Dual-therapy CD34 antibody-covered sirolimus-eluting COMBO stents versus sirolimus-eluting Orsiro stents in patients treated with percutaneous coronary intervention: the three-year outcomes of the SORT OUT X randomised clinical trial.

BACKGROUND: Target lesion failure (TLF) remains an issue with contemporary drug-eluting stents. The dual-therapy sirolimus-eluting and CD34 antibody-coated COMBO stent (DTS) was designed to improve early healing. AIMS: We aimed to compare the 3-year outcomes of the DTS and the sirolimus-eluting Orsiro stent (SES) in all-comer patients treated with percutaneous coronary intervention. METHODS: The SORT OUT X trial is a prospective multicentre randomised clinical trial with a registry-based follow-up comparing DTS and SES. The primary endpoint, TLF, is a composite of cardiac death, myocardial infarction or target lesion revascularisation (TLR). RESULTS: A total of 3,146 patients were randomised to treatment with the DTS (1,578 patients) or the SES (1,568 patients). At 3 years, an intention-to-treat analysis showed that 155 patients (9.8%) who were assigned the DTS and 118 patients (7.5%) who were assigned the SES met the primary endpoint (incidence rate ratio for TLF=1.33, 95% confidence interval: 1.04-1.70; p=0.02). This difference was caused by a significantly higher TLF rate in the DTS group compared to the SES group within the first year, which was mainly explained by a higher incidence of TLR in the DTS group compared to the SES group. Of note, the TLF rates were almost identical from 1 year to 3 years in both stent groups. CONCLUSIONS: At 3 years, the SES was superior to the DTS, mainly because the DTS was associated with an increased risk of TLF within the first year but not from 1 to 3 years. CLINICALTRIALS: gov: NCT03216733.

Randomized Clinical Comparison of the Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Combo Stent With the Sirolimus-Eluting Orsiro Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT X Trial.

BACKGROUND: Target lesion failure remains an issue with contemporary drug-eluting stents. Thus, the dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo stent (DTS) was designed to further improve early healing. This study aimed to investigate whether the DTS is noninferior to the sirolimus-eluting Orsiro stent (SES) in an all-comers patient population. METHODS: The SORT OUT X (Combo Stent Versus Orsiro Stent) trial, was a large-scale, randomized, multicenter, single-blind, 2-arm, noninferiority trial with registry-based follow-up. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, analyzed using intention-to-treat. The trial was powered for assessing target lesion failure noninferiority of the DTS compared with the SES with a predetermined noninferiority margin of 0.021. RESULTS: A total of 3146 patients were randomized to treatment with the DTS (1578 patients; 2008 lesions) or SES (1568 patients; 1982 lesions). At 12 months, intention-to-treat analysis showed that 100 patients (6.3%) assigned the DTS and 58 patients (3.7%) assigned the SES met the primary end point (absolute risk difference, 2.6% [upper limit of 1-sided 95% CI, 4.1%]; P (noninferiority)=0.76). The SES was superior to the DTS (incidence rate ratios for target lesion failure, 1.74 [95% CI, 1.26-2.41]; P=0.00086). The difference was explained mainly by a higher incidence of target lesion revascularization in the DTS group compared with the SES group (53 [3.4%] vs. 24 [1.5%]; incidence rate ratio, 2.22 [95% CI, 1.37-3.61]; P=0.0012). CONCLUSIONS: The DTS did not confirm noninferiority to the SES for target lesion failure at 12 months in an all-comer population. The SES was superior to the DTS mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the 2 stent groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03216733.

Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial.

BACKGROUND: In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared with a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is noninferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention. METHODS: The SORT OUT IX trial (Scandinavian Organization for Randomized Trials With Clinical Outcome IX), was a large-scale, registry-based, randomized, multicenter, single-blind, 2-arm, noninferiority trial. The primary end point, major adverse cardiovascular events, was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess noninferiority for major adverse cardiovascular events of the BioFreedom stent compared with the Orsiro stent with a predetermined noninferiority margin of 0.021. RESULTS: Between December 14, 2015 and April 21, 2017, 3151 patients were assigned to treatment with the BioFreedom stent (1572 patients, 1966 lesions) or to the Orsiro stent (1579 patients, 1985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of patients, and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary end point (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; Pnoninferiority=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI, 1.66-4.62]; P<0.0001). CONCLUSIONS: The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for major adverse cardiovascular events at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02623140.

Everolimus-Eluting Versus Biolimus-Eluting Coronary Stent Implantation in Patients With and Without Diabetes Mellitus.

Diabetes mellitus is associated with a higher risk of target lesion revascularization after percutaneous coronary intervention. We compared clinical outcomes in patients with and without diabetes mellitus, treated with everolimus-eluting stents (EES; Synergy; Boston Scientific, Marlborough, Massachusetts) or biolimus-eluting stents (BES; BioMatrix NeoFlex; Biosensors Interventional Technologies Pte Ltd., Singapore). In total, 2,764 patients were randomized to stent implantation with EES (n = 1,385, diabetes: n = 250) or the BES (n = 1,379, diabetes: n = 262), stratified by gender and diabetes. The primary end point, target lesion failure (TLF), was a composite of cardiac death, target-lesion myocardial infarction, or target lesion revascularization at 12 months. Secondary end points included individual components of TLF, all-cause death, and stent thrombosis. TLF was 2.1% lower in the EES versus the BES groups in patients with diabetes (3.6% vs 5.7%; rate ratios 0.61, 95% confidence interval [CI] 0.27 to 1.41) and similar in patients without diabetes (4.1% vs 4.0%; rate ratios 0.99, 95% CI 0.66 to 1.51). In patients with diabetes, the point estimates of the individual components of TLF also favored the EES but CIs were wide. No interaction between stent type and presence of diabetes was found. The current subgroup analysis found that a thin-strut EES as compared with a thicker strut BES had a numerically lower TLF rate in patients with diabetes, but the subgroup analysis was underpowered for definite conclusions.

Everolimus-Eluting Versus Biolimus-Eluting Stents With Biodegradable Polymers in Unselected Patients Undergoing Percutaneous Coronary Intervention: A Randomized Noninferiority Trial With 1-Year Follow-Up (SORT OUT VIII Trial).

OBJECTIVES: The aim of this study was to compare the thin-strut biodegradable-polymer everolimus-eluting platinum-chromium stent (EES) with the biodegradable-polymer biolimus-eluting stainless-steel stent (BES). BACKGROUND: Currently available drug-eluting coronary stents have been refined to reduce the risk for coronary events following implantation. METHODS: This randomized, multicenter, all-comers, noninferiority trial was undertaken at 3 sites in western Denmark. Patients with clinical indications for percutaneous coronary intervention were eligible for inclusion. Patients were randomly assigned (1:1) to either EES or BES. The primary endpoint, target lesion failure, was a composite of safety (cardiac death and myocardial infarction not clearly attributable to a nontarget lesion) and efficacy (target lesion revascularization) at 12 months, analyzed using intention-to-treat principles. The trial was powered to assess target lesion failure noninferiority of the EES compared with the BES with a predetermined noninferiority margin of 3%. RESULTS: A total of 1,385 patients were assigned to treatment with EES and 1,369 patients to treatment with BES. The analysis showed that 55 patients (4.0%) assigned to the EES and 60 (4.4%) assigned to the BES met the primary endpoint (absolute risk difference 0.4%; upper limit of 1-sided 95% confidence interval: 1.7%; p < 0.001). CONCLUSIONS: At 1-year follow-up, the EES was found to be noninferior to the BES with respect to target lesion failure. (Everolimus-eluting SYNERGY Stent Versus Biolimus-Eluting Biomatrix NeoFlex Stent-SORT-OUT VIII; NCT02093845).

Impact of diabetes on clinical outcomes after revascularization with sirolimus-eluting and biolimus-eluting stents with biodegradable polymer from the SORT OUT VII trial.

OBJECTIVES: In this substudy of the SORT OUT VII trial, the clinical outcomes among patient with diabetes mellitus treated with Orsiro sirolimus-eluting stent (O-SES; Biotronik, Bülach, Switzerland) or Nobori biolimus-eluting stent (N-BES; Terumo, Tokyo, Japan) were compared. BACKGROUND: Diabetes is associated with increased risk of target lesion failure (TLF) after percutaneous coronary intervention. METHODS: In total, 2525 patients were randomized to stent implantation with O-SES (n = 1261, diabetes: n = 236) or N-BES (n = 1264, diabetes: n = 235). The primary endpoint, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 2 years. RESULTS: At 2 year, TLF did not differ between O-SES vs N-BES in diabetic (9.3% vs 9.4%; RR 0.98, 95% CI 0.54-1.78) patients. The individual components of the primary endpoint did not differ among stent type. In diabetics, cardiac death occurred in 3% of O-SES-treated and in 3.8% of N-BES-treated patients (RR 0.77, 95% CI 0.29-2.08), MI occurred in 3.0% of O-SES-treated and in 3.8% of N-BES-treated patients (RR 0.76, 95% CI 0.28-2.06) and TLR occurred in 5,5% of O-SES-treated and in 6.0% of N-BES-treated patients (RR 0.91, 95% CI 0.43-1.95). CONCLUSION: TLF did not differ between O-SES- and N-BES-treated diabetic patients.

Chronic total coronary occlusion: treatment results.

OBJECTIVES: To describe the clinical and procedural coronary chronic total occlusion (CTO) treatment results in a Nordic PCI centre during the implementation of a CTO treatment program. DESIGN: In a retrospective registry study, we assessed; (1) indication for the procedure, (2) Canadian Cardiovascular Society angina pectoris score (CCS)/New York Heart Association (NYHA) heart failure score, (3) lesion complexity and (4) adverse events during hospital stay and three months following the index procedure. RESULTS: The study cohort included 503 patients (594 lesions). From 2010 to 2013 96% of procedures were performed with antegrade wire-escalation technique and 4% performed using retrograde techniques, from 2013-2016 the corresponding numbers were 83% and 17.0%. The procedural success rate was 69%, increasing from 64% before to 72% (p = .06) after routinely using the retrograde approach. No individual patient characteristic, lesion variable or score was strongly associated with procedural success or failure. There were 4% serious procedure related complications. In patients with PCI of a CTO lesion only, 87% were in CCS or NYHA functional class ≥2 before the index procedure vs. 22% at follow-up. CONCLUSIONS: Routine use of retrograde techniques tended to increase the procedural success rate. Clinical results after three months were acceptable, but the complication rate was higher than for non-CTO PCI. Individual patient and lesion characteristics had a low predictability for procedural success. Therefore, clinical symptoms, objective signs of myocardial ischemia and procedural risk should be focus points in coronary chronic total occlusion treatment strategies.

Fractional Flow Reserve-Guided Complete Revascularization Improves the Prognosis in Patients With ST-Segment-Elevation Myocardial Infarction and Severe Nonculprit Disease: A DANAMI 3-PRIMULTI Substudy (Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization).

BACKGROUND: The impact of disease severity on the outcome after complete revascularization in patients with ST-segment-elevation myocardial infarction and multivessel disease is uncertain. The objective of this post hoc study was to evaluate the impact of number of diseased vessel, lesion location, and severity of the noninfarct-related stenosis on the effect of fractional flow reserve-guided complete revascularization. METHODS AND RESULTS: In the DANAMI-3-PRIMULTI study (Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization), we randomized 627 ST-segment-elevation myocardial infarction patients to fractional flow reserve-guided complete revascularization or infarct-related percutaneous coronary intervention only. In patients with 3-vessel disease, fractional flow reserve-guided complete revascularization reduced the primary end point (all-cause mortality, reinfarction, and ischemia-driven revascularization; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.17-0.64; P=0.001), with no significant effect in patients with 2-vessel disease (HR, 0.77; 95% CI, 0.47-1.26; P=0.29; P for interaction =0.046). A similar effect was observed in patients with diameter stenosis ≥90% of noninfarct-related arteries (HR, 0.32; 95% CI, 0.18-0.62; P=0.001), but not in patients with less severe lesions (HR, 0.72; 95% CI, 0.44-1.19; P=0.21; P for interaction =0.06). The effect was most pronounced in patients with 3-vessel disease and noninfarct-related stenoses ≥90%, and in this subgroup, there was a nonsignificant reduction in the end point of mortality and reinfarction (HR, 0.32; 95% CI, 0.08-1.32; P=0.09). Proximal versus distal location did not influence the benefit from complete revascularization. CONCLUSIONS: The benefit from fractional flow reserve-guided complete revascularization in ST-segment-elevation myocardial infarction patients with multivessel disease was dependent on the presence of 3-vessel disease and noninfarct diameter stenosis ≥90% and was particularly pronounced in patients with both of these angiographic characteristics. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01960933.

Effect of Ischemic Postconditioning During Primary Percutaneous Coronary Intervention for Patients With ST-Segment Elevation Myocardial Infarction: A Randomized Clinical Trial.

Importance: Ischemic postconditioning of the heart during primary percutaneous coronary intervention (PCI) induced by repetitive interruptions of blood flow to the ischemic myocardial region immediately after reopening of the infarct-related artery may limit myocardial damage. Objective: To determine whether ischemic postconditioning can improve the clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Design, Setting, And Participants: In this multicenter, randomized clinical trial, patients with onset of symptoms within 12 hours, STEMI, and thrombolysis in myocardial infarction (TIMI) grade 0-1 flow in the infarct-related artery at arrival were randomized to conventional PCI or postconditioning. Inclusion began on March 21, 2011, through February 2, 2014, and follow-up was completed on February 2, 2016. Analysis was based on intention to treat. Interventions: Patients were randomly allocated 1:1 to conventional primary PCI, including stent implantation, or postconditioning performed as 4 repeated 30-second balloon occlusions followed by 30 seconds of reperfusion immediately after opening of the infarct-related artery and before stent implantation. Main Outcome and Measures: A combination of all-cause death and hospitalization for heart failure. Results: During the inclusion period, 1234 patients (975 men [79.0%] and 259 women [21.0%]; mean [SD] age, 62 [11] years) underwent randomization in the trial. Median follow-up was 38 months (interquartile range, 24-58 months). The primary outcome occurred in 69 patients (11.2%) who underwent conventional primary PCI and in 65 (10.5%) who underwent postconditioning (hazard ratio, 0.93; 95% CI, 0.66-1.30; P = .66). The hazard ratios were 0.75 (95% CI, 0.49-1.14; P = .18) for all-cause death and 0.99 (95% CI, 0.60-1.64; P = .96) for heart failure. Conclusions and Relevance: Routine ischemic postconditioning during primary PCI failed to reduce the composite outcome of death from any cause and hospitalization for heart failure in patients with STEMI and TIMI grade 0-1 flow at arrival. Trial Registration: clinicaltrials.gov Identifier: NCT01435408.

Comparison of Durable-Polymer Zotarolimus-Eluting and Biodegradable-Polymer Biolimus-Eluting Coronary Stents in Patients With Coronary Artery Disease: 3-Year Clinical Outcomes in the Randomized SORT OUT VI Trial.

OBJECTIVES: The authors sought to compare the safety and efficacy of the biocompatible durable-polymer zotarolimus-eluting stent with the biodegradable-polymer biolimus-eluting stent in unselected coronary patients. BACKGROUND: Biodegradable-polymer biolimus-eluting stents are superior to first-generation durable-polymer drug-eluting stents in long-term randomized all-comer trials. Long-term data comparing them to second-generation durable-polymer drug-eluting stents are lacking. METHODS: The study was a randomized, multicenter, all-comer, noninferiority trial in patients with chronic stable coronary artery disease or acute coronary syndromes and at least 1 coronary artery lesion requiring treatment with a drug-eluting stent. Endpoints included major adverse cardiac events (MACE), a composite of safety (cardiac death and myocardial infarction not clearly attributable to a non-target lesion) and efficacy (target lesion revascularization); the individual endpoints of MACE; all-cause mortality; any myocardial infarction; target vessel revascularization; and definite or probable stent thrombosis at 36 months. RESULTS: From March 2011 to August 2012, 2,999 patients were randomly assigned (1:1) to receive either the zotarolimus-eluting (1,502 patients) or the biolimus-eluting (1,497 patients) stent. At 3-year follow-up, MACE occurred in 128 (8.6%) patients assigned to the durable-polymer zotarolimus-eluting stent and in 144 (9.6%) assigned to the biodegradable-polymer biolimus-eluting stent (p = 0.36). Occurrence of cardiac death (2.7% vs. 3.4%), myocardial infarction not clearly attributable to a non-target lesion (2.7% vs. 2.5%), and target lesion revascularization (5.4% vs. 5.5%) did not differ significantly between the 2 groups. Definite very late stent thrombosis occurred in 6 (0.4%) patients assigned to the durable-polymer zotarolimus-eluting stent and in 10 (0.7%) assigned to the biodegradable-polymer biolimus-eluting stent (p = 0.33). CONCLUSIONS: At 3-year follow-up, the durable-polymer zotarolimus-eluting stent and the biodegradable-polymer biolimus-eluting stent were similar in clinical outcome, with no significant difference in safety and efficacy outcomes, including stent thrombosis.

Randomized Comparison of a Biodegradable Polymer Ultrathin Strut Sirolimus-Eluting Stent With a Biodegradable Polymer Biolimus-Eluting Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT VII Trial.

BACKGROUND: Coronary drug-eluting stents with biodegradable polymers have been designed to improve safety and efficacy. METHODS AND RESULTS: The Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) VII trial-a large-scale registry-based randomized, multicenter, single-blind, 2-arm, noninferiority trial-compared 2 biodegradable polymer drug-eluting stents: the thin-strut cobalt-chromium sirolimus-eluting Orsiro stent and the stainless steel biolimus-eluting Nobori stent in an all-comer patient population. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction (not related to other than index lesion), or target lesion revascularization within 1 year, analyzed by intention to treat (noninferiority margin of 3.0%). Clinically driven event detection based on Danish registries was used. A total of 1261 patients were assigned to receive the sirolimus-eluting stent (1590 lesions) and 1264 patients to the biolimus-eluting stent (1588 lesions). At 1 year, the composite end point target lesion failure occurred in 48 patients (3.8%) in the sirolimus-eluting group and in 58 patients (4.6%) in the biolimus-eluting group (absolute risk difference, -0.78% [upper limit of 1-sided 95% confidence interval, 0.61%]; P<0.0001). Rates of definite stent thrombosis occurred in 5 (0.4%) of the sirolimus-eluting group compared with 15 (1.2%) biolimus-eluting stent-treated patients (rate ratio, 0.33; 95% confidence interval, 0.12-0.92; P=0.034), which largely was attributable to a lower risk of subacute definite stent thrombosis: 0.1% versus 0.6% (rate ratio, 0.12; 95% confidence interval, 0.02-1.00; P=0.05). CONCLUSIONS: The thin-strut sirolimus-eluting Orsiro stent was noninferior to the biolimus-eluting Nobori stent in unselected patients for target lesion failure at 1 year. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01879358.

Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial.

BACKGROUND: Despite successful treatment of the culprit artery lesion by primary percutaneous coronary intervention (PCI) with stent implantation, thrombotic embolisation occurs in some cases, which impairs the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the clinical outcomes of deferred stent implantation versus standard PCI in patients with STEMI. METHODS: We did this open-label, randomised controlled trial at four primary PCI centres in Denmark. Eligible patients (aged >18 years) had acute onset symptoms lasting 12 h or less, and ST-segment elevation of 0·1 mV or more in at least two or more contiguous electrocardiographic leads or newly developed left bundle branch block. Patients were randomly assigned (1:1), via an electronic web-based system with permuted block sizes of two to six, to receive either standard primary PCI with immediate stent implantation or deferred stent implantation 48 h after the index procedure if a stabilised flow could be obtained in the infarct-related artery. The primary endpoint was a composite of all-cause mortality, hospital admission for heart failure, recurrent infarction, and any unplanned revascularisation of the target vessel within 2 years' follow-up. Patients, investigators, and treating clinicians were not masked to treatment allocation. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01435408. FINDINGS: Between March 1, 2011, and Feb 28, 2014, we randomly assigned 1215 patients to receive either standard PCI (n=612) or deferred stent implantation (n=603). Median follow-up time was 42 months (IQR 33-49). Events comprising the primary endpoint occurred in 109 (18%) patients who had standard PCI and in 105 (17%) patients who had deferred stent implantation (hazard ratio 0·99, 95% CI 0·76-1·29; p=0·92). Procedure-related myocardial infarction, bleeding requiring transfusion or surgery, contrast-induced nephopathy, or stroke occurred in 28 (5%) patients in the conventional PCI group versus 27 (4%) patients in the deferred stent implantation group, with no significant differences between groups. INTERPRETATION: In patients with STEMI, routine deferred stent implantation did not reduce the occurrence of death, heart failure, myocardial infarction, or repeat revascularisation compared with conventional PCI. Results from ongoing randomised trials might shed further light on the concept of deferred stenting in this patient population. FUNDING: Danish Agency for Science, Technology and Innovation, and Danish Council for Strategic Research.

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3­PRIMULTI): an open-label, randomised controlled trial.

BACKGROUND: Patients with acute ST-segment elevation myocardial infarction (STEMI) and multivessel coronary disease have a worse prognosis compared with individuals with single-vessel disease. We aimed to study the clinical outcome of patients with STEMI treated with fractional flow reserve (FFR)-guided complete revascularisation versus treatment of the infarct-related artery only. METHODS: We undertook an open-label, randomised controlled trial at two university hospitals in Denmark. Patients presenting with STEMI who had one or more clinically significant coronary stenosis in addition to the lesion in the infarct-related artery were included. After successful percutaneous coronary intervention (PCI) of the infarct-related artery, patients were randomly allocated (in a 1:1 ratio) either no further invasive treatment or complete FFR-guided revascularisation before discharge. Randomisation was done electronically via a web-based system in permuted blocks of varying size by the clinician who did the primary PCI. All patients received best medical treatment. The primary endpoint was a composite of all-cause mortality, non-fatal reinfarction, and ischaemia-driven revascularization of lesions in non-infarct-related arteries and was assessed when the last enrolled patient had been followed up for 1 year. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01960933. FINDINGS: From March, 2011, to February, 2014, we enrolled 627 patients to the trial; 313 were allocated no further invasive treatment after primary PCI of the infarct-related artery only and 314 were assigned complete revascularization guided by FFR values. Median follow-up was 27 months (range 12­44 months). Events comprising the primary endpoint were recorded in 68 (22%) patients who had PCI of the infarct-related artery only and in 40 (13%) patients who had complete revascularisation (hazard ratio 0∙56, 95% CI 0∙38­0∙83; p=0∙004). INTERPRETATION: In patients with STEMI and multivessel disease, complete revascularisation guided by FFR measurements significantly reduces the risk of future events compared with no further invasive intervention after primary PCI. This effect is driven by significantly fewer repeat revascularisations, because all-cause mortality and non-fatal reinfarction did not differ between groups. Thus, to avoid repeat revascularisation, patients can safely have all their lesions treated during the index admission. Future studies should clarify whether complete revascularization should be done acutely during the index procedure or at later time and whether it has an effect on hard endpoints. FUNDING: Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.

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.

Differential clinical outcomes after 1 year versus 5 years in a randomised comparison of zotarolimus-eluting and sirolimus-eluting coronary stents (the SORT OUT III study): a multicentre, open-label, randomised superiority trial.

BACKGROUND: In head-to-head comparisons of coronary drug-eluting stents, the primary endpoint is traditionally assessed after 9-12 months. However, the optimum timepoint for this assessment remains unclear. In this study, we assessed clinical outcomes at up to 5 years' follow-up in patients who received two different types of drug-eluting stents. METHODS: We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (≥18 years of age) with an indication for drug-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone allocation service. The primary endpoint of the SORT OUT III study was a composite of major adverse cardiac events-cardiac death, myocardial infarction, and target vessel revascularisation-at 9 months' follow-up. In this study, endpoints included the occurrence of major adverse cardiac events and definite stent thrombosis at follow-up times of up to 5 years. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00660478. FINDINGS: We randomly allocated 1162 patients to receive the zotarolimus-eluting stent and 1170 to the sirolimus-eluting stent. At 5-year follow-up, rates of major adverse cardiac events were similar in patients treated with both types of stents (zotarolimus-eluting stents 197/1162 [17.0%] vs sirolimus-eluting stents 182/1170 [15.6%]; odds ratio [OR] 1.10, 95% CI 0.88-1.37; p=0.40). This finding was indicative of the directly contrasting results for rates of major adverse cardiac events at 1-year follow up (zotarolimus 93/1162 [8.0%] vs sirolimus 46/1170 [3.9%]; OR 2.13, 95% CI 1.48-3.07; p<0.0001) compared with those at follow-up between 1 and 5 years (104 [9.0%] vs 136 [11.6%]; OR 0.78, 95% CI 0.59-1.02; p=0.071). At 1-year follow-up, definite stent thrombosis was more frequent after implantation of the zotarolimus-eluting stent (13/1162 [1.1%]) than the sirolimus-eluting stent (4/1170 [0.3%]; OR 3.34, 95% CI 1.08-10.3; p=0.036), whereas the opposite finding was recorded for between 1 and 5 years' follow-up (zotarolimus-eluting stent 1/1162 [0.1%] vs sirolimus-eluting stent 21/1170 [1.8%], OR 0.05, 95% CI 0.01-0.36; p=0.003). 26 of 88 (30%) target lesion revascularisations in the zotarolimus-eluting stent group occurred between 1 and 5 years' follow-up, whereas 54 of 70 (77%) of those in the sirolimus-eluting stent group occurred during this follow-up period. INTERPRETATION: The superiority of sirolimus-eluting stents compared with zotarolimus-eluting stents at 1-year follow-up was lost after 5 years. The traditional 1-year primary endpoint assessment therefore might be insufficient to predict 5-year clinical outcomes in patients treated with coronary drug-eluting stent implantation. 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).

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).

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 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.

Outcome of sirolimus-eluting versus zotarolimus-eluting coronary stent implantation in patients with and without diabetes mellitus (a SORT OUT III Substudy).

Diabetes is associated with an increased risk of major adverse cardiac events after percutaneous coronary intervention. We compared clinical outcomes in patients with and without diabetes mellitus treated with the second-generation Endeavor zotarolimus-eluting stent (ZES) or the first-generation Cypher Select+ sirolimus-eluting stent (SES). We randomized 2,332 patients to treatment with ZESs (n = 1,162, n = 169 diabetics) or SESs (n = 1,170, n = 168 diabetics) and followed them for 18 months. Randomization was stratified by presence/absence of diabetes. The primary end point was major adverse cardiac events defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Secondary end points included these individual end points plus all-cause mortality and target lesion revascularization. In diabetic patients, use of ZES compared to SES was associated with an increased risk of major adverse cardiac events (18.3% vs 4.8%, hazard ratio 4.05, 95% confidence interval 1.86 to 8.82), myocardial infarction (4.7% vs 0.6%, hazard ratio 8.09, 95% confidence interval 1.01 to 64.7), target vessel revascularization (14.2% vs 3.0%, hazard ratio 4.99, 95% confidence interval 1.90 to 13.1), and target lesion revascularization (12.4% vs 1.2%, hazard ratio 11.0, 95% confidence interval 2.59 to 47.1). In patients without diabetes differences in absolute risk decrease were smaller but similarly favored SES. In conclusion, implantation of ZESs compared to SESs is associated with a considerable increased risk of adverse events in patients with diabetes at 18-month follow-up.

Late lumen loss and intima hyperplasia after sirolimus-eluting and zotarolimus-eluting stent implantation in diabetic patients: the diabetes and drug-eluting stent (DiabeDES III) angiography and intravascular ultrasound trial.

AIMS: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to neointimal hyperplasia (NIH). The aim of this study was to use quantitative coronary angiography (QCA) and volumetric intravascular ultrasound (IVUS) to evaluate the effects of the sirolimus-eluting Cypher® stent (SES) and the zotarolimus-eluting Endeavor® stent (ZES) on angiographic late lumen loss and intima hyperplasia in diabetic patients. METHODS AND RESULTS: In the DiabeDES III trial, 127 patients were randomised to SES or ZES stent implantation. Angiographic 10-month follow-up data were available in 105 patients, including 48 SES and 57 ZES treated patients. Angiographic endpoints were in-stent late lumen loss and minimal lumen diameter. IVUS endpoints included NIH volume and in-stent percent volume obstruction. Baseline clinical characteristics and lesion parameters were similar in the two groups. At 10-month follow-up, angiographic in-stent late lumen loss (0.14±0.37 mm vs. 0.74±0.45 mm, p<0.001) was reduced and minimum lumen diameter was higher (2.36±0.53 mm vs. 1.96±0.65, p<0.001) in the SES group as compared to the ZES group. As compared to the ZES group, NIH volume was significantly reduced in the SES group (median [interquartile range]: 0.0 mm3 [0.0 to 1.2] vs. 16.5 mm3 [6.2 to 31.1], p<0.001). In-stent% volume obstruction was significantly reduced in SES as compared to ZES (median [interquartile range]: 0.0% [0.0-0.7] vs. 13.0% [6.7-20.8], p<0.001). CONCLUSIONS: In diabetic patients, the SES reduced angiographic late lumen loss and inhibited NIH more effectively than ZES.