Effect of dexamethasone on dyspnoea in patients with cancer (ABCD): a parallel-group, double-blind, randomised, controlled trial.

BACKGROUND: Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea. METHODS: The parallel-group, double-blind, randomised, controlled ABCD (Alleviating Breathlessness in Cancer Patients with Dexamethasone) trial was done at the at the University of Texas MD Anderson Cancer Center and the general oncology clinic at Lyndon B Johnson General Hospital (both in Houston, TX, USA). Ambulatory patients with cancer, aged 18 years or older, and with an average dyspnoea intensity score on an 11-point numerical rating scale (NRS; 0=none, 10=worst) over the past week of 4 or higher were randomly assigned (2:1) to receive dexamethasone 8 mg orally every 12 h for 7 days followed by 4 mg orally every 12 h for 7 days, or matching placebo capsules for 14 days. Pharmacists did permuted block randomisation with a block size of six, and patients were stratified by baseline dyspnoea score (4-6 vs 7-10) and study site. Patients, research staff, and clinicians were masked to group assignment. The primary outcome was change in dyspnoea NRS intensity over the past 24 h from baseline to day 7 (±2 days). Analyses were done by modified intention-to-treat (ie, including all patients who were randomly assigned and started the study treatment, regardless of whether they completed the study). Enrolment was stopped after the second preplanned interim analysis, when the futility criterion was met. This study is registered with ClinicalTrials.gov (NCT03367156) and is now completed. FINDINGS: Between Jan 11, 2018, and April 23, 2021, we screened 2867 patients, enrolled 149 patients, and randomly assigned 128 to dexamethasone (n=85) or placebo (n=43). The mean change in dyspnoea NRS intensity from baseline to day 7 (±2 days) was -1·6 (95% CI -2·0 to -1·2) in the dexamethasone group and -1·6 (-2·3 to -0·9) in the placebo group, with no significant between-group difference (mean 0 [95% CI -0·8 to 0·7]; p=0·48). The most common all-cause grade 3-4 adverse events were infections (nine [11%] of 85 patients in the dexamethasone group vs three [7%] of 43 in the placebo group), insomnia (seven [8%] vs one [2%]), and neuropsychiatric symptoms (three [4%] vs none [0%]). Serious adverse events, all resulting in hospital admissions, were reported in 24 (28%) of 85 patients in the dexamethasone group and in three (7%) of 43 patients in the placebo group. No treatment-related deaths occurred in either group. INTERPRETATION: High-dose dexamethasone did not improve dyspnoea in patients with cancer more effectively than placebo and was associated with a higher frequency of adverse events. These data suggest that dexamethasone should not be routinely given to unselected patients with cancer for palliation of dyspnoea. FUNDING: US National Cancer Institute.

High-Flow Nasal Cannula Therapy for Exertional Dyspnea in Patients with Cancer: A Pilot Randomized Clinical Trial.

BACKGROUND: Exertional dyspnea is common in patients with cancer and limits their function. The impact of high-flow nasal cannula on exertional dyspnea in nonhypoxemic patients is unclear. In this double-blind, parallel-group, randomized trial, we assessed the effect of flow rate (high vs. low) and gas (oxygen vs. air) on exertional dyspnea in nonhypoxemic patients with cancer. PATIENTS AND METHODS: Patients with cancer with oxygen saturation >90% at rest and exertion completed incremental and constant work (80% maximal) cycle ergometry while breathing low-flow air at 2 L/minute. They were then randomized to receive high-flow oxygen, high-flow air, low-flow oxygen, or low-flow air while performing symptom-limited endurance cycle ergometry at 80% maximal. The primary outcome was modified 0-10 Borg dyspnea intensity scale at isotime. Secondary outcomes included dyspnea unpleasantness, exercise time, and adverse events. RESULTS: Seventy-four patients were enrolled, and 44 completed the study (mean age 63; 41% female). Compared with low-flow air at baseline, dyspnea intensity was significantly lower at isotime with high-flow oxygen (mean change, -1.1; 95% confidence interval [CI], -2.1, -0.12) and low-flow oxygen (-1.83; 95% CI, -2.7, -0.9), but not high-flow air (-0.2; 95% CI, -0.97, 0.6) or low-flow air (-0.5; 95% CI, -1.3, 0.4). Compared with low-flow air, high-flow oxygen also resulted in significantly longer exercise time (difference + 2.5 minutes, p = .009), but not low-flow oxygen (+0.39 minutes, p = .65) or high-flow air (+0.63 minutes, p = .48). The interventions were well tolerated without significant adverse effects. CONCLUSION: Our preliminary findings support that high-flow oxygen improved both exertional dyspnea and exercise duration in nonhypoxemic patients with cancer. (ClinicalTrials.gov ID: NCT02357134). IMPLICATIONS FOR PRACTICE: In this four-arm, double-blind, randomized clinical trial examining the role of high-flow nasal cannula on exertional dyspnea in patients with cancer without hypoxemia, high-flow oxygen, but not high-flow air, resulted in significantly lower dyspnea scores and longer exercise time. High-flow oxygen delivered by high-flow nasal cannula devices may improve clinically relevant outcomes even in patients without hypoxemia.

FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. OBJECTIVES: The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting ß2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD. METHODS: FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 µg twice daily), indacaterol (27.5 µg twice daily), glycopyrrolate (15.6 µg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. MEASUREMENTS AND MAIN RESULTS: In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups. CONCLUSIONS: Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251).

An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes.

Minimal clinically important differences in pharmacological trials.

The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term "minimum worthwhile incremental advantage" to describe this parameter.

Prospective validation of the endurance shuttle walking test in the context of bronchodilation in COPD.

This study focused on repeatability data and minimal important difference (MID) estimates of the endurance shuttle walking test (ESWT). 255 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s 54.7±13.2% predicted) completed four ESWTs at different times during the 8-week study: two under baseline conditions with tiotropium (1 week apart), one after a single dose and one after 4 weeks of either fluticasone propionate/salmeterol combination or placebo in addition to tiotropium. 97 patients performed all the tests with a portable metabolic system. Reproducibility of test performance and cardiorespiratory response was investigated with the data obtained on the first two ESWTs. The mean differences between the first two ESWT performances (-6.7±72.2 s and -7.3±113.1 m for endurance time and walking distance, respectively) were not statistically significant. The between-test end-exercise and isotime values for each cardiorespiratory parameter were not significantly different from each other. With the exception of arterial oxygen saturation by pulse oximetry, the repeatability of cardiorespiratory adaptations to ESWT was also confirmed with strong Pearson and intraclass correlation coefficients. Finally, changes of 56-61 s and 70-82 m in endurance time and distance walked, respectively, were perceived by patients. This study provides methodological information supporting the reliability of the ESWT and suggests MID estimates for this test.

Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study.

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 µg, placebo or tiotropium 18 µg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p<0.001) and tiotropium (LSM treatment difference 0.49, p=0.021). QVA149 provided significant improvements in lung function, with higher forced expiratory volume in 1 s area under the curve from 0-4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication.

Consideration and Assessment of Patient Factors When Selecting an Inhaled Delivery System in COPD.

Because guidelines and strategies for pharmacologic treatment of COPD focus on specific classes of inhaled medications, there is an unmet need for information to guide health care professionals for selecting an inhaled medication delivery system that matches the unique characteristics of individual patients. This article provides guidance for selecting an inhaled medication delivery system based on three "key" patient factors: cognitive function, manual dexterity/strength, and peak inspiratory flow. In addition, information is provided about specific tests to assess these patient factors. Cognitive impairment with an estimated prevalence of 25% among patients with COPD adversely affects patients' ability to correctly use a handheld device. To our knowledge, the prevalence of impaired manual dexterity/strength has not been reported in those with COPD. However, 79% of patients with COPD have reported one or more physical impediments that could influence their ability to manipulate an inhaler device. The measurement of peak inspiratory flow against the simulated resistance (PIFr) of a dry powder inhaler establishes whether the patient has the inhalation ability for creating optimal turbulent energy within the device. A suboptimal PIFr for low to medium-high resistance dry powder inhalers has been reported in 19% to 84% of stable outpatients with COPD. Health care professionals should consider cognitive function, manual dexterity/strength, and PIFr in their patients with COPD when prescribing inhaled pharmacotherapy. Impairments in these patient factors are common among those with COPD and can affect the individual's competency and effectiveness of using inhaled medications delivered by handheld devices.

Systematic review of the effects of patient errors using inhaled delivery systems on clinical outcomes in COPD.

BACKGROUND: Errors using inhaled delivery systems for COPD are common and it is assumed that these lead to worse clinical outcomes. Previous systematic reviews have included patients with both asthma and COPD and much of the evidence related to asthma. More studies in COPD have now been published. Through systematic review, the relationship between errors using inhalers and clinical outcomes in COPD, including the importance of specific errors, was assessed.MethodsElectronic databases were searched on 27 October 2023 to identify cohort, case-control or randomised controlled studies, which included patients with COPD, an objective assessment of inhaler errors and data on at least one outcome of interest (forced expiratory volume in 1 s, (FEV1), dyspnoea, health status and exacerbations). Study quality was assessed using the Newcastle and Ottawa scales. A narrative synthesis of the results was performed as there was insufficient detail in the publications to allow quantitative synthesis. There was no funding for the review. RESULTS: 19 publications were included (7 cohort and 12 case-control) reporting outcomes on 6487 patients. 15 were considered low quality, and most were confounded by the absence of adherence data. There was weak evidence that lower error rates are associated with better FEV1, symptoms and health status and fewer exacerbations. Only one considered the effects of individual errors and found that only some were related to worse outcomes. CONCLUSION: Evidence about the importance of specific errors using inhalers and outcomes would optimise the education and training of patients with COPD. Prospective studies, including objective monitoring of inhalation technique and adherence, are needed. PROSPERO REGISTRATION NUMBER: CRD42023393120.

Clinical Burden of Chronic Obstructive Pulmonary Disease in Patients with Suboptimal Peak Inspiratory Flow.

Introduction: Many patients with chronic obstructive pulmonary disease (COPD) may derive inadequate benefit from dry powder inhalers (DPIs) because of suboptimal peak inspiratory flow (sPIF). Objectives: To assess the clinical burden of COPD by characterizing the clinical characteristics of participants with sPIF against medium-low resistance DPIs versus those with optimal PIF (oPIF) from two phase 3 clinical trials. Methods: Baseline data were collected from two randomized, controlled, phase 3 trials (NCT03095456; NCT02518139) in participants with moderate-to-severe COPD. oPIF (60 L/min) against the medium-low resistance DPIs was used as the threshold for defining the PIF subgroups (<60 L/min (sPIF) vs ≥60 L/min (oPIF)). Results: Most participants included in this analysis were White (92%) and male (63%); the mean (range) age was 65 (43-87) years. Participants with sPIF had significantly greater dyspnea than those with oPIF as measured using the modified Medical Research Council scoring (mean (95% CI): 2.1 (2.0-2.2) vs 1.6 (1.4-1.7); P < 0.001) and baseline dyspnea index (mean (95% CI): 5.1 (4.9-5.4) vs 6.1 (5.8-6.3); P < 0.001). Based on COPD Assessment Test scores, participants with sPIF had a higher COPD symptom burden than those with oPIF (mean (95% CI): 21.5 (19.7-23.3) vs 19.5 (18.6-20.4); P = 0.05). Conclusion: In these trials, participants with COPD who had sPIF against the medium-low resistance DPIs had more dyspnea and worse health status than those with oPIF. These results demonstrate that sPIF is associated with a higher clinical burden as measured by patient-reported outcomes.

Guidance on Mitigating the Risk of Transmitting Respiratory Infections During Nebulization by the COPD Foundation Nebulizer Consortium.

BACKGROUND: Nebulizers are used commonly for inhaled drug delivery. Because they deliver medication through aerosol generation, clarification is needed on what constitutes safe aerosol delivery in infectious respiratory disease settings. The COVID-19 pandemic highlighted the importance of understanding the safety and potential risks of aerosol-generating procedures. However, evidence supporting the increased risk of disease transmission with nebulized treatments is inconclusive, and inconsistent guidelines and differing opinions have left uncertainty regarding their use. Many clinicians opt for alternative devices, but this practice could impact outcomes negatively, especially for patients who may not derive full treatment benefit from handheld inhalers. Therefore, it is prudent to develop strategies that can be used during nebulized treatment to minimize the emission of fugitive aerosols, these comprising bioaerosols exhaled by infected individuals and medical aerosols generated by the device that also may be contaminated. This is particularly relevant for patient care in the context of a highly transmissible virus. RESEARCH QUESTION: How can potential risks of infections during nebulization be mitigated? STUDY DESIGN AND METHODS: The COPD Foundation Nebulizer Consortium (CNC) was formed in 2020 to address uncertainties surrounding administration of nebulized medication. The CNC is an international, multidisciplinary collaboration of patient advocates, pulmonary physicians, critical care physicians, respiratory therapists, clinical scientists, and pharmacists from research centers, medical centers, professional societies, industry, and government agencies. The CNC developed this expert guidance to inform the safe use of nebulized therapies for patients and providers and to answer key questions surrounding medication delivery with nebulizers during pandemics or when exposure to common respiratory pathogens is anticipated. RESULTS: CNC members reviewed literature and guidelines regarding nebulization and developed two sets of guidance statements: one for the health care setting and one for the home environment. INTERPRETATION: Future studies need to explore the risk of disease transmission with fugitive aerosols associated with different nebulizer types in real patient care situations and to evaluate the effectiveness of mitigation strategies.

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity.

BACKGROUND: Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms. METHODS: A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 µg) and open-label tiotropium (18 µg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = 'less dyspnoea'; scores ≥2 = 'more dyspnoea'). Outcomes were assessed after 26 weeks. RESULTS: The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose ('trough') forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 µg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated. CONCLUSIONS: In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 µg may be a useful treatment option for patients with COPD who experience more severe breathlessness.

An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea.

BACKGROUND: Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. PURPOSE: The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. METHODS: An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. RESULTS: Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. CONCLUSIONS: Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.

Personalizing Selection of Inhaled Delivery Systems in Chronic Obstructive Pulmonary Disease.

It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the multiple individual and combinations of inhaled medications available in numerous delivery systems. Guidance on the selection of an inhaled delivery system has received limited attention compared with the emphasis on prescribing the class of the inhaled molecule(s). Although numerous recommendations and algorithms have been proposed to guide the selection of an inhaled delivery system for patients with COPD, no specific approach has been endorsed in COPD guidelines/strategies or by professional organizations. To provide recommendations for an inhaler selection strategy at initial and follow-up appointments, we examined the impact of patient errors using handheld inhalers on clinical outcomes and performed a focused narrative review to consider patient factors (continuity of the inhaled delivery system, cognitive function, manual function/dexterity, and peak inspiratory flow) when selecting an inhaled delivery system. On the basis of these findings, five questions are proposed for HCPs to consider in the initial selection of an inhaler delivery system and three questions to consider at follow-up. We propose that HCPs consider the inhaled medication delivery system as a unit and to match appropriate medication(s) with the unique features of the delivery system to individual patient factors. Assessment of inhaler technique and adherence together with patient outcomes/satisfaction at each visit is essential to determine whether the inhaled medication delivery system is providing benefits. Continued and repeated education on device features and correct technique is warranted to optimize efficacy.