Author + information
- Received January 6, 2008
- Revision received January 7, 2009
- Accepted January 12, 2009
- Published online April 28, 2009.
- Giora Weisz, MD*,* (, )
- Martin B. Leon, MD*,
- David R. Holmes Jr, MD†,
- Dean J. Kereiakes, MD‡,
- Jeffrey J. Popma, MD§,
- Paul S. Teirstein, MD∥,
- Sidney A. Cohen, MD, PhD¶,#,
- Hong Wang, MD, MPH#,
- Donald E. Cutlip, MD** and
- Jeffrey W. Moses, MD*
- ↵*Reprint requests and correspondence:
Dr. Giora Weisz, Center for Interventional Vascular Therapy (CIVT), Columbia University Medical Center, Herbert Irving Pavilion, 161 Fort Washington Avenue, 5th Floor, New York, New York 10032
Objectives The aim of this study was to examine the 5-year clinical safety and efficacy outcomes in patients enrolled in the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial.
Background The SIRIUS trial was a double-blinded randomized study that demonstrated that sirolimus-eluting stents (SES) significantly improved angiographic results (at 8 months) and clinical outcomes (at 9 and 12 months) compared with bare-metal stents (BMS).
Methods Patients (n = 1,058) with de novo native coronary artery lesions were randomized to either SES (n = 533) or control BMS (n = 525) and were followed for 5 years.
Results Between 1 and 5 years, additional clinical events were similarly distributed among the sirolimus and control groups. At 5 years, in sirolimus versus control patients, target lesion revascularization was 9.4% versus 24.2% (p < 0.001) and major adverse cardiovascular events and target vessel failure rates were 20.3% versus 33.5% and 22.5% versus 33.5%, respectively (p < 0.0001 for both). There were no significant differences in death, myocardial infarction, and nontarget lesion revascularization. No significant differences were observed in the cumulative incidence of stent thrombosis for sirolimus versus control patients with either protocol-derived (1.0% vs. 0.8%) or Academic Research Consortium definitions (3.9% vs. 4.2%).
Conclusions In patients with noncomplex coronary artery disease, clinical outcomes 5 years after implantation of SES continue to demonstrate significant reduction in the need for repeat revascularization, with similar safety (death and myocardial infarction) compared with BMS, without evidence for either disproportionate late restenosis or late stent thrombosis.
Sirolimus-eluting stents (SES) have shown significant improvement in angiographic outcomes, with reduced rates of restenosis and need for revascularization compared with bare-metal stent (BMS) controls (1–5). These favorable clinical outcomes have resulted in the frequent use of drug-eluting stents during percutaneous coronary revascularization procedures over the past several years in the U.S. and around the world. However, reports of drug-eluting stent very late stent thrombosis, associated with possible increased mortality, have elicited long-term safety concerns (6–11).
The SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) multicenter, blinded, randomized trial examined the safety and efficacy of SES for up to 2 years and indicated significant reduction in both restenosis and target lesion revascularization (TLR) (3–5). This report extends the clinical follow-up of the original SIRIUS patient cohort to determine whether the early and midterm safety and efficacy of SES is maintained at 5 years.
Study design and eligibility criteria
The methods of the SIRIUS trial were previously reported (3). 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.
Data collection and follow-up
Patients had clinical evaluations at 30 days and 6, 9, 12, 24, 36, 48, and 60 months. The treatment identity (sirolimus or BMS) remained blinded throughout the follow-up period to both patients and investigators. Complete data compliance for all 5-year follow-up end points was 93.6% for the BMS group and 94.0% for the SES group.
Study end points: repeat revascularization
This 5-year follow-up study focuses on late safety and effectiveness, namely clinical restenosis or TLR. This was defined as the need for clinically driven repeat revascularization of the target lesion. In the absence of objective criteria for ischemia, an in-lesion diameter stenosis by quantitative coronary angiography ≥70% was also considered of sufficient severity to justify repeat revascularization. The independent Clinical Events Committee blindly adjudicated all revascularization episodes.
Other secondary end points
SIRIUS secondary clinical end points included non-TLR target vessel revascularization (non-TLR TVR), target vessel failure (TVF), and major adverse cardiac events (MACE). Non-TLR TVR was defined as any clinically driven repeat percutaneous intervention of the target vessel or bypass surgery of the target vessel for a lesion other than the target lesion. A non–Q-wave myocardial infarction (MI) was defined as an increase in the creatine kinase level to more than twice the upper limit of the normal range accompanied by an increased level of creatine kinase-myocardial band in the absence of new Q waves on the electrocardiogram. Cardiac death was defined as death due to obvious cardiovascular events and procedure-related causes or any death in which a cardiac cause could not be excluded. Noncardiac death was defined as any death clearly not due to cardiac causes (e.g., malignancy). A TVF was defined as any TVR (either target vessel coronary bypass surgery or target vessel percutaneous coronary intervention), MI (Q-wave or non–Q-wave), or cardiac death that could not be clearly attributed to a vessel other than the target vessel. Major adverse cardiac event was defined as a composite of death (cardiac and noncardiac), MI (Q-wave or non–Q-wave), and any TLR (either target vessel coronary bypass surgery or target lesion percutaneous coronary intervention).
Early stent thrombosis, either acute (within 24 h) or subacute (between 24 h and 30 days), was defined according to protocol as angiographic documentation of target vessel occlusion or any death or MI occurring within 30 days that was not clearly related to causes other than stent occlusion. The protocol definition of late stent thrombosis was MI occurring >30 days after the index procedure and attributable to the target vessel and 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.
For the purposes of this report, we used both the protocol-derived and the recently suggested Academic Research Consortium (ARC) (12) definitions of stent thrombosis. The ARC definitions consider distinct reportable time points: acute stent thrombosis (0 to 24 h after stent implantation); subacute stent thrombosis (>24 h to 30 days); late stent thrombosis (30 days to 1 year); and very-late stent thrombosis (more than 1 year after stent implantation). The ARC definitions also recognize 3 categories of evidence in defining stent thrombosis: confirmed/definite, probable, and possible. “Confirmed/definite” stent thrombosis was defined as an acute coronary syndrome with symptoms, electrocardiogram changes, or more than 2-fold elevation in creatine phosphokinase combined with either angiographic or pathologic confirmation of stent thrombosis. “Probable” stent thrombosis was defined as any unexplained death within the first 30 days or irrespective of the time after the index procedure, or any MI in the absence of an obvious cause that is related to documented acute ischemia in the territory (target vessel) of the implanted stent without angiographic confirmation of stent thrombosis. “Possible” stent thrombosis was defined as any unexplained death more than 30 days after the index procedure. The ARC definitions did not censor stent thrombosis events that occurred after an intervening revascularization of the target vessel.
Analyses were performed on a modified intent-to-treat population; deregistered patients were not included in the analysis, because they received neither study treatment (3).
Continuous variables are summarized as mean ± SD and were compared between treatment groups with the ttest. Categorical variables are summarized as frequencies and percentages and were compared between treatment groups with the Fisher exact test. Differences and 95% confidence intervals (CIs) between the 2 comparison groups were also calculated. Event-free incidence or cumulative incidences of selected long-term outcomes were summarized with the Kaplan-Meier method and compared between treatment groups with log-rank tests. To identify the risk factors for the major long-term outcomes, a series of univariate and multivariate predictor analyses were performed; multivariate predictors were chosen with an entry criterion of 0.20 and with a stay criterion of 0.10. All tests are 2-sided with a significant level of 0.05. All statistical analyses were performed with SAS software (version 8.2, SAS, Cary, North Carolina). The data were managed and analyzed exclusively by the Harvard Clinical Research Institute during the 5-year follow-up. The authors had full access to the data and take responsibility for its integrity.
As previously reported, both groups had similar baseline clinical and angiographic characteristics, procedural factors, and acute (in-hospital) results (3).
Revascularization and clinical events
After 5 years, the significant differences between the SES and BMS groups in TLR, TVR, TVF, and MACE were all maintained (Table 1,Fig. 1).During the follow-up from 1 to 5 years, in both groups there were similar increases in the rates of all clinical end points.
The comparison of survival curves in freedom from death or MI showed no significant differences over the follow-up period (Fig. 1A). The event-free curves of TLR, TVR, MACE, and TVF stayed separated and parallel throughout the extended follow-up after 1 year (Figs. 1B and 1C).
Various higher restenosis risk patient and lesion subgroups (including diabetes, left anterior descending coronary artery lesion location, small vessel size, and long lesion length) were examined (Fig. 2).In all cases, the significant reduction in TLR associated with SES compared with BMS controls in these selected subgroups was maintained at 5 years.
Multivariate analyses identified the following predictors of TLR: treatment with control stent (vs. SES; odds ratio [OR]: 3.44, p < 0.0001), diabetes mellitus (OR: 1.86, p < 0.001), prior coronary artery bypass graft surgery (OR: 1.78, p = 0.04), total numbers of stent implanted (OR: 1.70/mm stent-length increase, p < 0.0001), left anterior descending coronary artery (vs. other locations; OR: 1.52, p = 0.02), post-procedure in-stent minimal luminal diameter (/mm, OR: 0.52, p = 0.003), and age (/year, OR: 0.98, p = 0.04).
Multivariate analyses identified the following independent predictors of death and MI: age (OR: 1.05, p < 0.0001), stent length (OR: 1.04, p = 0.002), smoking during the last year before procedure (OR: 1.94, p = 0.005), congestive heart failure (OR: 2.06, p = 0.02), reference vessel diameter (OR: 0.62, p = 0.03), hypertension (OR: 1.55, p = 0.047), prior MI (OR: 1.47, p = 0.054), and post-procedure hospital length of stay (OR: 1.32, p = 0.004).
Stent thrombosis episodes (according to either the protocol or ARC definitions) are reported as early events up to 30 days after the index procedure, late events from 30 days to 1 year, and very late events between 1 and 5 years for both the sirolimus-eluting and the control stent patients (Table 2).Early stent thrombosis was rare, irrespective of the definition. In the late time period between 30 days and 1 year after stent placement, with both types of definitions there were low rates of stent thrombosis with control stents and SES (0.6% vs. 0.2% with the protocol definition of stent thrombosis; 0.7% vs. 0.2% with the “definite” plus “probable” ARC definition). During the last 4 years of follow-up, the very late period (years 1 to 5), there were 3 events with the protocol definition of stent thrombosis but none with control stents (p = 0.16). With the ARC definitions of very late “definite” stent thrombosis, there were 4 cases of “definite” stent thrombosis with SES and 2 with BMS (0.8% and 0.4%, p = 0.57). There was only 1 case of “probable” very late stent thrombosis in the BMS group and none in the SES group and no significant difference in the rates of “possible” very late stent thrombosis between SES and BMS (2.6% vs. 2.3%, p = 0.74).
After 5 years of follow-up (Table 2, Fig. 3),the overall cumulative incidence of protocol-defined stent thrombosis was not significantly different between SES and BMS patients (1.0% vs. 0.8%; p = 0.75). With ARC definitions compared with protocol definitions of stent thrombosis, there was an increase in the number of stent thrombosis events (to 41 from 9) due to a lack of censoring stent thromboses after repeat revascularization events and the more expansive categories of “probable” and especially “possible” late stent thrombosis. The “definite” category of the ARC-defined stent thrombosis events added only 1 case to each stent group compared with the protocol-based definition, but the “probable” category included 4 additional cases (all BMS) and the “possible” category included 26 additional cases (14 SES and 12 BMS). There were no significant differences between SES and BMS in the overall frequency of stent thrombosis with ARC definitions (cumulative incidence SES 3.9% vs. BMS 4.2%; p = 0.85).
A total of 279 patients (26.4%) had diabetes mellitus, and the baseline demographic data, lesion characteristics, and short-term outcomes of the diabetic patients have been reported previously (13). The long-term clinical outcomes of the patients with diabetes mellitus are summarized in Table 3.Diabetic patients generally had higher frequencies of clinical events compared with patients without diabetes in each treatment group (Table 3). In SES patients, diabetic patients had more frequent cardiac death than nondiabetic patients (9.9% vs. 4.2%, p = 0.0004) and in BMS patients, diabetic patients had more frequent TLR events (33.1% vs. 20.7%, p = 0.0045). When comparing SES versus BMS at 5 years in both diabetic and nondiabetic patients, there were significant reductions in the frequency of TLR, TVR, MACE, and TVF, but no significant differences were observed in the rates of death and MI. A nonsignificant increased rate of cardiac death with SES versus BMS in diabetic patients was observed (9.9% vs. 4.7%; p = 0.11). This was associated with a cluster of death events in the SES group in the first one-half of the third year after the index procedure (Fig. 4).
In the diabetic subgroup, there were no significant differences in overall protocol-defined stent thrombosis after SES treatment (SES: 2 events [1.6%] vs. BMS: 1 event [0.7%]; p = 0.48), and there were also no significant differences in ARC “definite” plus “probable” stent thrombosis (SES: 3 events [2.6%] vs. BMS: 4 events [2.9%]; p = 0.85). Due to the increased cardiac death events during follow-up in the diabetic SES patients, there was a trend toward more frequent ARC “possible” stent thrombosis (SES: 9 events [7.5%] vs. BMS: 4 events [3.0%]; p = 0.09). The overall cumulative incidence of ARC-defined stent thrombosis was 9.9% (12 events) in SES patients and 5.9% (8 events) in BMS patients (p = 0.22).
The results related to the diabetic patients in the SIRIUS trial should be interpreted with caution. The number of diabetic patients in this study was small, and further studies focused on this group of patients are needed.
The SIRIUS trial is the largest randomized study (n = 1,058) of patients with symptomatic coronary disease comparing treatment of the culprit lesion with SES with the predicate BMS (3). Eight-month angiographic follow-up in 703 patients and 9-month clinical follow-up in all patients indicated a marked reduction in late lumen loss (in-stent: 1.00 mm vs. 0.17 mm, p < 0.001), binary in-lesion restenosis (36.3% vs. 8.9%, p < 0.001), and clinically driven TLR (16.6% vs. 4.1%, p < 0.001) when comparing control BMS with the SES. When clinical follow-up was extended to 12 and 24 months, the improvement in clinical restenosis (clinically driven TLR) was maintained after SES treatment (4,5). On the basis of these angiographic and clinical outcomes from the SIRIUS trial, the Food and Drug Administration approved the use of SES in April 2003.
The 5-year SIRIUS follow-up analysis shows no evidence of disproportionate late clinical events with SES, including death, MI, stent thrombosis, and repeat revascularizations (Tables 1 and 2, Figs. 1 to 3). The major findings of this 5-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 anti-restenosis efficacy; and 2) late complications such as stent thrombosis, MI, and death between 1 and 5 years were uncommon and occurred with similar frequency in sirolimus and BMS groups.
On the basis of previous experience with potent antiproliferative strategies to prevent in-stent restenosis, such as brachytherapy (14–16), concerns were expressed regarding the long-term durability of the anti-restenosis efficacy associated with SES. The 5-year results from the SIRIUS trial demonstrate that the significant differences in rates of revascularization, both TLR and TVR, were maintained without late catch-up phenomenon (Table 1, Fig. 1). With SES, the need for revascularization between 1 and 5 years was uncommon (TLR 1.1%; TVR 2.3%/year) and similar to control stents. At 5-year follow-up, the long-term clinically driven TLR was still markedly reduced (by 61%) from 24.2% in the control group to 9.4% in SES-treated patients (p < 0.001). Thus, by using an SES in the SIRIUS trial, at 5 years, 149 repeat revascularization events were prevented for every 1,000 patients treated (Fig. 2). This demonstration of the potency and durability of the anti-restenosis effect of SES is clearly distinguished from previous strategies to prevent in-stent restenosis.
No important safety differences were observed comparing SES versus control stents, examining the hard clinical end points of death (all and cardiac) and MI (all and Q-wave), alone or in combination. The mean annual frequency (after year 1) was <1% for both cardiac death and MI. These long-term events are comparable to previously published natural history reports in patients with coronary disease treated with percutaneous coronary revascularization modalities (17–19).
Stent thrombosis is a dramatic clinical event associated with MI and frequent mortality. Recent publications including long-term follow-up of randomized trials and registries as well as some meta-analyses have indicated that drug-eluting stents (both SES and paclitaxel-eluting stents) might be associated with increased rates of very late stent thrombosis (after 1 year), compared with BMS (7,9,11,20–22). For patients similar to those enrolled in the SIRIUS trial, the incremental very late stent thrombosis event rates have been small, approximately 2 patients/year/1,000 patients treated. Therefore, rigorous late clinical follow-up of the blinded randomized trials using re-adjudicated standardized definitions becomes essential to ensure patient safety. The SIRIUS trial's 5-year follow-up confirms a low rate of very late stent thrombosis events associated with SES and BMS (3 and 0 events, respectively; p = 0.1556). However, after re-adjudicating all follow-up events with the ARC definitions, which both broadens the classification of events captured as stent thrombosis and no longer censors events after an intervening repeat revascularization, the differences between SES and BMS are substantially diminished (“definite” plus “probable”: 4 vs. 3 events, respectively) (Table 2). The cumulative 5-year frequencies of stent thrombosis—applying the ARC definitions—also indicated a similar occurrence of stent thrombosis in the SES and BMS patients (“definite”: approximately 0.2%/year; and combined “definite,” “probable,” and “possible”: approximately 0.8%/year for both SES and BMS patients). Thus, in the SIRIUS patient population—constituting what is now considered “on-label” use—in a carefully conducted, randomized, double-blind study with almost complete long-term follow-up, the use of SES did not lead to an increase in stent thrombosis.
Diabetes mellitus is a well-known risk factor for increased restenosis and worse prognosis (death and MI) in patients with coronary artery disease treated with percutaneous transcatheter interventions (23–26). During follow-up, the diabetic patients enrolled in SIRIUS had more repeat revascularization events than the nondiabetic patients, in both the SES and BMS treatment groups (Table 3). The time course of restenosis seemed unaltered, with the vast majority of events occurring in the first year. Importantly, despite an absolute increase in the frequency of events, the relative antirestenosis efficacy of SES was similar in diabetic versus nondiabetic patients (TLR decrease by SES was 59% in diabetic patients and 61% in nondiabetic patients, and the actual number of TLR events prevented/1,000 patients treated was actually greater in diabetic patients than in nondiabetic patients.
A recent pooled analysis raised concerns that SES might adversely affect mortality in patients with diabetes (27). This pooled analysis examined the 4-year outcomes from 4 blinded, randomized studies comparing SES with BMS, including the SIRIUS trial, which comprised 65% of the overall patient cohort. There were significant differences in long-term mortality that might be explained by an unexpectedly low frequency of deaths in the diabetic control stent population. In the SIRIUS 5-year follow-up analysis, there is a statistically nonsignificant higher overall noncardiac mortality in diabetic patients treated with SES versus BMS (overall mortality: 15.3% vs. 9.5%, difference 5.8%, 95% CI: −1.9% to 13.6%; and cardiac mortality: 9.9% vs. 4.7%, difference 5.2%, 95% CI: −1.0% to 11.4%). The mortality differences were largely the result of a cluster of cardiac death events occurring in the first portion of year 3 (Fig. 4). Once again, there was an unexpectedly low frequency of cardiac deaths in diabetic BMS patients (<1%/year), which contributed to the apparent differences. Follow-up from dedicated randomized trials in diabetic patients and large registries is ongoing and should further clarify this hypothesis-generating observation.
Diabetes has previously been reported as a predictor for stent thrombosis in drug-eluting stent clinical studies (6–8,21). In the SIRIUS trial, the overall 5-year stent thrombosis frequencies (both protocol-defined and ARC “definite” and “probable”) were not different in diabetic patients compared with nondiabetic patients and uninfluenced by SES versus BMS treatment. Due to the aforementioned unexplained late increase in cardiac deaths with SES in diabetic patients, there was a likewise statistically nonsignificant increase in 5-year ARC “possible” stent thrombosis events (SES vs. CS: 9.9% vs. 5.9%, p = 0.22).
The SIRIUS trial was the first large randomized trial evaluating the clinical outcomes of a new drug-eluting stent compared with a blinded BMS control. As such, the patient population was restricted in complexity, and so-called “off label” anatomic categories that might result in higher clinical event rates were systematically excluded (6,7,28). The use of dual antiplatelet therapy (aspirin and clopidogrel) was only mandated by protocol for 3 months, and no long-term information on use of antiplatelet agents was collected.
Diabetic patients were neither randomized nor stratified for enrollment in this study; thus, evaluations of outcomes in diabetic patients were not pre-specified and are post hoc analyses. Reported outcomes in diabetic patients are thus subject to the limitations of such an analysis.
The 5-year follow-up of the double-blinded, randomized SIRIUS trial comparing SES with BMS confirms the long-term safety and efficacy of SES in patients with simple and medium complexity native coronary lesions. All anti-restenosis efficacy parameters of reduced revascularization, all safety end points (death, MI, and stent thrombosis), and composite safety and efficacy end points (MACE and TVF) suggested maintained benefit of SES in reducing subsequent revascularization events without adversely affecting safety. Undoubtedly, because this study only represents a slice of the patient population currently treated with SES, additional long-term follow-up studies are essential to determine the safety and efficacy of SES in more complex patient groups and higher-risk anatomic subsets.
Dr. Leon has served on the advisory board and received consulting fees from Cordis, Johnson & Johnson. Dr. Kereiakes has served on the scientific advisory boards of Boston Scientific Corp., Reva Medical, and Abbott Vascular, and served as consultant for Cordis, Reva Medical, Medtronic, Eli Lilly, and Daichi-Sanyo. Dr. Popma has received a research grant for study and served on the advisory board for Cordis, Johnson & Johnson. Dr. Teirstein has received research grants and consulting fees from Cordis, Johnson & Johnson, and served as consultant to and received honorarium from Boston Scientific, Medtronic, and Abbott. Drs. Cohen and Wang are employees of Cordis, Johnson & Johnson. Dr. Moses has received consulting fees from Cordis, Johnson & Johnson.
- Abbreviations and Acronyms
- Academic Research Consortium
- bare-metal stent(s)
- major adverse cardiac event(s)
- myocardial infarction
- odds ratio
- sirolimus-eluting stent(s)
- target lesion revascularization
- target vessel failure
- target vessel revascularization
- Received January 6, 2008.
- Revision received January 7, 2009.
- Accepted January 12, 2009.
- American College of Cardiology Foundation
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