cardiology, The Feiring Heart Clinic, N-2093 Feiring, Norway
The purpose of this study was to assess the clinical and angiographic benefits of elective stenting in coronary arteries with a reference diameter of 2.1 to 3.0 mm, as compared with traditional percutaneous transluminal coronary angioplasty (PTCA).
The problems related to small-vessel stenting might be overcome using modern stents designed for small vessels, combined with effective antiplatelet therapy.
In five centers, 145 patients with stable or unstable angina were randomly assigned to elective stenting treatment with the heparin (Hepamed)-coated beStent or PTCA. Control angiography was performed after six months. The primary end point was the minimal lumen diameter (MLD) at follow-up. Secondary end points were the restenosis rate, event-free survival and angina status.
At follow-up, there was a trend toward a larger MLD in the stent group (1.69 ± 0.52 mm vs. 1.57 ± 0.44 mm, p = 0.096). Event-free survival at follow-up was significantly higher in the stent group: 90.5% vs. 76.1% (p = 0.016). The restenosis rate was low in both groups (9.7% and 18.8% in the stent and PTCA groups, respectively; p = 0.15). Analyzed as treated, both the MLD and restenosis rate were significantly improved in patients who had stents as compared with PTCA.
In small coronary arteries, both PTCA and elective stenting are associated with good clinical and angiographic outcomes after six months. Compared with PTCA, elective treatment with the heparin-coated beStent improves the clinical outcome; however, there was only a nonsignificant trend toward angiographic improvement.
Elective stenting treatment in small coronary arteries is not yet supported by randomized trials. Despite this, small-vessel angioplasty constitutes nearly half of all stent procedures in some centers (1,2). The relatively high incidence of restenosis and early thrombosis reported after small-vessel angioplasty (3)might be reduced by using second-generation stents designed for small dimensions, combined with modern antiplatelet therapy.
To investigate the potential benefit of elective stenting as opposed to conventional percutaneous transluminal coronary angioplasty (PTCA) in small arteries, we conducted the Stenting In Small Coronary Arteries (SISCA) trial, a randomized, controlled, multicenter study. The study device chosen was the small beStent (Medtronic InStent, Minneapolis, Minnesota). To optimize the stenting treatment maximally, we used a heparin-coated version (Hepamed, Medtronic Bakken Research Center, Maastricht, The Netherlands), developed exclusively for this trial.
Eligible patients were those referred for elective or immediate angioplasty, who had single-vessel or multivessel disease, stable or unstable angina and no contraindications to the study medication. Angiographic inclusion criteria were de novo in vessels with a reference diameter (RD) of 2.1 to 3.0 mm, with a diameter stenosis (DS) >50%, suitable for treatment with a single 15-mm stent. Exclusion criteria were functionally occluded vessels, vessels with multiple lesions or visible thrombus, bifurcational lesions, vessels with patent grafts and ongoing myocardial infarction. Multivessel and multistage angioplasty was allowed. However, study inclusion was restricted to one lesion per patient. The study was approved by the regional Ethics Committee and conducted in compliance with the Declaration of Helsinki. Oral and written, informed consent was obtained from all patients.
Angioplasty and randomization
The patients were pretreated with aspirin, and heparin and glycoprotein IIb/IIIa inhibitors were given according to local standards. A loading dose of ticlopidine (500 mg) or clopidogrel (300 mg) was given immediately after the intervention. A central office coordinated the randomization, which was stratified per center and per treatment in a block design.
The small 15-mm beStent used in this study was coated with Hepamed, a heparin-coating. The coating process and properties were identical to those developed for the Hepamed-coated Wiktor stent, as described in detail elsewhere (4). The lower recommended expansion size of the beStent was 2.3 mm, allowing vessels with a RD of ≥2.1 mm to be included, provided that the balloon/artery (BA) ratio was 1.1. The stents were hand-crimped on the appropriate balloon catheter.
High-pressure stent dilation was recommended, aiming at a BA ratio of 1.1. Crossing over from balloon to stent treatment was indicated if the final PTCA resulted in a residual DS >50%, or in case of impaired flow due to severe dissection or thrombus formation. Post-procedural medical treatment consisted of at least one-month continuation of ≥75 mg aspirin, supplemented by a thienopyridine for one month in patients who had received a stent.
Quantitative coronary angiography
Angiographic inclusion criteria were evaluated by on-line quantitative coronary angiographic (QCA) analysis, displaying the target lesion preferably in at least two near orthogonal angles. Administration of 0.1 to 0.2 mg of intracoronary nitroglycerin preceded angiographic runs acquired for QCA analysis. Calibration was performed on the contrast-filled catheter. The lesions were analyzed by the worst-view approach. The BA ratio was calculated from the ratio of the largest inflated RD of the balloon to the RD of the vessel. Angiographic recordings were stored on film or compact disk according to local equipment. Core laboratory analysis was performed by HeartCore B.V. (Leiden, The Netherlands), using the QCA-Cardiovascular Measurement System (CMS), versions 4.0 and 4.1, analysis packages (Medis, Leiden, The Netherlands).
The patients were monitored for per and post-procedure acute myocardial infarction by serial electrocardiograms and creatine kinase levels. The patients were contacted after one month to assess clinical events and functional angina class, according to the Canadian Cardiovascular Society (CCS) classification (5). After six months, they were scheduled for clinical and angiographic control studies. Angiograms obtained for clinical reasons before four months were accepted for follow-up analysis provided that the study lesion had reached an end point.
Study end points and definitions
The primary objective of the study was to investigate the minimal lumen diameter (MLD) at follow-up. Secondary angiographic end points were the dichotomous restenosis rates, net gain and angiographic and procedural success rates. The clinical end points were the occurrence of major adverse cardiac events (MACE), acute (<24 h) and subacute (1 to 30 days) stent thrombosis and clinical angina, according to the CCS and Braunwald classifications of unstable angina (6)at follow-up.
Cardiac death, acute myocardial infarction, target lesion revascularization and target vessel revascularization comprised MACE. Angiographic success was defined as residual DS <50% after the intervention. Procedural success was present when angiographic success was achieved without crossing over, and in the absence of in-hospital MACE. Acute myocardial infarction was present when two of the following three criteria were met: prolonged chest pain of cardiac origin not relieved by nitroglycerin, a rise in creatine kinase of more than twice the upper reference limit or new Q waves on the electrocardiogram. Acute myocardial infarction related to closure of a nonstudy vessel was not considered as a MACE. Target vessel revascularization was present when the culprit lesion of a repeat revascularization was located outside the target lesion, but within the segment instrumented by the guide wire at the index procedure. Death was not considered as a MACE if the clinical setting or an autopsy indicated a noncardiac cause. All events were reviewed by an external Safety Board.
Restenosis was defined as DS >50% during follow-up. The acute gain was the difference in MLD between post-intervention and baseline; late loss was the difference in MLD between post-intervention and follow-up; and net gain was the difference in MLD between follow-up and baseline. The acute-gain index, relative loss and net gain index expressed the acute gain, late loss and net gain normalized for vessel size, divided by the RD. Lesions were characterized according to the modified American Heart Association/American College of Cardiology classification (7). Dissections were classified according to the criteria of the National Heart, Lung and Blood Institute (8). Occlusion was defined as Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 (9).
The sample size was calculated by assuming 0.2 mm to be the difference of interest in mean MLD between the two groups, with a standard deviation of 0.5 mm. Two hundred patients would be sufficient to detect this difference, with a significance level of 5% and a power of 80% (10). This sample size would also be sufficient to detect a reduction in restenosis from 45% to 25%. Both assumptions are supported by published data (11–13). The results are presented as the mean value ± SD. Continuous variables were compared by using the Student ttest or the Kruskal-Wallis test if the variables deviated significantly from normal distribution, as judged by the Lilliefors version of the Kolmogorov-Smirnov test. Frequencies were compared by using the chi-square test or Fisher exact test, as appropriate. Survival free of MACE was analyzed by means of Kaplan-Meier survival curves, and the differences between the groups were assessed by the log-rank test. The main analysis was based on the intention-to-treat principle.
The SISCA study recruited patients in five Scandinavian centers between February 1998 and November 1999. The protocol prescribed a total of 200 patients, but inclusion was terminated prematurely because of expiration of the biologic activity of the heparin coating. Hence, a total of 145 patients were included: 74 patients assigned to stenting treatment and 71 patients assigned to PTCA. No one was excluded from follow-up analysis. The baseline clinical and angiographic characteristics are displayed in Tables 1 and 2. ⇓⇓The groups were well matched.
In-hospital and one-month clinical outcomes
In the stenting and PTCA groups, 3 (4.1%) and 10 patients (14.1%), respectively, crossed over to the alternative treatment modality. All patients who crossed over fulfilled the criteria of angiographic success. An additional stent was implanted in five lesions. Abciximab was administered in two patients who underwent stenting and in six patients who had PTCA.
Balloon size, balloon pressure and angiographic and procedural success rates are shown in Table 2. Two patients experienced events during the first month: one patient with a stent, a protocol violator not receiving aspirin, developed acute stent thrombosis. One patient who had PTCA suffered from severe recoil on the first day, requiring a repeat intervention. Creatine kinase release above the normal reference level (250 IU), in the absence of chest pain or Q-wave development, was found in one patient with a stent (327 IU) and in two patients who had PTCA (269 and 529 IU).
Late clinical outcomes (day 30 to follow-up)
Clinical data at six-month follow-up were obtained for all patients (Table 3). Survival free of MACE in the stent group was significantly higher than that in the PTCA group. This difference was also significant at day 150 (p = 0.026), which was before the scheduled angiographic control study. The different outcome was generated by a higher rate of repeat interventions. At follow-up, 91.9% of the patients in the stent group had angina pectoris CCS ≤II, as compared with 78.9% in the PTCA group (p = 0.033 by the Fisher exact test). In both groups, the improvement in functional angina status was significantly different from the baseline status (p < 0.001 by the McNemar test). One patient who had PTCA died of heart failure caused by cardiac amyloidosis, displaying open coronary arteries on the control angiogram and subsequent autopsy. There were no noncardiac deaths and no acute myocardial infarctions related to occlusions of nonstudy vessels. Table 3shows the total number of clinical end points.
Angiographic follow-up was performed after 179 ± 35 days, and follow-up QCA analysis was obtained in 141 patients (97.2%). The QCA data are shown in Table 4. Intention-to-treat analysis demonstrated that net gain was significantly larger (p = 0.022) and DS was significantly lower (p = 0.025) in the stent group than in the PTCA group. The MLD at follow-up, however, did not improve significantly by stenting (p = 0.096). The restenosis rate in the stent group was 9.7%, as compared with 18.8% in the PTCA group (p = 0.15). Analysis of the main angiographic measurements, based on de facto treatment (i.e., per-protocol approach), showed significant differences between the stent-treated and PTCA-treated patients: MLD 1.71 ± 0.49 vs. 1.54 ± 47 mm (p = 0.029); restenosis rate: 6.3% vs. 24.2% (p = 0.003), respectively.
The present trial has demonstrated that both PTCA and elective stenting in small coronary arteries are associated with good clinical and angiographic outcomes after six months. Compared with PTCA, elective treatment with the heparin-coated beStent improves the clinical outcome. However, there was only a nonsignifcant trend toward angiographic improvement by the intention-to-treat analysis.
In general, angioplasty in small coronary arteries was safe, with no deaths related to ischemic heart disease and only two patients with acute myocardial infarction. When comparing the two treatment modalities, elective placement of the heparin-coated beStent provided an even better result than did PTCA, with respect to the clinical outcome. Survival free of MACE was significantly higher in the stent group than in the PTCA group (90.5% vs. 76.1%, p = 0.016 by the log-rank test). Repeat interventions constituted the major part of these events and were significantly less frequent in the stent group (9.6% vs. 23.2%, p = 0.041). The Kaplan-Meier plot in Figure 1shows that the curves diverge early. Already after 150 days of follow-up (i.e., well before the scheduled angiographic control study), MACE-free survival was significantly higher in the stent group (p = 0.026 by the log-rank test). This finding is strongly suggestive of a true clinical benefit of stenting, because the events before day 150 were clinically driven and not initiated by the scheduled angiographic control study.
Intention-to-treat analysis of the angiographic outcome at follow-up showed a significant benefit of stenting, with respect to net gain and DS. For the primary end point of MLD, as well as the restenosis rate, there was only a nonsignificant trend toward improvement (Table 4). However, when analyzing these last two variables in a per-protocol approach, a statistically significant difference in favor of stenting, as compared with PTCA, was present. This might indicate that the analysis of MLD and the restenosis rate in the present trial suffer from a type II error in the intention-to-treat model. The improved event-free survival in the stent group could support such an interpretation.
Comparison with other trials
The remarkably low incidence of restenosis in the present study differs from the findings in the small vessel stent trial of Kastrati et al. (14), in which the restenosis rates in the stent and PTCA groups were 35% and 37%, respectively. Preliminary data from other trials have also demonstrated higher restenosis rates than those found in our study (1). This might be explained by the clinical and lesion-specific characteristics of the present study group. There was only one calcified lesion and no type C lesions. Total occlusions were excluded. Furthermore, the pre-interventional DS was relatively low. Thus, the lesions studied probably carried a low inherent risk of relapse after angioplasty, facilitating good results.
The use of heparin-coated stents also distinguishes the present study from similar ones. However, we have no data to indicate that the Hepamed coating was responsible for the low restenosis rate in the present trial. This is in agreement with a study using another heparin coating (15). In a recent report on provisional small-vessel stenting, we also demonstrated a low restenosis rate using the uncoated 15- or 25-mm beStent in complex lesions (11). Therefore, the design of the beStent may be more important than the coating in terms of the outcome.
Finally, the stent implantation technique itself might influence the outcome. Although “the bigger the better” approach has been supported by numerous reports, recent evidence of the detrimental effect of media damage through aggressive angioplasty might challenge this hypothesis (16,17). In the present study, a less aggressive approach may have been used, as reflected by the modest BA ratio (1.06) and the final DS of 11.3 ± 8%. However, high-pressure deployment was used, probably yielding sufficient stent apposition in such discrete lesions. Careful balloon sizing, avoiding overstretching of the vessel, may therefore have contributed to the favorable results.
First, because the trial was terminated prematurely, a type II error in statistical analysis might have occurred. The near-complete follow-up may have compensated, in part, for this limited sample size. Second, QCA measurements may not reflect the true vessel dimensions, because the method relies on the lumen size, rather than the true vessel size. Its potential to detect diffuse disease, often present in small vessels, is limited. Also, QCA does not always detect the physiologic importance of a lesion. However, both the QCA-CMS system and the core laboratory analysis are extensively validated (18). Finally, the protocol restricted the inclusion to discrete lesions. Because the present study is from the same group that conducted the Stenting In Chronic Coronary Occlusion (SICCO) trial (19), in which stenting in vessels >2.5 mm was shown to be superior to PTCA after recanalization of chronic total occlusions, it was considered unethical to include occlusions in the present trial.
Both balloon angioplasty and elective stenting of discrete lesions in small coronary arteries are associated with favorable angiographic and clinical outcomes after six months. Compared with PTCA, elective stenting using the Hepamed-coated beStent does not improve the angiographic outcome significantly, but it decreases the need for repeat revascularization. The low restenosis rate in the stent group might be related to the stent design, making this device particularly useful in small vessels. The present results might translate into a more liberal approach regarding catheter-based treatment and stenting, in particular, of small coronary arteries.
☆ This study was supported by Medtronic AVE (Minneapolis, Minnesota) by grants and supply of the study stents.
- balloon/artery ratio
- diameter stenosis
- major adverse cardiac event
- minimal lumen diameter
- percutaneous transluminal coronary angioplasty
- quantitative coronary angiography
- reference diameter
- Stenting In Small Coronary Arteries trial
- Received January 9, 2001.
- Revision received June 5, 2001.
- Accepted August 13, 2001.
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