Knud Nørregaard Hansen

Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial.

BACKGROUND In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery disease who were receiving routine clinical care with no direct follow-up. METHODS We did a single-blind, all-comer superiority trial in adult patients with chronic stable coronary artery disease or acute coronary syndromes, and at least one target lesion. Patients were treated at one of five percutaneous coronary intervention centres between January, 2006, and August, 2007. Computer-generated block randomisation and a telephone allocation service were used to randomly assign patients to receive the zotarolimus-eluting or the sirolimus-eluting stent. Data for follow-up were obtained from national Danish administrative and health-care registries. The primary endpoint was a composite of major adverse cardiac events within 9 months: cardiac death, myocardial infarction, and target vessel revascularisation. Intention-to-treat analyses were done at 9-month and 18-month follow-up. This trial is registered with ClinicalTrials.gov, number NCT00660478. FINDINGS 1162 patients (1619 lesions) were assigned to receive the zotarolimus-eluting stent, and 1170 patients (1611 lesions) to receive the sirolimus-eluting stent. 67 patients (72 lesions) had stent failure, and six patients were lost to follow-up. All randomly assigned patients were included in analyses at 9-month follow-up; 2200 patients (94%) had completed 18-month follow-up by the time of our assessment. At 9 months, the primary endpoint had occurred in a higher proportion of patients treated with the zotarolimus-eluting stent than in those treated with the sirolimus-eluting stent (72 [6%] vs 34 [3%]; HR 2.15, 95% CI 1.43-3.23; p=0.0002). At 18-month follow-up, this difference was sustained (113 [10%] vs 53 [5%]; 2.19, 1.58-3.04; p<0.0001). For patients receiving the zotarolimus-eluting stent and those receiving the sirolimus-eluting stent, all cause-mortality was similar at 9-month follow-up (25 [2%] vs 18 [2%]; 1.40, 0.76-2.56; p=0.28), but was significantly different at 18-month follow-up (51 [4%] vs 32 [3%]; 1.61, 1.03-2.50; p=0.035). INTERPRETATION The sirolimus-eluting stent is superior to the zotarolimus-eluting stent for patients receiving routine clinical care. FUNDING Cordis and Medtronic.

Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial

BACKGROUND Third-generation biodegradable polymer drug-eluting stents might reduce the risk of stent thrombosis compared with first-generation permanent polymer drug-eluting stents. We aimed to further investigate the effects of a biodegradable polymer biolimus-eluting stent compared with a durable polymer-coated sirolimus-eluting stent in a population-based setting. METHODS This randomised, multicentre, all-comer, non-inferiority trial was undertaken at three sites across western Denmark. Eligible patients were aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes, and at least one coronary artery lesion (>50% diameter stenosis). We randomly assigned patients (1:1) using an independently managed computer-generated allocation sequence to receive either a biolimus-eluting biodegradable polymer stent (Nobori, Terumo, Tokyo, Japan) or a sirolimus-eluting permanent polymer stent (Cypher Select Plus, Cordis, Johnson & Johnson, Warren, NJ, USA). The primary endpoint was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularisation) at 9 months, analysed by intention to treat (non-inferiority margin of 0·02). This trial is registered with ClinicalTrials.gov, number NCT01254981. FINDINGS From July, 2009, to January, 2011, we assigned 1229 patients (1532 lesions) to receive the biolimus-eluting stent and 1239 (1555 lesions) to receive the sirolimus-eluting stent. One patient was lost to follow-up because of emigration. Intention-to-treat analysis showed that 50 (4·1%) patients who were assigned the biolimus-eluting stent and 39 (3·1%) who were assigned the sirolimus-eluting stent met the primary endpoint (risk difference 0·9% [upper limit of one-sided 95% CI 2·1%]; p(non-inferiority)=0·06). Significantly more patients in the biolimus-eluting stent group had definite stent thrombosis at 12 months than did those in the sirolimus-eluting stent group (9 [0·7%] vs 2 [0·2%], risk difference 0·6% [95% CI 0·0-1·1]; p=0·034). Per-protocol analysis showed that 45 (3·8%) of 1193 patients who received a biolimus-eluting stent and 39 (3·2%) of 1208 who received a sirolimus-eluting stent met the primary endpoint (risk difference 0·5% [upper limit of one-sided 95% CI 1·8%]; p(non-inferiority)=0·03). INTERPRETATION At 1 year follow-up, the biodegradable polymer biolimus-eluting Nobori stent did not improve clinical results compared with a first-generation sirolimus-eluting stent. We will need to obtain long-term data before we can make recommendations for the role of this biolimus-eluting stent in routine clinical practice. FUNDING Terumo and Cordis (Johnson & Johnson).

Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated With Percutaneous Coronary Intervention The Scandinavian Organization for Randomized Trials With Clinical Outcome IV (SORT OUT IV)

Background —Among drug-eluting stents released to date, the sirolimus-eluting stent has demonstrated the least amount of late lumen loss, but its efficacy and safety have not been compared head-to-head with the next-generation everolimus-eluting stent. Methods and Results —The S candinavian O rganization for R andomized T rials with Clinical O utcome IV trial was a randomized multicenter, single-blind, all-comer, two-arm, non-inferiority trial comparing the everolimus-eluting stent with the sirolimus-eluting stent in patients with coronary artery disease. The primary end point was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The non-inferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9-month and 18-month follow-up. 1,390 patients were assigned to receive the everolimus-eluting stent, and 1,384 patients were assigned to receive the sirolimus-eluting stent. At 9-month follow-up, 68 \[4.9%] patients treated with the everolimus-eluting stent versus 72 [5.2%] patients treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio (HR) =0.94; 95% confidence interval (CI): 0.67-1.31) ( p for non-inferiority=0.01). At 18-month follow-up, this differential remained: 99 [7.2%] patients treated with the everolimus-eluting stent versus 105 [7.6%\] (HR=0.94, 95% CI: 0.71-1.23). At 9-month follow-up, rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 [0.1%] patients versus 9 [0.7%] patients, (HR=0.22, 95% CI:0.05-1.02)).At 18-monthfollow-up, this difference was sustained (3 [0.2%] patients versus 12 [0.9%] patients; (HR=0.25, 95% CI:0.07-0.88). Conclusions —The everolimus-eluting stent was found to be non-inferior to the sirolimus-eluting stent. Clinical Trial Registration Information —ClinicalTrials.gov; [NCT00552877][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00552877&atom=%2Fcirculationaha%2Fearly%2F2012%2F02%2F03%2FCIRCULATIONAHA.111.063644.atomBackground— Among drug-eluting stents released to date, the sirolimus-eluting stent has demonstrated the least amount of late lumen loss, but its efficacy and safety have not been compared head-to-head with the next-generation everolimus-eluting stent. Methods and Results— The Scandinavian Organization for Randomized Trials with Clinical Outcome IV (SORT OUT IV) trial was a randomized multicenter, single-blind, all-comer, 2-arm, noninferiority trial comparing the everolimus-eluting stent with the sirolimus-eluting stent in patients with coronary artery disease. The primary end point was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The noninferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9- and 18-month follow-ups. A total of 1390 patients were assigned to receive the everolimus-eluting stent and 1384 patients to the sirolimus-eluting stent. At the 9-month follow-up, 68 patients (4.9%) treated with the everolimus-eluting stent compared with 72 patients (5.2%) treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio, 0.94; 95% confidence interval, 0.67–1.31; P for noninferiority=0.01). At the 18-month follow-up, this differential remained: 99 patients (7.2%) treated with the everolimus-eluting stent versus 105 (7.6%) treated with the sirolimus-eluting stent (hazard ratio, 0.94; 95% confidence interval, 0.71–1.23). At the 9-month follow-up, the rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 patients [0.1%] versus 9 patients [0.7%]; hazard ratio, 0.22; 95% confidence interval, 0.05–1.02). At the 18-month follow-up, this difference was sustained (3 patients [0.2%] versus 12 patients [0.9%]; hazard ratio, 0.25; 95% confidence interval, 0.07–0.88). Conclusion— The everolimus-eluting stent was found to be noninferior to the sirolimus-eluting stent. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00552877.

2-Year Clinical Outcomes After Implantation of Sirolimus-Eluting, Paclitaxel-Eluting, and Bare-Metal Coronary Stents : Results From the WDHR (Western Denmark Heart Registry)

OBJECTIVES This registry study assessed the safety and efficacy of the 2 types of drug-eluting stents (DES), sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES), compared with bare-metal stents (BMS). BACKGROUND Drug-eluting stents may increase the risk of stent thrombosis (ST), myocardial infarction (MI), and death. METHODS A total of 12,395 consecutive patients with coronary intervention and stent implantation recorded in the Western Denmark Heart Registry from January 2002 through June 2005 were followed up for 2 years. Data on death and MI were ascertained from national medical databases. We used Cox regression analysis to control for confounding. RESULTS The 2-year incidence of definite ST was 0.64% in BMS patients, 0.79% in DES patients (adjusted relative risk [RR]: 1.09; 95% confidence interval [CI]: 0.72 to 1.65), 0.50% in SES patients (adjusted RR: 0.63, 95% CI: 0.35 to 1.15), and 1.30% in PES patients (adjusted RR: 1.82, 95% CI: 1.13 to 2.94). The incidence of MI was 3.8% in BMS-treated patients, 4.5% in DES-treated patients (adjusted RR: 1.24, 95% CI: 1.02 to 1.51), 4.1% in SES-treated patients (adjusted RR: 1.15, 95% CI: 0.91 to 1.47), and 5.3% in PES-treated patients (adjusted RR: 1.38, 95% CI: 1.06 to 1.81). Whereas overall 2-year adjusted mortality was similar in the BMS and the 2 DES stent groups, 12- to 24-month mortality was higher in patients treated with PES (RR 1.46, 95% CI: 1.02 to 2.09). Target lesion revascularization was reduced in both DES groups. CONCLUSIONS During 2 years of follow-up, patients treated with PES had an increased risk of ST and MI compared with those treated with BMS and SES. Mortality after 12 months was also increased in PES patients.

Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial

BACKGROUND New-generation drug-eluting coronary stents have reduced the risk of coronary events, especially in patients with complex disease or lesions. To what extent different stent platforms, polymers, and antiproliferative drugs affect outcomes, however, is unclear. We investigated the safety and efficacy of a third-generation stent by comparing a highly biocompatible durable-polymer-coated zotarolimus-eluting stent with a biodegradable-polymer-coated biolimus-eluting stent. METHODS This open-label, randomised, multicentre, non-inferiority trial was done at three sites across western Denmark. All patients who presented with stable coronary artery disease or acute coronary syndromes and at least one coronary artery lesion (more than 50% stenosis) from March, 2011, to August, 2012, were assessed for eligibility. Patients were randomly assigned in a 1:1 ratio to receive either the durable-polymer zotarolimus-eluting stent or the biodegradable-polymer biolimus-eluting stent. The primary endpoint was a composite of safety (cardiac death and myocardial infarction not clearly attributable to a non-target lesion) and efficacy (target-lesion revascularisation) at 12 months, analysed by intention to treat. The trial was powered to assess non-inferiority of durable-polymer zotarolimus-eluting stent compared with the biodegradable-polymer biolimus-eluting stent with a predetermined non-inferiority margin of 0·025. This trial is registered with ClinicalTrials.gov, number NCT01956448. FINDINGS Of 7103 screened, 1502 patients with 1883 lesions were assigned to receive the durable-polymer zotarolimus-eluting stent and 1497 patients with 1791 lesions to receive the biodegradable-polymer biolimus-eluting stent. 79 (5·3%) and 75 (5·0%) patients, respectively, met the primary endpoint (absolute risk difference 0·0025, upper limit of one-sided 95% CI 0·016%; p=0·004). The individual components of the primary endpoint did not differ significantly between stent types at 12 months. INTERPRETATION The durable-polymer-coated zotarolimus-eluting stent was non-inferior to the biodegradable-polymer-coated biolimus-eluting stent in unselected patients. FUNDING Medtronic Cardiovascular and Biosensors Interventional Technologies.

Comparison of the Sirolimus-Eluting Versus Paclitaxel-Eluting Coronary Stent in Patients With Diabetes Mellitus: The Diabetes and Drug-Eluting Stent (DiabeDES) Randomized Angiography Trial

The aim of the present study was to evaluate angiographic late luminal loss after the implantation of sirolimus-eluting Cypher stents and paclitaxel-eluting Taxus stents in patients with diabetes. The study was a Danish multicenter, open-label, randomized trial. One hundred fifty-three patients with diabetes with coronary artery disease were randomized to Cypher (n = 76) or Taxus (n = 77) stent implantation. All patients were followed for 8 months. The primary end point was 8-month angiographic in-stent late luminal loss. This primary end point was reduced in the Cypher group compared with the Taxus group (0.23 +/- 0.54 vs 0.44 +/- 0.52 mm, p = 0.025). Angiographic in-segment restenosis at 8-month follow-up, a secondary end point, was present in 16 patients (Cypher, n = 6; Taxus, n = 10; p = 0.24). Target lesion revascularization was performed in 5 patients (6.5%) and 9 patients (11.8%) in the Cypher and Taxus groups, respectively (p = 0.25). Definite stent thrombosis was observed in 2 patients (in the Taxus group), no patients had probable stent thrombosis, and 1 patient in each group had possible stent thrombosis. Major adverse cardiac events (cardiac death, myocardial infarction, definite stent thrombosis, or target lesion revascularization) were observed in 17 patients (Cypher, n = 6; Taxus, n = 11; p = 0.19). In conclusion, angiographic in-stent late luminal loss is significantly reduced in patients with diabetes by use of the sirolimus-eluting Cypher stent compared with the paclitaxel-eluting Taxus stent.

Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents: 5-Year Results From SORT OUT IV

BACKGROUND Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown. OBJECTIVES This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical Outcome) trial. METHODS Five-year follow-up was completed for 2,771 patients (99.9%). Primary endpoint was a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), and definite stent thrombosis. RESULTS At 5-years, MACE occurred in 14.0% and 17.4% in the EES and SES groups, respectively (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.66 to 0.97; p = 0.02). The MACE rate did not differ significantly within the first year (HR: 0.96, 95% CI: 0.71 to 1.19; p = 0.79), but from years 1 through 5, the MACE rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR: 0.16, 95% CI: 0.05 to 0.53). When censoring the patients at the time of stent thrombosis, we found no significant differences between the 2 stent groups for MACE rates (HR: 0.89, 95% CI: 0.73 to 1.08; p = 0.23), target lesion revascularization (HR: 0.90, 95% CI: 0.64 to 1.27; p = 0.55), and MI (HR: 0.93, 95% CI: 0.64 to 1.36; p = 0.72). CONCLUSIONS At 5-year follow-up, MACE rate was significantly lower with EES- than with SES-treated patients, due largely due to a lower risk of very late definite stent thrombosis. (Randomized Clinical Comparison of the Xience V and the Cypher Coronary Stents in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877).

2-year patient-related versus stent-related outcomes: the SORT OUT IV (Scandinavian Organization for Randomized Trials With Clinical Outcome IV) Trial.

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.

3-Year clinical outcomes in the randomized SORT OUT III superiority trial comparing zotarolimus- and sirolimus-eluting coronary stents.

OBJECTIVES This study sought to examine the 3-year clinical outcomes in patients treated with the Endeavor (Medtronic, Santa Rosa, California) zotarolimus-eluting stent (ZES) or the Cypher (Cordis, Johnson & Johnson, Warren, New Jersey) sirolimus-eluting stent (SES) in routine clinical practice. BACKGROUND The long-term clinical outcome in patients treated with ZES in comparison with SES is unclear. METHODS The authors randomized 2,332 patients to ZES (n = 1,162) or SES (n = 1,170) implantation. Endpoints included major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction, or target vessel revascularization; the individual endpoints of MACE; and definite stent thrombosis. RESULTS At 3-year follow-up, the MACE rate was higher in patients treated with ZES than in patients treated with SES (148 [12.9%] vs. 116 [10.1%]; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.04 to 1.69; p = 0.022). Target vessel revascularization was more frequent in the ZES group compared with the SES group (103 [9.1%] vs. 76 [6.7%]; HR: 1.40, 95% CI: 1.04 to 1.89; p = 0.025), whereas the occurrence of myocardial infarction (3.8% vs. 3.3%) and cardiac death (2.8% vs. 2.8%) did not differ significantly. Although the rate of definite stent thrombosis was similar at 3-year follow-up (1.1% vs. 1.4%), very late (12 to 36 months) definite stent thrombosis occurred in 0 (0%) patients in the ZES group versus 12 (1.1%) patients in the SES group (p = 0.0005). CONCLUSIONS Although the 3-year MACE rate is higher in patients treated with ZES versus SES, our data highlight a late safety problem concerning definite stent thrombosis with the use of SES. This finding underscores the importance of long-term follow-up in head-to-head comparisons of drug-eluting stents. (Randomized Clinical Comparison of the Endeavor and the Cypher Coronary Stents in Non-selected Angina Pectoris Patients [SORT OUT III]; NCT00660478).

Comparison of Outcomes in Patients With Versus Without Diabetes Mellitus After Revascularization With Everolimus- and Sirolimus-Eluting Stents (from the SORT OUT IV Trial)

Diabetes is associated with increased risk of major adverse cardiac events (MACEs) after percutaneous coronary intervention. The purpose of this substudy of the SORT OUT IV trial was to compare clinical outcomes in patients with and without diabetes mellitus treated with everolimus-eluting stents (EESs) or sirolimus-eluting stents (SESs). In total 2,774 patients (390 with diabetes, 14.1%) were randomized to stent implantation with EESs (n = 1,390, diabetes in 14.0%) or SESs (n = 1,384, diabetes in 14.2%). Randomization was stratified by presence/absence of diabetes. The primary end point was MACEs, a composite of cardiac death, myocardial infarction, definite stent thrombosis, or target vessel revascularization within 18 months. MACEs were higher in diabetic than in nondiabetic patients (13.1% vs 6.4%, hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.51 to 2.86). In diabetic patients, MACEs were seen in 10.3% of those treated with EESs and in 15.8% of those treated with SESs (HR 0.63, 95% CI 0.36 to 1.11). In nondiabetic patients, MACEs occurred in 6.6% of EES-treated and in 6.3% SES-treated patients (HR 1.06, 95% CI 0.77 to 1.46). In diabetics, cardiac death occurred in 3.1% of EES-treated and in 4.6% of SES-treated patients (HR 0.67, 95% CI 0.24 to 1.89), myocardial infarction occurred in 0.5% of EES-treated and in 3.6% of SES-treated patients (HR 0.14, 95% CI 0.02 to 1.16), and clinically driven target lesion revascularization was needed in 3.1% of EES-treated and in 7.7% of SES-treated patients (HR 0.40, 95% CI 0.15 to 1.02). No interaction between diabetes status and type of drug-eluting stent was found for the end points. In conclusion, patients with diabetes have higher MACE rates than nondiabetics. No significant differences in safety or efficacy outcomes after EES or SES implantation were present in nondiabetic or diabetic patients.