A Randomized Trial Comparing Stenting With Balloon Angioplasty in Small Vessels in Patients With Symptomatic Coronary Artery Disease
Background—More than 30% of the lesions currently treated with interventional approaches are situated in vessels smaller in size than those representing an established indication for stenting. The objective of this randomized trial was to assess whether compared with PTCA, stenting of small coronary vessels is associated with a reduction of restenosis.
Methods and Results—Patients with symptomatic coronary artery disease with lesions situated in native coronary vessels between 2 and 2.8 mm in size were randomly assigned to be treated with either stenting (n=204) or PTCA (n=200). Adjunct therapy consisted of abciximab, ticlopidine, and aspirin. Repeat angiography at 6-month follow-up was performed in 83% of the patients. The primary end point of the study was the incidence of angiographic restenosis (≥50% diameter stenosis) at follow-up; adverse clinical events, such as death, myocardial infarction, stroke, or target vessel revascularization, were assessed as secondary end points. After 7 months, there were no significant differences in the infarct-free survival rates between the 2 study groups: 96.6% for stent patients, and 97.0% for PTCA patients (P=0.80). Target vessel revascularization was needed in 20.1% of the stent patients and 16.5% of the PTCA patients (P=0.35). The primary end point of angiographic restenosis was found in 35.7% of the stent patients and 37.4% of the PTCA patients (P=0.74). The net lumen gain observed at follow-up was identical (0.76±0.78 in the stent group versus 0.76±0.63 mm in the PTCA group, P=0.93).
Conclusions—Stenting and PTCA are associated with equally favorable results when used for treating lesions in small coronary vessels.
Vessel size is inversely correlated with the risk of restenosis and adverse outcome after percutaneous coronary interventions.1 2 3 This is because a smaller vessel is more limited in the ability to accommodate lumen renarrowing, which invariably occurs to some degree in most vessels after balloon dilatation.4 5 Interventions in small coronary vessels (<2.8 to 3.0 mm) constitute a considerable proportion (30% to 50%)1 2 3 6 7 8 of the >1 million coronary catheter-based procedures performed worldwide each year. PTCA and stenting are the 2 most frequently used interventions in patients with coronary artery disease.9 Large coronary vessels represent an established indication for stenting because of its superiority compared with PTCA, as shown in several randomized clinical trials.10 11 12 On this basis, the Food and Drug Administration approved the Palmaz-Schatz stent for use in large coronary arteries (≥3 mm). Stenting is associated with increased procedural costs9 ; however, the improved outcome, with a reduction in the need for reinterventions, achieved when large vessels are stented has rendered this technique more cost-effective in the long term than PTCA.12 13 A retrospective analysis has shown that stenting might also be superior to PTCA in small coronary vessels.14 Nevertheless, because of the absence of appropriately designed randomized studies, there are no well-defined recommendations15 regarding the intervention of choice for coronary vessels smaller than those included in the clinical stent trials referred to above. This is currently perceived as a limitation in interventional cardiology.16
Consequently, the objective of this randomized trial was to assess whether stenting of small coronary vessels in patients with symptomatic coronary artery disease, compared with PTCA, is associated with a reduction of restenosis.
Patients were considered eligible for randomization if they complained of angina pectoris or had exercise-induced ischemia in the presence of angiographically significant lesions (≥70% diameter stenosis) in a native coronary vessel between 2.0 and 2.8 mm in size (online measurement after intracoronary injection of nitroglycerin), provided that they had given written informed consent for participation in the study. Intervention in the setting of acute myocardial infarction (within the last 72 hours before the intervention), lesions situated in the left main coronary artery, lesions produced by in-stent restenosis, and contraindications to the antithrombotic medication used in the present study (see below) served as exclusion criteria. On the basis of the above criteria, the patients were randomly assigned to receive either stenting or PTCA. Immediately after successful passage of the guidewire through the index stenosis, randomization was performed by using sealed envelopes containing the randomization sequence generated by computer before the initiation of the trial. The present study was conducted according to the principles of the Declaration of Helsinki and was approved by the ethics committees of the participating institutions.
Procedures and Antithrombotic Treatment
During the intervention, patients received intravenous heparin (7500 U) and aspirin (500 mg) as well as a bolus of abciximab (0.25 mg/kg body wt), followed by continuous infusion (0.125 μg/kg per minute for 12 hours). All patients received a combination of oral therapy with 250 mg ticlopidine plus 100 mg aspirin twice daily for 4 weeks after stenting or 2 weeks after plain PTCA; aspirin was taken indefinitely.
Stent placement and balloon angioplasty procedures were performed according to standard methods. The study protocol recommended the achievement of a final diameter stenosis of <30% and Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 at the end of procedures; it allowed the implantation of a stent(s) in patients allocated to PTCA if there were large dissections (>5 mm) or TIMI flow grade <3 on the angiogram. The premounted MULTI-LINK stent on ≥2.5 mm balloons (Guidant, Advanced Cardiovascular Systems, Inc.) was the recommended stent type in this trial.
Lesions were classified by using the modified American College of Cardiology/American Heart Association grading system.17 Digital angiograms were analyzed offline with the automated edge detection system CMS (Medis Medical Imaging Systems) in the Angiographic Core Laboratory. Matched views were selected for angiograms recorded before and immediately after the intervention and at follow-up. Each angiographic sequence was preceded by an intracoronary injection of nitroglycerin. The parameters obtained were minimal lumen diameter (MLD), reference diameter, diameter of the stenosis, and diameter of the maximally inflated balloon during the index procedure. Acute lumen gain was the difference between MLD at the end of the intervention and MLD before balloon dilatation. Late lumen loss was calculated as the difference in MLD noted between measurements after the procedure and at follow-up. Loss index was calculated by dividing late lumen loss by acute lumen gain. Net lumen gain was defined as the difference between MLD at follow-up and MLD before balloon dilatation.
Definitions and End Points of the Study
The primary end point of the present study was angiographic restenosis at follow-up (defined as diameter stenosis ≥50%). The secondary end points of the study were the adverse clinical events, such as all-cause death, myocardial infarction, stroke, and target vessel revascularization (PTCA or CABG). The diagnosis of acute myocardial infarction was based on the presence of new pathological Q waves or a value of creatine kinase or its MB isoenzyme at least 3 times the upper limit.18 Creatine kinase was determined before and immediately after the procedure, every 8 hours for the first 24 hours after the procedure, and daily afterward until discharge. A diagnosis of stroke required confirmation by CT or MRI of the head. Target vessel revascularization was performed in the presence of angiographic restenosis and symptoms or signs of ischemia. Cardiac events were monitored throughout the follow-up period and analyzed at 30 days (phone interview in 100% of the patients) and 7 months (clinical visit in 90% and phone interview in 10% of the patients).
The number of patients included in the present study was based on the sample size estimation for our primary end point of angiographic restenosis. On the basis of previous observations for the vessel size range treated in the present study, we assumed a restenosis rate of 38.6% after stenting2 and 55% after PTCA.14 The assumed 30% reduction of restenosis for stenting is comparable to that verified in previous randomized trials for larger coronary vessels.10 11 For a power of 80% to detect this difference at a 2-sided α level of 0.05, 200 patients in each group were needed if a follow-up angiography rate of at least 75% was assumed.
The main analysis was performed on an intention-to-treat basis, and the results are expressed as mean±SD or proportions (%). The differences between groups were assessed by the χ2 test or Fisher exact test for categorical data and by t test or Wilcoxon test for continuous data. The homogeneity of the treatment effect across strata was assessed by the test of Breslow and Day.19 Survival analysis was made by the Kaplan-Meier method, and differences in survival parameters were assessed by the log-rank test. Statistical significance was accepted for 2-sided value of P<0.05.
We enrolled 404 patients in this trial: 204 were assigned to stenting, and 200 were assigned to PTCA. Table 1⇓ shows the clinical characteristics of the patients. The groups were well matched with respect to these characteristics. Table 2⇓ shows the baseline angiographic characteristics of the patients, with only a trend for PTCA patients to have a smaller vessel size and MLD as well as a tighter diameter stenosis before the procedure. Procedural data are displayed in Table 3⇓. Among patients allocated to the stent treatment arm, 4.4% received only plain PTCA because of an inability to place the prosthesis. On the other hand, in 16.5% of the patients assigned to PTCA treatment, the placement of at least 1 stent was necessary. The stented segment length in the stent group was 20.8±10.9 mm; in only 6.4% of the stent patients did the operator chose to use a hand-mounted stent on a 2.0-mm balloon. The procedure was completed with a significantly better acute result in the stent group.
Clinical follow-up was complete for all patients. The adverse events observed after 30 days are shown in Table 4⇓. No cases of stroke were recorded, and overall, the incidence of adverse events was low and comparable in both groups. In addition, bleeding complications requiring blood transfusion occurred in 4 stent patients and 2 PTCA patients (P=0.70).
During the 7-month follow-up period, 2 patients in the stent group (1.0%) and 3 patients in the PTCA group (1.5%) died (P=0.73). Figure 1⇓ displays the almost identical curves of infarct-free survival: 96.6% of the patients randomly assigned to stenting and 97.0% of the patients randomly assigned to PTCA survived without myocardial infarction (P=0.80). Also, there were no significant differences regarding the reintervention rates: 7 stent patients (3.4%) and 5 PTCA patients (2.5%) needed bypass surgery (P=0.58), and 34 stent patients (16.7%) and 28 PTCA patients (14.0%) required repeat balloon angioplasty (P=0.46). Thus, the incidence of target vessel revascularization (either CABG or repeat PTCA) was 20.1% among stent and 16.5% among PTCA patients (P=0.35, Figure 2⇓). At the end of the follow-up period, 77% of the stent patients and 81% of the PTCA patients survived without an adverse event (P=0.22).
Repeat angiography at follow-up was performed in 334 patients (or 83% of the entire study population) in a comparable proportion between stent (83.8%) and PTCA (81.5%) patients (P=0.54). Our primary end point of restenosis according to the conventional definition of ≥50% diameter stenosis was encountered in 35.7% of the patients assigned to stenting and 37.4% of the patients assigned to PTCA (P=0.74, Figure 2⇑). Also, there was no significant difference with respect to more severe restenosis (≥70% diameter stenosis), with 22.2% among stent patients and 18.4% among PTCA patients (P=0.39, Figure 2⇑). Table 5⇓ summarizes the follow-up angiographic data. As expected, compared with PTCA, stenting was associated with a higher late lumen loss. Other quantitative indexes of restenosis, such as MLD and diameter stenosis, were comparable between the 2 randomization arms. Despite a much better acute gain achieved in the stent arm, net gain at follow-up was identical in the 2 groups, as graphically displayed in Figure 3⇓.
We performed additional analyses beyond the main analysis on the basis of the intention-to-treat principle. No significant differences were seen when the restenosis analysis was performed on an as-treated basis, ie, when patients who actually received stenting were compared with those who actually received PTCA irrespective of the randomization. The restenosis rate was 36.5% for those patients actually treated with stenting versus 36.6% for those treated with plain PTCA. Patients with single-lesion interventions had a restenosis rate of 36.2% in the stent arm and 36.8% in the PTCA arm (P=0.93). When the patients were subdivided in 3 groups (tertiles) according to vessel size (<2.3, 2.3 to 2.5, and >2.5 mm), the restenosis rates in the stent and PTCA arms were 38.9% versus 37.7%, 30.2% versus 33.3%, and 36.5% versus 40.7% in the first, second, and third tertile, respectively. The homogeneity test yielded a value of P=0.90, showing no significant difference in treatment effect associated with vessel size. Finally, when the analysis was confined to procedures for which a nominal balloon size of ≥2.5 mm was chosen, the restenosis rate was 34.8% in the stent arm and 37.6% in the PTCA arm (P=0.63).
Percutaneous interventions in small coronary vessels are usually associated with an increased risk of restenosis.20 This represents an important limitation in the treatment of coronary artery disease because of the frequency with which interventions involve small coronary arteries. Stenting has been the first successful intervention for the reduction of restenosis10 11 since the introduction of PTCA. Using angiographic restenosis as a primary end point and assessing the clinical results after 7 to 8 months after the intervention, 2 landmark trials unequivocally demonstrated the advantages of stenting over PTCA for large coronary vessels ≥3 mm.10 11 It is conceivable to expect even a major impact of stenting in subsets with a higher likelihood of restenosis, such as small coronary arteries. We also chose angiographic restenosis as the primary end point of the present study and were able to perform an angiographic restudy at follow-up in 83% of the patients.
In the present trial, small coronary arteries were defined as vessels ≤2.8 mm in size according to online digital measurement. We aimed at creating a clear distinction from the vessel size that characterized previous randomized trials, which focused on lesions in large coronary arteries.10 11 In fact, mean vessel size was ≈3.0 mm in studies of Serruys et al10 and Fischman et al,11 suggesting the inclusion of a considerable number of vessels that were below the limit defined by their study protocols. This is perhaps an inevitable consequence of differences between visual estimates or online measurements and quantitative evaluation based on automatic contour detection techniques. With an average vessel size of 2.4 mm, the present trial provides implications for a population that is clearly distinct from the populations of previous clinical trials comparing stenting with PTCA.10 11
In the present trial, we chose to use the MULTI-LINK stent. Although there is abundant experimental evidence about differences in stent performance, it has been difficult for clinicians to observe a relevant impact of stent type on clinical outcome.21 In a randomized clinical trial comparing 5 stent designs, including the classic Palmaz-Schatz stent, the MULTI-LINK stent was associated with the most favorable outcome.22
Small vessel size negatively affects both early23 and late2 outcome of patients undergoing coronary interventions. Glycoprotein IIb/IIIa inhibition with abciximab has significantly reduced the incidence of adverse events,18 especially in high-risk subsets. The 30-day incidence of ischemic events in the present trial was low (2.9% in the stent group and 1.5% in the PTCA group) and compares favorably with early event rates reported previously for this category of vessel size after either PTCA8 14 or stenting.2 3 14 This is probably the result of the routine use of abciximab in the present trial. It should be pointed out that as in previous trials comparing these 2 approaches, a direct comparison between stenting and PTCA with respect to the early ischemic events is hindered by the provisional use of stents in 16.5% of PTCA patients who were considered at a higher risk for early complications.
We also found no significant difference in adverse event rates during the entire follow-up period, with 23% in the stent group and 19% in the PTCA group. These data seem to compare favorably with previously published findings from nonrandomized studies, although the comparison is difficult because of differences in adjunct antithrombotic therapy. Past retrospective large-scale reports with stenting in small coronary vessels have shown adverse event rates of 30%2 to 37%.3 Savage et al14 found an event rate of 22% among 163 patients who received stenting in vessels with an average diameter of 2.7 mm and who were selected for a subgroup analysis from a prior randomized trial.11 Fewer data are available about restenosis-driven clinical events in patients undergoing PTCA in small coronary arteries. Among 168 patients with small-vessel lesions treated with PTCA, the adverse event rate was 33%.14 The reason for the difference with the results achieved in our group with PTCA probably resides not only in the different antithrombotic therapy but also in the different acute results immediately after the procedure: residual diameter stenosis was only 19% in the PTCA arm of the present trial, which was markedly lower than that of 34% in the report mentioned above.14 This also indicates that the availability of stents may currently allow a more aggressive dilation strategy during PTCA.
The lack of significant differences in our primary end point, restenosis, explains the similarity in clinical results achieved with stenting and PTCA in the present trial. Despite a much greater acute lumen gain obtained with stenting, it was offset by an excess in lumen loss occurring during follow-up, and the net gain result was strikingly similar in both groups. These findings as well as the differences in loss index suggest that “the bigger, the better” may not be a valid criterion for comparing stenting with PTCA for lesions in small coronary arteries. The acute gain achievable with stenting is limited by the smaller vessel size, and this seems to reduce the accommodation potential for subsequent neointimal hyperplasia. The present restenosis findings for both stent and PTCA reveal our limited ability to mechanically attenuate the excess risk connected with smaller vessel size and underscore the need of rendering smaller coronary vessels a specific target of antirestenotic approaches.
In conclusion, stenting and PTCA with optimized antiplatelet therapy are associated with equally favorable results when used for treating lesions in small coronary vessels. Therefore, for lesions in small coronary arteries, no additional benefit in outcome is provided by systematic stenting compared with a strategy based on plain PTCA and provisional stenting in <20% of the cases.
The following centers and investigators participated in the Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries (ISAR-SMART) Study:
A. Schömig (chairman), A. Kastrati, J. Dirschinger, and F.-J. Neumann.
Data Coordinating Center
A. Kastrati, M. Hadamitzky, and H. Kreuzberg, Deutsches Herzzentrum, Munich.
Angiographic Core Laboratory
J. Mehilli, A. Redl, and D. Kiemoser, Deutsches Herzzentrum, Munich.
Clinical Follow-Up Center
N. von Welser, D. Hall, H. Holle, K. Hösl, and W. Krämer, Deutsches Herzzentrum, Munich.
Deutsches Herzzentrum, Munich: J. Dirschinger (principal investigator), R. Blasini, C. Schmitt, and M. Gawaz; 1. Medizinische Klinik rechts der Isar, Munich: F.-J. Neumann (principal investigator), E. Alt, M. Seyfarth, and H. Schühlen; Medizinische Klinik I, Garmisch-Partenkirchen: F. Dotzer (principal investigator) and M. Fleckenstein.
This trial was supported by grants from the Technische Universität München, Munich; Lilly Deutschland GmbH, Bad Homburg; and Guidant GmbH & Co, Isernhagen, Germany. We highly appreciate the invaluable contribution of the medical and technical staffs operating in the catheterization laboratories and wards of the participating institutions.
↵1 The centers and investigators participating in the Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries (ISAR-SMART) Study are listed in the Appendix.
- Received May 17, 2000.
- Revision received July 6, 2000.
- Accepted July 7, 2000.
- Copyright © 2000 by American Heart Association
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