Transition Dyspnea Index Research Articles

Effect of ensifentrine on dyspnea in patients with moderate-to-severe chronic obstructive pulmonary disease: pooled analysis of the ENHANCE trials

ABSTRACT Background Dyspnea is a critical component of chronic obstructive pulmonary disease (COPD). We report the effect of ensifentrine, a novel PDE3/PDE4 inhibitor, on dyspnea using pooled data from the Phase 3 ENHANCE-1/2 trials. Methods The pooled population (ensifentrine, n = 975; placebo, n = 574) included patients aged 40–80 years with post-bronchodilator FEV1/FVC <0.7, FEV1 30–70% predicted, mMRC Dyspnea Scale score ≥2, and a smoking history ≥10 pack-years. Patients taking dual LAMA/LABA or LAMA/LABA/ICS triple therapy were excluded. Dyspnea measures included the Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms (E-RS), and rescue medication use. Results After 24 weeks, ensifentrine significantly improved TDI scores (least-squares mean difference, 0.97; 95% CI, 0.64, 1.30; p < 0.001) and across all TDI subdomains. Ensifentrine-treated patients were more likely to be TDI responders at week 24 (p < 0.001), which was consistent across clinically relevant subgroups. Ensifentrine-treated patients had improved E-RS breathlessness subdomain scores (p = 0.053) and reduced rescue medication use (p = 0.002). Conclusion Ensifentrine produced clinically meaningful improvements in multiple dyspnea measures in patients with symptomatic, moderate-to-severe COPD. A limitation of this study was the exclusion of patients taking dual LAMA/LABA and LAMA/LABA/ICS triple therapy. Clinical trial registration www.clinicaltrials.gov identifiers are ENHANCE-1: NCT04535986; ENHANCE-2: NCT04542057.

Self-reported dyspnoea and shortness of breathing deterioration in long-term survivors after segmentectomy or lobectomy for early-stage lung cancer.

The aim of this study was to assess the self-reported current dyspnoea and perioperative changes of dyspnoea in long-term survivors after minimally invasive segmentectomy or lobectomy for early-stage lung cancer. Cross-sectional telephonic survey of patients alive and disease-free as of March 2023, with pathologic stage IA1-2, non-small-cell lung cancer, assessed 1-5 years after minimally invasive segmentectomy or lobectomy (performed from January 2018 to January 2022). Current dyspnoea level: Baseline Dyspnoea Index score <10. Perioperative changes of dyspnoea were assessed using the Transition Dyspnoea Index. A negative Transition Dyspnoea Index focal score indicates perioperative deterioration in dyspnoea. Mixed effect models were used to examine demographic, medical and health-related correlates of current dyspnoea and changes in dyspnoea level. A total of 152 of 236 eligible patients consented or were available to respond to the telephonic interview(67% response rate): 90 lobectomies and 62 segmentectomies. The Baseline Dyspnoea Index score was lower (greater dyspnoea) in lobectomy patients (median 7, interquartile range 6-10) compared to segmentectomy (median 9, interquartile range 6-11), P = 0.034. 70% of lobectomy patients declared to have a current dyspnoea vs 53% after segmentectomy, P = 0.035. 82% of patients after lobectomy reported a perioperative deterioration in their dyspnoea compared to 57% after segmentectomy, P = 0.002. Mixed effect logistic regression analysis adjusting for patient-related factors and time elapsed from operation showed that segmentectomy was associated with a reduced risk of perioperative dyspnoea deterioration (as opposed to lobectomy) (Odds ratio (OR) 0.31, P = 0.004). Our findings may be valuable to inform the shared decision-making process by complementing objective data on perioperative changes of pulmonary function.

Long-acting muscarinic antagonist and long-acting β2-agonist combination for the treatment of maintenance therapy-naïve patients with chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy-naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy-naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy-naïve patients with COPD, as recommended by the GOLD 2024 report.

Elastic tape reduces dyspnea and improves health status in the short term in nonobese COPD males: A randomized controlled trial

Introduction and objectivesThe elastic tape (ET) is a novel intervention that acutely improves exercise capacity in laboratory tests; however, its effect on a patient's daily life remains unknown. This randomized controlled trial evaluated the effects of ET on daily life physical activity (DLPA), dyspnea symptoms, health status, and health-related quality of life (HRQoL) in individuals with COPD. MethodsFifty males with moderate to very severe COPD were randomly assigned to an intervention group (ETG, n = 25), receiving ET on the chest wall and abdomen, or a control group (CG, n = 25). The intervention was for 14 days. DLPA (accelerometry; steps per day, and sedentary time), dyspnea symptoms (transition dyspnea index, TDI; and modified Medical Research Council, mMRC), health status (COPD assessment test, CAT), and health-related quality of life (HRQoL, CRQ) were evaluated at baseline and on Day 21 after the intervention. ResultsNo change in the DLPA was observed in between-group comparison. CG presented a reduction in step counts after 21days (-707,p <0.05) while ETG. maintained (-114,p > 0.94). However, ET reduced dyspnea symptoms in all TDI domains (functional, task, and effort) and on the mMRC scale after 14 days compared with CG (p < 0.01). Also, the ETG improved CAT score compared to the CG, reaching minimal clinical important difference (MCID) (-4.4 score, p <0.01). The ETG also improved in most CRQ domains reaching MCID after 21 days. ConclusionsET does not modify DLPA but reduces dyspnea and improves health status and HRQoL in nonobese males with moderate to very severe COPD in the short term. This novel and low-cost intervention improves COPD symptoms.

Cyclophosphamide in Patients with Systemic Sclerosis-associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis.

Background: The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with cyclophosphamide. Data Sources: A literature search was conducted across the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases through June 2022 for studies using cyclophosphamide to treat patients with SSc-ILD. Data Extraction: Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group method was used to assess the quality of evidence. Synthesis: Five studies were included; two randomized controlled trials compared cyclophosphamide versus placebo, and one randomized controlled trial and two retrospective case-control studies compared cyclophosphamide versus mycophenolate. Compared with placebo, there was a 2.83% reduction in the decline at 12 months for forced vital capacity (FVC) % predicted using cyclophosphamide (95% confidence interval [CI], 0.80-4.87; low evidence). There were improvements in breathlessness (Transition Dyspnea Index mean difference [MD], 2.90; 95% CI, 1.94-3.86; minimum clinically important difference, 1; moderate evidence) and disability (Health Assessment Questionnaire-Disability Index MD, -0.16; 95% CI, -0.28 to -0.04; minimum clinically important difference, -0.14; moderate evidence). There were increased risks of leukopenia and constitutional symptoms using cyclophosphamide, but no difference in mortality. When cyclophosphamide was compared with mycophenolate, there were differences in diffusing capacity of the lung for carbon monoxide % predicted favoring mycophenolate at 6 months (MD, -3.67%; 95% CI, -6.3% to -1.1% unadjusted; MD, -4.88%; 95% CI, -7.3% to -2.5% adjusted for alveolar volume; moderate evidence), 12 months (MD, -5.90%; 95% CI, -8.4% to -3.4% adjusted for alveolar volume; moderate evidence), and 18 months (MD, -3.26%; 95% CI, -6.1% to -0.4%; moderate evidence), but not at 24 months. There were no differences in FVC % predicted, mortality, or quality-of-life outcomes, but participants were more likely to prematurely discontinue cyclophosphamide compared with mycophenolate (relative risk, 1.70; 95% CI, 1.10-2.63; high-certainty evidence). Conclusions: A review of the published evidence shows that cyclophosphamide is effective in SSc-ILD compared with placebo, with an increased risk of side effects. However, mycophenolate may be equivocal or better than cyclophosphamide. Clinicians and patients should weigh the potential benefits and risks with respect to individual patient circumstances and preferences.

Efficacy and safety of aclidinium/formoterol versus monotherapies and aclidinium versus placebo in Chinese and other Asian patients with moderate-to-severe COPD: The AVANT Phase 3 study

AVANT was a Phase 3, 24-week, randomized, parallel-group, double-blind, double-dummy, placebo-controlled study to assess the efficacy and safety of aclidinium/formoterol 400 μg/12 μg combination vs monotherapies and aclidinium vs placebo (1:1:1:1) in Asian patients (∼70% of whom were Chinese) with moderate-to-severe stable chronic obstructive pulmonary disease. Endpoints were analyzed hierarchically to incorporate type I error control. At Week 24, aclidinium/formoterol demonstrated improvements from baseline in 1-h morning post-dose forced expiratory volume in 1 s (FEV1) vs aclidinium (least squares [LS] mean 92 mL; 95% confidence interval [CI] 60, 124 mL; p < 0.001), and in trough FEV1 vs formoterol (LS mean 85 mL; 95% CI 53, 117 mL; p < 0.001). Furthermore, aclidinium provided improvements in trough FEV1 vs placebo (LS mean 134 mL; 95% CI 103, 166 mL; p < 0.001). There was an improvement in transition dyspnea index focal score at Week 24 for aclidinium/formoterol vs placebo (LS mean 0.8; 95% CI 0.2, 1.3; p = 0.005) but not for aclidinium vs placebo (LS mean 0.4; 95% CI −0.1, 1.0; p = 0.132). Improvements in St George's Respiratory Questionnaire total scores occurred for aclidinium/formoterol vs placebo (LS mean −4.0; 95% CI −6.7, −1.4; p = 0.003) and aclidinium vs placebo (LS mean −2.9; 95% CI −5.5, −0.3; p = 0.031). Aclidinium/formoterol and aclidinium were well tolerated and safety findings were consistent with known profiles; rates of treatment-emergent adverse events (AEs) (aclidinium/formoterol: 54.8%; aclidinium: 47.4%; placebo: 53.9%), serious AEs (7.2, 7.9, and 7.8%, respectively), and AEs leading to discontinuation of study medication (2.3, 1.5, and 2.2%, respectively) were similar between groups.

Effects of inspiratory muscle training on exertional breathlessness in patients with unilateral diaphragm dysfunction: a randomised trial.

Unilateral diaphragm dysfunction (UDD) is an underdiagnosed cause of dyspnoea. Inspiratory muscle training (IMT) is the only conservative treatment for UDD, but the mechanisms of improvement are unknown. We characterised the effects of IMT on dyspnoea, exercise tolerance and respiratory muscle function in people with UDD. 15 people with UDD (73% male, 61±8 years) were randomised to 6 months of IMT (50% maximal inspiratory mouth pressure (PI,max), n=10) or sham training (10% PI,max, n=5) (30 breaths twice per day). UDD was confirmed by phrenic nerve stimulation and persisted throughout the training period. Symptoms were assessed by the transitional dyspnoea index (TDI) and exercise tolerance by constant-load cycle tests performed pre- and post-training. Oesophageal (Pes) and gastric (Pga) pressures were measured with a dual-balloon catheter. Electromyography (EMG) and oxygenation (near-infrared spectroscopy) of respiratory muscles were assessed continuously during exercise. The IMT group (from 45±6 to 62±23% PI,max) and sham group (no progression) completed 92 and 86% of prescribed sessions, respectively. PI,max, TDI scores and cycle endurance time improved significantly more after IMT versus sham (mean between-group differences: 28 (95% CI 13-28) cmH2O, 3.0 (95% CI 0.9-5.1) points and 6.0 (95% CI 0.4-11.5) min, respectively). During exercise at iso-time, Pes, Pga and EMG of the scalene muscles were reduced and the oxygen saturation indices of the scalene and abdominal muscles were higher post- versus pre-training only in the IMT group (all p<0.05). The effects of IMT on dyspnoea and exercise tolerance in UDD were not mediated by an improvement in isolated diaphragm function, but may reflect improvements in strength, coordination and/or oxygenation of the extra-diaphragmatic respiratory muscles.

The efficacy and safety of additional treatment with short-acting muscarinic antagonist combined with long-acting beta-2 agonist in stable patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

The rationale for additional treatment with short-acting bronchodilators combined with long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) is not adequately studied. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of a short-acting muscarinic antagonist (SAMA) therapy combined with a long-acting beta-2 agonist (LABA) in patients with stable COPD. Pulmonary function, dyspnea, health-related quality of life, exercise tolerance, physical activity, exacerbations of COPD, and adverse events during regular use were set as outcomes of interest. We included five controlled trials including two sets of publicly available online data without article publications for the meta-analysis. Additional use of SAMA plus LABA showed a significant improvement in the peak response in FEV1 (mean difference (MD) 98.70mL, p < .00001), transitional dyspnea index score (MD .85, p = .02), and St George's Respiratory Questionnaire score (MD -2.00, p = .008) compared to LABA treatment. There was no significant difference in the risk of exacerbation of COPD (p = .20) and only a slight trend of increased severe adverse events (OR: 2.16, p = .08) and cardiovascular events (OR: 2.38, p = .06). Additional treatment with SAMA combined with LABA could be a feasible choice due to its efficacy and safety.

Inspiratory muscle training, with or without concomitant pulmonary rehabilitation, for chronic obstructive pulmonary disease (COPD).

Inspiratory muscle training, with or without concomitant pulmonary rehabilitation, for chronic obstructive pulmonary disease (COPD).

Оценка эффективности третьего этапа реабилитации пациентов после перенесенного COVID-19 в условиях дневного стационара

Introduction. For patients with the consequences of COVID-19 it seems relevant to undergo a rehabilitation program to restore the respiratory function, oxygen uptake by tissues, increase exercise tolerance, etc. Rehabilitation includes aerobic-based exercises adequate to the patient’s state and physical capabilities, breathing exercises and physiotherapy modalities. Aim. To evaluate the effectiveness of the third stage rehabilitation in patients aged 18–45 years with the consequences of COVID-19 (U07.1) in a day hospital of multispecialty hospital. Materials and methods. One hundred and thirty-nine patients aged 18–45 years with a verified diagnosis of pneumonia associated with COVID-19 (U07.1) were examined in a day hospital of multispecialty hospital. The patients were divided into 2 groups: 107 patients of the 1st group underwent the third stage rehabilitation; 32 people from who made up the 2nd group refused rehabilitation. The severity of dyspnea was assessed using the Medical Research Council (MRC) Dyspnea Scale; functional impairment in the performance of activities of daily living – according to the Baseline Dyspnea Index and Transitional Dyspnea Index scales; exercise tolerance – according to the 6-minute walk test and the modified Borg Scale; the severity of anxiety and depression – according to the Hospital Anxiety and Depression Scale (HADS); pain intensity – according to the Visual Analogue Scale (VAS); quality of life – according to the EuroQoL Five-Dimension Questionnaire (EQ-5D). Statistical processing of the obtained results was carried out. Results. In the group of patients who completed rehabilitation, upon follow-up examination, there was a significant decrease in complaints, normalization of a number of hemodynamic parameters, an improvement in the 6-minute walk test scores, a decrease in the severity of dyspnea according to the MRC Dyspnea Scale by 1.8 times, a decrease in anxiety according to the HADS by 2.1 times, a decrease in pain according to the VAS by 3.2 times, an improvement in exercise tolerance according to the modified Borg Scale by 1.8 times and quality of life – according to the EQ-5D by 1.4 times. In the group of patients who refused rehabilitation, the change in these indicators was not significant. Conclusion. For patients who have had pneumonia associated with SARS-CoV-2, it is advisable to go through the third stage rehabilitation in a day hospital in order to restore the respiratory functions, increase exercise tolerance, reduce anxiety and improve quality of life.

Comparing the Efficacy and Safety Profile of Triple Fixed-Dose Combinations in COPD: A Meta-Analysis and IBiS Score.

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting β2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV1), transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia.

Comparative Efficacy of Umeclidinium/Vilanterol Versus Other Bronchodilators for the Treatment of Chronic Obstructive Pulmonary Disease: A Network Meta-Analysis.

IntroductionFew randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD.MethodsA systematic literature review (October 2015–November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented.ResultsThe NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation.ConclusionUMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02234-x.

Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis.

IntroductionRandomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting β2-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD.MethodsThis NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV1), annualized rate of combined moderate and severe exacerbations, St George’s Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible).ResultsThe NMA was informed by five trials reporting FEV1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6).ConclusionThe findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02231-0.

Dual bronchodilation for the treatment of COPD: From bench to bedside.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting β-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator.

Adjunctive Inspiratory Muscle Training During a Rehabilitation Program in Patients With Breast Cancer: An Exploratory Double-Blind, Randomized, Controlled Pilot Study

ObjectiveTo investigate whether inspiratory muscle training (IMT) offered adjunctively to an exercise training program reduces symptoms of dyspnea in survivors of breast cancer. DesignDouble-blind, parallel-group, randomized controlled trial. SettingOutpatient rehabilitation program in a university hospital. ParticipantsNinety-eight female patients with breast cancer who completed adjuvant treatment and subsequently entered cancer rehabilitation were screened for participation. Inclusion criteria were reduced inspiratory muscle strength and/or symptoms of dyspnea. Twenty patients (N=20) were randomly assigned to an intervention group (n=10) or a control group (n=10). InterventionBoth groups received a 3-month exercise training program in combination with either IMT (intervention) or sham-IMT (control). Main Outcome MeasuresChanges in dyspnea intensity perception (10-point Borg Scale) at comparable time points (isotime) during constant work rate cycling was the primary outcome. Secondary outcomes included changes in respiratory muscle function, exercise capacity, and changes in symptoms of dyspnea during daily life (Transitional Dyspnea Index [TDI]). ResultsThe intervention group achieved a larger reduction in exertional dyspnea at isotime compared with the control group (−1.8 points; 95% CI, −3.7 to 0.13; P=.066). The intervention group also exhibited larger improvements in dyspnea during daily life (TDI score, +2.9 points; 95% CI, 0.5-5.3; P=.022) and improved both respiratory muscle endurance (+472 seconds; 95% CI, 217-728; P=.001) and cycling endurance (+428 seconds; 95% CI, 223-633; P=.001) more than the control group. ConclusionsBecause of the limited sample size all obtained findings need to be interpreted with caution. The study offers initial insights into the potential of adjunctive IMT in selected survivors of breast cancer. Larger multicenter studies should be performed to further explore the potential role and general acceptance of this intervention as a rehabilitation tool in selected patients after breast cancer treatment.

Six-Week Hospital-Based Pulmonary Rehabilitation in Covid Pneumonia ICU Survivors: Experience from a Tertiary Care Center in Central India.

OBJECTIVEThere is very limited data on the usefulness of pulmonary rehabilitation in patients with coronavirus pneumonia who have survived intensive care unit care. The primary aim was to explore the feasibility of conducting a pulmonary rehabilitation program in patients with coronavirus disease-19 pneumonia surviving intensive care. The secondary aim was to study the impact of a hospital-based 6-week pulmonary rehabilitation program on exercise capacity, quality of life, and psychological parameters in these patients. This study was conducted at the Center for Pulmonary Rehabilitation, Department of Pulmonary Medicine of the institute.MATERIAL AND METHODSA total of 27 patients were enrolled. Among them, 14 patients who completed the desired 12 sessions over 6 weeks constituted the pulmonary rehabilitation group and 13 patients who either did not consent or defaulted within the first 2 weeks were considered as controls. Both groups had assessments at 0 and 6 weeks that included a 6-Minute Walk Test, Incremental Shuttle Walk Test, mMRC Dyspnea Scale, Baseline Dyspnea Index, and Transitional Dyspnea Index, Saint George's Respiratory Questionnaire score, and Depression, Anxiety, Stress Scale-21 score.RESULTSSignificant improvement in dyspnea by mMRC (P = .01) and exercise capacity as measured by 6-Minute Walk Test (P <.001) and Incremental Shuttle Walk Test (P = .025) was seen in the pulmonary rehabilitation group as compared to the control group. There was no significant improvement in quality of life and psychological parameters (Depression, Anxiety, Stress Scale 21 score) after 6 weeks of pulmonary rehabilitation program as measured in our study.CONCLUSIONPulmonary rehabilitation is feasible and appears promising in coronavirus disease acute respiratory distress syndrome survivors. However, data from other centers and a larger number of patients are required to imbibe conclusive results.

Inspiratory muscle training enhances recovery post-COVID-19: a randomised controlled trial.

BackgroundMany people recovering from coronavirus disease 2019 (COVID-19) experience prolonged symptoms, particularly breathlessness. We urgently need to identify safe and effective COVID-19 rehabilitative strategies. The aim of the current study was to investigate the potential rehabilitative role of inspiratory muscle training (IMT).Methods281 adults (age 46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” waitlist control arm. Health-related quality-of-life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (K-BILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength, and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary end-point was K-BILD total score, with the K-BILD domains and TDI being key secondary outcomes.ResultsAccording to intention to treat, there was no difference between groups in K-BILD total score post-intervention (control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the K-BILD domains for breathlessness (control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness.ConclusionsIMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long COVID, further research is warranted on the individual responses to rehabilitation; the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.

Quantitative analysis of efficacy and safety of LABA/LAMA fixed-dose combinations in the treatment of stable COPD.

Objective:This study aimed to quantitatively compare the efficacy and safety of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for the treatment of stable chronic obstructive pulmonary disease (COPD), especially in terms of their loss of efficacy in lung function.Methods:Randomized controlled clinical trials of LABA/LAMA FDCs for the treatment of stable COPD were comprehensively searched for in public databases. Pharmacodynamic models were established to describe the time course of the primary outcome [trough forced expiratory volume in the first second (FEV1)]. Secondary outcomes [COPD exacerbations, St. George’s Respiratory Questionnaire (SGRQ), Transition Dyspnoea Index (TDI), and rescue medication use] and safety outcomes [mortality, serious adverse events (SAEs), and withdrawals due to adverse events (AEs)] were also compared via a meta-analysis.Results:A total of 22 studies involving 16,486 participants were included in this study. The results showed that in terms of primary outcome (change from baseline in trough FEV1), the efficacy of vilanterol/umeclidinium was the highest, while the efficacy of formoterol/aclidinium was the lowest, with a maximum effect value (Emax) of 0.185 L [95% confidence interval (CI): 0.173–0.197 L] and 0.119 L (95% CI: 0.103–0.135 L), respectively. The efficacy of other drugs, such as formoterol/glycopyrronium, indacaterol/glycopyrronium, and olodaterol/tiotropium, were comparable, and their Emax values were 0.150–0.177 L. Except for vilanterol/umeclidinium, the other four LABA/LAMA FDCs showed a certain degree of loss of efficacy. Compared with the efficacy at 2 days, the trough FEV1 (L) relative to baseline at 24 weeks decreased by 0.029–0.041 L. In terms of secondary outcomes, the efficacy of different LABA/LAMA FDCs was similar in TDI and rescue medication use. However, formoterol/aclidinium was better in preventing the COPD exacerbations, while vilanterol/umeclidinium was the best in terms of SGRQ. In addition, different LABA/LAMA FDCs and placebo had similar safety outcomes.Conclusion:The present findings may provide necessary quantitative information for COPD medication guidelines.

Treatment efficacy of LAMA versus placebo for stable chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD. A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated. A total of 33 studies were included in this meta-analysis. LAMA significantly decreased the frequency of exacerbations compared to the placebo (OR 0.75; 95% CI 0.66 to 0.85; P<0.001). The mean changes in the St George's Respiratory Questionnaire score (mean difference, -3.61; 95% CI, -4.27 to -2.95; P<0.00001), transitional dyspnea index score (mean difference 1.00; 95% CI 0.83 to 1.17; P<0.00001), and trough FEV1 (mean difference 0.12; 95% CI 0.11 to 0.13; P<0.0001) indicated significantly greater improvement in the LAMA group than the placebo group. The number of withdrawals due to adverse events in the LAMA group was significantly fewer than that in the placebo group (OR -0.02; 95% CI -0.03 to -0.01; P=0.002). LAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV1, QoL, and dyspnea score for stable COPD.

Pulmonary rehabilitation for idiopathic pleuroparenchymal fibroelastosis: A retrospective study on its efficacy, feasibility, and safety.

The beneficial effects of pulmonary rehabilitation (PR) for patients with idiopathic pleuroparenchymal fibroelastosis (IPPFE) remain unknown. This study aimed to examine the efficacy, feasibility, and safety of PR for IPPFE. We retrospectively investigated 25 patients with IPPFE referred for PR between April 2007 and March 2017. The PR mainly consisted of a 10-week exercise training program. The primary outcome was a change in 6-min walk distance (6MWD). Secondary outcomes included changes in dyspnea (transition dyspnea index [TDI]), anxiety and depression (hospital anxiety and depression scale [HADS]), and health-related quality of life (HRQoL) (St George's respiratory questionnaire [SGRQ]). Thirteen patients participated in the PR program (PRP). Recurrent pneumothorax was the most common reason for patients not participating in the PRP. Four patients discontinued the PRP due to the recurrence of pneumothorax, new onset of pneumomediastinum, stroke, and another reason, respectively. Nine patients completed the PRP. Significant improvement was observed in 6MWD (median [interquartile range], 90m [55-116m]; P=0.033). Clinically important improvements in the 6MWD, and TDI, HADS-anxiety, HADS-depression, and SGRQ total domain scores were observed in seven (78%), five (56%), four (44%), four (44%), and five (56%) of the nine patients, respectively. Patients with IPPFE benefited from PR in terms of exercise capacity, dyspnea, anxiety, depression, and HRQoL. Pneumothorax and pneumomediastinum may impede the implementation of a PRP for patients with IPPFE. While careful patient selection is required, PR may be an efficacious non-pharmacological approach for managing disabilities in patients with IPPFE.