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Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention‐to‐treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention‐to‐treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per‐protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time‐varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all‐cause mortality or nonfatal Q‐wave myocardial infarction at 2 years. At 2‐year follow‐up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per‐protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75–1.03; P =0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79–1.26; P =0.99). The per‐protocol and intention‐to‐treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01813435.

Objectives: To validate a simplified core laboratory intravascular ultrasound (IVUS) analysis method based on frames with visually determined minimal lumen areas (MLAs) as compared with a comprehensive (per frame) analysis method. Background: IVUS-guided percutaneous coronary intervention has proven to be superior to angiography-guided stenting. In clinical practice, cross-sections with visually determined MLA are measured to determine lesion severity or minimal stent area (MSA), however, its accuracy has not been compared with a comprehensive per frame analysis method. Methods: A total of 50 stented coronary segments of anonymized core lab datasets were analyzed using a comprehensive analysis method and reanalyzed by two core lab analysts using the simplified method including a maximum of seven frames to be analyzed (the visually determined MSA, the first and last frame, and the MLA of each reference segment). The main parameters of interest were MSA, MLA in the reference segments, and plaque burden. Results: The simplified method showed moderate agreement for measurement of the proximal MLA (7.51 ± 2.52 vs. 6.32 ± 1.88 mm2, intraclass correlation coefficient [ICC] = 0.73), good agreement for the distal MLA (5.41 ± 1.85 vs. 5.11 ± 1.38 mm2, ICC = 0.84) and plaque burden proximal (0.49 ± 0.12 vs. 0.50 ± 0.11, ICC = 0.88), and excellent agreement for the MSA (5.35 ± 1.05 vs. 5.32 ± 0.99 mm2, ICC = 0.94) and plaque burden distal (0.47 ± 0.14 vs. 0.47 ± 0.12, ICC = 0.92), when compared with the comprehensive analysis method. Inter- and intraobserver analysis revealed good-to-excellent agreement for all parameters. Conclusions: Measuring poststenting IVUS cross-sections with visually determined MLAs by experienced core lab analysts is an accurate and reproducible method to identify MLAs.

Aims To evaluate long-term safety and efficacy of ticagrelor monotherapy in patients undergoing percutaneous coronary interventions (PCIs) in relation to chronic obstructive pulmonary disease (COPD) at baseline and the occurrence of dyspnoea reported as adverse event (AE) that may lead to treatment non-adherence. Methods and results This is a non-prespecified, post hoc analysis of the randomized GLOBAL LEADERS trial (n = 15 991), comparing the experimental strategy of 23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy (DAPT) after PCI with the reference strategy of 12-month DAPT followed by 12-month aspirin monotherapy. Impact of COPD and dyspnoea AE (as a time-dependent covariate) on clinical outcomes was evaluated up to 2 years. The primary endpoint was a 2-year all-cause mortality or non-fatal, centrally adjudicated, new Q-wave myocardial infarction. The presence of COPD (n = 832) was the strongest clinical predictor of 2-year all-cause mortality after PCI [hazard ratio (HR) 2.84; 95% confidence interval (CI) 2.21–3.66; P adjusted = 0.001] in this cohort (n = 15 991). No differential treatment effects on 2-year clinical outcomes were found in patients with and without COPD (primary endpoint: HR 0.88; 95% CI 0.58–1.35; P = 0.562; P int = 0.952). Overall, at 2 years dyspnoea was reported as an AE in 2101 patients, more frequently among COPD patients, irrespective of treatment allocation (27.2% in experimental arm vs. 14.5% in reference arm, P = 0.001). Its occurrence was not associated with a higher rate of the primary endpoint (P adjusted = 0.640) in the experimental vs. the reference arm. Conclusion In this exploratory analysis, COPD negatively impacted long-term prognosis after PCI. Despite higher incidence of dyspnoea in the experimental arm, in particular among COPD patients, the safety of the experimental treatment strategy appeared not to be affected. Clinical trial registration unique identifier NCT01813435.

Background: Impaired renal function (IRF) is associated with increased risks of both ischemic and bleeding events. Ticagrelor has been shown to provide greater absolute reduction in ischemic risk following acute coronary syndrome (ACS) in those with versus without IRF. Methods: A pre-specified sub-analysis of the randomized GLOBAL LEADERS trial (n = 15,991) comparing the experimental strategy of 23-month ticagrelor monotherapy (after 1-month ticagrelor and aspirin dual anti-platelet therapy [DAPT]) with 12-month DAPT followed by 12-month aspirin after percutaneous coronary intervention (PCI) in ACS and stable coronary artery disease (CAD) patients stratified according to IRF (glomerular filtration rate < 60 ml/min/1.73 m 2). Results: At 2 years, patients with IRF (n = 2171) had a higher rate of the primary endpoint (all-cause mortality or centrally adjudicated, new Q-wave myocardial infarction [MI](hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.35–1.98, p adj = 0.001), all-cause death, site-reported MI, all revascularization and BARC 3 or 5 type bleeding, compared with patients without IRF. Among patients with IRF, there were similar rates of the primary endpoint (HR 0.82, 95% CI 0.61–1.11, p = 0.192, p int = 0.680) and BARC 3 or 5 type bleeding (HR 1.10, 95% CI 0.71–1.71, p = 0.656, p int = 0.506) in the experimental versus the reference group. No significant interactions were seen between IRF and treatment effect for any of the secondary outcome variables. Among ACS patients with IRF, there were no between-group differences in the rates of the primary endpoint or BARC 3 or 5 type bleeding; however, the rates of the patient-oriented composite endpoint (POCE) of all-cause death, any stroke, MI, or revascularization (p int = 0.028) and net adverse clinical events (POCE and BARC 3 or 5 type bleeding) (p int = 0.045), were lower in the experimental versus the reference group. No treatment effects were found in stable CAD patients categorized according to presence of IRF. Conclusions: IRF negatively impacted long-term prognosis after PCI. There were no differential treatment effects found with regard to all-cause death or new Q-wave MI after PCI in patients with IRF treated with ticagrelor monotherapy. Clinical trial registration: The trial has been registered with ClinicalTrials.gov, number NCT01813435. Graphic abstract: [Figure not available: see fulltext.].

Background We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens. Methods GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75-100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75-100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01813435, and is closed to new participants, with followup completed. Findings Between July 1, 2013, and Nov 9, 2015, 15 968 participants were randomly assigned, 7980 to the experimental group and 7988 to the control group. At 2 years, 304 (3.81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4.37%) participants in the control group (rate ratio 0.87 [95% CI 0. 75-1. 01]; p=0.073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0.93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2.04% vs 2.12%; rate ratio 0.97 [95% CI 0. 78-1. 20]; p=0.77). Interpretation Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention. Copright (C) 2018 Elsevier Ltd. All rights reserved. European Clinical Research Institute; Biosensors International; AstraZeneca; Medicines Company; Canada Research Chairs Programme

Objectives This study sought to investigate the differences in detecting (e.g., triggering) periprocedural myocardial infarction (PMI) among 3 current definitions. Background PMI is a frequent component of primary endpoints in coronary device trials. Identification of all potential suspected events is critical for accurate event ascertainment. Automatic triggers based on study databases prevent underreporting of events. Methods We generated automated algorithms to trigger PMI based on each definition and compared results using data from the RESOLUTE all comers trial. Results The operationalization of current PMI definitions was achieved by defining programmable algorithms used to interrogate the study database. From a total of 636 PMI triggers, we identified 234 for the World Health Organization extended definition, 382 for the Third Universal definition, and 216 for the Society for Cardiovascular Angiography and Interventions definition. Differences among the biomarkers used, different cutoff values, and in the hierarchy among biomarkers within definitions, yielded a different number of triggers, and identified unique triggers for each definition. Only 38 triggers were consistently identified by all definitions. Availability of ECG data, eCRF data on clinical presentation, and the reporting of >2 post-procedural values of the same biomarker influenced considerably the number of PMI triggers identified. Conclusions PMI definitions are not interchangeable. The number of triggers identified and consequently the potential number of events varies significantly, highlighting the importance of rigorous methodology when PMI is a component of a powered endpoint. Emphasis on collection of biomarkers, ECG data, and clinical status at baseline may improve the correct identification of PMI triggers.

AIMS: Antiplatelet treatment in the elderly post percutaneous coronary interventions (PCI) remains a complex issue. Here we report the results of the pre-specified subgroup analysis of the GLOBAL LEADERS trial evaluating the long-term safety and cardiovascular efficacy of ticagrelor monotherapy among patients categorised according to the pre-specified cut-off value of 75 years of age. METHODS AND RESULTS: This was a pre-specified analysis of the randomised GLOBAL LEADERS trial (n=15,991), comparing 23-month ticagrelor monotherapy (after one month of DAPT) with the reference treatment (12-month DAPT followed by 12 months of aspirin). Among elderly patients (>75 years; n=2,565), the primary endpoint (two-year all-cause mortality or new Q-wave core lab-adjudicated myocardial infarction [MI]) occurred in 7.2% and 9.4% of patients in the ticagrelor monotherapy and the reference group, respectively (hazard ratio [HR] 0.75, 95% confidence interval [CI]: 0.58-0.99, p=0.041; pint=0.23); BARC-defined bleeding type 3/5 occurred in 5.2% and 4.1%, respectively (HR 1.29, 95% CI: 0.89-1.86; p=0.180; pint=0.06). The elderly with stable CAD had a higher rate of BARC 3/5 type bleeding (HR 2.05, 95% CI: 1.18-3.55) with ticagrelor monotherapy versus the reference treatment (pint=0.02). Elderly patients had a lower rate of definite or probable stent thrombosis (ST) with ticagrelor monotherapy (0.4% vs 1.4%, p=0.015, pint=0.01), compared with the reference group. CONCLUSIONS: In this pre-specified, exploratory analysis of the overall neutral trial, there was no differential treatment effect of ticagrelor monotherapy (after one-month dual therapy with aspirin) found in elderly patients undergoing PCI with respect to the rate of the primary endpoint of all-cause death or new Q-wave MI. The lower rate of ST in the elderly with ticagrelor monotherapy is hypothesis-generating. ClinicalTrials.gov identifier: NCT01813435.

Background: We evaluated the association of pulse pressure (PP) and different antiplatelet regimes with clinical and safety outcomes in an all-comers percutaneous coronary intervention (PCI) population. Methods: In this analysis of GLOBAL LEADERS (n = 15,936) we compared the experimental therapy of 23 months of ticagrelor after 1 month of dual-antiplatelet therapy (DAPT) versus standard DAPT for 12 months followed by aspirin monotherapy in subjects who underwent PCI and were divided into 2 groups according to the median PP (60 mm Hg). The primary end point (all-cause death or new Q-wave myocardial infarction) and the composite end points: patient-oriented composite end points (POCE), Bleeding Academic Research Consortium (BARC) 3 or 5, and net adverse clinical events (NACE) were evaluated. Results: At 2 years, subjects in the high-PP group (n = 7971) had similar rates of the primary end point (4.3% vs 3.9%; P = 0.058), POCE (14.9% vs 12.7%; P = 0.051), and BARC 3 or 5 (2.5% vs 1.7%; P = 0.355) and higher rates of NACE (16.4% vs 13.7%; P = 0.037) compared with the low-PP group (n = 7965). Among patients with PP < 60 mm Hg, the primary end point (3.4% vs 4.4%, adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.96), POCE (11.8% vs 13.5%, aHR 0.86, 95% CI 0.76-0.98), NACE (12.8% vs 14.7%, aHR 0.85, 95% CI 0.76-0.96), and BARC 3 or 5 (1.4% vs 2.1%, aHR 0.69, 95% CI 0.49-0.97) were lower with ticagrelor monotherapy compared with DAPT. The only significant interaction was for BARC 3 or 5 (P = 0.008). Conclusions: After contemporary PCI, subjects with high PP levels experienced high rates of NACE at 2 years. In those with low PP, ticagrelor monotherapy led to a lower risk of bleeding events compared with standard DAPT.

Item does not contain fulltext AIMS: The aim of this study was to evaluate the impact of 23-month ticagrelor monotherapy following one-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) on the rates of patient-oriented composite endpoints (POCE) and net adverse clinical events (NACE). METHODS AND RESULTS: The rates of site-reported Academic Research Consortium (ARC)-2 defined POCE (all-cause death, any stroke, any myocardial infarction or any revascularisation) and NACE (POCE or bleeding type 3 or 5 according to the Bleeding ARC [BARC]) were reported up to two years by intention-to-treat principle in the randomised, multicentre, open-label GLOBAL LEADERS study comparing two antiplatelet strategies in 15,991 patients undergoing PCI. The experimental strategy consisted of aspirin with ticagrelor for one month followed by ticagrelor monotherapy for 23 months, whereas the reference treatment consisted of 12-month DAPT followed by 12-month aspirin monotherapy. At two years, POCE occurred in 1,050 (13.2%) patients in the experimental group and in 1,131 (14.2%) in the reference group (HR 0.93, 95% CI: 0.85-1.01, p=0.085). NACE occurred in 1,145 (14.4%) patients in the experimental group and in 1,237 (15.5%) patients in the reference group (HR 0.92, 95% CI: 0.85-1.00, p=0.057). In pre-specified subgroup analyses, no significant treatment-by-subgroup interactions were found for either POCE or NACE at two years. CONCLUSIONS: The experimental treatment strategy of one-month DAPT followed by 23 months of ticagrelor alone did not result in a significant reduction in the rates of site-reported POCE or NACE, when compared to the reference treatment. ClinicalTrials.gov Identifier: NCT01813435.

OBJECTIVES This study sought to explore the association between biomarker elevation, with creatine kinase-myocardial band (CK-MB) or cardiac troponin (cTn), following percutaneous coronary intervention (PCI) and mortality in patients undergoing PCI for stable angina with normal baseline values. BACKGROUND Several studies have shown a strong association between post-PCI CK-MB elevation and subsequent mortality. However, the prognostic significance of troponin elevation following coronary intervention is still debated. METHODS Patient-level data from 5 contemporary coronary stent trials and 1 large registry were pooled. Mortality of patients with stable angina, with normal baseline biomarkers, was compared between patients with and those without different cutoff values of cTn and CK-MB. RESULTS A total of 13,452 patients were included in this pooled analysis. The overall percentage of patients with elevated biomarkers following PCI was 23.9% for CK-MB and 68.4% for cTn. In the patient cohort for whom both assays were available (n = 8,859), 2.4% had both CK-MB ≥5 × the upper limit of normal (ULN) and cTn ≥35 × ULN, while 92% had both CK-MB

Aims To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed. Methods and results Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46–0.85), P = 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients [HR 0.84 (95% CI 0.71–0.98), P = 0.024]. Conclusions Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after 4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical safety and efficacy of permanently implanted coronary stents. This trial is registered with ClinicalTrials.gov, number [NCT00476957][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00476957&atom=%2Fehj%2Fearly%2F2014%2F08%2F07%2Feurheartj.ehu318.atom

[Tomaniak, Mariusz; Chang, Chun-Chin; Onuma, Yoshinobu] Erasmus MC, Thorax Ctr, Dept Intervent Cardiol, Rotterdam, Netherlands. [Tomaniak, Mariusz; Chang, Chun-Chin; Onuma, Yoshinobu] Med Univ Warsaw, Dept Cardiol 1, Warsaw, Poland. [Chichareon, Ply; Kogame, Norihiro; Modolo, Rodrigo; Takahashi, Kuniaki] Acad Med Ctr, Amsterdam, Netherlands. [Klimczak, Dominika] Med Univ Warsaw, Dept Immunol Transplant Med & Internal Dis, Div Heart Failure & Cardiac Rehabil, Warsaw, Poland. [Komiyama, Hidenori; Rademaker-Havinga, Tessa] Cardialysis, Rotterdam, Netherlands. [Curzen, Nick] Univ Hosp Southampton, Southampton, Hants, England. [Haude, Michael] Lukaskrankenhaus Neuss, Neuss, Germany. [Hamm, Christian] Kerckhoff Clin, Bad Nauheim, Germany. [Steg, Philippe Gabriel] Grp Hosp Bichat Claude Bernard, Paris, France. [Juni, Peter] Univ Toronto, Toronto, ON, Canada. [Vranckx, Pascal] Hartctr Hasselt, Hasselt, Belgium. [Valgimigli, Marco] Inselpsital, Swiss Cardiovasc Ctr, Bern, Switzerland. [Windecker, Stephan] Univ Bern, Bern Univ Hosp, Inselspital, Bern, Switzerland. [Anderson, Richard] Univ Hosp Wales, Cardiff, S Glam, Wales. [Serruys, Patrick] Imperial Coll, London, England.

Ischemic and bleeding risk prediction scores designed for guiding antiplatelet therapy after percutaneous coronary intervention (PCI) remain underused in daily clinical practice, including particularly susceptible subsets such as elderly patients. We aimed to evaluate the efficacy and safety of

Objectives The purpose of this study was to compare the safety and efficacy of the Xience V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) with the Taxus Liberte (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) at 2-year follow-up. Background COMPARE (Comparison of the everolimus eluting XIENCE-V stent with the paclitaxel eluting TAXUS LIBERTE stent in all-comers: a randomized open label trial) demonstrated a superior clinical outcome of EES over PES at 1 year in all comers. Whether this superiority is maintained after discontinuation, at 12 months, of dual antiplatelet therapy is unclear. Methods Patients undergoing percutaneous coronary intervention with limited exclusion criteria were randomly allocated to EES or PES. The 2-year pre-specified endpoints are composites of safety and efficacy and stent thrombosis. Results Follow-up was completed in 1,795 of 1,800 patients (99.7%). The groups had similar baseline characteristics. At 2 years, significantly fewer EES patients took dual antiplatelet therapy (11.4% vs. 15.4%, p = 0.02). The primary composite of all death, nonfatal myocardial infarction, and target vessel revascularization occurred in 9.0% of EES patients and 13.7% of PES patients (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.50 to 0.86) driven by a lower rate of myocardial infarction (3.9% vs. 7.5%; RR: 0.52; 95% CI: 0.35 to 0.77) and target vessel revascularization (3.2% vs. 8.0%; RR: 0.41; 95% CI: 0.27 to 0.62), in parallel with a lower rate of definite or probable stent thrombosis (0.9% vs. 3.9%; RR: 0.23; 95% CI: 0.11 to 0.49). Differences significantly increased between 1- and 2-year follow-up for the primary composite endpoint (p = 0.04), target vessel revascularization (p = 0.02), and definite or probable stent thrombosis (p = 0.02). Conclusions The substantial clinical benefit of the EES over the PES with regard to measures of both safety and efficacy is maintained at 2 years in real-life practice with an increasing benefit in terms of safety and efficacy between 1 year and 2 years. Comparison of the everolimus eluting XIENCE-V stent with the paclitaxel eluting TAXUS LIBERTE stent in all-comers: a randomized open label trial: The COMPARE Trial [COMPARE 1]; NCT01016041 )