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Original Contribution
Direct Versus Predilatation Drug-Eluting Stenting: A Randomized Clinical Trial
October 2006
Several randomized studies with bare-metal stents (BMS) have demonstrated the feasibility of direct stenting in a high percentage of coronary lesions, with low crossover rates of approximately 6%.1–13 Most studies have failed to detect significant differences by means of restenosis rates or major cardiac events between direct stenting and predilatation.5,6,9–13 There is, however, some evidence that direct stenting can reduce procedural costs and fluoroscopy time,1,2,4 restenosis and target lesion revascularization (TLR) rates,3 and myocardial necrosis,7,8 and thus perhaps improve postintervention outcomes.14,15
Few data exist on direct stenting with drug-eluting stents (DES). Direct stenting seems to be safe and feasible with both sirolimus- and paclitaxel-eluting stents,16–18 and comparative studies have shown a trend towards decreased restenosis and major adverse cardiac events (MACE) with direct sirolimus-eluting stent placement.19,20 However, no randomized comparisons of the two strategies using DES have been published. We have conducted a randomized trial comparing direct DES (with sirolimus- or paclitaxel-eluting stents) with a conventional predilatation strategy.
Methods
Patients. Between January 2003 and March 2004, 95 consecutive, consenting patients with indication for coronary stenting of a de novo coronary lesion were recruited. In total, 166 lesions were randomly allocated into two groups: (1) Group A: direct stenting and (2) Group B: conventional balloon predilatation followed by stenting. The rationale for randomizing lesions instead of patients was that factors determining restenosis, as well as stent deliverability, are mainly related to artery and lesion characteristics rather than to the patient in general.
All patients were treated with either a sirolimus-eluting (Cypher™, Cordis Corp., Miami, Florida) or paclitaxel-eluting stent (Taxus®, Boston Scientific Corp., Natick, Massachusetts), according to the operator’s discretion and stent availability. Patients were not eligible for enrollment if they had unprotected left main coronary artery stenosis, left ventricular ejection fraction 1.7 mg/100 mL, were not considered as contraindications for stenting.
The study was approved by our Institutional Review Board, and all patients provided written, informed consent.
Stenting Procedure
Before stent implantation, patients were premedicated with aspirin (100 mg), clopidogrel (loading dose 300 mg), and enoxaparin. Patients with acute coronary syndromes, diabetes and multiple or long stents were also treated with glycoprotein IIb/IIIa receptor antagonists. Stents were deployed with or without predilatation according to standard techniques. For predilatation, care was taken to use a balloon shorter in length than the anticipated stent length. Post-deployment high-pressure dilatation with a balloon shorter in length than the implanted stent was performed at the operator’s discretion. Postdilatation was performed as necessary to achieve a residual diameter stenosis Angiographic analysis. Coronary angiograms were obtained in multiple views after patients had received an intracoronary injection of nitrates. Stenoses were classified according to the American Heart Association/American College of Cardiology (AHA/ACC) classification, and as complex (eccentric, with overhanging edges, irregular borders, and/or showing ulceration or thrombus) or smooth (concentric or eccentric lesions with smooth edges, in the absence of complex features), and concentric (symmetric narrowing of a coronary artery, with an identical or near-identical appearance of the stenosis in orthogonal projections; symmetry index > 0.5–1.0), or eccentric (asymmetric narrowing; index 0.0–0.5), as previously described.21 For quantitative analysis, angiograms were analyzed through the use of a computer-based system (QCA-CMS 6.0, Medis Medical Imaging Systems, Leiden, The Netherlands). Quantitative coronary angiographic endpoints included reference vessel diameter, minimum lumen diameter, percent diameter stenosis (% DS). Binary restenosis was defined as > 50% diameter stenosis at the target lesion site and classified as: (1) in-stent, if inside the stent, or (2) edge restenosis, if located within 5-mm segments distal or proximal to the stent margins.
Patient follow up. At 2, 6 and 12 months, patients underwent evaluation of anginal status according to the Canadian Cardiovascular Society Classification of angina and the Braunwald Classification for unstable angina, as well as monitoring of major adverse cardiac events (MACE) or additional revascularization of the index target lesion. Dobutamine stress echocardiography was performed at each visit in all patients by dedicated echocardiography specialists who were blinded to treatment allocation. Follow-up angiography was performed in case of symptoms or a positive stress echocardiography test, and lesion revascularization was decided on the basis of significant (> 50% diameter) restenosis and evidence of ischemia from the relevant myocardial territory. Details on the dobutamine stress echocardiography technique performed in our laboratory have been published elsewhere.22Study endpoints. The primary endpoint of our trial was TLR, which was defined as emergency or elective coronary artery bypass grafting or repeat percutaneous coronary intervention in the target vessel. MACE were defined as death from any-cause, Q-wave myocardial infarction, target vessel revascularization (TVR) and stent thrombosis (subacute or late). Q-wave myocardial infarction was defined as development of Q-waves in > 2 contiguous leads with postprocedural creatine kinase-MB isoenzyme (CK-MB) levels elevated above normal. TVR was defined as emergency or elective CABG or repeat PCI in the target vessel. Subacute stent thrombosis was defined as stent thrombosis occurring between 24 hours to 1 month after the procedure, whereas late thrombosis was thrombosis that happened more than 1 month after the procedure. TLR, as well as MACE such as myocardial infarction or death, were adjudicated and registered by an independent Clinical Events Committee.
Statistical analysis. Prospective power analysis during the design of the study had suggested that we need 182 lesions in each group in order to achieve a power of 80% to detect a difference in rates of revascularization of 0.05 between the two groups, with a two-sided significance level of p p = 0.05 was considered as significant. SPSS statistical software (SPSS Inc., Chicago, Illinois) used in all data analyses.
Results
Patient characteristics. During the study period, 95 patients were enrolled (mean age 59 ± 11 years; 12 women). Baseline demographics and clinical characteristics of patients are given in Table 1. One out of 3 patients presented with acute coronary syndromes. A history of myocardial infarction was present in 23% of the patients, while 6% of patients had prior coronary artery bypass grafting.
Lesion characteristics. In total, 166 lesions were randomized to direct stenting (n = 88) or predilatation followed by stenting (n = 78). In 21 patients, 49 coronary lesions located at the same vessel were randomized to different treatment strategies. The left anterior descending artery was more likely to be the target vessel in both strategies. Moreover, no difference was observed in lesion length, vessel size, and target lesion location between the two groups (Table 2).
Procedural characteristics. With the exemption of stent length, which was significantly longer in the predilatation group, no difference was observed in the procedural characteristics between the two strategies (Table 3). In the majority of lesions treated, only 1 stent, as well as a paclitaxel-eluting (Taxus) stent, were more likely to be used.
The success rate was 100% in the predilatation group. Crossover to conventional balloon predilatation was necessary for successful stenting of 6 lesions (7%) in the direct stenting group. Characteristics of the lesions crossed over to predilatation are presented in Table 4. Mean minimum lumen diameter, lesion length, and % diameter stenosis were 0.57 ± 0.25 mm, 14.02 ± 9.16 mm, and 78 ± 12, respectively. No significant difference was detected between lesions that were successfully treated with direct stenting and those in which direct stenting failed.
Although 13% of lesions (3/23) could not be crossed with a Cypher stent, as opposed to 4% with a Taxus stent, this difference did not reach statistical significance (p = 0.114).
Angiographic characteristics. Table 5 illustrates pre- and postprocedural angiographic characteristics. No statistically-significant difference was observed in the minimum lumen diameter, lesion length, % diameter stenosis and acute gain (the difference between the minimum lumen diameter after stenting and the minimum lumen diameter at baseline) between the direct stenting and conventional predilatation strategy.
Follow up. Four patients (with 6 treated lesions) were lost to follow up after the initial procedure, so these observations were considered censored at this time. Of the remaining patients, 15 (with 28 lesions) underwent a dobutamine stress echocardiography test that indicated ischemia at the relevant territory. Coronary angiography was performed in 13 patients (24 lesions). The remaining 2 patients refused to undergo repeat angiography due to the complete absence of previously-significant symptoms on maximum effort. Lesions in patients who had a negative dobutamine stress echocardiography test by the end of the follow-up period, in patients with a positive dobutamine stress echocardiography test who did not undergo follow-up angiography, and in those whose follow-up angiography did not show a binary restenosis, were considered as censored observations after the time the final dobutamine stress echocardiography or the coronary angiography was performed. Moreover, lesions crossed over from direct stenting to predilatation were considered as censored at the time of crossover. As mentioned above, we observed that TLR was required in only 4 lesions, all of which were randomized to the predilatation group. No patient with restenosis was diabetic. Characteristics of the lesions requiring repeat coronary intervention are shown in Table 6. The log-rank test showed statistically significant differences on target lesion revascularization-free survival curves between the two groups (p = 0.04) (Figure 1). No myocardial infarctions or deaths occurred in either group during the follow-up period.
Discussion
Direct stenting with BMS has been shown to reduce procedural time and costs, but no significant effect on clinical outcomes such as TLR or MACE has been demonstrated. Direct stenting with DES is particularly attractive when considering the increased cost of these devices. Although initial concerns regarding potential damage of the stent polymer were not substantiated and this strategy is now considered safe, its potential advantages over conventional predilatation have not been demonstrated thus far. Data from registries and nonrandomized comparisons have been inconclusive. Analysis of subgroups from the E-SIRIUS and C-SIRIUS studies 19 as well as the TAXUS-II trials 17 have suggested reduced restenosis, TLR and MACE rates with direct stenting, but results failed to achieve statistical significance. Similar trends were also found by the DIRECT trial investigators.20 Munoz et al,18 in an intravascular ultrasound study, also detected a trend towards edge segment positive remodeling in the direct stenting group, but not in the predilatation group. All these reports, however, represented post hoc analyses comparing direct stenting groups with historical controls. Brueck et al,3 in a randomized study on 335 patients, demonstrated reduced angiographic restenosis (20% vs. 31%; p = 0.048) and TLR (18% vs. 28%; p = 0.03) rates for direct versus predilatation stenting, respectively. In the setting of acute myocardial infarction, direct stenting has been shown to result in improved ST-segment resolution compared to predilatation stenting.7 In another study on diabetic patients, direct stenting has also produced similar results compared to predilatation stenting.9
Our study is the first randomized comparison between the two treatment strategies. The results of our study clearly suggest that direct stenting when using DES is feasible, safe and associated with a low TLR rate. Arterial balloon trauma outside the stented segment has been associated with restenosis of DES.23 In our series, although care was taken to use shorter balloons in the event that predilatation was required, our cases of “edge restenosis” can be attributed to inappropriate balloon trauma outside the stented segment. This is in keeping with our previous experience with DES in which edge restenosis in a previous observational report from our laboratory was seen only in lesions subjected to balloon predilatation.24
Experimental data argue in favor of direct stenting regarding the risk of in-stent restenosis.25,26 Rogers et al26 have elegantly demonstrated the different vascular responses to partial versus complete endothelial denudation caused by balloon-expanded stents. Predilatation with a balloon before stent deployment may result in extensive endothelial damage and denudation. They have therefore proposed that if some endothelium is present in atherosclerotic vessels, stents used without balloon predilatation may provide a means for dilating arteries while avoiding complete endothelial ablation. Thus, the undamaged remnant endothelial cells that remain between struts regenerate, negating the need for smooth muscle cell proliferation. Post-stent dilatation that invariably tends to be at higher pressures annihilates the advantage created by direct stenting by destroying these remaining cells. As also occurred in our study, balloon predilatation is usually associated with the use of longer stents, which is consistent with more excessive vessel wall trauma.
Clinical implications. Our results may have potential clinical implications. First, they demonstrate that direct stenting can be safely performed with DES in at least 93% of cases. Second, they indicate that this approach results in a reduced rate of TLR apart from lower costs. Thus, adoption of direct stenting is clearly advocated by our study.
Study Limitations. The main limitation of our report is the small sample size and low power of the study. Nevertheless, results have reached statistical significance at this level. Second, the randomization of lesions does not allow direct comparisons between patients. As previously stated, however, factors determining restenosis as well as stent deliverability are mainly related to the artery and lesion characteristics rather than the patient in general. Third, follow-up angiograms were not obtained from all patients, and results were based on criteria such as angina recurrence and positive stress echocardiography. Finally, due to ethical and cost considerations, serial cardiac enzyme measurements were not conducted in our patients, although we and others have shown that even minor elevations may have prognostic significance after coronary intervention.27Conclusions
Direct stenting is safe and technically feasible in the majority of coronary lesions. In successful cases, adoption of the direct stenting approach results in a significantly reduced rate of target lesion revascularization compared to the conventional predilatation technique.
References
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