In multiple blinded randomized clinical trials, drug-eluting stents (containing sirolimus or paclitaxel) have shown significant improvement in angiographic and clinical outcomes compared with bare-metal stents (BMS) (1- 9). However, there are sparse data supporting the long-term benefits of drug-eluting stents in patients with coronary lesions beyond the first year after stent implantation (10- 11). The Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) multicenter blinded randomized trial examined the safety and efficacy of sirolimus-eluting stents (SES) in 1,058 patients, and results up to one year indicated significant reduction in both restenosis and target lesion revascularization (TLR) (2- 3). This report extends the clinical follow-up of the original SIRIUS patient cohort to determine if the early and middle-term safety and efficacy of SES is maintained at two years.

The methods of the SIRIUS trial were previously reported (2). Patients enrolled in the study had a clinical history of angina and single coronary target lesions, 15 to 30 mm in length, in vessels 2.5 to 3.5 mm in diameter. Major exclusion criteria included recent myocardial infarction, left ventricular ejection fraction <25%, target lesion in an ostial or bifurcation location, or a thrombotic or severely calcified lesion.

Patients had clinical evaluations at 30 days and 6, 9, 12, and 24 months. Two-year clinical follow-up was supervised by the physician investigators and the study coordinators from each of the enrolling sites. Patients were queried by telephone interview, and in the case of clinical events, source medical documents were retrieved and reviewed and adjudicated by an independent Clinical Events Committee blinded to the treatment assignment. Complete data compliance for all two-year follow-up end points was 91.6% for the BMS group and 92.3% for the SES group.

This two-year follow-up study focuses on clinical restenosis or TLR, defined as the need for clinically driven repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel. Clinical indications for repeat revascularizations included a positive noninvasive functional study, ischemic electrocardiogram changes at rest in a distribution consistent with the target vessel, or ischemic symptoms and an in-lesion diameter stenosis by quantitative coronary angiography of ≥50%. In addition, in the absence of the aforementioned objective criteria for ischemia, an in-lesion diameter stenosis by quantitative coronary angiography of ≥70% was also considered of sufficient severity to justify repeat revascularization. The independent Clinical Events Committee blindly adjudicated all clinically driven revascularization episodes. The SIRIUS secondary clinical end points included non-TLR target vessel revascularization (TVR), target vessel failure (TVF), and major adverse cardiac events (MACE). The definitions of these end points have been previously described (2).

Early stent thrombosis, either acute (within 24 h) or subacute (between 24 h and 30 days), was defined as angiographic documentation of target vessel occlusion or any death or myocardial infarction occurring within 30 days that is not clearly related to causes other than stent occlusion. The protocol definition of late stent thrombosis was myocardial infarction occurring >30 days after the index procedure and attributable to the target vessel, angiographic documentation (site-reported or by quantitative coronary angiography) of thrombus or total occlusion of the target site, and freedom from an interim revascularization of the target vessel. This very stringent definition represents definite late stent thrombosis. For the purposes of this report, we have extended the definition of late stent thrombosis to include additional categories of possible and cannot exclude late stent thrombosis. The definition of possible late stent thrombosis includes patients with myocardial infarction occurring >30 days after the index procedure and attributable to the target vessel, no identifiable “culprit” lesion elsewhere, and freedom from an interim revascularization of the target vessel. The definition of cannot exclude late stent thrombosis includes patients with sudden cardiac death >30 days after the index procedure, no identifiable “culprit” lesion elsewhere (as suggested by nontarget vessel electrocardiogram changes or autopsy evidence of a patent target vessel), and freedom from interim TVR.

The effectiveness analysis and the safety evaluation were performed on a modified intent-to-treat population; de-registered patients were not included in the analysis because they received neither study treatment.

Continuous variables are summarized as means and standard deviations and compared between treatment groups using t test. Categorical variables are summarized as frequencies and percentages and compared between treatment groups using the Fisher exact test. Out-of-hospital outcomes are summarized as Kaplan-Meier event rates and compared between treatment groups using log-rank tests. All tests are two-sided with a significance level of 0.05. Multivariate predictors were identified by using a Cox model with an entry/stay criteria of 0.10/0.15. All statistical analyses were performed with SAS software (version 6.12; SAS Institute, Cary, North Carolina).

As previously reported, both groups had similar baseline clinical and angiographic characteristics, procedural factors, and acute (in-hospital) results (2).

At two years, the significant differences between the SES and BMS groups in TLR, TVR, TVF, and MACE were all maintained ((Table 1),Figure 1). There were small increases in both groups and still no differences in death or myocardial infarction. The specific etiologies of all-cause mortality between one and two years, included cardiac deaths in two patients (chest pain followed by cardiac arrest, one case in each group) and noncardiac deaths in five patients (one case of documented noncardiac sudden death in the SES group, two deaths due to severe chronic lung disease in the SES group, and two deaths due to malignancy in the control group). There were infrequent late TLR events in both groups between one and two years (0.9% for SES and 1.3% for control stents), and the magnitude of reduction in clinical restenosis was the same at one and two years (TLR 5.8% for SES group and 21.3% for controls at two years; p < 0.001).

Various higher restenosis-risk patient and lesion subgroups (including diabetes, left anterior descending coronary artery [LAD] lesion location, small vessel size, and long lesion length) were examined by univariate analysis (Figure 2). In all cases, the significant reduction in TLR associated with SES compared with BMS controls in these selected subgroups was maintained at two years. Factors that predicted TLR at two years were evaluated using multiple logistic regression analysis in the entire study group and in the SES group alone. In the entire study group, independent predictors of TLR included assignment to sirolimus treatment (hazard ratio [HR] 0.21; p < 0.001), reference vessel diameter (HR 0.55; p < 0.02), diabetes mellitus (HR 1.56; p = 0.03), LAD location (HR 1.06; p = 0.03), and total stent length (relative 3% increase in risk for each 1-mm increase in stent length; p < 0.0001).

Stent thrombosis episodes (definite, possible, and cannot exclude) were distributed into early events (up to 30 days after the index procedure), late events up to 1 year, and late events between 1 and 2 years for both the SES and the control patients (Table 2). Early stent thrombosis and definite late stent thrombosis up to one year was observed in two SES patients (0.4%) and in four control patients (0.8%). Definite late stent thrombosis between one and two years was seen in one additional SES patient and in no control patients (overall definite stent thrombosis frequency up to two years was 0.6% for SES and 0.8% for control; nonsignificant difference). Possible late stent thrombosis occurred in no SES patients and in two control patients (one between 30 days and 1 year and one between 1 and 2 years). Cannot exclude late stent thrombosis occurred in two SES patient (one between 30 days and 1 year and one between 1 and 2 years) and in two control patients (one between 30 days and 1 year and one between 1 and 2 years). Overall cumulative stent thrombosis (including all categories of late stent thrombosis) up to two years after the index procedure occurred in five SES (0.9%) and in eight control BMS patients (1.5%, p = 0.11).

Over the past two years, since the introduction of drug-eluting stents into the U.S., there has been an evolving change in the treatment paradigm such that the vast majority of current patients receive SES or paclitaxel-eluting stents (PES) during percutaneous coronary interventions. Studies examining angiographic, intravascular ultrasound, and clinical end points have demonstrated safety and efficacy of these devices during the first year after therapy (1- 9,12- 13). Long-term follow-up after drug-eluting stent implantation is only available for small numbers of patients with focal uncomplicated lesion morphologies (10- 11). Therefore, rigorous late clinical follow-up of the earliest patient cohorts from large randomized clinical trials exposed to drug-eluting stents becomes essential to ensure patient safety and to determine if antirestenosis efficacy is maintained. The major findings of this two-year follow-up report involving patients treated with SES from the SIRIUS trial are: 1) clinical restenosis (with blinded adjudication of all clinically driven TLR events) shows maintained antirestenosis efficacy; and 2) late complications such as stent thrombosis between one and two years were rare and occurred with similar frequency in SES and BMS groups.

The concern of late restenosis (after 6 to 12 months) with potent antiproliferative therapies derives from experiences with intravascular radiation (vascular brachytherapy) which was introduced for the prevention of recurrent in-stent restenosis. Despite the significant short-term efficacy of vascular brachytherapy systems (14- 18), long-term follow-up results have been less gratifying. A small series of patients with serial angiography and intravascular ultrasound demonstrated relatively early “catch-up” or delayed restenosis (manifested as increased late-loss lumen loss) between 6 and 12 months after beta-vascular brachytherapy (19). More importantly, the five-year follow-up of the gamma-vascular brachytherapy Washington Radiation for In-Stent Restenosis Trial (WRIST) (in-stent restenosis patients) showed that between 6 and 60 months, patients treated with intravascular radiation compared with placebo had four times greater late TLR (21.6% vs. 4.7%; p = 0.04) (20). This late “catch-up” or delayed restenosis phenomena has also been observed with some of the earlier drug-eluting stents. In a small study involving in-stent restenosis patients, the QuaDS-QP2 stent (polymer sleeve eluting a taxane derivative, Quanam Medical Corp., Santa Clara, California) resulted in excellent reduction in restenosis at 6 months, but marked deterioration in angiographic and clinical outcomes after 12-month evaluations (21). The current analysis from the SIRIUS trial, the largest randomized study (1,058 patients) treating patients with SES (2), is particularly meaningful because there was no evidence of disproportionate late clinical events with SES, including death, myocardial infarctions, stent thrombosis, and repeat revascularizations after two-year follow-up ((Table 1), Figure 1).

A recent report (22) has raised concerns that PES and SES may be associated with an increased frequency of late stent thrombosis episodes, in the setting of cessation of antiplatelet therapy. A total of four patients (two with SES and two with PES) experienced late stent thrombosis (at least six months after the index procedure), within days after the cessation of all antiplatelet therapy (both aspirin and clopidogrel). In three of these four patients, the thrombotic episodes were during or after surgical or endoscopic procedures, and in two of the patients stent thrombosis was only in the drug-eluting stent target vessel, whereas BMS in other vessels were confirmed to be patent. Based on these concerns, the SIRIUS patients were analyzed in far greater detail employing an expanded definition of late stent thrombosis to include those patients without angiographic documentation of stent thrombus or occlusion and even in those patients with unexplained sudden cardiac death (Table 2). Of note, dual antiplatelet therapy using aspirin and clopidogrel was maintained for only three months in SIRIUS patients, whereupon the aspirin was routinely continued and the clopidogrel was stopped. Overall, we could not determine any differences in definite, possible, and cannot exclude late stent thrombosis (up to two years) when comparing the SES and BMS treated patients. Cumulative overall stent thrombosis using the less rigorous definitions was 0.9% in SES patients and 1.5% in control patients (p = 0.11). Interestingly, there were two episodes of possible late stent thrombosis that occurred in the BMS group, one soon after cessation of aspirin therapy in a woman anticipating a scheduled elective hysterectomy (clopidogrel had already been stopped months previously) and another during noncardiac surgery after both aspirin and clopidogrel had been stopped. Thus, although we recognize that late stent thrombosis will continue to be a carefully scrutinized clinical complication after drug-eluting stent implantation, especially in an environment where more complex lesion subsets are being treated, we cannot ascertain in the SIRIUS trial any differences in overall and late stent thrombosis between SES and BMS.

The maintained clinical safety and improved efficacy at two years in SIRIUS patients should provide some confidence that late untoward events are unlikely to be associated with SES. Nevertheless, the SIRIUS trial only included patients with intermediate lesion complexity, and the results cannot be extrapolated to all patient subsets and lesion subgroups. Therefore, additional clinical data are required in more complex patients and lesions to make categorical statements about long-term safety and efficacy of SES. Importantly, annual follow-up of the SIRIUS patients will continue for five years to provide further assurance that this frequently utilized and important interventional device fulfills the most rigorous standards of long-term safety and efficacy.