Change-points in antibiotic consumption in the community, European Union/European Economic Area, 1997-2017.

OBJECTIVES: Surveillance of antibiotic consumption in the community is of utmost importance to inform and evaluate control strategies. Data on two decades of antibiotic consumption in the community were collected from 30 EU/European Economic Area (EEA) countries. This article reviews temporal trends and the presence of abrupt changes in subgroups of relevance in antimicrobial stewardship. METHODS: For the period 1997-2017, data on yearly antibiotic consumption in the community, aggregated at the level of the active substance, were collected using the WHO ATC classification and expressed in DDD (ATC/DDD index 2019) per 1000 inhabitants per day. We applied a range of non-linear mixed models to assess the presence of changes in the consumption of antibacterials for systemic use (ATC group J01) and eight antibiotic subgroups. RESULTS: For the majority of the studied groups, a country-specific change-point model provided the best fit. Depending on the antibiotic group/subgroup and on the country, change-points were spread out between 2000 and 2013. CONCLUSIONS: Due to the heterogeneity in antibiotic consumption in the community across EU/EEA countries, a country-specific change-point model provided the better fit. Given the limitations of this model, our recommendation for the included countries is to carefully interpret the country-specific results presented in this article and to use the tutorial included in this series to conduct their own change-point analysis when evaluating the impact of changes in regulations, public awareness campaigns, and other national interventions to improve antibiotic consumption in the community.

Quantifying Ischemic Risk After Percutaneous Coronary Intervention Attributable to High Platelet Reactivity on Clopidogrel (From the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents Study).

Patients at high risk of thrombotic events after percutaneous coronary intervention (PCI) may potentially benefit from intensified antiplatelet therapy. However, more potent antiplatelet therapy would be expected to only overcome risk that is mediated by high platelet reactivity (PR). We used mediation analysis to determine the contribution of residual PR to the 2-year risk of major adverse cardiac events (MACE; the composite of cardiac death, myocardial infarction, or stent thrombosis) associated with clinical risk factors after PCI with drug-eluting stents (DES) in 8,374 patients from the prospective, multicenter Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) registry. Residual PR on clopidogrel, as measured by the VerifyNow P2Y12 point-of-care assay, was included as a continuous linear mediator variable in Cox proportional hazards regression. Among 7 factors independently associated with 2-year MACE, residual PR partly mediated the effect of diabetes (13.4% attributable risk), anemia (22.9% attributable risk), and acute coronary syndromes (7.3% attributable risk). A PR-mediated effect inversely affected the MACE risk associated with smoking (10.4% attributable risk). The increased ischemic risk of chronic kidney disease, multivessel disease, and previous myocardial infarction were not mediated by residual PR. In conclusion, high residual PR mediates little or none of the increased 2-year MACE risk associated with baseline risk factors in patients treated with clopidogrel after successful PCI with DES. Intensifying antiplatelet therapy is therefore unlikely to substantially mitigate the excess ischemic risk from these variables.

Impact of Chronic Total Occlusions on Revascularization Scores and Outcome Prediction.

OBJECTIVES: To evaluate the contribution of chronic total occlusion (CTO)-related SYNTAX score (SS) to the overall SS for patients with CTO and compare the traditional SS to a simplified variant. The SS algorithm assigns CTO lesions a greater weight (5× points) than non-CTO lesions (50% to <100% diameter stenosis; 2× points). METHODS: We calculated the SS and the simplified SS (2× points also to CTO lesions) for 4356 patients from the angiographic substudy of the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial. We compared the association between SS and 1-year mortality and major adverse cardiac events for patients with and without a CTO. We also compared the simplified SS with the traditional SS. RESULTS: The median SS was 20 (interquartile range, 13-27.5) for patients with a CTO and 8 (interquartile range, 2-16) for patients without a CTO. For patients with a CTO, the CTO lesion(s) contributed 67 ± 26% of the total SS. The simplified SS reclassified 187/603 (31.0%) of patients with a SS >22 to a SS ≤22. The traditional SS did not improve discrimination indices for predicting outcomes compared with the simplified SS. CONCLUSIONS: CTO lesions contribute considerably to the total SS in patients with a CTO. A simplified SS that does not differentiate between CTO and non-CTO lesions appeared equivalent to the traditional SS for risk prediction, but reclassified a substantial proportion of patients to a SS ≤22 and may impact choice of revascularization strategy for patients with complex coronary artery disease involving a CTO lesion.

The SYNTAX Score Does Not Predict Risk of Adverse Events in Patients With Non-ST Elevation Acute Coronary Syndrome Who Undergo Coronary Artery Bypass Graft Surgery.

OBJECTIVES: We tested the ability of the SYNTAX score (SS) to predict 1-year adverse outcomes for patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) who undergo coronary artery bypass graft (CABG) surgery. BACKGROUND: The SS effectively risk stratifies patients who undergo percutaneous coronary intervention, but not patients with stable coronary disease who undergo CABG. METHODS: We calculated the SS for 457 patients with NSTE-ACS in the angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial who underwent CABG. We stratified and compared patients according to SS tertiles. We tested the ability of the SS, as a linear covariate, to predict adverse events by univariate analyses and by univariate and multivariable Cox proportional hazards model. We also tested the predictive abilities of the Age, Creatinine Clearance, and Ejection Fraction (ACEF) score, the clinical SS, and the logistic clinical SS. RESULTS: The median SS was 23 (interquartile range, 15-30). Baseline clinical characteristics were similar among the groups. One-year mortality and major adverse cardiovascular events (all-cause death, myocardial infarction, any stroke, or urgent revascularization) were similar between the groups (P=.13 and P=.62, respectively). Receiver operating characteristic curves, net reclassification indices, and integrated discrimination indices did not improve with SS, clinical SS, or logistic clinical SS compared with the ACEF score. CONCLUSIONS: The anatomical SS does not appear to be useful in risk stratifying patients with NSTE-ACS who undergo CABG. Clinical variables may better risk stratify patients with complex coronary artery disease considered for CABG.

Bleeding Events Before Coronary Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Upstream administration of antithrombotic drugs to patients with non-ST-segment elevation acute coronary syndromes before coronary angiography is a common practice despite an incomplete understanding of the risks and benefits. OBJECTIVES: The authors analyzed the incidence of bleeding and ischemic events occurring before angiography and assessed their association with antithrombotic drugs and mortality risk. METHODS: All patients from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with planned angiography after enrollment were included. Bleeding events were classified according to the ACUITY scale as major or nonmajor bleeding. Kaplan-Meier and Cox proportional hazards analyses were performed. RESULTS: Of 13,726 patients, 275 (2.0%) bled before angiography, including 52 (0.4%) with major bleeding. Forty-four (0.3%) experienced myocardial infarction. The median time from randomization to coronary angiography was 4.5 h (interquartile ratio [IQR]: 1.7 to 19.7 h) for patients who did not bleed while waiting for angiography and 27.9 h (IQR: 21.9 to 65.6 h) for patients who bled while waiting for angiography (p < 0.001). Bleeding events accrued linearly over time, reaching 10.4% at 96 h post-randomization. Independent predictors of bleeding before angiography included age (adjusted hazard ratio [HR]: 1.03 per year of age; 95% confidence interval [CI]: 1.01 to 1.04; p < 0.001), renal insufficiency (adjusted HR: 1.48; 95% CI: 1.07 to 2.04; p = 0.02), and use of multiple antithrombotic drugs (adjusted HR: 1.33; 95% CI: 1.14 to 1.56; p < 0.001). Bleeding before coronary angiography was associated with longer hospitalization (4.8 days [IQR: 3.0 to 8.9 days] vs. 3.0 days [IQR: 1.9 to 5.9 days]; p < 0.001). Patients who bled before angiography were more likely to die within 1 year than patients who did not bleed (8.5% vs. 4.1%; p < 0.001; adjusted HR: 1.89 (95% CI: 1.23 to 2.90; p = 0.004). CONCLUSIONS: Upstream antithrombotic treatment of patients with non-ST-segment elevation acute coronary syndromes awaiting coronary angiography is associated with excess bleeding with mortality implications. Bleeding avoidance strategies before angiogram, including early angiography, may negate the need to prolong upstream antithrombotic treatment and improve the overall risk-benefit balance for these patients. (Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY]; NCT00093158).

Impact of time to treatment on the effects of bivalirudin vs. glycoprotein IIb/IIIa inhibitors and heparin in patients undergoing primary percutaneous coronary intervention: insights from the HORIZONS-AMI trial.

AIMS: In the HORIZONS-AMI trial, bivalirudin compared to unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) improved net clinical outcomes in patients undergoing primary percutaneous coronary intervention (PCI) at the cost of an increased rate of acute stent thrombosis. We sought to examine whether these effects are dependent on time to treatment. METHODS AND RESULTS: The interaction between anticoagulation regimen and symptom onset to first balloon inflation time (SBT) on the 30-day and three-year rates of major adverse cardiac events (MACE) was examined in 3,199 randomised patients according to SBT ≤3 hours versus >3 hours. Among patients with an SBT ≤3 hours, bivalirudin resulted in higher 30-day rates of MACE compared to UFH plus a GPI. Non-significant differences were observed in patients with an SBT >3 hours. Similar results were found for MACE at three years and stent thrombosis and reinfarction at 30 days and three years. By multivariable analysis, bivalirudin was an independent predictor of MACE at 30 days and three years in patients with an SBT ≤3 hours, but not in patients with SBT >3 hours. CONCLUSIONS: Bivalirudin compared to UFH plus a GPI is associated with an increased rate of stent thrombosis and MACE in patients with short SBTs, but not in those with longer SBTs.

Dedicated Bifurcation Stent for the Treatment of Bifurcation Lesions Involving Large Side Branches: Outcomes From the Tryton Confirmatory Study.

OBJECTIVES: The aim of this study was to prospectively study and confirm the safety and efficacy of the Tryton Side Branch Stent in the treatment of coronary artery bifurcations involving large side branches (SBs). BACKGROUND: The TRYTON Pivotal randomized controlled trial (RCT) was designed to compare the Tryton stent with standard provisional SB stenting in large vessels. The trial inadvertently enrolled patients with too small SBs (<2.25 mm). The overall trial did not meet its primary endpoint, because of an increased rate of periprocedural myocardial infarction in the Tryton stent arm. A post hoc analysis restricted to the intended population showed that the trial would have met its endpoint if only patients with SBs ≥2.25 mm in diameter (by core laboratory quantitative coronary angiography) had been enrolled. METHODS: The Tryton Confirmatory Study was a prospective, single-arm extension of the TRYTON Pivotal RCT that enrolled an additional 133 patients treated with the Tryton Side Branch Stent. It was designed to confirm the results of the post hoc analysis and emphasized the inclusion of appropriately sized SBs. The primary endpoint was noninferiority with regard to periprocedural myocardial infarction (creatine kinase myocardial band 3 times the upper limit of normal) compared with a performance goal based on the TRYTON Pivotal RCT. RESULTS: Among the 133 enrolled patients, 132 (99.2%) had SBs ≥2.25 mm. Baseline clinical and angiographic parameters were similar in this study and the RCT. Periprocedural myocardial infarction occurred in 10.5% of patients, which was numerically lower than the provisional group in the TRYTON Pivotal RCT (11.9%). The 95% confidence bounds did not extend beyond the pre-defined performance goal of 17.9%, meeting the noninferiority primary endpoint. CONCLUSIONS: The Tryton Confirmatory Study, in conjunction with the post hoc analysis of the intended population in the TRYTON Pivotal RCT, supports the safety and efficacy of the Tryton Side Branch Stent for treatment of bifurcation lesions involving large SBs.

Which Intraprocedural Thrombotic Events Impact Clinical Outcomes After Percutaneous Coronary Intervention in Acute Coronary Syndromes?: A Pooled Analysis of the HORIZONS-AMI and ACUITY Trials.

OBJECTIVES: This study sought to determine the extent to which individual components of intraprocedural thrombotic events (IPTEs) are associated with adverse events. BACKGROUND: IPTEs occurring during percutaneous coronary intervention (PCI) are associated with adverse in-hospital and late outcomes in patients with acute coronary syndromes. METHODS: A total of 6,591 patients who underwent PCI for non-ST-segment elevation acute coronary syndromes/ST-segment elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) and HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trials underwent detailed frame-by-frame core laboratory angiographic analysis to assess for IPTEs. The associations of IPTE components with death, major bleeding, and major adverse cardiac events at 30 days were assessed using univariable analyses and multivariable models. RESULTS: The overall incidence of IPTEs was 7.7%, with a greater incidence in ST-segment elevation myocardial infarction patients (12.2%) compared with non-ST-segment elevation acute coronary syndromes patients (3.5%). Specific components of IPTEs included no-reflow/slow reflow in 58.0%, new/worsened thrombus in 35.3%, distal embolization in 34.9%, abrupt closure in 19.8%, and intraprocedural stent thrombosis (IPST) in 9.5% of patients. Each IPTE component was independently associated with 30-day death, major bleeding, and MACE in multivariable models, with the strongest association observed for IPST (MACE hazard ratio: 7.51 [95% confidence interval: 4.36 to 12.94]). CONCLUSIONS: The occurrence of IPTEs is not infrequent among high-risk acute coronary syndromes patients undergoing PCI, and each IPTE component was associated with subsequent adverse events. Although IPST represented <10% of IPTE events overall, it was the component with the strongest association with adverse events.

Clinical and Functional Outcomes Associated With Myocardial Injury After Transfemoral and Transapical Transcatheter Aortic Valve Replacement: A Subanalysis From the PARTNER Trial (Placement of Aortic Transcatheter Valves).

OBJECTIVES: This study sought to clarify the clinical and echocardiographic prognostic implication of myocardial injury after transcatheter aortic valve replacement (TAVR). BACKGROUND: The clinical significance of cardiac biomarker elevation after TAVR remains unclear. METHODS: Patients treated with TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) trial were divided into tertiles (T1, T2, T3) based on the difference between the values on post-procedure day 1 and the baseline values of 2 cardiac biomarkers: cardiac troponin I (ΔcTnI); and creatine kinase-myocardial band (ΔCK-MB) fraction. Patients were stratified according to their access route: transfemoral (TF) (n = 1,840) or transapical (TA) (n = 1,173). RESULTS: At 30 days after TF-TAVR, patients in the highest tertile (T3) of cardiac biomarker elevation had a higher rate of all-cause mortality (ΔcTnI: T3: 5.4% vs. T1: 0.5%, p = 0.006; ΔCK-MB: T3: 5.7% vs. T1: 0.9%, p = 0.006) and cardiovascular mortality (ΔcTnI: T3: 4.9% vs. T1: 0.5%, p = 0.01; ΔCK-MB: T3: 3.9% vs. T1: 0.5%, p = 0.02). At 1 year, only patients in the highest CK-MB tertile had higher rates of all-cause (25.4% vs. 16.8%, p = 0.02) and cardiovascular (10.3% vs. 5.0%) mortality. Multivariable analysis demonstrated that greater release of cardiac biomarkers was independently associated with increased mortality in the TF population. After TA-TAVR, being in the highest tertile of cardiac biomarker elevation had no influence on clinical and echocardiographic outcomes at 30 days and 1 year. CONCLUSIONS: After TF-TAVR, a greater degree of myocardial injury was associated with higher rates of 30-day all-cause and cardiovascular mortality. At 1 year, being in the highest tertile of ΔCK-MB was correlated with a higher rate of all-cause and cardiac mortality. Finally, the level of myocardial injury after TA-TAVR had no impact on clinical and echocardiographic outcomes.

Estimating the impact of school closure on social mixing behaviour and the transmission of close contact infections in eight European countries.

BACKGROUND: Mathematical modelling of infectious disease is increasingly used to help guide public health policy. As directly transmitted infections, such as influenza and tuberculosis, require contact between individuals, knowledge about contact patterns is a necessary pre-requisite of accurate model predictions. Of particular interest is the potential impact of school closure as a means of controlling pandemic influenza (and potentially other pathogens). METHODS: This paper uses a population-based prospective survey of mixing patterns in eight European countries to study the relative change in the basic reproduction number (R0--the average number of secondary cases from a typical primary case in a fully susceptible population) on weekdays versus weekends and during regular versus holiday periods. The relative change in R0 during holiday periods and weekends gives an indication of the impact collective school closures (and prophylactic absenteeism) may have during a pandemic. RESULTS: Social contact patterns differ substantially when comparing weekdays to the weekend and regular to holiday periods mainly due to the reduction in work and/or school contacts. For most countries the basic reproduction number decreases from the week to weekends and regular to holiday periods by about 21% and 17%, respectively. However for other countries no significant decrease was observed. CONCLUSION: We use a large-scale social contact survey in eight different European countries to gain insights in the relative change in the basic reproduction number on weekdays versus weekends and during regular versus holiday periods. The resulting estimates indicate that school closure can have a substantial impact on the spread of a newly emerging infectious disease that is transmitted via close (non sexual) contacts.