Author + information
- Received April 23, 2012
- Revision received June 15, 2012
- Accepted July 2, 2012
- Published online September 25, 2012.
- Lisette Okkels Jensen, MD, DMSci, PhD⁎,⁎ (, )
- Per Thayssen, MD, DMSci⁎,
- Evald Høj Christiansen, MD, PhD†,
- Hans Henrik Tilsted, MD‡,
- Michael Maeng, MD, PhD†,
- Knud Nørregaard Hansen, MD⁎,
- Anne Kaltoft, MD, PhD†,
- Henrik Steen Hansen, MD, DMSci⁎,
- Hans Erik Bøtker, MD, DMSci, PhD†,
- Lars Romer Krusell, MD⁎,
- Jan Ravkilde, MD, DMSci‡,
- Morten Madsen, MSc§,
- Leif Thuesen, MD, DMSci†,
- Jens Flensted Lassen, MD, PhD†,
- SORT OUT IV Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Lisette Okkels Jensen, Department of Cardiology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark
Objectives There are limited head-to-head randomized data on patient-related versus stent-related outcomes for everolimus-eluting stents (EES) and sirolimus-eluting stents (SES).
Background In the SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) trial, comparing the EES with the SES in patients with coronary artery disease, the EES was noninferior to the SES at 9 months.
Methods The primary endpoint was a composite: cardiac death, myocardial infarction (MI), definite stent thrombosis, or target vessel revascularization. Safety and efficacy outcomes at 2 years were further assessed with specific focus on patient-related composite (all death, all MI, or any revascularization) and stent-related composite outcomes (cardiac death, target vessel MI, or symptom-driven target lesion revascularization). A total of 1,390 patients were assigned to receive the EES, and 1,384 patients were assigned to receive the SES.
Results At 2 years, the composite primary endpoint occurred in 8.3% in the EES group and in 8.7% in the SES group (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.73 to 1.22). The patient-related outcome: 15.0% in the EES group versus 15.6% in the SES group, (HR: 0.95, 95% CI: 0.78 to 1.15), and the stent-related outcome: 5.2% in the EES group versus 5.3% in the SES group (HR: 0.97, 95% CI: 0.70 to 1.35) did not differ between groups. Rate of definite stent thrombosis was lower in the EES group (0.2% vs. 0.9%, (HR: 0.23, 95% CI: 0.07 to 0.80).
Conclusions At 2-year follow-up, the EES was found to be noninferior to the SES with regard to both patient-related and stent-related clinical outcomes. (The SORT OUT IV TRIAL [SORT OUT IV]; NCT00552877)
In percutaneous coronary interventions (PCI), drug-eluting stent (DES) implantation has reduced the need for repeat revascularization compared with bare-metal stents (1). Although DES are widely accepted as effective and safe, debate continues on the safety of first-generation DES, given the potential for late stent thrombosis, especially after discontinuation of dual antiplatelet therapy (2). The first commercially available second-generation DES, the zotarolimus-eluting Endeavor stent (Medtronic, Minneapolis, Minnesota), did not appear superior to the sirolimus-eluting stent (SES) in routine practice (3), whereas the next second-generation DES, the everolimus-eluting stent (EES) (4–6), zotarolimus-eluting Resolute (7) stent (Medtronic), and the biolimus-eluting (8) stent, have showed reduced target vessel failure and a lower rate of stent thrombosis within the first year. The SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) trial aimed to compare the safety and efficacy outcomes at 2 years with specific focus on patient-related composite and stent-related composite outcomes of the first-generation SES Cypher Select+ (Cordis, Bridgewater, New Jersey) and the second-generation EES Xience V/Promus stent (Abbott Vascular, Santa Clara, California; Abbott’s privately-labeled XIENCE V Everolimus Eluting Coronary Stent System distributed by Boston Scientific Corporation) in a population-based setting, using registry detection of clinically driven events.
Patients and study design
SORT OUT IV is a randomized, multicenter, single-blind, all-comer, 2-arm, noninferiority trial comparing the EES with the SES in treating atherosclerotic coronary artery lesions. The study period was August 2007 to June 2009. The detailed study protocol can be found in the main publication (9).
Definition of endpoints are provided elsewhere (9). The primary endpoint was a combination of safety (cardiac death, myocardial infarction [MI], definite stent thrombosis) and efficacy (clinically indicated target vessel revascularization) parameters within 9 months of stent implantation. In the present study, we further focused on patient-related composite (all death, all MI, or any revascularization) and stent-related composite outcomes (cardiac death, target vessel MI, or symptom-driven target lesion revascularization). Individual components of the primary endpoint comprised the secondary endpoints, and stent thrombosis was classified according to the Academic Research Consortium definition (10).
Clinical event detection
Clinically driven event detection was used. Data on mortality, hospital admission, coronary angiography, repeat PCI, and coronary bypass surgery were obtained for all randomly allocated patients from the national Danish administrative and healthcare registries (11,12). An independent event committee, whose members were blinded to treatment group assignment, adjudicated all endpoints.
Distributions of continuous variables were compared between study groups using the 2-sample t test or the Mann-Whitney U test. Distributions of categorical variables were compared using the chi-square test. In analyses of every endpoint, follow-up continued until the date of an endpoint event, death, emigration, or 24 months after stent implantation, whichever came first. Survival curves were constructed based on time to events, accounting for the competing risk of death (13). Hazard ratios (HR) were computed using Cox proportional hazards regression analysis. We performed 2-sided 95% confidence intervals (CI) and 2-sided p values for superiority for all endpoints. A 2-sided p value of <0.05 was considered to indicate statistical significance. Analyses were conducted using SAS software (version 9.2, SAS Institute, Cary, North Carolina).
A total of 2,774 patients with 3,584 lesions were randomly assigned to receive either the EES (1,390 patients with 1,805 lesions) or the SES (1,384 patients with 1,779 lesions). Three patients were lost to follow-up. The trial's flow diagram is provided in Figure 1. Baseline and lesion characteristics are summarized in Tables 1 and 2.⇓⇓
At 2 years, the composite primary endpoint occurred in 114 patients (8.3%) in the EES group and in 120 patients (8.7%) in the SES group (HR: 0.94, 95% CI: 0.73 to 1.22) (Fig. 2, Table 3). The patient-related outcome: 202 (15.0%) patients treated with the EES versus 211 (15.6%) patients treated with the SES (HR: 0.95, 95% CI: 0.78 to 1.15), and the stent-related outcome: 70 (5.2%) patients treated with the EES versus 72 (5.3%) patients treated with the SES (HR: 0.97, 95% CI: 0.70 to 1.35) did not differ between groups (Fig. 2, Table 3).
At 2 years, the rate of definite stent thrombosis was lower in the EES group (3 [0.2%] patients versus 13 [0.9%] patients, [HR: 0.23, 95% CI: 0.07 to 0.80]) (Fig. 3, Table 3). Very late definite stent thrombosis was seen in 1 patient in the EES group and in 4 patients in the SES group (HR: 0.25, 95% CI: 0.03 to 2.22). Among patients with definite or probable stent thrombosis within the first year, 22 of 22 patients (100%) were in dual antiplatelet therapy with aspirin and clopidogrel (Table 4). Patients with very late definite stent thrombosis were all on monotherapy with aspirin, and 3 of 5 patients had stopped clopidogrel within 2, 3, and 5 weeks, respectively, before the event with very late definite stent thrombosis. Of the patients with acute definite stent thrombosis, all 3 patients were treated for stable angina pectoris with a SES. These patients were all treated with aspirin for at least a week before the PCI procedure, and clopidogrel was initiated on the day of the PCI procedure (before the intervention).
Clinically driven target lesion revascularization was performed in 40 patients (2.9%) in the EES group and in 49 patients (3.5%) in the SES group (HR: 0.81, 95% CI: 0.53 to 1.23) (Table 3, Fig. 3). In patients treated with EES, 5 patients with in-stent restenosis presented with non–ST-segment elevation MI, whereas the clinical presentation in SES-treated patients with clinically symptoms of in-stent restenosis was stable angina pectoris.
Our trial provides the first long-term head-to-head randomized comparison of the EES versus the SES. At 9 months follow-up, we documented noninferiority of the EES overall; and across a variety of patient and lesion subgroups, the 2 treatments yielded similar composite endpoint results. This result was maintained at 2 years for the primary endpoint. We further focused on patient-related and stent-related composite outcomes, where the 2 stents also showed similar clinical outcomes except for the rate of definite stent thrombosis, which was lower in the EES group.
The second-generation EES has previously been compared with the first-generation paclitaxel-eluting stents in the COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trial (6) and the SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) trial (4), where both studies showed a lower target vessel failure rate in the EES group after 2 years compared with the paclitaxel-eluting stent group. The target vessel failure rates for the EES group of 6.9% in the COMPARE trial (6) and 9.0% in the SPIRIT IV trial (4) were comparable to our results after 2 years. The rate of very late definite stent thrombosis was comparable between the 3 studies in the EES groups, with 3 cases (0.3%) in the COMPARE trial (6), 2 (0.1%) in the SPIRIT IV trial (4), and 1 (0.1%) in our study. A similar result was observed in the RESOLUTE (RESOLUTE-III All-Comers Trial: A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) trial (7), in which the EES was associated with significantly less definite stent thrombosis than the zotarolimus-eluting stent (Resolute) and the rate of very late definite stent thrombosis was 3 (0.3%). In contrast to the other 2 all-comer trials (6,7), we did not find any probable stent thrombosis after the first year. The Danish National Health Service provides universal tax-supported health care, guaranteeing residents free access to hospitals along with emergency medical service transportation, and 1 explanation for the lack of probable stent thrombosis could be that patients who had documented acute ischemia in a territory of a previously implanted stent would be scheduled for a re-angiogram, either acute or subacute, depending on the changes in the electrocardiogram.
In the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial (8), an increasing divergence in outcomes was showed over 4 years in favor of the biolimus-eluting stent. The rate of very late definite stent thrombosis was 0.1% in the biolimus-eluting stent group compared with 0.6% per year from 1 to 4 years in the SES group. In the ISAR-TEST-4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents With Different Polymer Coatings) trial (14), which compared the EES with the SES, clinical events continued to accrue at a low rate out to 3 years in both groups. There was no significant difference between the EES and SES groups with regard to the primary endpoint, and the rate of definite/probable stent thrombosis did not differ significantly between the 2 groups (1.4% vs. 1.9%%). The EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) angiographic trial (15) found EES to be noninferior to SES in inhibition of late lumen loss after stenting, which was corroborated by similar rates of clinical outcomes. Rate of stent thrombosis was numerically lower for EES than for SES within 9 months, though this was not statistically significant.
Finally, as composite endpoints in cardiovascular trials often include a wide range of events, comparison of composite endpoints can be difficult because of the lack of consensus definitions. We retrospectively combined the patient-related and stent-related endpoints to compare our endpoint to that of the all-comer RESOLUTE trial (7). As in the RESOLUTE trial, we found a substantially high numerical difference between patient-related and stent-related outcomes: stent-related outcomes constituted only one-third of patient-related outcomes for both stent types in our study. Despite using the same composite endpoint definition, the rates may still differ between studies as in the RESOLUTE trial and our study. Two-thirds of the patient-related outcomes were not stent related and may be related to disease progression and noncardiac events (noncardiac death). A long-term follow-up from the BASKET (Basel Stent Kosten-Effektivitäts Trial) (16) has recently shown a 25% event rate after 5 years with new ischemic perfusion defects detected in 23.3% of the patients, although being silent in the majority of the patients.
The EES was found to be noninferior to the SES for patients treated with PCI, accompanied by a lower rate of definite stent thrombosis.
Equal unrestricted grants were received from Abbott Vascular, Boston Scientific, and Cordis, Johnson & Johnson. These companies did not have a role in study design, data collection, data analysis, or interpretation of results. They also did not have access to the clinical trial database or an opportunity to review the manuscript. Dr. Jensen has received honoraria from Abbott Vascular and Cordis (Clinical Events Committee member). Drs. Thayssen, Kaltoft, Ravkilde, Thuesen, and Lassen have received unrestricted grants from Abbott Vascular and Cordis to their institutions. Drs. Thuesen and Lassen have received unrestricted grants from Boston Scientific to their institution. Dr. Christiansen has received honoraria and travel grants from Abbott Vascular and Cordis; and study grants from Cordis and Terumo. Dr. Tilsted has received travel grants from Abbott Vascular and Cordis to his institution. Dr. Kaltoft has received unrestricted grants from Abbott Vascular, Boston Scientific, and Cordis to her institution, and honoraria from Cordis. Dr. Maeng has received travel grants from Cordis, Abbott, Medtronic, and Boston Scientific. Dr. Ravkilde has received honoraria from Abbott Vascular; research grants from Medtronic, Cordis Johnson & Johnson, Terumo, Boston Scientific, and Biosensors; and is on the advisory board for Abbott. Dr. Thuesen has received honoraria from Abbott Vascular, Cordis, and Boston Scientific. Dr. Lassen has received speaking honoraria from Abbott Vascular, Cordis, Medtronic, Eli Lilly, Boston Scientific, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- drug eluting stent(s)
- everolimus-eluting stent(s)
- hazard ratio
- myocardial infarction
- percutaneous coronary intervention
- sirolimus-eluting stent(s)
- Received April 23, 2012.
- Revision received June 15, 2012.
- Accepted July 2, 2012.
- American College of Cardiology Foundation
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