Impact of prediabetes and diabetes on 3-year outcome of patients treated with new-generation drug-eluting stents in two large-scale randomized clinical trials.

BACKGROUND: Diabetes is associated with adverse outcomes after percutaneous coronary intervention with drug-eluting stents (DES), but for prediabetes this association has not been definitely established. Furthermore, in patients with prediabetes treated with contemporary stents, bleeding data are lacking. We assessed 3-year ischemic and bleeding outcomes following treatment with new-generation DES in patients with prediabetes and diabetes as compared to normoglycemia. METHODS: For this post-hoc analysis, we pooled patient-level data of the BIO-RESORT and BIONYX stent trials which both stratified for diabetes at randomization. Both trials were multicenter studies performed in tertiary cardiac centers. Study participants were patients of whom glycemic state was known based on hemoglobin A1c, fasting plasma glucose, or medically treated diabetes. Three-year follow-up was available in 4212/4330 (97.3 %) patients. The main endpoint was target vessel failure, a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. RESULTS: Baseline cardiovascular risk profiles were progressively abnormal in patients with normoglycemia, prediabetes, and diabetes. The main endpoint occurred in 54/489 patients with prediabetes (11.2 %) and 197/1488 with diabetes (13.7 %), as compared to 142/2,353 with normoglycemia (6.1 %) (HR: 1.89, 95 %-CI 1.38-2.58, p < 0.001, and HR: 2.30, 95 %-CI 1.85-2.86, p < 0.001, respectively). In patients with prediabetes, cardiac death and target vessel revascularization rates were significantly higher (HR: 2.81, 95 %-CI 1.49-5.30, p = 0.001, and HR: 1.92, 95 %-CI 1.29-2.87, p = 0.001), and in patients with diabetes all individual components of the main endpoint were significantly higher than in patients with normoglycemia (all p ≤ 0.001). Results were consistent after adjustment for confounders. Major bleeding rates were significantly higher in patients with prediabetes and diabetes, as compared to normoglycemia (3.9 % and 4.1 % vs. 2.3 %; HR:1.73, 95 %-CI 1.03-2.92, p = 0.040, and HR:1.78, 95 %-CI 1.23-2.57, p = 0.002). However, after adjustment for confounders, differences were no longer significant. CONCLUSIONS: Not only patients with diabetes but also patients with prediabetes represent a high-risk population. After treatment with new-generation DES, both patient groups had higher risks of ischemic and bleeding events. Differences in major bleeding were mainly attributable to dissimilarities in baseline characteristics. Routine assessment of glycemic state may help to identify patients with prediabetes for intensified management of cardiovascular risk factors. TRIAL REGISTRATION: BIO-RESORT ClinicalTrials.gov: NCT01674803, registered 29-08-2012; BIONYX ClinicalTrials.gov: NCT02508714, registered 27-7-2015.

Acute myocardial infarction treated with novel Resolute Onyx and Orsiro stents in the randomized BIONYX trial.

OBJECTIVES: To compare 2-year outcome following treatment with drug-eluting stents (DES) for acute myocardial infarction (MI) versus non-MI clinical syndromes. In acute MI patients, a stent-level comparison was performed, comparing Resolute Onyx versus Orsiro stents. BACKGROUND: In patients presenting with acute MI, higher adverse event rates have been reported. So far, no clinical results >1 year have been published of acute MI patients treated with Resolute Onyx. METHODS: This post-hoc analysis of the randomized BIONYX trial(NCT02508714) assessed the main outcome target vessel failure (TVF: cardiac death, target vessel MI, or target vessel revascularization) with Kaplan-Meier methods. RESULTS: Of all 2,488 trial participants, acute MI patients (n = 1,275[51.2%]) were significantly younger and had less comorbidities than non-MI patients (n = 1,213[48.8%]). TVF rates were lower in acute MI patients (77/1,275[6.1%] vs. 103/1,213[8.6%], HR:0.70, 95%-CI 0.52-0.94; plog-rank  = 0.02), mainly driven by target vessel revascularization (4.1 vs. 6.1%, plog-rank  = 0.03). Multivariate analysis showed no independent association of clinical syndrome with TVF (adjusted-HR: 0.81, 95%-CI 0.60-1.10; p = .17). In MI patients treated with Resolute Onyx (n = 626) versus Orsiro (n = 649), there was no difference in TVF (6.2 vs. 6.1%; plog-rank  = 0.97) and its components. There was only 1(0.2%) definite-or-probable stent thrombosis in RO-ZES and 8(1.2%) in O-SES (p = .053). CONCLUSIONS: Two years after treatment with thin-strut DES in this randomized trial, patients treated for acute MI had lower adverse event rates than non-MI patients. Yet, these findings were mainly attributable to between-group differences in patient and lesion characteristics. In patients who underwent PCI for acute MI, both Resolute Onyx and Orsiro showed favorable and similar 2-year outcomes.

New-generation drug-eluting coronary stents in octogenarians: Patient-level pooled analysis from the TWENTE I-IV trials.

BACKGROUND: Patients aged ≥80 years are often treated with new-generation drug-eluting stents (DES), but data from randomized studies are scarce owing to underrepresentation in most trials. We assessed 1-year clinical outcome of octogenarians treated with new-generation DES versus younger patients. METHODS: We pooled patient-level data of 9,204 participants in the TWENTE, DUTCH PEERS, BIO-RESORT, and BIONYX (TWENTE I-IV) randomized trials. The main clinical end point was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction (MI), or clinically indicated target vessel revascularization. RESULTS: The 671 octogenarian trial participants had significantly more comorbidities. TVF was higher in octogenarians than in 8,533 patients <80 years (7.3% vs 5.3%, hazard ratio [HR]: 1.36, 95% CI: 1.0-1.83, P = .04). The cardiac death rate was higher in octogenarians (3.9% vs 0.8%, P < .001). There was no significant between-group difference in target vessel MI (2.3% vs 2.3%, P = .88) and repeat target vessel revascularization (1.9% vs 2.8%, P = .16). In multivariate analyses, age ≥ 80 years showed no independent association with TVF (adjusted HR: 1.04, 95% CI: 0.76-1.42), whereas the risk of cardiac death remained higher in octogenarians (adjusted HR: 3.38, 95% CI: 2.07-5.52, P < .001). In 6,002 trial participants, in whom data on major bleeding were recorded, octogenarians (n = 459) showed a higher major bleeding risk (5.9% vs 1.9%; HR: 3.08, 95% CI: 2.01-4.74, P < .001). CONCLUSIONS: Octogenarian participants in 4 large-scale randomized DES trials had more comorbidities and a higher incidence of the main end point TVF. Cardiac mortality was higher in octogenarians, whereas there was no increase in MI or target vessel revascularization rates. Treatment of octogenarian patients with new-generation DES appears to be safe and effective.

Three-year clinical outcome in all-comers with "silent" diabetes, prediabetes, or normoglycemia, treated with contemporary coronary drug-eluting stents: From the BIO-RESORT Silent Diabetes study.

BACKGROUND: Patients with coronary disease may have unknown diabetes or prediabetes. We evaluated 3-year outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents (DES) in patients with silent diabetes, prediabetes, and normoglycemia. METHODS: All BIO-RESORT trial (NCT01674803) participants without known diabetes, enrolled at our center, were invited for oral glucose tolerance testing (OGTT) and measurements of fasting plasma glucose and glycated hemoglobin (HbA1c). RESULTS: OGTT detected silent diabetes in 68 (6.9%), prediabetes in 132 (13.4%), and normoglycemia in 788 (79.8%) of all 988 study participants. Follow-up was available in 986 (99.8%) patients. The main endpoint target vessel failure (TVF: cardiac death, target vessel-related myocardial infarction [MI], or target vessel revascularization) differed between groups (14.8, 9.9, and 5.6%; p = .002), driven by MI during the first 48 hr and by cardiac death (p < .001; p = .026). Between 48 hr and 3-years, there was no significant between-group difference in TVF, target vessel MI, and target vessel revascularization. Multivariable analysis demonstrated that silent diabetes was independently associated with TVF (adjusted HR: 2.52, 95%-CI: 1.26-5.03). An alternative diagnostic approach-HbA1c and fasting plasma glucose-detected silent diabetes and prediabetes in 33 (3.3%) and 217 (22.0%) patients, and normoglycemia in 738 (74.7%); TVF rates were 12.1, 7.9, and 6.0% (p = .23). CONCLUSION: In patients without known diabetes, abnormal glucose metabolism by OGTT was independently associated with higher 3-year TVF rates after PCI with contemporary DES. This difference was driven by periprocedural MI and cardiac death. After the first 48 hr, the rates of TVF, target vessel MI, and target vessel revascularization were low and did not differ significantly between metabolic groups.

Thin composite wire strut, durable polymer-coated (Resolute Onyx) versus ultrathin cobalt-chromium strut, bioresorbable polymer-coated (Orsiro) drug-eluting stents in allcomers with coronary artery disease (BIONYX): an international, single-blind, randomised non-inferiority trial.

BACKGROUND: During the past decade, many patients had zotarolimus-eluting stents implanted, which had circular shape cobalt-chromium struts with limited radiographic visibility. The Resolute Onyx stent was developed to improve visibility while reducing strut thickness, which was achieved by using a novel composite wire with a dense platinum-iridium core and an outer cobalt-chromium layer. We did the first randomised clinical trial to assess the safety and efficacy of this often-used stent compared with the Orsiro stent, which consists of ultrathin cobalt-chromium struts. METHODS: We did an investigator-initiated, assessor-blinded and patient-blinded, randomised non-inferiority trial in an allcomers population at seven independently monitored centres in Belgium, Israel, and the Netherlands. Eligible participants were aged 18 years or older and required percutaneous coronary intervention with drug-eluting stents. After guide wire passage with or without predilation, members of the catheterisation laboratory team used web-based computer-generated allocation sequences to randomly assign patients (1:1) to either the Resolute Onyx or the Orsiro stent. Randomisation was stratified by sex and diabetes status. Patients and assessors were masked to allocated stents, but treating clinicians were not. The primary endpoint was target vessel failure at 1 year, a composite of cardiac death, target-vessel-related myocardial infarction, and target vessel revascularisation, and was assessed by intention to treat (non-inferiority margin 2·5%) on the basis of outcomes adjudicated by an independent event committee. This trial is registered with ClinicalTrials.gov, number NCT02508714. FINDINGS: Between Oct 7, 2015, and Dec 23, 2016, 2516 patients were enrolled, 2488 of whom were included in the intention-to-treat analysis (28 withdrawals or screening failures). 1243 participants were assigned to the Resolute Onyx group, and 1245 to the Orsiro group. Overall, 1765 (70·9%) participants presented with acute coronary syndromes and 1275 (51·2%) had myocardial infarctions. 1-year follow-up was available for 2478 (99·6%) patients. The primary endpoint was met by 55 (4·5%) patients in the Resolute Onyx group and 58 (4·7%) in the Orsiro group. Non-inferiority of Resolute Onyx to Orsiro was thus established (absolute risk difference -0·2% [95% CI -1·9 to 1·4]; upper limit of the one-sided 95% CI 1·1%; pnon-inferiority=0·0005). Definite or probable stent thrombosis occurred in one (0·1%) participant in the Resolute Onyx group and nine (0·7%) in the Orsiro group (hazard ratio 0·11 [95% CI 0·01-0·87]; p=0·0112). INTERPRETATION: The Resolute Onyx stent was non-inferior to Orsiro for a combined safety and efficacy endpoint at 1-year follow-up in allcomers. The low event rate in both groups suggests that both stents are safe, and the very low rate of stent thrombosis in the Resolute Onyx group warrants further clinical investigation. FUNDING: Biotronik and Medtronic.

Bioresorbable Polymer-Coated Orsiro Versus Durable Polymer-Coated Resolute Onyx Stents (BIONYX): Rationale and design of the randomized TWENTE IV multicenter trial.

AIM: The aim was to compare in a noninferiority trial the efficacy and safety of 2 contemporary drug-eluting stents (DESs): a novel, durable polymer-coated stent versus an established bioabsorbable polymer-coated stent. METHODS AND RESULTS: The BIONYX trial (ClinicalTrials.gov-no.NCT02508714) is an investigator-initiated, prospective, randomized, patient- and assessor-blinded, international, multicenter study in all-comer patients with all types of clinical syndromes and lesions who require percutaneous coronary interventions with DES. Patients at 7 study sites in the Netherlands, Belgium, and Israel were randomly assigned (1:1, stratified for gender and diabetes mellitus) to treatment with the novel, zotarolimus-eluting, durable polymer-coated Resolute Onyx stent that has a radiopaque, thin-strut, CoreWire stent platform versus the sirolimus-eluting, bioresorbable polymer-coated Orsiro stent (reference device) that has a very thin-strut, cobalt-chromium stent backbone. The primary end point is the 1-year incidence of the composite clinical end point target vessel failure consisting of cardiac death, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization. A power calculation, assuming a target vessel failure rate of 6.0% (noninferiority margin 2.5%), revealed that 2,470 study patients would give the study 80% power (α level 5%), allowing for up to 3% loss to follow-up. The first patient was enrolled on October 7, 2015; on December 23, 2016, the last patient entered the study. CONCLUSIONS: BIONYX is a large-scale, prospective, randomized, international, multicenter trial comparing a novel DES with durable coating versus a reference DES with biodegradable coating in all-comers. The study is the first randomized assessment of the Resolute Onyx stent, which is an often-used DES outside the United States.

Patient preference for radial versus femoral vascular access for elective coronary procedures: The PREVAS study.

OBJECTIVES: To explore patient preference for vascular access site in percutaneous coronary procedures, the perceived importance of benefits and risks of transradial access (TRA) and transfemoral access (TFA) were assessed. In addition, direct preference for vascular access and preference for shared decision making (SDM) were evaluated. BACKGROUND: TRA has gained significant ground on TFA during the last decades. Surveys on patient preference have mostly been performed in dedicated TRA trials. METHODS: In the PREVAS study (Clinicaltrials.gov: NCT02625493) a stated preference elicitation method best-worst scaling (BWS) was used to determine patient preference for six treatment attributes: bleeding, switch of access-site, postprocedural vessel quality, mobilization and comfort, and over-night stay. Based on software-generated treatment scenarios, 142 patients indicated which characteristics they perceived most and least important in treatment choice. Best-minus-Worst scores and attribute importance were calculated. RESULTS: Bleeding risk was considered most important (attribute importance 31.3%), followed by length of hospitalization (22.6%), and mobilization(20.2%). Most patients preferred the approach of their current procedure (85.9%); however, 71.1% of patients with experience with both access routes favored TRA (P < 0.001). Most patients (38.0%) appreciated SDM, balanced between patient and cardiologist. CONCLUSIONS: Patients appreciate lower bleeding risk and early ambulation, factors favoring TRA. Previous experience with a single access route has a major impact on preference, while experience with both routes generally resulted in preference for TRA. Most patients prefer balanced SDM. © 2017 The Authors Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc.

High Bleeding Risk Patients Treated with Very Thin-Strut Biodegradable Polymer or Thin-Strut Durable Polymer Drug-Eluting Stents in the BIO-RESORT Trial.

PURPOSE: Patients with high bleeding risk (HBR) who undergo percutaneous coronary intervention also have an increased risk of ischemic events and represent an overall high-risk population. The coating of durable polymer drug-eluting stents (DP-DES) may induce inflammation and delay arterial healing, which might be reduced by novel biodegradable polymer DES (BP-DES). We aimed to evaluate the safety and efficacy of treating HBR patients with very thin-strut BP-DES versus thin-strut DP-DES. METHODS: Participants in BIO-RESORT (NCT01674803), an investigator-initiated multicenter, randomized all-comers trial, were treated with very thin-strut BP-DES (Synergy or Orsiro) or thin-strut DP-DES (Resolute Integrity). For the present analysis, patients were classified following HBR criteria based on previous trials. The primary endpoint was target vessel failure: a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization at 1 year. RESULTS: Of all 3514 patients, 1009 (28.7%) had HBR. HBR patients were older (p < 0.001) and had more co-morbidities than non-HBR patients (p < 0.001). At 1-year follow-up, HBR patients had significantly higher rates of target vessel failure (6.7 vs. 4.2%, p = 0.003), cardiac death (1.9 vs. 0.4%, p < 0.001), and major bleeding (3.3 vs. 1.5%, p = 0.001). Of all 1009 HBR patients, 673 (66.7%) received BP-DES and 336 (33.3%) had DP-DES. The primary endpoint was met by 43/673 (6.5%) patients treated with BP-DES and 24/336 (7.3%) treated with DP-DES (HR 0.88 [95%CI 0.54-1.46], p = 0.63). There were no significant between-group differences in the most global patient-oriented clinical endpoint (9.7 vs. 10.5%, HR 0.92 [95%CI 0.61-1.39], p = 0.69) and other secondary endpoints. CONCLUSIONS: At 1-year follow-up, very thin-strut BP-DES showed similar safety and efficacy for treating HBR patients as thin-strut DP-DES.

Serial assessment of endothelial function 1, 6, and 12 months after ST-elevation myocardial infarction.

Knowledge about the changes in endothelial function after ST-elevation myocardial infarction (STEMI) is of substantial interest, but serial data are scarce. The aim of the present study was to noninvasively evaluate whether endothelial function, as assessed shortly after primary percutaneous coronary intervention (PPCI) for STEMI, may improve until 12-month follow-up. This prospective observational cohort study was performed in patients in the RESPONSE randomized trial who participated in a substudy and underwent noninvasive assessment of endothelial function at 1 (baseline), 6, and 12-month follow-up after treatment of a STEMI by PPCI. The reactive hyperemia peripheral artery tonometry (RH-PAT) method was used to assess endothelial function (higher RH-PAT index signifies better function). Of the 70 study participants, who were 57.4 ± 9.7 years of age, 55 (78.6%) were male and 9 (13%) had diabetes. The endothelial function deteriorated significantly during follow-up: the RH-PAT index at baseline, 6, and 12-month follow-up was 1.90 ± 0.58, 1.81 ± 0.57, and 1.69 ± 0.49, respectively (p = 0.04). Although patients were carefully treated in outpatient clinics and adequate pharmacological therapy was prescribed, we noted an increase in total cholesterol (p = 0.001), LDL cholesterol (p = 0.002), HbA1C (p = 0.054), and diastolic blood pressure (p = 0.047) However, multivariate analysis revealed that this increase in cardiovascular risk factors could not explain the observed deterioration in endothelial function. In patients with STEMI, we observed a significant deterioration in endothelial function during 12 months after PPCI that could not be explained by changes in the traditional cardiovascular risk profile.

Are component endpoints equal? A preference study into the practice of composite endpoints in clinical trials.

OBJECTIVES: To examine patients' perspectives regarding composite endpoints and the utility patients put on possible adverse outcomes of revascularization procedures. DESIGN: In the PRECORE study, a stated preference elicitation method Best-Worst Scaling (BWS) was used to determine patient preference for 8 component endpoints (CEs): need for redo percutaneous coronary intervention (PCI) within 1 year, minor stroke with symptoms <24 hours, minor myocardial infarction (MI) with symptoms <3 months, recurrent angina pectoris, need for redo coronary artery bypass grafting (CABG) within 1 year, major MI causing permanent disability, major stroke causing permanent disability and death within 24 hours. SETTING: A tertiary PCI/CABG centre. PARTICIPANTS: One hundred and sixty patients with coronary artery disease who underwent PCI or CABG. MAIN OUTCOME MEASURES: Importance weights (IWs). RESULTS: Patients considered need for redo PCI within 1 year (IW: 0.008), minor stroke with symptoms <24 hours (IW: 0.017), minor MI with symptoms <3 months (IW: 0.027), need for redo CABG within 1 year (IW: 0.119), recurrent angina pectoris (IW: 0.300) and major MI causing permanent disability (IW: 0.726) less severe than death within 24 hours (IW: 1.000). Major stroke causing permanent disability was considered worse than death within 24 hours (IW: 1.209). Ranking of CEs and the relative values attributed to the CEs differed among subgroups based on gender, age and educational level. CONCLUSION: Patients attribute different weight to individual CEs. This has significant implications for the interpretation of clinical trial data.

Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial.

BACKGROUND: In patients with coronary artery disease, treated with durable polymer-coated drug-eluting stents, the life-long presence of the polymer might delay arterial healing. Novel very thin strut biodegradable polymer stents, which leave only a bare metal stent after polymer resorption, might improve long-term outcome. We investigated in allcomers the safety and efficacy of three stents eluting either everolimus, sirolimus, or zotarolimus, often clinically used but never compared, of which the biodegradable polymer everolimus-eluting stent was never before assessed in allcomers. METHODS: The large-scale, investigator-initiated, multicentre, assessor and patient blinded, three-arm, randomised, BIO-RESORT non-inferiority trial was done at four clinical sites in the Netherlands. All-comer patients were aged 18 years or older, capable of providing informed consent, and required a percutaneous coronary intervention with drug-eluting stent implantation according to clinical guidelines or the operators' judgment. Exclusion criteria were: participation in another randomised drug or device study before reaching the primary endpoint of that study; planned surgery necessitating interruption of dual antiplatelet therapy within the first 6 months; known intolerance to components of the investigational product or medication required; uncertainty about the adherence to follow-up procedures or an assumed life expectancy of less than 1 year; or known pregnancy. Web-based computer-generated allocation sequences randomly assigned patients (1:1:1) to treatment with very thin strut biodegradable polymer everolimus-eluting or sirolimus-eluting stents (which differ substantially in type, amount, distribution, and resorption speed of their respective coating), or thin strut durable polymer zotarolimus-eluting stents. The primary endpoint was a composite of safety (cardiac death or target vessel-related myocardial infarction) and efficacy (target vessel revascularisation) at 12 months of follow up with a very thin strut biodegradable polymer of either everolimus-eluting or sirolimus-eluting stents, compared with durable polymer zotarolimus-eluting stents, analysed by intention to treat (non-inferiority margin 3·5%). This trial was registered with ClinicalTrials.gov, number NCT01674803. FINDINGS: From Dec 21, 2012, to Aug 24, 2015, 3514 patients were enrolled and analysed, of whom 2449 (70%) had acute coronary syndromes, which included 1073 (31%) ST-elevation myocardial infarctions. 12 month follow-up of 3490 (99%) patients (three lost to follow-up; 21 withdrawals) was available. The primary endpoint was met by 55 (5%) of 1172 patients assigned to everolimus-eluting stents, 55 (5%) of 1169 assigned to sirolimus-eluting stents and 63 (5%) of 1173 assigned to zotarolimus-eluting stents. Non-inferiority of the everolimus-eluting stents and sirolimus-eluting stents compared with zotarolimus-eluting stents was confirmed (both -0·7% absolute risk difference, 95% CI -2·4 to 1·1; upper limit of one sided 95% CI 0·8%, pnon-inferiority<0·0001). Definite stent thrombosis (defined by the Academic Research Consortium) occurred in four (0·3%) of 1172 patients who were allocated to everolimus-eluting stents, four (0·3%) of 1169 patients who were allocated to sirolimus-eluting stents, and three (0·3%) of 1173 patients who were allocated to zotarolimus-eluting stents (log-rank p=0·70 for both comparisons with zotarolimus-eluting stents). INTERPRETATION: At 12 month follow-up, both very thin strut drug-eluting stents with dissimilar biodegradable polymer coatings (eluting either everolimus or sirolimus) were non-inferior to the durable polymer stent (eluting zotarolimus) in treating allcomers with a high proportion of patients with acute coronary syndromes. The absence of a loss of 1 year safety and efficacy with the use of these two biodegradable polymer-coated stents is a prerequisite before assessing their potential longer-term benefits. FUNDING: Biotronik, Boston Scientific, and Medtronic.

Three-Year Clinical Outcome of Patients with Coronary Disease and Increased Event Risk Treated with Newer-Generation Drug-Eluting Stents: From the Randomized DUTCH PEERS Trial.

OBJECTIVE: Limited data is available on the long-term outcome of patients with increased cardiovascular event risk, treated with newer-generation durable polymer drug-eluting stents (DES). METHODS: We therefore assessed 3-year follow-up data of high-risk versus low- to intermediate-risk patients of the randomized DUTCH PEERS trial (NCT01331707). In both risk groups we also compared patients treated with Resolute Integrity versus Promus Element DES. Patients were categorized as "high-risk" if they met ≥1 of the following criteria: (1) diabetes (17.9%); (2) previous myocardial infarction (21.9%); (3) previous coronary revascularization (25.8%); (4) chronic renal failure (3.5%); (5) left ventricular ejection fraction ≤30% (1.5%); and (6) age ≥75 years (17.3%). RESULTS: At the 3-year follow-up, the incidence of the composite endpoint target vessel failure (TVF) (13.2 vs. 7.5%; logrank p < 0.001) and 2 of its components - cardiac death (4.7 vs. 1.5%; logrank p < 0.001) and target vessel revascularization (7.3 vs. 4.7%; logrank p = 0.03) - was higher in high-risk (n = 957) versus low- to intermediate-risk patients (n = 854). Among high-risk patients, treatment with Resolute Integrity (n = 481) and Promus Element stents (n = 476) was similarly safe and efficacious (TVF: 13.3 vs. 13.1%; logrank p = 0.95; definite-or-probable stent thrombosis: 1.7 vs. 1.7%; logrank p = 1.00). CONCLUSIONS: The newer-generation Resolute Integrity and Promus Element stents showed similar results in terms of safety and efficacy for treating high-risk patients, who had significantly higher event rates than patients with low-to-intermediate risk.

Small-vessel treatment with contemporary newer-generation drug-eluting coronary stents in all-comers: Insights from 2-year DUTCH PEERS (TWENTE II) randomized trial.

BACKGROUND: Treatment of lesions in small vessels was associated with worse clinical outcome, and various definitions of "small vessels" have been used. Data with novel drug-eluting stents are scarce. METHODS: To compare the outcome of patients with vs without small-vessel treatment, we assessed 2-year follow-up data of the DUTCH PEERS randomized trial (ClinicalTrials.gov: NCT01331707), in which 1,811 all-comers were treated with contemporary zotarolimus-eluting (Resolute Integrity) or everolimus-eluting (Promus Element) stents. Primary end point was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization. RESULTS: The rates of TLF (9.5% vs 5.4%; P log rank = .001) and 2 individual components thereof-target vessel myocardial infarction (3.1% vs 1.3%; P log rank = .006) and target lesion revascularization (4.8% vs 2.8%; P log rank = .02)-were higher among 798 (44.1%) patients treated in at least one small vessel (<2.50 mm by quantitative coronary angiography). Multivariate analysis with propensity score adjustment demonstrated that treatment of small-vessel lesions independently predicted TLF at 2-year follow-up (hazard ratio 1.60, 95% CI 1.09-2.34). Patients with the smallest target vessel being <2.25 mm had TLF rates similar to patients with smallest target vessels of 2.25 to <2.50 mm; however, patients treated in vessels no smaller than 2.50 to <3.00 mm and patients treated in vessels ≥3.00 mm had lower TLF rates (9.3%, 9.8%, 5.0%, and 5.8%, respectively; P log rank = .009). CONCLUSION: Patients treated with novel drug-eluting stents in small-vessel lesions had higher adverse event rates than did patients who had no small-vessel treatment. Our data suggest that with current stents, a vessel diameter <2.50 mm is a suitable threshold to identify small target vessels.

Impact of severe lesion calcification on clinical outcome of patients with stable angina, treated with newer generation permanent polymer-coated drug-eluting stents: A patient-level pooled analysis from TWENTE and DUTCH PEERS (TWENTE II).

BACKGROUND: The outcome of percutaneous coronary intervention with newer generation permanent polymer-coated drug-eluting stents (DES) in patients with severely calcified lesions is greatly unknown. We assessed the impact of severe lesion calcification on clinical outcome in patients with stable angina who underwent percutaneous coronary intervention with newer generation DES. METHODS: TWENTE and DUTCH PEERS randomized trials enrolled 1423 patients with stable angina, who were categorized into patients with versus without severe target lesion calcification. A patient-level pooled analysis assessed clinical outcome, including target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization (TVR). RESULTS: Patients with severe calcification (n = 342) were older (66.6 ± 9.1 vs 64.2 ± 9.8 years, P < .001) and had more diabetes (25.7% vs 20.4%, P = .04) than other patients (n = 1081). Patients with calcified lesions had higher rates of TVF (16.4% vs 9.8%, pLogrank = .001), cardiac death (4.4% vs 1.5%, P = .03), target vessel myocardial infarction (7.6% vs 3.4%, P = .001), and definite stent thrombosis (1.8% vs 0.4%, P = .02). Multivariate analysis demonstrated that severe calcification was an independent risk factor of 2-year TVF (HR 1.42, 95% CI: 1.02-1.99, pLogrank = .04); landmark analysis showed that this was based on a difference during the first year (periprocedural: 5.8% vs. 3.1%, pLogrank = .02; first year: 7.5% vs. 3.8%, pLogrank = .007; second year: 4.1% vs. 3.3%, pLogrank = .54). CONCLUSION: In patients with stable angina, severe target lesion calcification is associated with an increased risk of adverse cardiovascular events following treatment with newer generation permanent polymer-coated DES. This increase in risk is restricted to the first year of follow-up, which is an encouraging finding.

Long-term outcome and chest pain in patients with true versus non-true bifurcation lesions treated with second-generation drug-eluting stents in the TWENTE trial.

The objective of this study is to assess 3-year clinical outcome of patients with true bifurcation lesions (TBLs) versus non-true bifurcation lesions (non-TBLs) following treatment with second-generation drug-eluting stents (DES). TBLs are characterized by the obstruction of both main vessel and side-branch. Limited data are available on long-term clinical outcome following TBL treatment with newer-generation DES. We performed an explorative sub-study of the randomized TWENTE trial among 287 patients who had bifurcated target lesions with side-branches ≥2.0 mm. Patients were categorized into TBL (Medina classes: 1.1.1; 1.0.1; 0.1.1) versus non-TBL to compare long-term clinical outcome. A total of 116 (40.4 %) patients had TBL, while 171 (59.6 %) had non-TBL only. Target-lesion revascularization rates were similar (3.5 vs. 3.5 %; p = 1.0), and definite-or-probable stent thrombosis rates were low (both <1.0 %). The target-vessel myocardial infarction (MI) rate was 11.3 versus 5.3 % (p = 0.06), mostly driven by (periprocedural) MI ≤48 h from PCI. All-cause mortality and cardiac death rates were 8.7 versus 3.5 % (p = 0.06) and 3.5 versus 1.2 % (p = 0.22), respectively. The 3-year major adverse cardiac event rate for patients with TBL versus non-TBL was 20.0 versus 11.7 % (p = 0.05). At 1-, 2-, and 3-year follow-up, 6.5, 13.0, and 11.0 % of patients reported chest pain at less than or equal moderate physical effort, respectively, without any between-group difference. Patients treated with second-generation DES for TBL had somewhat higher adverse event rates than patients with non-TBL, but dissimilarities did not reach statistical significance. Up to 3-year follow-up, the vast majority of patients of both groups remained free from chest pain.

Three-year clinical outcome of patients with bifurcation treatment with second-generation Resolute and Xience V stents in the randomized TWENTE trial.

BACKGROUND: Only limited data from large randomized clinical trials have been published on the long-term performance of second-generation drug-eluting stents in bifurcation lesions. METHODS: We investigated in patients in the randomized TWENTE trial the long-term safety and efficacy of treating bifurcation lesions with 2 widely applied second-generation drug-eluting stents, the zotarolimus-eluting Resolute stent (Medtronic Inc, Santa Rosa, CA) and the everolimus-eluting Xience V stent (Abbott Vascular, Santa Clara, CA). Three-year follow-up was available in 99.3%. Patients were categorized into treatment for ≥1 bifurcation lesion versus treatment for nonbifurcation lesions only. RESULTS: Among the 1,391 patients of the TWENTE trial, 362 (26%) were treated for bifurcation lesions. At 3-year follow-up, target-vessel failure did not differ between patients treated for bifurcation versus nonbifurcation lesions (13.1% vs 12.6%; P = .84), whereas the periprocedural myocardial infarction rate was higher in patients with bifurcation lesions (6.9% vs 3.1%; P < .01). Of the 362 patients with bifurcation lesion treatment, 179 (49.4%) were treated with Resolute and 183 (50.6%) with Xience V. There was no significant difference in target-vessel failure between the Resolute and Xience V groups with bifurcation treatment (13.6% vs 12.6%; P = .78), and their incidence of definite-or-probable stent thrombosis was low and similar (1.1% vs 0.5%, respectively; P = .62). CONCLUSION: Despite a significant difference in periprocedural myocardial infarction, 3-year clinical outcome after implantation of second-generation stents was favorable and similar for patients with and without bifurcation lesions. In addition, we observed no difference in long-term clinical outcome after bifurcation lesion treatment with Resolute and Xience V stents.

Final 5-Year Report of the Randomized BIO-RESORT Trial Comparing 3 Contemporary Drug-Eluting Stents in All-Comers.

Background In a previous trial, higher 5-year mortality was observed following treatment with biodegradable polymer Orsiro sirolimus-eluting stents (SES). We assessed 5-year safety and efficacy of all-comers as well as patients with diabetes treated with SES or Synergy everolimus-eluting stents (EES) versus durable polymer Resolute Integrity zotarolimus-eluting stents (ZES). Methods and Results The randomized BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population) trial enrolled 3514 all-comer patients at 4 Dutch cardiac centers. Patients aged ≥18 years who required percutaneous coronary intervention were eligible. Participants were stratified for diabetes and randomized to treatment with SES, EES, or ZES (1:1:1). The main end point was target vessel failure (cardiac mortality, target vessel myocardial infarction, or target vessel revascularization). Five-year follow-up was available in 3183 of 3514 (90.6%) patients. The main end point target vessel failure occurred in 142 of 1169 (12.7%) patients treated with SES, 130 of 1172 (11.6%) treated with EES, versus 157 of 1173 (14.1%) treated with ZES (hazard ratio [HR], 0.89 [95% CI, 0.71-1.12], Plog-rank=0.31; and HR, 0.82 [95% CI, 0.65-1.04], Plog-rank=0.10, respectively). Individual components of target vessel failure showed no significant between-stent difference. Very late definite stent thrombosis rates were low and similar (SES, 1.1%; EES, 0.6%; ZES, 0.9%). In patients with diabetes, target vessel failure did not differ significantly between stent-groups (SES, 19.8%; EES, 19.2%; versus ZES, 21.1% [Plog-rank=0.69 and Plog-rank=0.63]). Conclusions Orsiro SES, Synergy EES, and Resolute Integrity ZES showed similar 5-year outcomes of safety and efficacy, including mortality. A prespecified stent comparison in patients with diabetes also revealed no significant differences in 5-year clinical outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01674803.

Treating diabetic all-comers with contemporary drug-eluting stents: Prespecified comparisons from the BIO-RESORT and the BIONYX randomized trials.

BACKGROUND: Patients with diabetes have more extensive coronary disease, resulting in higher risks of adverse clinical events following stenting. In all-comer patients, contemporary DES have shown excellent safety and efficacy, but data on diabetic patients are scarce. Separately for the BIO-RESORT and BIONYX trials, we assessed the 2-year clinical outcomes of diabetic patients, treated with various contemporary drug-eluting stents (DES). METHODS: We performed two prespecified secondary analyses of two randomized DES trials, which both stratified for diabetes. The main endpoint was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. Follow-up was finished before the COVID-19 pandemic. RESULTS: In BIO-RESORT, 624/3514 (17.8%) had diabetes: 211 received Orsiro sirolimus-eluting stents (SES), 203 Synergy everolimus-eluting stents (EES), and 210 Resolute Integrity zotarolimus-eluting stents (RI-ZES). TVF did not differ between SES (10.2%) and EES (10.0%) versus RI-ZES (12.7%) (SES vs. RI-ZES HR:0.78, 95%-CI [0.44-1.40]; p = 0.40, EES vs. RI-ZES HR:0.79, 95%-CI [0.44-1.40]; p = 0.42). In BIONYX, 510/2488 (20.5%) patients had diabetes: 250 received SES and 260 Resolute Onyx zotarolimus-eluting stents (RO-ZES). There was no difference in TVF between SES (10.7%) versus RO-ZES (12.2%) (HR:0.88, 95%-CI [0.52-1.48]; p = 0.63). CONCLUSIONS: There was no difference in 2-year clinical outcome among patients with diabetes, who were treated with SES, or EES, versus RI-ZES. In addition there was no difference in clinical outcome in diabetic patients, who were treated with SES versus RO-ZES. These findings may be considered as a signal of safety and efficacy of the studied DES in patients with diabetes.

1-Year Clinical Outcomes of All Comers Treated With 2 Bioresorbable Polymer-Coated Sirolimus-Eluting Stents: Propensity Score-Matched Comparison of the COMBO and Ultrathin-Strut Orsiro Stents.

OBJECTIVES: The aim of this study was to determine 1-year safety and efficacy after treatment with the COMBO and Orsiro stents. BACKGROUND: The COMBO stainless-steel stent has an anti-CD34+ antibody coating to capture endothelial progenitor cells, thereby promoting faster endothelialization. The Orsiro is an ultrathin-strut cobalt-chromium stent, covered by an extremely thin layer of amorphous silicon carbide to minimize ion leakage. Both devices elute sirolimus from biodegradable polymers. METHODS: For this analysis we included European patients from the COMBO collaboration, a patient-level pooling of 2 prospective all-comers registries of COMBO stent implantation (n = 2,775), and all patients randomized to the Orsiro stent (n = 1,169) from the Dutch BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population) randomized trial. The main outcome of interest was 1-year target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization evaluated using propensity score-matched analysis. RESULTS: At baseline, COMBO patients were older and had more insulin-treated diabetes, renal insufficiency, and other comorbidities. However, Orsiro patients included more current smokers and more acute coronary syndrome presentations. Orsiro patients also received longer stents and had more complex target lesions. After propensity score-matched analysis (n = 862/arm), 1-year target lesion failure occurred in 4.1% of COMBO-treated and 2.7% of Orsiro-treated patients (hazard ratio: 1.55; 95% confidence interval: 0.92 to 2.62; p = 0.10). Definite stent thrombosis occurred in 0.5% of COMBO-treated and 0.5% of Orsiro-treated patients (p = 0.99). CONCLUSIONS: A propensity score-matched comparison of all comers treated with the COMBO or Orsiro stent showed no statistically significant differences. Stent thrombosis risk was low and similar between the stents. (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population [BIO-RESORT], NCT01674803; MASCOT-Post Marketing Registry [MASCOT], NCT02183454; Prospective Registry to Assess the Long-term Safety and Performance of the Combo Stent [REMEDEE Reg], NCT01874002).

Outcomes in Patients Treated With Thin-Strut, Very Thin-Strut, or Ultrathin-Strut Drug-Eluting Stents in Small Coronary Vessels: A Prespecified Analysis of the Randomized BIO-RESORT Trial.

Importance: Stenting small-vessel lesions has an increased adverse cardiovascular event risk. Very thin-strut or ultrathin-strut drug-eluting stents might reduce this risk, but data are scarce. Objective: To assess the outcome of all-comer patients with small coronary vessel lesions treated with 3 dissimilar types of drug-eluting stents. Design: This is a prespecified substudy of the Comparison of Biodegradable Polymer and Durable Polymer Drug-eluting Stents in an All Comers Population (BIO-RESORT) trial, an investigator-initiated, randomized, patient-blinded comparative clinical drug-eluting stent trial. Patients treated with ultrathin-strut sirolimus-eluting stents, very thin-strut everolimus-eluting stents, or previous-generation thin-strut zotarolimus-eluting stents were enrolled from December 2012 to August 2015. This multicenter trial was conducted in 4 Dutch centers for cardiac intervention. Of all 3514 all-comer BIO-RESORT participants, 1506 patients with treatment in at least 1 small-vessel lesion (reference vessel <2.5 mm) were included. Data were analyzed between September 2018 and February 2019. Main Outcomes and Measures: Target lesion failure at 3-year follow-up, a composite of cardiac death, target vessel-related myocardial infarction, or target lesion revascularization, analyzed by Kaplan-Meier methods. Results: In 1452 of 1506 participants (96.4%) (1057 men [70.2%]; 449 women [29.8%]; mean [SD] age, 64.3 [10.4] years), follow-up was available. Target lesion failure occurred in 36 of 525 patients (7.0%) treated with sirolimus-eluting stents, 46 of 496 (9.5%) with everolimus-eluting stents, and 48 of 485 (10.0%) with zotarolimus-eluting stents (sirolimus-eluting vs zotarolimus-eluting hazard ratio [HR], 0.68; 95% CI, 0.44-1.05; P = .08; everolimus-eluting vs zotarolimus-eluting HR, 0.93; 95% CI, 0.62-1.39; P = .72). There was a difference in target lesion revascularizations between sirolimus-eluting and zotarolimus-eluting stents (2.1% vs 5.3%; HR, 0.40; 95% CI, 0.20-0.81; P = .009) that emerged after the first year of follow-up (1.0% vs 3.7%; P = .006); multivariate analysis showed that sirolimus-eluting stent implantation was independently associated with a lower target lesion revascularization rate at 3-year follow-up (adjusted HR, 0.42; 95% CI, 0.20-0.85; P = .02). In the everolimus-eluting stents, the revascularization rate was 4.0% (vs zotarolimus-eluting, HR, 0.74; 95% CI, 0.41-1.34; P = .31). There was no significant between-stent difference in cardiac death, target vessel myocardial infarction, or stent thrombosis. Conclusions and Relevance: Patients stented in small coronary vessels experienced fewer repeated revascularizations if treated with ultrathin-strut sirolimus-eluting stents vs previous generation thin strut zotarolimus-eluting stents. Further research is required to evaluate the potential effect of particularly thin stent struts. Trial Registration: ClinicalTrials.gov identifier: NCT01674803.