Temporal Risk of Nonfatal Cardiovascular Events After Chronic Obstructive Pulmonary Disease Exacerbation: A Population-based Study.

Rationale: Cardiovascular events after chronic obstructive pulmonary disease (COPD) exacerbations are recognized. Studies to date have been post hoc analyses of trials, did not differentiate exacerbation severity, included death in the cardiovascular outcome, or had insufficient power to explore individual outcomes temporally.Objectives: We explore temporal relationships between moderate and severe exacerbations and incident, nonfatal hospitalized cardiovascular events in a primary care-derived COPD cohort.Methods: We included people with COPD in England from 2014 to 2020, from the Clinical Practice Research Datalink Aurum primary care database. The index date was the date of first COPD exacerbation or, for those without exacerbations, date upon eligibility. We determined composite and individual cardiovascular events (acute coronary syndrome, arrhythmia, heart failure, ischemic stroke, and pulmonary hypertension) from linked hospital data. Adjusted Cox regression models were used to estimate average and time-stratified adjusted hazard ratios (aHRs).Measurements and Main Results: Among 213,466 patients, 146,448 (68.6%) had any exacerbation; 119,124 (55.8%) had moderate exacerbations, and 27,324 (12.8%) had severe exacerbations. A total of 40,773 cardiovascular events were recorded. There was an immediate period of cardiovascular relative rate after any exacerbation (1-14 d; aHR, 3.19 [95% confidence interval (CI), 2.71-3.76]), followed by progressively declining yet maintained effects, elevated after one year (aHR, 1.84 [95% CI, 1.78-1.91]). Hazard ratios were highest 1-14 days after severe exacerbations (aHR, 14.5 [95% CI, 12.2-17.3]) but highest 14-30 days after moderate exacerbations (aHR, 1.94 [95% CI, 1.63-2.31]). Cardiovascular outcomes with the greatest two-week effects after a severe exacerbation were arrhythmia (aHR, 12.7 [95% CI, 10.3-15.7]) and heart failure (aHR, 8.31 [95% CI, 6.79-10.2]).Conclusions: Cardiovascular events after moderate COPD exacerbations occur slightly later than after severe exacerbations; heightened relative rates remain beyond one year irrespective of severity. The period immediately after an exacerbation presents a critical opportunity for clinical intervention and treatment optimization to prevent future cardiovascular events.

Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study.

BACKGROUND: An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation. METHODS: We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization. RESULTS: Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45). Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15). CONCLUSIONS: Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

The effects of benralizumab on airway geometry and dynamics in severe eosinophilic asthma: a single-arm study design exploring a functional respiratory imaging approach.

BACKGROUND: Severe eosinophilic asthma (SEA) is characterised by elevated blood/sputum eosinophil counts and airway inflammation, which can lead to mucus plug-mediated airway obstruction, increased exacerbation frequency, declines in lung function, and death. Benralizumab targets the alpha-subunit of the interleukin-5 receptor found on eosinophils, leading to rapid and near complete eosinophil depletion. This is expected to result in reduced eosinophilic inflammation, reduced mucus plugging and improved airway patency and airflow distribution. METHODS: BURAN is an interventional, single-arm, open-label, uncontrolled, prospective, multicentre study during which participants will receive three 30 mg subcutaneous doses of benralizumab at 4-week intervals. This study will use functional respiratory imaging (FRI), a novel, quantitative method of assessing patients' lung structure and function based on detailed, three-dimensional models of the airways, with direct comparison of images taken at Weeks 0 and 13. Patients aged ≥ 18 years with established SEA who may be receiving oral corticosteroids and/or other asthma controller medications, who are inadequately controlled on inhaled corticosteroid-long-acting ß2-agonist therapies and who have had ≥ 2 asthma exacerbations in the previous 12 months will be included. The objectives of BURAN are to describe changes in airway geometry and dynamics, measured by specific image-based airway volume and other FRI endpoints, following benralizumab therapy. Outcomes will be evaluated using descriptive statistics. Changes in FRI parameters, mucus plugging scores and central/peripheral ratio will be quantified as mean percent change from baseline (Week 0) to Week 13 (± 5 days) and statistical significance will be evaluated using paired t-tests. Relationships between FRI parameters/mucus plugging scores and conventional lung function measurements at baseline will be assessed with linear regression analyses for associations between outcomes, scatterplots to visualise the relationship, and correlation coefficients (Spearman's rank and Pearson's) to quantify the strength of these associations. CONCLUSIONS: The BURAN study will represent one of the first applications of FRI-a novel, non-invasive, highly sensitive method of assessing lung structure, function and health-in the field of biologic respiratory therapies. Findings from this study will increase understanding of cellular-level eosinophil depletion mechanisms and improvements in lung function and asthma control following benralizumab treatment. Trial registration EudraCT: 2022-000152-11 and NCT05552508.

Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands.

BACKGROUND: People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. METHODS: Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1-7, 8-14, 15-30, 31-180 and 181-365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. RESULTS: 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8-20.0) in days 1-7 to 1.3 (1.0-1.8) in days 181-365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3-4.8) in days 1-7 to 1.6 (1.3-2.1) in days 31-180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9-64.0) in days 1-7 down to 1.6 (1.0-2.6) in days 181-365]. Increase in risk concerned all categories of severe CV events. CONCLUSIONS: Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

Relationship between risk, cumulative burden of exacerbations and mortality in patients with COPD: modelling analysis using data from the ETHOS study.

BACKGROUND: The major drivers of cost-effectiveness for chronic obstructive pulmonary disease (COPD) therapies are the occurrence of exacerbations and deaths. Exacerbations, including acute and long-term events, can cause worsening of COPD and lead to an increased risk of further exacerbations, and ultimately may elevate the risk of death. In contrast to this, health economic models are based on COPD severity progression. In this post hoc analysis of the ETHOS study, we focus on the progression of COPD due to exacerbations and deaths. METHODS: We fitted semi-parametric and fully parametric multi-state Markov models with the following five progressive states: State 1, no exacerbation; State 2, 1 moderate exacerbation; State 3, ≥ 2 moderate exacerbations; State 4, ≥ 1 severe exacerbations; State 5, death. The models only allowed a patient to transition to a worsened health state, and transitions did not necessarily have to be to the next adjacent state. We used the multi-state models to analyse data from ETHOS, a phase III, 52-week study assessing the efficacy and safety of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate in moderate-to-very severe COPD. RESULTS: The Weibull multi-state Markov model showed good fit of the data. In line with clinical evidence, we found a higher mortality risk after a severe exacerbation (11.4-fold relative ratio increase [95% CI, 7.7-17.0], 6.4-fold increase [95% CI, 3.8-10.8] and 5.4-fold increase [95% CI, 2.9-10.3] relative to no exacerbations, 1 moderate exacerbation or ≥ 2 moderate exacerbations, respectively). One moderate exacerbation increased mortality risk 1.8-fold (95% CI, 1.1-2.9) vs no exacerbations. We also found a higher risk of severe exacerbation and mortality following ≥ 2 moderate exacerbations. CONCLUSION: Multi-state modelling of patients with COPD in ETHOS found an acute and chronic effect of severe exacerbations on mortality risk. Risk was also increased after a moderate exacerbation. Clinical management with effective pharmacotherapies should be optimised to avoid even moderate exacerbations. Modelling with exacerbations could be an alternative to current COPD models focused on disease progression. TRIAL REGISTRATION: NCT02465567.

Incorporating external evidence on between-trial heterogeneity in network meta-analysis.

In a network meta-analysis, between-study heterogeneity variances are often very imprecisely estimated because data are sparse, so standard errors of treatment differences can be highly unstable. External evidence can provide informative prior distributions for heterogeneity and, hence, improve inferences. We explore approaches for specifying informative priors for multiple heterogeneity variances in a network meta-analysis. First, we assume equal heterogeneity variances across all pairwise intervention comparisons (approach 1); incorporating an informative prior for the common variance is then straightforward. Models allowing unequal heterogeneity variances are more realistic; however, care must be taken to ensure implied variance-covariance matrices remain valid. We consider three strategies for specifying informative priors for multiple unequal heterogeneity variances. Initially, we choose different informative priors according to intervention comparison type and assume heterogeneity to be proportional across comparison types and equal within comparison type (approach 2). Next, we allow all heterogeneity variances in the network to differ, while specifying a common informative prior for each. We explore two different approaches to this: placing priors on variances and correlations separately (approach 3) or using an informative inverse Wishart distribution (approach 4). Our methods are exemplified through application to two network metaanalyses. Appropriate informative priors are obtained from previously published evidence-based distributions for heterogeneity. Relevant prior information on between-study heterogeneity can be incorporated into network meta-analyses, without needing to assume equal heterogeneity across treatment comparisons. The approaches proposed will be beneficial in sparse data sets and provide more appropriate intervals for treatment differences than those based on imprecise heterogeneity estimates.

Implementing informative priors for heterogeneity in meta-analysis using meta-regression and pseudo data.

Many meta-analyses combine results from only a small number of studies, a situation in which the between-study variance is imprecisely estimated when standard methods are applied. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, providing the potential for more robust inference on the effect size of interest. We present a method for performing Bayesian meta-analysis using data augmentation, in which we represent an informative conjugate prior for between-study variance by pseudo data and use meta-regression for estimation. To assist in this, we derive predictive inverse-gamma distributions for the between-study variance expected in future meta-analyses. These may serve as priors for heterogeneity in new meta-analyses. In a simulation study, we compare approximate Bayesian methods using meta-regression and pseudo data against fully Bayesian approaches based on importance sampling techniques and Markov chain Monte Carlo (MCMC). We compare the frequentist properties of these Bayesian methods with those of the commonly used frequentist DerSimonian and Laird procedure. The method is implemented in standard statistical software and provides a less complex alternative to standard MCMC approaches. An importance sampling approach produces almost identical results to standard MCMC approaches, and results obtained through meta-regression and pseudo data are very similar. On average, data augmentation provides closer results to MCMC, if implemented using restricted maximum likelihood estimation rather than DerSimonian and Laird or maximum likelihood estimation. The methods are applied to real datasets, and an extension to network meta-analysis is described. The proposed method facilitates Bayesian meta-analysis in a way that is accessible to applied researchers. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Two new methods to fit models for network meta-analysis with random inconsistency effects.

BACKGROUND: Meta-analysis is a valuable tool for combining evidence from multiple studies. Network meta-analysis is becoming more widely used as a means to compare multiple treatments in the same analysis. However, a network meta-analysis may exhibit inconsistency, whereby the treatment effect estimates do not agree across all trial designs, even after taking between-study heterogeneity into account. We propose two new estimation methods for network meta-analysis models with random inconsistency effects. METHODS: The model we consider is an extension of the conventional random-effects model for meta-analysis to the network meta-analysis setting and allows for potential inconsistency using random inconsistency effects. Our first new estimation method uses a Bayesian framework with empirically-based prior distributions for both the heterogeneity and the inconsistency variances. We fit the model using importance sampling and thereby avoid some of the difficulties that might be associated with using Markov Chain Monte Carlo (MCMC). However, we confirm the accuracy of our importance sampling method by comparing the results to those obtained using MCMC as the gold standard. The second new estimation method we describe uses a likelihood-based approach, implemented in the metafor package, which can be used to obtain (restricted) maximum-likelihood estimates of the model parameters and profile likelihood confidence intervals of the variance components. RESULTS: We illustrate the application of the methods using two contrasting examples. The first uses all-cause mortality as an outcome, and shows little evidence of between-study heterogeneity or inconsistency. The second uses "ear discharge" as an outcome, and exhibits substantial between-study heterogeneity and inconsistency. Both new estimation methods give results similar to those obtained using MCMC. CONCLUSIONS: The extent of heterogeneity and inconsistency should be assessed and reported in any network meta-analysis. Our two new methods can be used to fit models for network meta-analysis with random inconsistency effects. They are easily implemented using the accompanying R code in the Additional file 1. Using these estimation methods, the extent of inconsistency can be assessed and reported.

Methods for calculating confidence and credible intervals for the residual between-study variance in random effects meta-regression models.

BACKGROUND: Meta-regression is becoming increasingly used to model study level covariate effects. However this type of statistical analysis presents many difficulties and challenges. Here two methods for calculating confidence intervals for the magnitude of the residual between-study variance in random effects meta-regression models are developed. A further suggestion for calculating credible intervals using informative prior distributions for the residual between-study variance is presented. METHODS: Two recently proposed and, under the assumptions of the random effects model, exact methods for constructing confidence intervals for the between-study variance in random effects meta-analyses are extended to the meta-regression setting. The use of Generalised Cochran heterogeneity statistics is extended to the meta-regression setting and a Newton-Raphson procedure is developed to implement the Q profile method for meta-analysis and meta-regression. WinBUGS is used to implement informative priors for the residual between-study variance in the context of Bayesian meta-regressions. RESULTS: Results are obtained for two contrasting examples, where the first example involves a binary covariate and the second involves a continuous covariate. Intervals for the residual between-study variance are wide for both examples. CONCLUSIONS: Statistical methods, and R computer software, are available to compute exact confidence intervals for the residual between-study variance under the random effects model for meta-regression. These frequentist methods are almost as easily implemented as their established counterparts for meta-analysis. Bayesian meta-regressions are also easily performed by analysts who are comfortable using WinBUGS. Estimates of the residual between-study variance in random effects meta-regressions should be routinely reported and accompanied by some measure of their uncertainty. Confidence and/or credible intervals are well-suited to this purpose.

De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus-associated oropharyngeal squamous cell carcinomas are a distinct subgroup of tumours that may have a better prognosis than traditional tobacco/alcohol-related disease. Iatrogenic complications, associated with conventional practice, are estimated to cause mortality of approximately 2% and high morbidity. As a result, clinicians are actively investigating the de-escalation of treatment protocols for disease with a proven viral aetiology. OBJECTIVES: To summarise the available evidence regarding de-escalation treatment protocols for human papillomavirus-associated, locally advanced oropharyngeal squamous cell carcinoma. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials; PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 25 June 2013. SELECTION CRITERIA: Randomised controlled trials investigating de-escalation treatment protocols for human papillomavirus-associated, locally advanced oropharyngeal carcinoma. Specific de-escalation categories were: 1) bioradiotherapy (experimental) versus chemoradiotherapy (control); 2) radiotherapy (experimental) versus chemoradiotherapy (control); and 3) low-dose (experimental) versus standard-dose radiotherapy (control). The outcomes of interest were overall and disease-specific survival, treatment-related morbidity, quality of life and cost. DATA COLLECTION AND ANALYSIS: Three authors independently selected studies from the search results and extracted data. We planned to use the Cochrane 'Risk of bias' tool to assess study quality. MAIN RESULTS: We did not identify any completed randomised controlled trials that could be included in the current version of this systematic review. We did, however, identify seven ongoing trials that will meet our inclusion criteria. These studies will report from 2014 onwards. We excluded 30 studies on methodological grounds (seven randomised trials with post hoc analysis by human papillomavirus status, 11 prospective trials and 12 ongoing studies). AUTHORS' CONCLUSIONS: There is currently insufficient high-quality evidence for, or against, de-escalation of treatment for human papillomavirus-associated oropharyngeal carcinoma. Future trials should be multicentre to ensure adequate power. Adverse events, morbidity associated with treatment, quality of life outcomes and cost analyses should be reported in a standard format to facilitate comparison with other studies.

Increased Risk of Severe Cardiovascular Events Following Exacerbations of Chronic Obstructive Pulmonary Disease: Results of the EXACOS-CV Study in Japan.

INTRODUCTION: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are known to increase the risk of cardiovascular events. However, this association has not been investigated specifically in patients with COPD in Japan, whose characteristics may differ from those of Western patients (i.e., western Europe, the US, and Canada). METHODS: This longitudinal retrospective cohort study analyzed secondary claims data and included patients aged ≥ 40 years with COPD (International Classification of Diseases-10 codes J41-J44). All exacerbations occurring during follow-up were measured. Time-dependent Cox models were used to estimate hazard ratios (HRs) for the association between time periods following an exacerbation of COPD (vs. time prior to a first exacerbation) and occurrence of a first hospitalization for a severe fatal or non-fatal cardiovascular event. RESULTS: The analysis included 152,712 patients with COPD with a mean age of 73.8 years and 37.6% of whom were female. During a median follow-up of 37 months, 63,182 (41.4%) patients experienced ≥ 1 exacerbation and 13,314 (8.7%) patients experienced ≥ 1 severe cardiovascular event. Following an exacerbation of COPD, the risk of a severe cardiovascular event was increased in the first 30 days [adjusted HR (aHR) 1.44, 95% confidence interval (CI) 1.33-1.55] and remained elevated for 365 days post-exacerbation (aHR 1.13, 95% CI 1.04-1.23). Specifically, the risks of acute coronary syndrome or arrhythmias remained significantly increased for up to 180 days, and the risk of decompensated heart failure for 1 year. CONCLUSION: Among Japanese patients with COPD, the risk of experiencing a severe cardiovascular event increased following a COPD exacerbation and remained elevated for 365 days, emphasizing the need to prevent exacerbations.

Risk of severe cardiovascular events following COPD exacerbations: results from the EXACOS-CV study in Spain.

INTRODUCTION AND OBJECTIVES: This real-world study-the first of its kind in a Spanish population-aimed to explore severe risk for cardiovascular events and all-cause death following exacerbations in a large cohort of patients with chronic obstructive pulmonary disease (COPD). METHODS: We included individuals with a COPD diagnosis code between 2014 and 2018 from the BIG-PAC health care claims database. The primary outcome was a composite of a first severe cardiovascular event (acute coronary syndrome, heart failure decompensation, cerebral ischemia, arrhythmia) or all-cause death following inclusion in the cohort. Time-dependent Cox proportional hazards models estimated HRs for associations between exposed time periods (1-7, 8-14, 15-30, 31-180, 181-365, and >365 days) following an exacerbation of any severity, and following moderate or severe exacerbations separately (vs unexposed time before a first exacerbation following cohort inclusion). RESULTS: During a median follow-up of 3.03 years, 18 901 of 24 393 patients (77.5%) experienced ≥ 1 moderate/severe exacerbation, and 8741 (35.8%) experienced the primary outcome. The risk of a severe cardiovascular event increased following moderate/severe COPD exacerbation onset vs the unexposed period, with rates being most increased during the first 1 to 7 days following exacerbation onset (HR, 10.10; 95%CI, 9.29-10.97) and remaining increased >365 days after exacerbation onset (HR, 1.65; 95%CI, 1.49-1.82). CONCLUSIONS: The risk of severe cardiovascular events or death increased following moderate/severe exacerbation onset, illustrating the need for proactive multidisciplinary care of patients with COPD to prevent exacerbations and address other cardiovascular risk factors.

Cardiovascular events after exacerbations of chronic obstructive pulmonary disease: Results from the EXAcerbations of COPD and their OutcomeS in CardioVascular diseases study in Italy.

INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease (COPD) can increase the risk of severe cardiovascular events. OBJECTIVE: Assess the crude incidence rates (IR) of cardiovascular events and the impact of exacerbations on the risk of cardiovascular events within different time periods following an exacerbation. METHODS: COPD patients aged ≥45 years between 01/01/2015 and 12/31/2018 were identified from the Fondazione Ricerca e Salute administrative database. IRs of severe non-fatal and fatal cardiovascular events were obtained for post-exacerbation time periods (1-7, 8-14, 15-30, 31-180, 181-365 days). Time-dependent Cox proportional hazard models compared cardiovascular risks between periods with and without exacerbations. RESULTS: Of 216,864 COPD patients, >55 % were male, mean age was 74 years, frequent comorbidities were cardiovascular, metabolic and psychiatric. During an average 34-month follow-up, 69,620 (32 %) patients had ≥1 exacerbation and 46,214 (21 %) experienced ≥1 cardiovascular event. During follow-up, 55,470 patients died; 4,661 were in-hospital cardiovascular-related deaths. Among 10,269 patients experiencing cardiovascular events within 365 days post-exacerbation, the IR was 15.8 per 100 person-years (95 %CI 15.5-16.1). Estimated hazard ratios (HR) for the cardiovascular event risk associated with periods post-exacerbation were highest within 7 days (HR: 34.3, 95 %CI: 33.1-35.6), especially for heart failure (HR 50.6; 95 %CI 48.6-52.7) and remained elevated throughout 365 days (HR 1.1, 95 %CI 1.02-1.13). CONCLUSIONS: COPD patients in Italy are at high risk of severe cardiovascular events following exacerbations, suggesting the need to prevent exacerbations and possible subsequent cardiovascular events through early interventions and treatment optimization.

Risk of Death and Cardiovascular Events Following an Exacerbation of COPD: The EXACOS-CV US Study.

Purpose: This study estimated the magnitude and duration of risk of cardiovascular events and mortality following acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and whether risks varied by number and severity of exacerbation in a commercially insured population in the United States. Methods: This was a retrospective cohort study of newly diagnosed COPD patients ≥40 years old in the Healthcare Integrated Research Database from 2012 to 2019. Patients experiencing exacerbations comprised the "exacerbation cohort". Moderate exacerbations were outpatient visits with contemporaneous antibiotic or glucocorticoid administration; severe exacerbations were emergency department visits or hospitalizations for AECOPD. Follow-up started on the exacerbation date. Distribution of time between diagnosis and first exacerbation was used to assign index dates to the "unexposed" cohort. Cox proportional hazards models estimated risks of a cardiovascular event or death following an exacerbation adjusted for medical and prescription history and stratified by follow-up time, type of cardiovascular event, exacerbation severity, and rank of exacerbation (first, second, or third). Results: Among 435,925 patients, 170,236 experienced ≥1 exacerbation. Risk of death was increased for 2 years following an exacerbation and was highest during the first 30 days (any exacerbation hazard ratio (HR)=1.79, 95% CI=1.58-2.04; moderate HR=1.22, 95% CI=1.04-1.43; severe HR=5.09, 95% CI=4.30-6.03). Risks of cardiovascular events were increased for 1 year following an AECOPD and highest in the first 30-days (any exacerbation HR=1.34, 95% CI=1.23-1.46; moderate HR=1.23 (95% CI 1.12-1.35); severe HR=1.93 (95% CI=1.67-2.22)). Each subsequent AECOPD was associated with incrementally higher rates of both death and cardiovascular events. Conclusion: Risk of death and cardiovascular events was greatest in the first 30 days and rose with subsequent exacerbations. Risks were elevated for 1-2 years following moderate and severe exacerbations, highlighting a sustained increased cardiopulmonary risk associated with exacerbations.

Heightened long-term cardiovascular risks after exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To examine the risk of adverse cardiovascular (CV) events following an exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: This retrospective cohort study identified patients with COPD using administrative data from Alberta, Canada from 2014 to 2019. Exposure periods were 12 months following moderate or severe exacerbations; the reference period was time preceding a first exacerbation. The primary outcome was the composite of all-cause death or a first hospitalisation for acute coronary syndrome, heart failure (HF), arrhythmia or cerebral ischaemia. Time-dependent Cox regression models estimated covariate-adjusted risks associated with six exposure subperiods following exacerbation. RESULTS: Among 1 42 787 patients (mean age 68.1 years and 51.7% men) 61 981 (43.4%) experienced at least one exacerbation and 34 068 (23.9%) died during median follow-up of 64 months. The primary outcome occurred in 43 564 (30.5%) patients with an incidence rate prior to exacerbation of 5.43 (95% CI 5.36 to 5.50) per 100 person-years. This increased to 95.61 per 100 person-years in the 1-7 days postexacerbation (adjusted HR 15.86, 95% CI 15.17 to 16.58) and remained increased for up to 1 year. The risk of both the composite and individual CV events was increased following either a moderate or a severe exacerbation, though greater and more prolonged following severe exacerbation. The highest magnitude of increased risk was observed for HF decompensation (1-7 days, HR 72.34, 95% CI 64.43 to 81.22). CONCLUSION: Moderate and severe COPD exacerbations are independent risk factors for adverse CV events, especially HF decompensation. The impact of optimising COPD management on CV outcomes should be evaluated.

Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta-analysis.

Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC.

Elucidating the risk of cardiopulmonary consequences of an exacerbation of COPD: results of the EXACOS-CV study in Germany.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) represent a period of vulnerability. This study explored the association between time periods following an exacerbation and the risk of severe cardiovascular (CV) events or death in Germany. METHODS: A longitudinal cohort study was conducted using routinely collected healthcare data. Individuals with COPD were identified between 2014 and 2018. Exposure was moderate or severe exacerbation of COPD. Periods at risk were the 1-7, 8-14, 15-30, 31-180 and 181-365 days following each exacerbation onset occurring after cohort entry. The main outcome of interest was the first hospitalisation for a CV event or all-cause death. Time-dependent Cox proportional hazards models estimated the HR for the association between subperiods versus periods outside exacerbations, and the risk of outcome. RESULTS: Among 126 795 patients, 58 720 (46.3%) exacerbated at least once and 48 982 (38.6%) experienced at least one CV event or died during a median follow-up of 36 months. The rate of outcome was increased during 1-7 days following a severe exacerbation onset (HR 15.84, 95% CI 15.26 to 16.45), and remained elevated for up to a year (181-365 days HR 1.17, 95% CI 1.11 to 1.23). In the 1-7 days following a moderate exacerbation onset, the increased rate was HR 1.17, 95% CI 1.05 to 1.31). CONCLUSION: The risk of a CV event or death increased in time periods following both moderate and severe exacerbations of COPD, emphasising the need to promptly manage the risk of CV events following the onset of an exacerbation, to prevent exacerbations of any severity, and more generally, to address the cardiopulmonary risk in patients with COPD.

EXAcerbations of COPD and their OutcomeS on CardioVascular diseases (EXACOS-CV) Programme: protocol of multicountry observational cohort studies.

INTRODUCTION: In patients with chronic obstructive pulmonary disease (COPD), the risk of certain cardiovascular (CV) events is increased by threefold to fivefold in the year following acute exacerbation of COPD (AECOPD), compared with a non-exacerbation period. While the effect of severe AECOPD is well established, the relationship of moderate exacerbation or prior exacerbation to elevated risk of CV events is less clear. We will conduct cohort studies in multiple countries to further characterise the association between AECOPD and CV events. METHODS AND ANALYSIS: Retrospective longitudinal cohort studies will be conducted within routinely collected electronic healthcare records or claims databases. The study cohorts will include patients meeting inclusion criteria for COPD between 1 January 2014 and 31 December 2018. Moderate exacerbation is defined as an outpatient visit and/or medication dispensation/prescription for exacerbation; severe exacerbation is defined as hospitalisation for COPD. The primary outcomes of interest are the time to (1) first hospitalisation for a CV event (including acute coronary syndrome, heart failure, arrhythmias or cerebral ischaemia) since cohort entry or (2) death. Time-dependent Cox proportional hazards models will compare the hazard of a CV event between exposed periods following exacerbation (split into these periods: 1-7, 8-14, 15-30, 31-180 and 181-365 days) and the unexposed reference time period, adjusted on time-fixed and time-varying confounders. ETHICS AND DISSEMINATION: Studies have been approved in Canada, Japan, the Netherlands, Spain and the UK, where an institutional review board is mandated. For each study, the results will be published in peer-reviewed journals.

Alternative weighting schemes when performing matching-adjusted indirect comparisons.

Methods for indirect comparisons and network meta-analysis use aggregate level data from multiple studies. A very common, and closely related, scenario is where a company has individual patient data (IPD) from its own trial, but only has published aggregate data from a competitor's trial, and an indirect comparison of the treatments evaluated in these two trials is required. Matching-Adjusted Indirect Comparison (MAIC) has been developed for this situation, where we use the available IPD to adjust for between-trial imbalances in the distributions of observed baseline covariates between the two trials. We extend the current MAIC methodology, where we compute the weights that satisfy the conventional method of moments and result in the largest possible effective sample size (ESS). We show that the approach proposed by Zubizarreta in a previous study can be used for this purpose. We derive a new analytical result that shows why this alternative approach provides a larger ESS than a conventional MAIC. We also derive a new formula for the maximum ESS that can be achieved, even when permitting negative weights, when adjusting for one covariate. This can be used as an easily computed new metric that quantifies the difficulty in adjusting for covariates. What is already known: MAIC is an established way to perform population adjustment in the situation where IPD is available from one trial but only aggregate level data is available from another trial, and an indirect comparison is required. However the effective sample size (ESS) can be small after making the adjustment. What is new: We show that an alternative method can result in a larger ESS. We provide new analytical results showing why this is the case. We derive a new descriptive statistic that is based on maximising the ESS that quantifies the difficulties in adjusting for particular covariates. Potential impact for RSM readers outside the authors' field: Reweighting methods for population adjustment are becoming more commonly used and their implications for research synthesis methodology is now considerable. This paper provides important new links between the theoretical literature, and the more applied research synthesis methodology literature, relating to this topic.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II-IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy.