Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Preventing adverse cardiac events (PACE) in chronic obstructive pulmonary disease (COPD): study protocol for a double-blind, placebo controlled, randomised controlled trial of bisoprolol in COPD.

INTRODUCTION: Heart disease in chronic obstructive pulmonary disease (COPD) is a common but neglected comorbidity. Patients with COPD are frequently excluded from clinical trials of treatments aimed at reducing cardiac morbidity and mortality, which has led to undertreatment of cardiovascular disease in patients with COPD. A particular concern in COPD is the underuse of beta (ß)-blockers. There is observational evidence that cardioselective ß-blockers are safe and may even reduce mortality risk in COPD, although some evidence is conflicting. There is an urgent need to answer the research question: Are cardioselective ß-blockers safe and of benefit in people with moderately severe COPD? The proposed study will investigate whether cardioselective ß-blocker treatment in patients with COPD reduces mortality and cardiac and respiratory morbidity. METHODS AND ANALYSES: This is a double-blind, randomised controlled trial to be conducted in approximately 26 sites in Australia, New Zealand, India, Sri Lanka and other countries as required. Participants with COPD will be randomised to either bisoprolol once daily (range 1.25-5 mg, dependent on tolerated dose) or matched placebo, in addition to receiving usual care for their COPD over the study duration of 24 months.The study will enrol 1164 participants with moderate to severe COPD, aged 40-85 years. Participants will be symptomatic from their COPD and have a postbronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and ≤70% predicted and a history of at least one exacerbation requiring systemic corticosteroids, antibiotics or both in the prior 24 months. ETHICS AND DISSEMINATION: The study protocol has been approved by the Sydney Local Health District Human Research Ethics Committee at The Concord Repatriation General Hospital. TRIAL REGISTRATION NUMBERS: NCT03917914; CTRI/2020/08/027322.

The Oxygen project: a prospective study to assess the effectiveness of a targeted intervention to improve oxygen management in hospitalised patients.

BACKGROUND: Oxygen is commonly used in the acute care setting. However, used inappropriately, oxygen therapy can result in adverse consequences, including progressive respiratory failure and death. AIM: To investigate the effectiveness of a targeted intervention to improve prescribing practice and therapeutic application of supplemental oxygen. METHODS: Respiratory, Oncology and Surgery wards were targeted for the intervention. Nursing and junior medical staff from these wards undertook an education programme about safe use of oxygen. Cross-sectional data about oxygen prescribing, administration and monitoring were collected on inpatients in these wards at baseline, and at 3 and 6 months post-intervention, using a modified version of the British Thoracic Society Oxygen Audit Tool. RESULTS: At baseline, there was a written prescription for oxygen in 56% of patients (n = 43) using oxygen and this increased to 75% (n = 44) at 3 months, and remained at 65% (n = 48) at 6 months. However, the increased prescription rates were not statistically significant when compared to baseline (χ2 = 3.54, df = 1, P = 0.06 and χ2 = 0.73, df = 1, P = 0.40, respectively). The observed increase in oxygen prescriptions was driven by the medical wards: Oncology ward at 3 months (χ2 = 8.24, df = 1, P = 0.004); and Respiratory ward at 3 months (χ2 = 3.31, df = 1, P = 0.069) and 6 months (χ2 = 4.98, df = 1, P = 0.026). CONCLUSION: The education programme intervention to improve oxygen prescription showed promise in the medical wards but did not impact outcomes in the surgical ward setting, where different strategies may be needed.

Screening for comorbidities in COPD.

Due to growing recognition of comorbidities, COPD is no longer considered a disease affecting only the respiratory system. Its management now entails the early diagnosis and treatment of comorbidities. However, although many studies have examined the impact of comorbidities on the evolution of COPD and patients' quality of life, very few have explored the means to systematically identify and manage them. The aims of this article are to summarise the state of current knowledge about comorbidities associated with COPD and to propose a possible screening protocol in the outpatient setting, emphasising the areas needing further research.

Pleurisy and pulmonary embolism: physician sees through patient eyes.

As a respiratory physician personally affected by pulmonary thromboembolism, I bring a unique perspective to managing this condition. It has made me realise that sometimes we do not see in detail the ways our colleagues practise, even working alongside them, although general management principles are the same. While banned from work, but permitted 'as much paperwork as I like' (the sole compromise that would ensure this patient's adherence), I sought to learn from my time as patient, hoping that other clinicians might gain from my experience in both roles. When it came to deciding which insights would be most useful to impart for the benefit of our patients, the leading concepts were not novel but important to emphasise in our current medical world, which prioritises both efficiency and quality of patient care.

Does device matter for inhaled therapies in advanced chronic obstructive pulmonary disease (COPD)? A comparative trial of two devices.

OBJECTIVE: COPD patients have challenges for effective use of inhalers due to advanced age, fixed airflow obstruction and comorbid medical conditions. Published clinical trials investigate drug efficacy but rarely consider the inhaler device. This trial investigates device efficacy, comparing clinical outcomes for the same medication via two different devices. Our intention was to communicate the results and to critically appraise the study protocol to inform planning of future device comparison research. Subjects with spirometry confirming at least moderate COPD were randomly assigned to inhaler sequence; starting with Accuhaler or metered dose inhaler and spacer (MDI/s). After baseline testing, subjects were assigned to fluticasone propionate/salmeterol xinafoate (SFC) 500/50 mcg twice daily via the first device for 6 weeks' duration, then changed to the alternate device for the following 6 weeks. Subjects were reassessed in terms of health-related quality of life (HRQL), exercise endurance and lung function after each exposure period. RESULTS: The recruitment target was not achieved due to unanticipated developments within the pharmaceutical industry, potentially compromising the study's power. Study outcomes did not differ significantly according to the allocated inhaler device even after adjusting for baseline lung function or inhaler technique. Recommendations for future device comparison protocols are offered. Trial registration Australia and New Zealand Clinical Trials Registry, Current Controlled Trials ACTRN12618000075280, date of registration: 18.01.2018. Retrospectively registered.

Treatable traits can be identified in a severe asthma registry and predict future exacerbations.

BACKGROUND AND OBJECTIVE: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. METHODS: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. RESULTS: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. CONCLUSION: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Implementation challenges in delivering team-based care ('TEAMcare') for patients with chronic obstructive pulmonary disease in a public hospital setting: a mixed methods approach.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is considered a multisystem disease, in which comorbidities feature prominently. COPD guidelines recommend holistic assessment and management of relevant comorbid diseases but there is limited information as to how this is best achieved. This pilot study aimed to explore the views of stakeholders, including patients and the healthcare team, on the feasibility, acceptability and barriers to a collaborative, multidisciplinary team-based care intervention ('TEAMcare') to improve health outcomes in COPD patients, within the context of a local hospital outpatient clinic. METHODS: A mixed methods study design was used. A COPD care algorithm was developed based on the Australasian guidelines, COPDX. COPD participants were consecutively recruited from an outer metropolitan hospital's respiratory clinic. Participants attended for follow up visits at 5 and 10 months to ascertain clinical status, algorithm compliance and to review and revise management recommendations. The intervention was conducted using existing resources, involving collaboration with general practice and the publicly-funded local chronic disease management programme (Medicare Local). Stakeholders provided qualitative feedback about the intervention in terms of feasibility, acceptability and barriers via structured and semi-structured interviews. All interviews were recorded, transcribed verbatim and analysed using qualitative thematic analysis to identify key concepts and themes. RESULTS: The study protocol was abandoned prematurely due to clear lack of feasibility. Of 12 participants, 4 withdrew and none completed pulmonary rehabilitation (PR). The main reasons for non-participation or study withdrawal related to reluctance to attend PR (6 of 16) and the burden of increased appointments (4 of 16). PR conflicted with employment hours, which presented problems for some participants. Similarly, themes that emerged from qualitative data indicate healthcare provider perception of deficiencies in funding (for infrastructure and staffing). Health literacy, motivation, organisation and functional impairment were issues for patients. CONCLUSIONS: Available data from this small pilot provided valuable insights to inform future design and implementation strategies. Delivering structured team-based care to COPD patients presents challenges. In addition to enhancing health resources for engaging COPD patients, a focus on health literacy and improving health service access, including colocalisation and access outside business hours, may be required. TRIAL REGISTRATION: ACTRN12616000342415 ; 16/03/2016.

The association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and functional capacity in chronic obstructive pulmonary disease: a systematic review.

OBJECTIVE: This systematic review sought to identify the association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and function in people with chronic obstructive pulmonary disease (COPD). DATA SOURCES: We searched electronic databases including PubMed, CINAHL, MEDLINE, EMBASE, The Cochrane Library, ProQuest Dissertations and Theses, Scopus, Google Scholar, Trove, and WHO International Clinical Trials Registry Platform and reference lists of retrieved articles published prior to August 2014. INCLUSION CRITERIA: We considered observational studies that evaluated dietary intake of omega-3 (eicosapentaenoic acid, docosahexaenoic acid or α-linolenic acid) and/or omega-6 fatty acids (γ-linoleic acid or arachidonic acid), and experimental studies that evaluated omega-3 fatty acid supplementation (containing predominantly one or more omega-3 fatty acids) on airway and systemic inflammatory markers and/or functional capacity outcomes in people with COPD-related diagnoses. DATA SYNTHESIS: Since statistical pooling was not possible, the findings were presented in narrative form including tables and figures to aid in data presentation when appropriate. RESULTS: One 8-week randomized controlled trial conducted in 80 COPD patients in the Netherlands showed polyunsaturated fatty acid supplementation significantly improved exercise capacity compared with the control condition [between-group difference in mean peak workload was 9.7 W (2.5-17.0; P = 0.009); and mean duration was 4.3 min (0.6-7.9; P = 0.023)]. One cross-sectional study conducted in 250 COPD patients in Spain found associations of specific dietary omega-3 fatty acids with inflammation were inconsistent. CONCLUSIONS: Limited evidence provides weak support for the use of omega-3 fatty acid supplementation for reducing chronic inflammation and some support for improving functional capacity in COPD patients. There is no consistent evidence showing that low dietary intake of specific omega-3 fatty acids worsens inflammation and/or function. More evidence is required before routinely incorporating this therapy within COPD management plans.

Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis.

OBJECTIVE: Low testosterone level may be a reversible risk factor for functional disability and deterioration in patients with chronic obstructive pulmonary disease (COPD). We sought to systematically assess the endogenous testosterone levels and effect of testosterone therapy on exercise capacity and health-related quality of life (HRQoL) outcomes in COPD patients, as well as to inform guidelines and practice. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Scopus, Cochrane Library, CINAHL, Health Source Nursing and PsychINFO and the reference lists of retrieved articles published before May 2012. INCLUSION CRITERIA: Observational studies on endogenous testosterone levels in people with chronic lung disease compared with controls, or randomised controlled trials (RCTs) on testosterone therapy for exercise capacity and/or HRQoL outcomes in COPD patients were eligible. DATA EXTRACTION AND ANALYSIS: Data on the mean difference in endogenous total testosterone (TT) values, and the mean difference in exercise capacity and HRQoL values were extracted and pooled using random effects meta-analysis. RESULTS: Nine observational studies in 2918 men with COPD reported consistently lower levels of TT compared with controls (weighted mean difference was -3.21 nmol/L (95% CI -5.18 to -1.23)). Six RCTs in 287 participants yielded five studies on peak muscle strength and peak cardiorespiratory fitness outcomes (peak oxygen uptake (VO2) and workload) and three studies on HRQoL outcomes. Testosterone therapies significantly improved peak muscle strength (standardised mean difference (SMD) was 0.31 (95% CI 0.05 to 0.56)) and peak workload (SMD was 0.27 (95% CI 0.01 to 0.52)) compared with control conditions (all but one used placebo), but not peak VO2 (SMD was 0.21 (95% CI -0.15 to 0.56)) or HRQoL (SMD was -0.03 (95% CI -0.32 to 0.25)). CONCLUSIONS: Men with COPD have clinically relevant lower than normal TT levels. Insufficient evidence from short-term studies in predominately male COPD patients suggests that testosterone therapy improves exercise capacity outcomes, namely peak muscle strength and peak workload.

Bidirectional associations between clinically relevant depression or anxiety and COPD: a systematic review and meta-analysis.

BACKGROUND: The longitudinal associations between depression or anxiety and COPD, and their comorbid effect on prognosis, have not been adequately addressed by previous reviews. We aimed to systematically assess these associations to inform guidelines and practice. METHODS: We searched electronic databases for articles published before May 2012. Longitudinal studies in adult populations that reported an association between clinically relevant depression or anxiety and COPD, or that reported their comorbid effect on exacerbation and/or mortality, were eligible. Risk ratios (RRs) were pooled across studies using random-effects models and were verified using fixed-effects models. Heterogeneity was explored with subgroup and metaregression analyses. RESULTS: Twenty-two citations yielded 16 studies on depression or anxiety as predictors of COPD outcomes (incident COPD/chronic lung disease or exacerbation) and/or mortality, in 28,759 participants followed for 1 to 8 years, and six studies on COPD as a predictor of depression in 7,439,159 participants followed for 1 to 35 years. Depression or anxiety consistently increased the risk of COPD outcomes (RR, 1.43; 95% CI, 1.22-1.68), particularly in higher-quality studies and in people aged ≤ 66 years. Comorbid depression increased the risk of mortality (RR, 1.83; 95% CI, 1.00-3.36), particularly in men. Anxiety (or psychologic distress) increased the risk of COPD outcomes/mortality in most studies (RR, 1.27; 95% CI, 1.02-1.58). Finally, COPD consistently increased the risk of depression (RR, 1.69; 95% CI, 1.45-1.96). CONCLUSIONS: Depression and anxiety adversely affect prognosis in COPD, conferring an increased risk of exacerbation and possibly death. Conversely, COPD increases the risk of developing depression. These bidirectional associations suggest potential usefulness of screening for these disease combinations to direct timely therapeutic intervention.

Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum.

OBJECTIVE: Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated. METHODOLOGY: Nine patients with bronchiectasis inhaled 400 mg of mannitol once daily for 12 days. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ). Sputum was analysed for viscosity, elasticity, spinnability, surface tension, contact angle, solids, mucociliary transportability (MCTR) on a frog palate, and cough transportability (CTR) on a simulated cough machine. RESULTS: Lung function was unchanged with treatment (baseline FEV1 82.0 +/- 16.2%) apart from an improvement in FEF from 85.4 +/- 13% (baseline) to 90.7 +/- 14.4% (P < 0.05; 12th treatment; visit 7). The total SGRQ score (mean +/- SD) of 49.3 +/- 13.8 at baseline, decreased by 12.4 +/- 10.2 (P < 0.01; visit 7) and 10.1 +/- 9.4 units (P < 0.02) 6-10 days after treatment cessation. The baseline subscores for symptoms (72.9 +/- 11.8), activity (44.7 +/- 20.9) and impact (44.4 +/- 14.3) were reduced by 0.8 +/- 9.1 (P > 0.7), 8.4 +/- 16.0 (P > 0.1) and 19.2 +/- 13.7 (P < 0.005) units, respectively (visit 7). Mannitol reduced the baseline (mean +/- SE) surface tension from 94.5 +/- 1.4 to 84.7 +/- 2.1 mN/m (P < 0.0001), contact angle from 51.1 +/- 2.8 to 33.2 +/- 2.4 degrees (P < 0.0001), spinnability from 11.6 +/- 0.4 to 10.0 +/- 0.2 mm (P < 0.005), and solids from 5.7 +/- 0.4 to 4.3 +/- 0.7% (P < 0.02), acutely (visit 7). Viscosity, elasticity and MCTR did not change significantly, while CTR was increased from 25.8 +/- 1.0 to 34.1 +/- 2.7 mm (P < 0.003). CONCLUSION: Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.