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Background: In patients with multivessel disease with successful primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction, the FLOWER-MI trial (Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction) showed that a fractional flow reserve (FFR)-guided strategy was not superior to an angiography-guided strategy for treatment of noninfarct-related artery lesions regarding the 1-year risk of death from any cause, myocardial infarction, or unplanned hospitalization leading to urgent revascularization. The extension phase of the trial was planned using the same primary outcome to determine whether a difference in outcomes would be observed with a longer follow-up., Methods: In this multicenter trial, we randomly assigned patients with ST-segment-elevation myocardial infarction and multivessel disease with successful percutaneous coronary intervention of the infarct-related artery to receive complete revascularization guided by either FFR (n=586) or angiography (n=577)., Results: After 3 years, a primary outcome event occurred in 52 of 498 patients (9.40%) in the FFR-guided group and in 44 of 502 patients (8.17%) in the angiography-guided group (hazard ratio, 1.19 [95% CI, 0.79-1.77]; P =0.4). Death occurred in 22 patients (4.00%) in the FFR-guided group and in 23 (4.32%) in the angiography-guided group (hazard ratio, 0.96 [95% CI, 0.53-1.71]); nonfatal myocardial infarction in 23 (4.13%) and 14 (2.56%), respectively (hazard ratio, 1.63 [95% CI, 0.84-3.16]); and unplanned hospitalization leading to urgent revascularization in 21 (3.83%) and 18 (3.36%; hazard ratio, 1.15 [95% CI, 0.61-2.16]), respectively., Conclusions: Although event rates in the trial were lower than expected, in patients with ST-segment-elevation myocardial infarction undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization up to 3 years., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02943954., Competing Interests: Disclosures None.

Background: Whether ticagrelor in chronic coronary syndrome patients undergoing complex percutaneous coronary intervention (PCI) can prevent cardiovascular events is unknown., Objectives: The authors sought to evaluate outcomes of complex PCI and the efficacy of ticagrelor vs clopidogrel in stable patients randomized in the ALPHEUS (Assessment of Loading with the P2Y 12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting) trial., Methods: All PCI procedures were blindly reviewed and classified as complex if they had at least 1 of the following criteria: stent length >60 mm, 2-stent bifurcation, left main, bypass graft, chronic total occlusion, use of atherectomy or guiding catheter extensions, multiwire technique, multiple stents. The primary endpoint was a composite of type 4a or b myocardial infarction (MI) and major myocardial injury during the 48 hours after PCI. We compared the event rates according to the presence or not of complex PCI criteria and evaluated the interaction with ticagrelor or clopidogrel., Results: Among the 1,866 patients randomized, 910 PCI (48.3%) were classified as complex PCI. The primary endpoint was more frequent in complex PCI (45.6% vs 26.6%; P < 0.001) driven by higher rates of type 4 MI and angiographic complications (12.2% vs 4.8 %; P < 0.001 and 19.3% vs 8.6%; P < 0.05, respectively). The composite of death, MI, and stroke at 48 hours (12.7% vs 5.1 %; P < 0.05) and at 30 days (13.4% vs 5.3%; P < 0.05) was more frequent in complex PCI. No interaction was found between PCI complexity and the randomized treatment for the primary endpoint (P interaction  = 0.47) nor the secondary endpoints., Conclusions: In chronic coronary syndrome, patients undergoing a complex PCI have higher rates of periprocedural and cardiovascular events that are not reduced by ticagrelor as compared with clopidogrel., Competing Interests: Funding Support and Author Disclosures The ALPHEUS trial was led by the ACTION Study Group, an academic research organization based at the Pitié-Salpêtrière Hospital (Paris, France). The study was sponsored by Assistance Publique-Hopitaux de Paris and was funded by an unrestricted grant from AstraZeneca. The present work was supported by a grant of the French Federation of Cardiology. Prof Lattuca has received research grants from Biotronik, Boston Scientific, Daiichi Sankyo, Fédération Française de Cardiologie, and the Institute of CardioMetabolism and Nutrition; consulting fees from Daiichi Sankyo and Eli Lilly; and lecture fees from AstraZeneca, Medtronic, and Novartis. Prof Cayla has received consulting fees from Edwards Lifesciences, Medtronic, and Microport CRM; and lecture fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Microport, Medtronic, Pfizer, and Sanofi. Prof Ducrocq has received speaker and consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Novo Nordisk, and Sanofi; has served on steering committees for Amgen, Novo Nordisk, and Janssen; and has been a proctor for Boston Scientific. Dr Laredo has received speaker or consulting fees from Abbott and Biotronik. Dr Kala has received consulting fees from Boston Scientific; and lecture fees from AstraZeneca, Edwards Lifesciences, Novartis, Servier, and Terumo. Prof Varenne has received research grants from Abbott and Boston Scientific; and lecture fees from Abbott, AstraZeneca, Boston Scientific, and Servier. Prof Spaulding has received consulting fees from Edwards Lifesciences, Medtronic, Sonivie, Techwald, and Valcare; has received speaker fees from Amgen and Edwards Lifesciences; and is stock shareholder of Techwald and Valcare. Prof Beygui has received consulting and lecture fees from Medtronic, Novartis, and Pfizer; and research grants from Biosensors and Medtronic. Dr Rangé has received speaker or consulting fees from Abbott and Microport. Prof Vicaut has received consulting or speaker fees from Abbott, Amgen, Bristol Myers Squibb, Celgene, LFB, Pfizer, and Sanofi. Prof Collet has received consulting and lecture fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, COR2ED, Lead-Up, Medtronic, and WebMD. Prof Montalescot has received research grants and consulting or speaker fees from Abbott, Amgen, AstraZeneca, Ascendia, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Celecor, CSL Behring, Idorsia, Lilly, Novartis, Novo, Opalia, Pfizer, Quantum Genomics, Sanofi, and Terumo. Prof Silvain has received research grants and consulting or speaker fees from AstraZeneca, Bayer HealthCare SAS, Abbott Medical, Biotronik, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, and Sanofi France; and is stock Shareholder of Pharmaseeds, Terumo, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There are dated and conflicting data about the optimal timing of initiation of P2Y 12 inhibitors in elective percutaneous coronary intervention (PCI). Peri-PCI myocardial necrosis is associated with poor outcomes. We aimed to assess the impact of the P2Y 12 inhibitor loading time on periprocedural myocardial necrosis in the population of the randomized Assessment of Loading With the P2Y 12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting (ALPHEUS) trial, which compared ticagrelor with clopidogrel in high-risk patients who received elective PCI., Methods: The ALPHEUS trial divided 1809 patients into quartiles of loading time. The ALPHEUS primary outcome was used (type 4 [a or b] myocardial infarction or major myocardial injury) as well as the main secondary outcome (type 4 [a or b] myocardial infarction or any type of myocardial injury)., Results: Patients in the first quartile group (Q1) presented higher rates of the primary outcome (P = 0.01). When compared with Q1, incidences of the primary outcome decreased in patients with longer loading times (adjusted odds ratio [adjOR], 0.70 [0.52.-0.95]; P = 0.02 for Q2; adjOR 0.65 [0.48-0.88]; P < 0.01 for Q3; adjOR 0.66 [0.49-0.89]; P < 0.01 for Q4). Concordant results were found for the main secondary outcome. There was no interaction with the study drug allocated by randomization (clopidogrel or ticagrelor). Bleeding complications (any bleeding ranging between 4.9% and 7.3% and only 1 major bleeding at 48 hours) and clinical ischemic events were rare and did not differ among groups., Conclusions: In elective PCI, administration of the oral P2Y 12 inhibitor at the time of PCI could be associated with more frequent periprocedural myocardial necrosis than an earlier administration. The long-term clinical consequences remain unknown., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

In patients with non-ST-elevation myocardial infarction (NSTEMI), total occlusion of the culprit coronary artery (OCA) is not uncommon. We sought to determine the frequency and clinical impact of OCA at presentation in a large population of patients presenting with NSTEMI and who underwent systematic early invasive management. We performed a post hoc analysis of the TAO (Treatment of Acute Coronary Syndrome with Otamixaban) randomized trial, which included patients with NSTEMI with systematic coronary angiography within 72 hours. We compared the baseline characteristics and outcomes of patients according to whether the culprit vessel was occluded (thrombolysis in myocardial infarction flow grade [TFG] 0 to 1) or patent (TFG 2 to 3) at presentation. A total of 7,473 patients with NSTEMI with only 1 culprit lesion identified were enrolled, of whom 1,702 patients had OCA (22.8%). In the OCA group, coronary angiography was performed earlier (18 ± 15 vs 20 ± 16 hours, p <0.01), the culprit lesion was less likely to be the left anterior descending artery (26.5% vs 41.4%, p <0.001) but with more frequent angiographic thrombus (49.9% vs 22.7%, p <0.01). Culprit artery percutaneous coronary intervention during the index procedure was also more frequent (88.5% vs 78.1%, p <0.001) but with a lower rate of TFG grade 3 after the procedure and higher subsequent peak troponin I levels (8.3 ± 13.6 µg/L vs 5.6 ± 11.9 µg/L, p <0.001). At day 7, patients with OCA had higher mortality, and this persisted after adjustment on gender, Grace risk score, cardiovascular risk factors, and culprit vessel location (0.9% vs 0.4%, p = 0.02; adjusted odds ratio [OR] = 2.55, 95% confidence interval [CI] 1.23 to 5.29, p = 0.01). The absolute difference of mortality was maintained through 30 days: 1.2% versus 0.8%, p = 0.13; OR: 1.72, 95% CI 0.97 to 3.05, but mortality rates were similar by 180 days: 1.5% versus 1.6%, p = 0.8, adjusted OR = 1.11, 95% CI 0.69 to 1.80, p = 0.66. In conclusion, a significant proportion of patients with NSTEMI have a totally occluded culprit vessel at presentation. These patients are at higher risk of early mortality but not at 6 months., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry., Methods and Results: The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy., Conclusions: In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.', Clinical Trial Registration: http://www., Clinicaltrials: gov identifier: NCT01991795., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population., Methods: The population was divided into tertiles: score ≤22, 23 to 33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (net adverse clinical events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted., Results: Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (P interaction  = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (P interaction  = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; P interaction  = .012)., Conclusions: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In patients with ST-elevation myocardial infarction (STEMI) who have multivessel disease, percutaneous coronary intervention (PCI) for nonculprit lesions (complete revascularization) is superior to treatment of the culprit lesion alone. However, whether complete revascularization that is guided by fractional flow reserve (FFR) is superior to an angiography-guided procedure is unclear., Methods: In this multicenter trial, we randomly assigned patients with STEMI and multivessel disease who had undergone successful PCI of the infarct-related artery to receive complete revascularization guided by either FFR or angiography. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 1 year., Results: The mean (±SD) number of stents that were placed per patient for nonculprit lesions was 1.01±0.99 in the FFR-guided group and 1.50±0.86 in the angiography-guided group. During follow-up, a primary outcome event occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 patients (4.2%) in the angiography-guided group (hazard ratio, 1.32; 95% confidence interval, 0.78 to 2.23; P = 0.31). Death occurred in 9 patients (1.5%) in the FFR-guided group and in 10 (1.7%) in the angiography-guided group; nonfatal myocardial infarction in 18 (3.1%) and 10 (1.7%), respectively; and unplanned hospitalization leading to urgent revascularization in 15 (2.6%) and 11 (1.9%), respectively., Conclusions: In patients with STEMI undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization at 1 year. However, given the wide confidence intervals for the estimate of effect, the findings do not allow for a conclusive interpretation. (Funded by the French Ministry of Health and Abbott; FLOWER-MI ClinicalTrials.gov number, NCT02943954.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Few data are available on procedural complications of percutaneous coronary intervention (PCI) in the setting of acute coronary syndrome in the contemporary era., Aim: We sought to describe the prevalence of procedural complications of PCI in a non-ST-segment elevation acute coronary syndrome (NSTE ACS) cohort, and to identify their clinical characteristics and association with clinical outcomes., Methods: Patients randomized in TAO (Treatment of Acute coronary syndrome with Otamixaban), an international randomized controlled trial (ClinicalTrials.gov Identifier: NCT01076764) that compared otamixaban with unfractionated heparin plus eptifibatide in patients with NSTE ACS who underwent PCI, were included in the analysis. Procedural complications were collected prospectively, categorized and adjudicated by a blinded Clinical Events Committee, with review of angiograms. A multivariable model was constructed to identify independent clinical characteristics associated with procedural complications., Results: A total of 8656 patients with NSTE ACS who were enrolled in the TAO trial underwent PCI, and 451 (5.2%) experienced at least one complication. The most frequent complications were no/slow reflow (1.5%) and dissection with decreased flow (1.2%). Procedural complications were associated with the 7-day ischaemic outcome of death, myocardial infarction or stroke (24.2% vs. 6.0%, odds ratio 5.01, 95% confidence interval 3.96-6.33; P<0.0001) and with Thrombolysis In Myocardial Infarction major and minor bleeding (6.2% vs. 2.3%, odds ratio 2.79, 95% confidence interval 1.86-4.2; P<0.0001). Except for previous coronary artery bypass grafting, multivariable analysis did not identify preprocedural clinical predictors of complications., Conclusions: In a contemporary NSTE ACS population, procedural complications with PCI remain frequent, are difficult to predict based on clinical characteristics, and are associated with worse ischaemic and haemorrhagic outcomes., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: Previous studies have observed poorer outcomes in females with myocardial infarction, but older age and lower use of percutaneous coronary intervention in females are factors that potentially explain the worse outcome. This study sought to determine if female sex is an independent factor of ischemic and bleeding outcomes in non-ST-segment-elevation acute coronary syndrome treated with a systematic invasive approach., Methods: The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with non-ST-segment-elevation acute coronary syndrome treated invasively to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, the primary ischemic end point (all-cause death, myocardial infarction within 180 days) and the primary safety end point (Thrombolysis in Myocardial Infarction major or minor bleeding within 30 days) were analyzed according to sex., Results: Of 13 229 randomized patients, 3980 (30.1%) were females and 9249 (69.9%) were males. Females were older (64.8±11.0 versus 60.7±11.1 years), had more comorbidities, received less peri-procedural antithrombotic therapy, and underwent less frequently revascularization. Overall, females experienced a higher risk of ischemic (10.2% versus 9.1%; odds ratio [OR], 1.15 [1.01-1.30]) and bleeding events (4.2% versus 3.4%; OR, 1.23 [1.02-1.49]) than males. After multivariate analysis, the risk of ischemic outcomes (OR, 1.04 [0.90-1.19]), death (OR, 1.00 [0.75-1.23]), or bleeding (OR, 1.05 [0.85-1.28]), were similar between females and males. Only, noncoronary artery bypass graft related Thrombolysis in Myocardial Infarction major bleeding were increased in females (OR, 1.69 [1.11-2.56])., Conclusions: In patients with non-ST-segment-elevation acute coronary syndrome with systematic invasive management, ischemic outcomes, bleeding events, and mortality were higher in females. After multivariate analyses, female sex was not an independent predictor of ischemic and bleeding events although noncoronary artery bypass graft related Thrombolysis in Myocardial Infarction major bleeding was higher in females. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764.

Background: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI., Methods: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290., Findings: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070)., Interpretation: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI., Funding: ACTION Study Group and AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI)., Methods: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status., Results: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001)., Conclusion: In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups., Competing Interests: Disclosures PG Steg Research grants: Amarin, Bayer, Sanofi, and Servier Clinical trials (Steering committee or CEC or DMC), speaker or consultant : Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Mylan, Novo-Nordisk, Novartis, Pfizer, Sanofi, Servier. CV Pollack Consultant for Sanofi. J W Jukema : JW Jukema/his department has received research grants from and/or was speaker (with or without lecture fees) on a.o.(CME accredited) meetings sponsored by Amgen, Athera, Astra-Zeneca, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands (CVON), the Netherlands Heart Institute and the European Community Framework KP7 Programme. M Cohen : speaker Sanofi, Consultant to and research support from AstraZeneca. SD Wiviott: Sanofi Aventis, AstraZeneca, Merck, Eli Lilly/Daiichi Sankyo, Boehringer Ingelheim. SR Mehta: Research grants AstraZeneca and Boston scientific; M Sabatine : to be suppressed Sunil V Rao A.Erglis , C Bode, T Cuisset, T Moccetti, G Ducrocq Y Elbez None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y 12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting., Methods: Assessment of Loading with the P2Y 12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier)., Conclusion: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To describe the characteristics and outcomes of patients receiving bailout glycoprotein IIb/IIIa inhibitors (GPI) for thrombotic complications of percutaneous coronary intervention (PCI) in a large, contemporary trial., Methods and Results: In the CHAMPION PHOENIX trial, the use of GPI was restricted to bailout for thrombotic complications. We describe the characteristics and outcomes of patients requiring bailout GPI compared to patients not receiving GPIs, with adjustment through propensity-score. A multivariable model was constructed to identify independent correlates associated with bailout GPI use. A total of 380 out of 10,942 patients received GPI (3.5%); GPI patients were younger, more frequently male, more likely to present with ST segment elevation myocardial infarction and less frequently treated with cangrelor. At 48 h, GPI patients experienced higher rates of the primary composite outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) (19.2% vs 4.8%; adjusted OR: 5.65(4.08, 7.82), p < 0.0001) and a higher rate of GUSTO severe or moderate bleeding (2.6% vs 0.4% adjusted OR: 4.90 (1.98, 12.18), p = 0.0006) compared with non GPI patients. Independent correlates of GPI use were STEMI, use of unfractionated heparin, drug-eluting stents and longer procedure duration., Conclusions: In a large contemporary trial, patients receiving bailout GPI for thrombotic complications of PCI experienced very high risks of both ischemic and bleeding complications, suggesting that prevention of periprocedural complications rather than bailout GPI may be preferable., Clinical Trial Registration: http://www.clinicaltrials.gov identifier: NCT01156571., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In patients undergoing percutaneous coronary intervention (PCI), who did not receive P2Y 12 inhibitor pretreatment, the optimal timing of P2Y 12 inhibitor loading dose remains debated. We sought to examine whether the choice of administration of the clopidogrel loading dose before or after the start of PCI had an impact on periprocedural complications, including bleeding., Methods and Results: The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) double-blind randomized trial compared cangrelor with clopidogrel loading dose at the time of PCI. Pretreatment with clopidogrel before randomization was not permitted per protocol. In the clopidogrel-only group (n=5438), a loading dose was given before (early load [EL]) or after the start of PCI (late load [LL]) according to physician choice. Overall, 3442 (63.3%) patients had EL and 1997 LL (36.7%). Median times were 5 minutes before and 20 minutes after the start of PCI, respectively. EL was more frequently used among patients with ST-segment-elevation myocardial infarction (84.4%) and non-ST-segment-elevation acute coronary syndromes (71.5%) than in stable patients (53.7%). At 48 hours, rates of the primary outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis were similar (6.0% versus 5.4%) for EL versus LL, respectively (odds ratio [OR], 1.11 [95% CI, 0.87-1.41]; P=0.41), and remained so after adjustment for potential confounders, including clinical presentation (OR [95% CI], 1.39 [0.90-2.15]; P=0.14). Compared with clopidogrel, cangrelor consistently reduced the primary outcome in both EL (4.8% versus 6.0%; OR [95% CI], 0.80 [0.64-0.98]) and LL (4.3% versus 5.4%; OR [95% CI], 0.79 [0.59-1.06]; interaction P=0.99). Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding rates were similar between treatment arms for both EL (OR [95% CI], 1.24 [0.58-2.66]) and LL (OR [95% CI], 2.53 [0.98-6.54]; interaction P=0.25)., Conclusions: In a nonrandomized comparison of patients with clopidogrel loading before or after the start of PCI, the rates of periprocedural PCI complications, including bleeding, were similar, as were the benefits of cangrelor, regardless of the timing., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Background: Monitoring anticoagulation with activated clotting time (ACT) has been proposed to reduce ischemic or bleeding events. However, the value of using ACT to improve outcomes is uncertain. This study sought to determine the relationship between ACT and outcomes during percutaneous coronary intervention in patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) treated by unfractionated heparin with GPIs (glycoprotein IIb/IIIa inhibitors)., Methods and Results: From the randomized TAO trial (Treatment of Acute Coronary Syndromes With Otamixaban), we analyzed the value of ACT to predict ischemic and bleeding outcomes in the 3275 patients receiving unfractionated heparin plus eptifibatide. Ischemic and safety outcomes were analyzed according to ACT to determine the best threshold. Median peak ACT was 225 s. There was no correlation ( r =-0.02; P =0.24) between the unfractionated heparin dose received and the ACT value before percutaneous coronary intervention. There was no evidence of a nonlinear association between ACT and either ischemic or bleeding events ( P =0.66; P =0.07). No threshold was found to predict ischemic complications. Conversely, increased bleeding was observed with ACT >230 s with an optimal threshold of ACTs ≥250 s (4.53% versus 6.17%; odds ratio, 1.46; 95% confidence interval, 1.04-2.06; P =0.028). This optimal threshold varied according to access site: ≥250 s (6.86% versus 10.18%; odds ratio, 1.57; 95% confidence interval, 1.00-2.45; P =0.047) by femoral approach and ≥290 s (2.86% versus 5.43%; odds ratio, 2.24; 95% confidence interval, 1.05-4.44; P =0.027) by radial approach., Conclusions: In the TAO trial, peak procedural ACT ≥250 s was associated with increased bleeding risk in non-ST-segment-elevation acute coronary syndrome patients treated with unfractionated heparin plus GPIs. This threshold was increased to 290 s when performing radial approach., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01076764., (© 2018 American Heart Association, Inc.)

Background: Many sites routinely continue anticoagulation after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI), despite an unclear benefit-risk ratio. We evaluated the impact of this strategy on 30-day outcomes from a pooled patient-level database of two large primary percutaneous coronary intervention trials., Methods: EUROMAX and HORIZONS-AMI were both multicentre, international randomised trials comparing bivalirudin to heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary percutaneous coronary intervention. Outcomes at 30 days were analysed according to the use of post-procedural anticoagulation (unfractionated or low-molecular-weight heparins or fondaparinux) outside of the catheterisation laboratory., Results: Among 5239 patients undergoing primary percutaneous coronary intervention, 2153 (41.1%) received post-procedural anticoagulation. After adjusting for differences in baseline variables, there were no differences in the 30-day rates of adverse ischaemic events between patients without versus with post-procedural anticoagulation: adjusted odds ratio for major adverse cardiac events 0.80; 95% confidence interval 0.60-1.07; P=0.14; adjusted odds ratio for stent thrombosis 0.82; 95% confidence interval 0.55-1.24; P=0.35; adjusted odds ratio for death 1.07; 95% confidence interval 0.69-1.66; P=0.77. Conversely, protocol-defined major bleeding was decreased without post-procedural anticoagulation: adjusted odds ratio 0.74; 95% confidence interval 0.58-0.94; P=0.01. Similar results were observed for Thrombolysis In Myocardial Infarction major and minor bleeding., Conclusions: In this large STEMI database, a substantial proportion of primary percutaneous coronary intervention patients received post-procedural anticoagulation, which in turn was associated with higher bleeding rates without any reduction in ischaemic events. Therefore, routine post-procedural anticoagulation after primary percutaneous coronary intervention seems to have an unfavourable benefit-risk profile and should be avoided unless a well-established indication is present., Clinical Trial Registration: ClinicalTrials.gov , EUROMAX Identifier NCT01087723; HORIZONS Identifier NCT00433966.

Early infarct-related artery (IRA) patency is associated with better clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Using the French Registry of ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2010 registry, we investigated factors related to IRA patency (thrombolysis in myocardial infarction [TIMI] 2/3 flow) at the start of procedure in patients admitted for primary percutaneous coronary intervention. FAST-MI 2010 is a nationwide French registry including 4,169 patients with acute MI. Of 1,452 patients with STEMI with primary percutaneous coronary intervention, 466 (32%) had TIMI 2/3 flow of IRA before the procedure. Mean age (62 ± 14 years in both groups), Global Registry of Acute Coronary Event score (141 ± 31 vs 142 ± 34), and time from onset to angiography (472 ± 499 vs 451 ± 479 minutes) did not differ according to IRA patency (TIMI 2/3 vs TIMI 0/1). Using multivariate logistic regression analysis, IRA patency was more frequently found in patients having called earlier (time from onset to electrocardiogram [ECG] <120 minutes; odds ratio [OR] 1.49; 95% confidence interval [CI] 1.17 to 1.89), or receiving rapid-onset of action (prasugrel or glycoprotein IIb-IIIa) antiplatelet therapy in the prehospital setting (OR 1.59, 95% CI 1.14 to 2.21). Increasing time from diagnostic ECG to angiography was also associated with IRA patency (>90 minutes; OR 1.37, 95% CI 1.08 to 1.75). In conclusion, preprocedural IRA patency is observed in one third of patients with STEMI, it is more frequently found in patients having received fast-acting antiplatelet therapy before angiography, and in patients having called early. Higher IRA patency with increasing time delays from qualifying ECG to angiography suggests an additional role of spontaneous or medication-mediated fibrinolysis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: We sought to describe the differential effect of bleeding events in acute coronary syndromes (ACS) on short- and long-term mortality according to their type and severity., Methods and Results: The PLATO trial randomised 18,624 ACS patients to clopidogrel or ticagrelor. Post-randomisation bleeding events were captured according to bleeding type (spontaneous or procedure-related), with PLATO, TIMI, and GUSTO definitions. The association of bleeding events with subsequent short-term (<30 days) and long-term (>30 days) all-cause mortality was assessed using time-dependent Cox proportional hazard models. A model was fitted to compare major and minor bleeding for mortality prediction. Of 18,624 patients, 2,189 (11.8%) had at least one PLATO major bleed (mean follow-up 272.2±123.5 days). Major bleeding was associated with higher short-term mortality (adjusted hazard ratio [HR] 9.28; 95% confidence interval [CI]: 7.50-11.48) but not with long-term mortality (adjusted HR 1.28; 95% CI: 0.93-1.75). Spontaneous bleeding was associated with short-term (adjusted HR 14.59; 95% CI: 11.14-19.11) and long-term (adjusted HR 3.38; 95% CI: 2.26-5.05) mortality. Procedure-related bleeding was associated with short-term mortality (adjusted HR 5.29; 95% CI: 4.06-6.87): CABG-related and non-coronary-procedure-related bleeding were associated with a higher short-term mortality, whereas PCI or angiography-related bleeding was not associated with either short- or long-term mortality. Similar results were obtained using the GUSTO and TIMI bleeding definitions., Conclusions: Major bleeding is associated with high subsequent mortality in ACS. However, this association is much stronger in the first 30 days and is strongest for spontaneous (vs. procedure-related) bleeding.

Although trials comparing antiplatelet strategies after percutaneous coronary intervention report average risks of bleeding and ischemia in a population, there is limited information to guide choices based on individual patient risks, particularly beyond 1 year after treatment. Patient-level data from Patient Related Outcomes With Endeavor vs Cypher Stenting Trial (PROTECT), a broadly inclusive trial enrolling 8,709 subjects treated with drug-eluting stents (sirolimus vs zotarolimus-eluting stent), and PROTECT US, a single-arm study including 1,018 subjects treated with a zotarolimus-eluting stent, were combined. The risk of ischemic events, cardiovascular death/non-periprocedural myocardial infarction (MI)/definite or probable stent thrombosis, and bleeding events, Global Use of Strategies to Open Occluded Arteries moderate or severe bleed, were predicted using logistic regression. At median follow-up of 4.1 years, major bleeding occurred in 260 subjects (2.8%) and ischemic events in 595 (6.3%). Multivariate predictors of bleeding were older age, smoking, diabetes mellitus, congestive heart failure, and chronic kidney disease (all p <0.05). Ischemic events shared all the same predictors with bleeding events and gender, body mass index, previous MI, previous coronary artery bypass graft surgery, ST-segment elevation MI on presentation, stent length, and sirolimus-eluting stent use (all p <0.05). Within individual subjects, bleeding and ischemic risks were strongly correlated; 97% of subjects had a greater risk of ischemic events than bleeding. In conclusion, individual patient risks of ischemia and bleeding are related to many common risk factors, yet the predicted risks of ischemic events are greater than those of major bleeding in the large majority of patients in long-term follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Activated clotting time (ACT) is widely used to guide unfractionated heparin dosing during percutaneous coronary intervention. However, its value in predicting complications is controversial in the modern era. We sought to examine the relationship between ACT and outcomes in non-ST-segment-elevation acute coronary syndrome patients., Methods and Results: In the Fondaparinux With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA/OASIS-8) trial, 2026 patients with non-ST-segment-elevation acute coronary syndrome treated with fondaparinux 2.5 mg/d and undergoing percutaneous coronary intervention were randomized to low-dose unfractionated heparin (50 U/kg) or standard-dose unfractionated heparin (85 U/kg or 60 U/kg with glycoprotein IIb/IIIa inhibitors, with ACT guidance). No difference was shown for major bleeding and there was a trend toward a reduction in ischemic events with standard-dose unfractionated heparin. To clarify the additional value of ACT guidance, we analyzed with logistic modeling peri-percutaneous coronary intervention outcomes according to peak ACT as a linear function. A threshold effect was then investigated. No linear correlation was found between ACT and thrombotic or bleeding events. In patients not receiving planned glycoprotein IIb/IIIa inhibitors, a significant increase in rates of death, myocardial infarction, and target vessel revascularization was identified in patients with an ACT≤300 s (4.86% versus 2.78%; adjusted odds ratio, 1.84; 95% confidence interval, 1.06-3.21; P=0.03). No threshold was found for hemorrhagic complications in patients with or without glycoprotein IIb/IIIa inhibitors., Conclusions: Non-ST-segment-elevation acute coronary syndrome patients undergoing percutaneous coronary intervention with an ACT≤300 s are at increased risk of thrombotic complications. ACT, however, does not predict hemorrhagic complications., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790907., (© 2015 American Heart Association, Inc.)

Objectives: This study sought to assess the impact of invasive strategy (IS) versus a conservative strategy (CS) on in-hospital complications and 3-year outcomes in patients with non-ST-segment elevation myocardial infarction (NSTEMI) from the FAST-MI (French Registry of Acute Coronary Syndrome)., Background: Results from randomized trials comparing IS and CS in patients with NSTEMI are conflicting., Methods: Of the 3,670 patients in FAST-MI, which included patients with acute myocardial infarction (within 48 h) over a 1-month period in France at the end of 2005, 1,645 presented with NSTEMI., Results: Of the 1,645 patients analyzed, 80% had an IS. Patients in the IS group were younger (67 ± 12 years vs. 80 ± 11 years), less often women (29% vs. 51%), and had a lower GRACE (Global Registry of Acute Coronary Events) risk score (137 ± 36 vs. 178 ± 34) than patients treated with CS. In-hospital mortality and blood transfusions were significantly more frequent in patients with CS versus IS (13.1% vs. 2.0%, 9.1% vs. 4.6%). Use of IS was associated with a significant reduction in 3-year mortality and cardiovascular death (17% vs. 60%, adjusted hazard ratio [HR]: 0.44, 95% confidence interval [CI]: 0.35 to 0.55 and 8% vs. 36%, adjusted HR: 0.37, 95% CI: 0.27 to 0.50). After propensity score matching (181 patients per group), 3-year survival was significantly higher in patients treated with IS., Conclusions: In a real-world setting of patients admitted with NSTEMI, the use of IS during the initial hospital stay is an independent predictor of improved 3-year survival, regardless of age. (French Registry of Acute Coronary Syndrome [FAST-MI]; NCT00673036)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)