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J Am Coll Cardiol, 2004; 43:1964-1972, doi:10.1016/j.jacc.2004.01.039 © 2004 by the American College of Cardiology Foundation |
* Division of Interventional Cardiology, Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
Manuscript received December 12, 2003; revised manuscript received January 9, 2004, accepted January 13, 2004.
* Reprint requests and correspondence: Dr. Raúl Moreno, Cardiología Intervencionista, Instituto Cardiovascular, Hospital Clínico San Carlos, Martín Lagos, s/n, 28040 Madrid, Spain.
raulmorenog{at}terra.es
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Abstract |
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BACKGROUND: Randomized studies on coronary stenting (CS) in small vessels have yielded controversial results.
METHODS: Eleven randomized trials on CS versus BA in small vessels, including angiographic re-evaluation at six months, were analyzed.
RESULTS: The BeStent (Medtronic Instent, Minneapolis, Minnesota) was used in four studies, the Multi-Link (Guidant, Advanced Cardiovascular Systems Inc., Santa Clara, California) in three trials, and the NIR (Boston Scientific Corp., Boston, Massachusetts), JoStent (Jomed International AB, Helsingborg, Sweden), Tenax (Biotronik, Berlin, Germany), and BioDivysio (Abbott Vascular Devices, Redwood City, California) in the remaining four trials. Overall, 3,541 patients were included (1,672 allocated to BA and 1,869 to stent). The rate of cross-over from balloon to stent in the pooled population was 19%, and unsuccessful stent deployment occurred in 2% of the patients allocated to stent. The pooled rates of restenosis were 25.8% and 34.2% in patients allocated to stent and balloon, respectively (p = 0.003) (risk ratio [RR] 0.77; 95% confidence interval [CI] 0.65 to 0.92). A smaller reference vessel diameter at baseline was associated with a higher risk reduction in the restenosis rate (y = –3.551 + 1.826 [x]; p = 0.012). Patients allocated to stent had lower rates of major adverse cardiac events (15.0% vs. 21.8%, p = 0.002; RR 0.70; 95% CI 0.57 to 0.87) and new target vessel revascularizations (12.5% vs. 17.0%, p = 0.004; RR 0.75, 95% CI 0.61 to 0.91).
CONCLUSIONS: Elective stenting is superior to provisional stenting in small coronary arteries. This benefit is more evident in smaller coronary arteries.
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The objective of this study was to carry out a meta-analysis of all available randomized trials comparing CS or BA and small vessels with angiographic re-evaluation at six months and to compare the relative effect of these two treatment strategies on the restenosis rate and clinical outcome.
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Methods |
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These 12 studies included 3,669 patients. One of the studies, the CORDIS Mini-crown stent In small Coronary Arteries (CORDIS-MICA) or Stent Restenosis Study (STRESS) IV trial, was designed to include 600 patients. However, it was prematurely interrupted owing to a very low inclusion rate and finally included only 128 patients. Angiographic re-evaluation was performed only in patients with recurrent symptoms, whereas the restenosis rates were 63% and 61% in those allocated to BA and CS, respectively. This study was not included in the meta-analysis, thus the final number of patients was 3,541. Of them, 1,672 were allocated to BA and 1,869 to CS.
Table 1 shows the study design followed in each trial, the number of patients allocated to each arm of treatment, the type of stent used, and their vessel size inclusion criteria. All trials were randomized, and most of them were multicenter. Six were performed in Europe, four in Asia, and one in Latin America.
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Cross-over from BA to CS was allowed in two circumstances: 1) as a bail-out procedure in the case of abrupt or threatened closure caused by a coronary dissection with compromised antegrade blood flow; and/or 2) in the case of a suboptimal result defined by a residual stenosis >50% in most studies, and >30% in the ISAR-SMART and in the study by Park et al. (7). Cross-over from CS to BA was codified as failure to deliver the stent. In the CHIVAS study, patients requiring cross-over were excluded from the study.
Most studies used CS after balloon predilation, although in some of them direct stent implantation was allowed.
All patients received heparin and aspirin, although in the COMPASS trial, patients treated with BA received cilostazol instead of aspirin. Those treated with CS also received ticlopidine or clopidogrel for one month. In the ISAR-SMART, all patients received abciximab (8). In most studies, however, glycoprotein IIb/IIIa inhibitors were not used (10), were discouraged and allowed only when necessary (11,12), or were used as local standards (9) or according to the physician's preference (14,15).
Angiographic analysis and definitions. Quantitative coronary analysis was performed using the CMS 4.0, 4.1, or 5.0 (Medis, Leiden, the Netherlands) edge-detection system in most studies. Intracoronary nitroglycerin was given before each angiography, and the contrast-filled catheter was used for calibration.
"Acute gain" was the difference in minimum lumen diameter (MLD) between post-intervention and baseline. "Late loss" was the difference in MLD between post-intervention and follow-up. "Net gain" was the difference in MLD between follow-up and baseline. "Loss index" was calculated by dividing late lumen loss by short-term gain. "Angiographic restenosis" was binarily defined as >50% diameter stenosis at follow-up.
The diagnosis of myocardial infarction was based on the presence of new pathologic Q waves and/or a value of creatine kinase level or its myocardial band of at least twice (9–14) or three times (7,8) the upper normal limit. Target vessel revascularization was performed in the presence of angiographic restenosis associated with angina or ischemia demonstrated by non-invasive studies.
Statistical analysis. The review was conducted according to the Quality of Reports of Meta-Analyses of Randomized Clinical Trials (QUOROM) recommendations (19). The Review Manager 4.1.1 (Cochrane Collaboration, Oxford, United Kingdom) and the SPSS 10.0 (SPSS Inc., Chicago, Illinois) statistical packages were used.
Quantitative variables are expressed as mean ± standard deviation, and discrete variables as proportions (percentages). Associations between categorical variables were studied by the chi-square test (Fisher correction in case any expected value was <5). The risk ratio (RR) for restenosis and late (6-month) clinical events, the absolute risk reduction, and their 95% confidence intervals (CI) were calculated comparing CS rates with BA rates using raw data for each study and for the pooled population. Inter-trial heterogeneity was calculated with the Q-test, and the Der Simonian and Laird's random effects model was used to estimate the combined effect weighting by the inverse variance estimated. The number of patients required to be treated with CS to prevent one restenosis was calculated as the inverse of the absolute risk reduction.
The primary objective was to evaluate the restenosis rate at six months in patients allocated to BA or CS on an intention-to-treat basis. Clinical outcomes for comparison were death, myocardial infarction, target lesion revascularization, and major adverse cardiac events at six months (the occurrence of at least one of the clinical end points listed previously).
The association between the benefit of CS in each study and continuous variables was evaluated by lineal regression analysis, calculating a and b coefficients. Statistical significance was considered in the presence of p < 0.05.
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Results |
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Balloon/vessel ratio was 
1.1 for both the BA and CS groups, without significant differences between both strategies. However, final pressure was higher in patients allocated to CS. In all studies, immediate results were better in the CS group, achieving higher short-term gain and larger MLD (Table 3).
Angiographic follow-up. The rate of angiographic re-evaluation ranged from 71.6% to 97.2% (82.1% in the pooled population) (Table 1). Patients allocated to CS had higher late loss and loss index, but as a result of a significantly higher short-term gain, net gain was higher in these patients. Only in the BESMART, RAP, and CHIVAS trials differences in the restenosis rate reached statistical significance (Table 4) (Fig. 1).
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Factors related to risk reduction in restenosis. The risk reduction of restenosis had a significant relationship with short-term gain in the BA group (y = 0.218 + 0.506 [x]; p = 0.039) and a significant relationship with MLD post-intervention (y = –1.043 + 0.821 [x]; p = 0.023), late loss (y = 0.083 + 0.957 [x]; p = 0.018), and loss index (y = –0.103 + 1.686 [x]; p = 0.046) in the CS group. Importantly, a smaller RVD at baseline was associated with higher risk reduction of restenosis (y = –3.551 + 1.826 [x]; p = 0.012) (Table 5) (Fig. 2). This was because a smaller RVD was associated with higher restenosis rate in patients allocated to BA (y = 148.421 – 48.838 [x]; p = 0.065) but not to CS (y = –6.490 + 13.266 [x]; p = 0.566).
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Clinical events at six months. The pooled rate of major adverse cardiac events was significantly lower in patients allocated to CS (15.0% vs. 21.8%, p = 0.002; RR 0.70, 95% CI 0.57 to 0.87) (Fig. 3) (Table 6). (absolute risk reduction 0.06, 95% CI 0.02 to 0.10, p = 0.041). This was mainly due to a reduction in the need for new revascularization procedures (Fig. 4). The proportion of patients requiring new revascularization procedures of the treated vessel was significantly lower among those allocated to CS (12.5% vs. 17.0%, p = 0.004; RR 0.75, 95% CI 0.61 to 0.91) (absolute risk reduction 0.04, 95% CI 0.01 to 0.7, p = 0.01).
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Discussion |
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Studies comparing provisional versus elective stenting in small coronary arteries have yielded contradictory results. Of the 11 studies included in the present meta-analysis, eight showed no significant differences in the rate of restenosis between patients allocated to BA or CS. Differences were statistically significant only for the BESMART, RAP, and CHIVAS trials. Probably, the number of patients was too low in some of these studies, taking into consideration two facts. First, there was a relatively high rate of cross-over from BA to CS (20%), higher than that reported in the STRESS and BElgian Netherlands STENT (BENESTENT) studies (6.9% and 5.1%, respectively). Second, the absolute reduction in restenosis rate in small vessels (8.4%) seems to be lower than in >3-mm vessels (10% to 15%) (1–3). In some trials on CS in small vessels, the number of patients was calculated assuming a 15% to 20% absolute reduction in restenosis rate and a lower rate of cross-over from balloon to stent (7,8,14).
In the pooled analysis, restenosis significantly decreased from 34.2% to 25.8% (8.4% absolute reduction). This reduction is lower than that reported for >3-mm vessels (10% to 15%) (1–3), probably owing to the relatively similar late loss after CS irrespective of stent diameter, thus CS presenting a higher loss index in small vessels (23). The higher cross-over rate from BA to CS in small vessels (20%, in comparison with 5% to 7% in >3-mm vessels) probably reflects the poorer angiographic results of BA in small vessels.
The explanation for the benefit of CS in small vessels was the better initial angiographic results (higher short-term gain and MLD post-procedure) for CS, despite the higher late loss observed in patients allocated to this treatment.
The reduction in restenosis in patients allocated to CS was reflected in an improvement in the outcome, especially because of a significant reduction in the need for new revascularization procedures.
Reasons for discrepancies between different studies and associated characteristics. Differences in immediate results of patients allocated to BA may be the main reason explaining discrepancies among studies. Higher short-term gain in patients allocated to BA, as well as higher late loss in patients allocated to CS, were associated with lower risk reductions.
Importantly, there was a significant association between RVD and the benefit of CS in reducing the restenosis rate: a smaller RVD, a lower RR for restenosis (higher risk reduction). In the BESMART trial, although the benefit of stenting in reducing restenosis was not statistically associated with RVD, the higher risk reduction was obtained in vessels 1.5 to 1.9 mm (70%, in comparison with 56% and 50% in vessels 2.0 to 2.4 mm and 2.5 to 2.9 mm, respectively). Probably, smaller RVD is associated with worse immediate angiographic results of BA, and the deleterious effect of smaller RVD on the midterm results of percutaneous coronary interventions could be more important in patients treated with BA. A post hoc analysis of the STRESS trial, showing that benefit of CS was more evident in <3-mm vessels, compared with larger coronary arteries, supports this hypothesis (24). Similar data were provided by the STent versus Angioplasty Restenosis Trial (START), in which restenosis decreased from 32% to 22% in 
3-mm vessels, and from 45% to 25% in <3-mm vessels (3).
In a subanalysis of the CHIVAS study, it was shown that the effect of CS in reducing restenosis in small vessels may be particularly evident in diabetic patients (25). We did not find, however, any significant correlation between the proportion of diabetic patients and the risk reduction. In the ongoing LASMAL-II trial, 188 diabetic patients with small vessels have been randomized to CS or BA. Angiographic follow-up of this trial is pending.
Stent design or type did not influence the effect of CS in restenosis. In the Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO-2) trial, patients treated with thin-strut (50-µm) stents had lower restenosis rate than those receiving 140-µm strut stents (26). Nevertheless, we did not find any significant association between strut thickness and risk reduction. This could be because differences among strut thickness of the stents used in the trials included in the meta-analysis were lower in comparison with the ISAR-STEREO-2 trial. In fact, in one study by a group in Milan, struts were considered thin and thick at <100 µm and 100 µm, respectively (27), and according to this criterion, only the stents used in the LASMAL-I trial and the study by Park et al. (7) could be considered to have thick struts. Finally, the use of heparin-coated stents did not confer any advantage over bare metal stents, as observed in the SISCA and COAST trials.
Drug-eluting stents can dramatically reduce the restenosis rate, and they constitute a recent revolution in interventional cardiology (28). However, we have to consider two important points. First, small vessels, although having a higher rate of angiographic restenosis, undergo subsequent new revascularization procedures less frequently, owing to the smaller amount of myocardium supplied by the vessel. Second, some recent data from the SIRIUS trial (Sirolimus-Eluting Stents versus Standard Stents in patients with stenosis in a native coronary artery) demonstrate that the restenosis risk reduction decreases as RVD decreases (29). In that study, the restenosis rate for sirolimus-eluting stent and bare metal stent, respectively, was 30.2% vs. 1.9% (93.7% risk reduction), 36.5% vs. 6.3% (82.7% risk reduction), and 42.9% vs. 18.6% (56.6% risk reduction) for vessels averaging 3.3 mm, 2.8 mm, and 2.3 mm in RVD, respectively (4, 3, and 4 patients needed to treat with sirolimus-eluting stent to prevent a restenosis, respectively). Because of all these findings, many interventional cardiologists believe that the clinical benefit, and thus the cost/effectiveness, of drug-eluting stents in small vessels may be less favorable than in larger vessels. However, the recently available data from the TAXUS-IV trial show a greater benefit of paclitaxel-eluting stent in small vessels. In that study, the restenosis rate was 15.2% vs. 6.8% (55.3% risk reduction), 27.8% vs. 6.7% (75.9% risk reduction), and 38.5% vs. 10.2% (73.5% risk reduction) for vessels >3.0 mm, 2.5 to 3.0 mm, and 
2.5 mm in RVD, respectively (30) (12, 5, and 4 patients needed to treat with paclitaxel-eluting stent to prevent a restenosis, respectively). It could be speculated that an increasing dose of paclitaxel per unit vessel surface area could partly explain this greater benefit of paclitaxel-eluting stent in small vessels.
The demonstration from this meta-analysis that the bare metal stent is a better treatment than BA for small vessels provides an important basis for future trials of drug-eluting stents in small vessels. Before the demonstration that drug-eluting stents are a better treatment for small vessels than bare metal stents, we have previously had the security that bare metal stents are better than BA for these vessels. In this meta-analysis, we have demonstrated that bare metal stents are not only of angiographic benefit (lower restenosis rate) but also of clinical benefit (lower rate of repeat revascularization procedures).
Study limitations.
As in other meta-analyses, the present one has the inherent limitations of heterogeneity in inclusion criteria and definitions of outcomes. Also, the conclusions are not applicable to patients not fulfilling the inclusion criteria of these studies. In particular, lesion length was relatively short (10 mm), and the benefit of CS over BA in longer lesions is not necessarily the same as shown in these trials. Second, data on restenosis rate were given as summary data, as provided from the trials included. Finally, most trials included in the meta-analysis used CS after predilation. Recently, the PIXEL trial demonstrated that the restenosis rate after CS in small vessels is lower when a no-predilation versus a predilation implantation strategy is used (31).
Conclusions. Coronary stenting reduces the restenosis rate in small vessels, which translates into fewer major adverse cardiac outcomes mainly because it reduces the need for new revascularization procedures. This benefit seems to be especially evident with smaller RVD.
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