One-Year Clinical Outcome after Coronary Stenting of Very Small Vessels Using 2.25 mm Sirolimus- and Paclitaxel-Eluting Stents:

Coronary stenting has significantly improved the angiographic and clinical outcomes in vessels with a reference diameter (RD) > 3 mm.^1–5 However, several randomized trials have shown conflicting results when comparing coronary stenting with standard balloon angioplasty (PTCA) for small vessels.^6–11 Nearly 50% of all percutaneous interventions are performed in vessels with a RD 12 a setting related to a higher incidence of early and late adverse outcomes.^13,14 The emerging use of drug-eluting stents (DES) has markedly decreased the incidence of restenosis, both with sirolimus–eluting stents (SES) and paclitaxel-eluting stents (PES).^15–18 More recently, several multi-center randomized trials evaluated the efficacy of DES for the treatment of vessels with reference diameters ? 3.0 mm and have shown a significant reduction in both restenosis and clinical events.^19–21 Furthermore, recently published data from our group showed low restenosis and target lesion revascularization rates with the implantation of sirolimus-eluting stents for the treatment of very small vessels.²² To our knowledge, there are currently no available data comparing the efficacy of PES and SES for the treatment of small-vessel disease. The present study was conducted with the aim of comparing one-year clinical outcomes after implantation of 2.25 mm diameter SES and PES. Methods Patient population and procedures. Since April 2002, SES implantation (Cypher™ Stent, Cordis Corporation, a Johnson & Johnson Company, Miami, Florida) has been adopted as the default strategy for all patients treated in our institution as part of the RESEARCH registry.23 Such a strategy continued until February 2003, when PES implantation (Taxus™ Stent, Boston Scientific Corporation, Santa Clara, California) became the default strategy for all patients treated at our institution as part of the Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) Registry. Both (RESEARCH and T-SEARCH) were single-center registries in which all patients were included, irrespective of clinical presentation and lesion characteristics. In this study, we included the 197 consecutive patients who received at least one 2.25 mm diameter SES or PES between October 2002 and February 2003. Overall, patients treated for small-vessel disease comprised 16% of the total population. All procedures were performed in accordance with standard techniques. All patients were pre-treated with 300 mg clopidogrel. The use of glycoprotein IIb/IIIa inhibitors was at the operator’s discretion. Patients treated with PES were prescribed at least 6 months of clopidogrel (75 mg/day), based on existing data from a randomized, controlled trial.²⁴ For patients treated with SES, clopidogrel was prescribed for at least 3 months, unless one of the following was present (in which case clopidogrel was maintained for at least 6 months): multiple SES implantation (> 3 stents), total stented length > 36 mm, chronic total occlusion, and bifurcations. Aspirin was maintained indefinitely. The study protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients. Coronary angiograms were obtained in multiple projections after administration of intracoronary nitrates. QCA analysis was performed using the Cardiovascular Angiographic Analysis System II validated software (CAAS II; Pie Medical, Maastricht, The Netherlands). The catheter tip was cleared of contrast for accurate calibration. Lesion measurements were performed using the “worst” view of an end-diastolic frame. Definitions and follow-up. Patients were prospectively followed up for the incidence of major adverse cardiac events (MACE) defined as death, non-fatal myocardial infarction or target lesion revascularization. Myocardial infarction (MI) was diagnosed by an increase in the creatine kinase MB level to more than three-fold the normal limit according to the AHA/ACC Guidelines.²⁵ Target lesion revascularization (TLR) was defined as any surgical or percutaneous re-intervention motivated by a significant luminal narrowing within the stent or in the 5 mm distal or proximal segments adjacent to the stent. Thrombotic stent occlusion was angiographically documented as a complete occlusion (TIMI flow 0 or 1), or flow-limiting thrombus (TIMI flow 1 or 2) of a previously successfully treated artery. Follow-up data were obtained for 105 patients (98.1%) in the sirolimus group, and for 91 patients (98.9%) in the paclitaxel group. Information about in-hospital outcomes was obtained from an electronic clinical database for patients kept in our institution and by review of the hospital records for those discharged to referring hospitals. Post-discharge survival status was obtained from the Municipal Civil Registries at 1, 6 and 12 months. Statistical analysis. Analysis was made on an intention-to-treat basis, and the results are expressed as mean ± SD for continuous variables and as frequencies and percentages for categorical variables. Differences between groups were assessed by the chi-square test or the Fisher’s exact test for categorical variables, and by the Student’s t-test for continuous variables. Survival analysis was made by the Kaplan-Meier method, and differences in survival parameters were assessed by the log-rank test. A two-sided p-value Results Table 1 shows baseline demographics of the study population. The groups were well matched, with a mean age of 61.3 ± 11.1 years in the SES group and 63.0 ± 12.4 years in the PES group. Two-thirds of the patients were male. There was a higher prevalence of smoking in the PES group (19% versus 31%; p = 0.05). Baseline angiographic and procedural data are presented in Table 2. The prevalence of multivessel disease (67.3% versus 73.6%; p = 0.32) and the ejection fraction (50.4 ± 9.7 versus 51.2 ± 9.5; p = 0.68) were similar in both groups. A larger stent, in addition to the 2.25 mm stent, was deployed in 76.6% and 85.6% of SES and PES patients, respectively (p = 0.11). The reference diameter was 1.86 mm ± 0.4 in the SES group, and 1.95 mm ± 0.4 in the PES group (p = 0.15). The clinical presentation was well-matched in both groups. The reason for stenting with a 2.25 mm device was also similar (14.6% of the SES patients and 9.8% of the PES patients received stents due to residual dissection or plaque shifting; p = 0.09). All of the other stents were deployed due to the presence of significant stenosis. Clinical outcome. There were 2 deaths in the PES group in the first month and none in the SES group. One patient presented with post-MI unstable angina and left ventricular dysfunction and died 24 hours after implantation of a 76 mm PES in the LAD due to recurrent ventricular fibrillation. The second patient died suddenly 3 days after stent deployment in the RCA and LAD, with subacute stent thrombosis as a highly suspected diagnosis. The incidence of peri-procedural MI was 2.8% in the SES group, and 3.3% in the PES group (p = 0.81). There were 2 episodes of angiographically documented stent thrombosis in the PES group (2.2%). One patient presented with stent thrombosis 4 days after stenting of an ostial lesion of the obtuse marginal artery in the context of a MI. The other occurred 14 days after recanalization of a chronic total occlusion. No intravascular ultrasound was available to evaluate potential mechanistic causes of such events. Furthermore, one patient died suddenly 3 days after deployment of a 2.75 mm and 2.25 mm PES in the LAD and RCA, respectively. After a 12-month follow-up period, 1 patient (0.9%) died in the SES group, and 4 patients (4.4%) died in the PES group (p = 0.11). There were no significant differences regarding MI (2.1% versus 5.0%; p = 0.18), and MI attributed to 2.25 stents (1.9% versus 3.3%; p = 0.51). In addition, the incidence of repeat TLR did not differ (1.4% versus 5.0%; p = 0.08). However, the cumulative event rate of occurrence of any events (MACE) was significantly higher in the PES group (5.6% versus 17.8%; p = 0.007), with a MACE-free survival rate of 94% and 82% (log rank p = 0.005) in SES and PES patients, respectively (Figure 1). Predictors of adverse events. We performed a multivariate analysis to determine independent predictors of MACE at 12 months. After adjustments for other significant univariate variables, presentation with acute coronary syndrome (adjusted OR 5.2 [95% CI 1.8–15.0]; p = 0.002) and PES utilization (adjusted OR 3.7 [95% CI 1.3–10.5]; p = 0.013) were found to be significant independent predictors of MACE. Discussion The main finding of this study was that SES implantation resulted in greater effectiveness, reducing the incidence of adverse events at 12 months, compared to PES implantation. It is noteworthy that the overall population included in these registries had a markedly higher clinical risk than any of the previous published studies on the subject.^6–10,20,26 Due to the unrestricted nature of our registries, we included clinical and procedural subsets commonly excluded from most of the studies such as acute myocardial infarction patients, total occluded vessels, thrombotic, ostial and bifurcation lesions, left ventricular dysfunction, and renal failure. In addition, there was a noticeably high prevalence of multi-vessel disease (70.4%), as well as a particularly smaller vessel reference (1.90 ± 0.38) than other studies.^6–10,20,26 Multivariate analysis identified a classical independent predictor of MACE, such as presentation with an acute coronary syndrome. In addition, the use of PES was also found to be an independent predictor of worse outcomes. Both SES and PES implantation have previously shown to markedly decrease the incidence of in-stent restenosis and the rate of adverse outcomes.^15–18,23 Their remarkable capacity to reduce the incidence of in-stent restenosis might be particularly beneficial in small coronary vessels, since neointimal hyperplasia is relatively constant and independent of stent size.^16,27,28 Previous reported data from our group showed low restenosis and target lesion revascularization rates with the implantation of sirolimus-eluting stents for the treatment of very small vessels.²² In addition, the efficacy of DES for the treatment of vessels with reference diameters ? 3.0 mm was recently evaluated in several multi-center randomized trials and showed a significant reduction in both restenosis and clinical events.^19–21 DES implantation is increasingly becoming a standard therapy in coronary interventions performed in industrialized countries. Accordingly, there is a call for comparative data between the only 2 DES approved by the Food and Drug Administration (FDA), SES and PES. The results of the present study confirm the effectiveness of DES for the treatment of small vessels in a daily clinical practice population and provide some evidence in favor of SES as a safer strategy. Conclusion In this study, we evaluated the efficacy of two different DES in the treatment of very small vessels. The use of SES was associated with better 12-month clinical outcomes, and the use of PES was identified as an independent predictor of adverse events. Limitations. These are results of a comparison between two consecutive registries where DES were unrestrictively used as the default strategy, thus representing the “real world.” In addition, the fact that the population included in the study had a large percentage of multivessel disease might have influenced the accuracy of the results. However, we compared a relatively well-matched population, therefore these results may offer valuable information about clinical outcomes using different DES for the treatment of small-vessel disease. Interpretation of the results of the multivariate analysis must be cautious due to the limited amount of events. Such results must be further confirmed by randomized studies. Email: gatoenholanda@yahoo.com.ar

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