Relationship between dyspnoea and related factors in patients with cancer: a cross-sectional study.

OBJECTIVES: Dyspnoea is a common and distressing symptom in patients with cancer. We aimed to analyse the association between dyspnoea and related factors and to estimate their causal relationship. METHODS: A cross-sectional study was conducted. Patients with cancer with dyspnoea and a mean Numerical Rating Scale (NRS) of ≥3 over 24 hours were enrolled at 10 institutions in Japan from December 2019 to February 2021. The outcomes included dyspnoea, cough and pain NRS over 24 hours, Eastern Cooperative Oncology Group Performance Status, Hospital Anxiety and Depression Scale, Somatosensory Amplification Scale, opioids for dyspnoea and respiratory failure. Path analyses were conducted to estimate the direct and indirect paths with reference to dyspnoea and related factors. RESULTS: A total of 209 patients were enrolled and 208 patients were included in the analysis. Cough worsened dyspnoea (ß=0.136), dyspnoea increased emotional distress (ß=1.104), emotional distress increased somatosensory amplification (ß=0.249) and somatosensory amplification worsened cough (ß=0.053) according to path analysis. CONCLUSION: There may be a vicious circle among dyspnoea and related factors: cough worsened dyspnoea, dyspnoea increased emotional distress, emotional distress increased somatosensory amplification and somatosensory amplification worsened cough. When treating dyspnoea in patients with cancer, managing these factors aimed at interrupting this vicious circle may be useful. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000038820).

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak.

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

ß-Elemene in zedoary turmeric oil injection induces dyspnea by binding to hemoglobin and upregulating HIF-1α.

ETHNOPHARMACOLOGICAL RELEVANCE: Zedoary turmeric oil injection (ZTOI) extracted from the rhizome extract of Curcuma phaeocaulis Valeton, Curcuma wenyujin Y. H. Chen et C. Ling or Curcuma kwangsiensis S. G. Lee et C. F. Liang, is widely used for the treatment of virus-induced upper respiratory tract infections, peptic ulcers, viral pneumonia, etc. However, it has attracted widespread attention because it often causes adverse drug reactions (ADRs), including dyspnea. However, little is known about the mechanism underlying dyspnea caused by ZTOI, which limits its clinical application. AIM OF THE STUDY: To investigate the major pathophysiologic signatures and underlying mechanism of ZTOI-related dyspnea. METHODS: Respiratory function detection was used to explore the pathophysiologic signature of dyspnea induced by ZTOI. UV-vis absorption spectroscopy and isothermal titration calorimetry were applied to test the interaction between ZTOI and hemoglobin (Hb). GC‒MS was used to identify the main components in ZTOI. Molecular docking, surface plasmon resonance, and circular dichroism spectroscopy were employed to test the reaction between ß-elemene and Hb. Western blot was performed to investigate the effect of ß-elemene on the hypoxia signaling pathway. RESULTS: The results showed that ZTOI-induced dyspnea was related to a decreased oxygen carrying capacity of Hb. The molecular interaction between ZTOI and Hb was proven. Notably, ß-elemene in ZTOI exhibited high binding affinity to Hb and altered its secondary structure. Furthermore, it was found that ß-elemene downregulated the expression of prolyl hydroxylase-domain protein 2 and upregulated the expression of hypoxia-inducible factor-1α. CONCLUSIONS: Our study is valuable for better understanding the pathophysiological characteristics and underlying mechanism of ZTOI to ensure its safe clinical application. We also provided a strategy to elucidate the underlying mechanism based on inspiration from clinical ADR phenotypes for investigating other medical products with ADRs in the clinic.

The impact of regular, low-dose, sustained-release morphine for chronic breathlessness on caregiver burden: An exploratory analysis of the BEAMS trial.

BACKGROUND: Chronic breathlessness adversely impacts people with chronic obstructive pulmonary disease and their caregivers (family and friends), who may, in turn, experience significant burden due to their caregiving role. Sustained-release morphine may reduce chronic breathlessness in some patients, which may have an impact on caregivers' perceived burden. AIM: To explore the impact on caregiver burden of active treatment of people with chronic breathlessness (modified Medical Research Council (mMRC) ⩾ 3) and chronic obstructive pulmonary disease (COPD) with regular, low-dose, sustained-release morphine within a multi-site, double-blind, randomised, placebo-controlled trial. DESIGN: Exploratory analysis of self-reported caregiver burden at baseline and end of week 3 in a randomised, double-blind, placebo-controlled study. Caregiver measures included: demographics and perceived burden (Zarit Burden Interview 12-item short-form questionnaire). Patient measures included: worst breathlessness and FitBitR-measures. SETTING/PARTICIPANTS: All consenting caregivers of trial patient participants in a multi-site study recruiting from palliative care and respiratory services. RESULTS: Caregivers (n = 49; 59% women; median age 68 years [IQR 50-75]) reported median baseline caregiver burden 12 [IQR 5-17], with 53% reporting high burden (⩾13). Eighty-four percent of caregivers reported no change in burden. In people whose worst breathlessness improved, caregiver burden moved in the same direction, though the correlation was not significant (rs = 0.25, p = 0.17). Conversely, caregiver burden worsened as patients' minutes lightly active increased, with the correlation being significant (rs = 0.56, p = 0.04). CONCLUSIONS: Caregivers reported high levels of caregiver burden, but patients' response to treatment in terms of their symptom and function may influence change in caregiver burden over a three-week period.

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.

Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis.

BACKGROUND: Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. METHODS: Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. RESULTS: In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. CONCLUSION: Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease.

BACKGROUND: Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear. OBJECTIVES: To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD. SEARCH METHODS: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 30 November 2022. We also searched ClinicalTrials.gov and the WHO ICTRP up to 30 November 2022. SELECTION CRITERIA: We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The primary outcomes were acute exacerbations of COPD, respiratory health-related quality of life, pneumonia and other serious adverse events. The secondary outcomes were symptom scores, lung function, physical capacity, and mortality. We used GRADE to assess certainty of evidence for studies that contributed data to our prespecified outcomes. MAIN RESULTS: Four studies with a total of 15,412 participants met the inclusion criteria. The mean age of study participants ranged from 64.4 to 65.3 years; the proportion of female participants ranged from 28% to 40%. Most participants had symptomatic COPD (COPD Assessment Test Score ≥ 10) with severe to very severe airflow limitation (forced expiratory volume in one second (FEV1) < 50% predicted) and one or more moderate-to-severe COPD exacerbations in the last 12 months. Trial medications differed amongst studies. The duration of follow-up was 52 weeks in three studies and 24 weeks in one study. We assessed the risk of selection, performance, and detection bias to be low in the included studies; one study was at high risk of attrition bias, and one study was at high risk of reporting bias. Triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence). Subgroup analysis stratifying by blood eosinophil counts showed there may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93) (test for subgroup differences: P < 0.01) (high/low cut-offs: 150 eosinophils/µL in three studies; 200 eosinophils/µL in one study). However, moderate-to-substantial heterogeneity was observed in both high- and low-eosinophil subgroups. These subgroup analyses are observational by nature and thus results should be interpreted with caution. Triple therapy may be associated with reduced rates of severe COPD exacerbations (RR 0.75, 95% CI 0.67 to 0.84; n = 14,131; low-certainty evidence). Triple therapy improved health-related quality of life assessed using the St George's Respiratory Questionnaire (SGRQ) by the minimal clinically important difference (MCID) threshold (4-point decrease) (35.3% versus 42.4%, odds ratio (OR) 1.35, 95% CI 1.26 to 1.45; n = 14,070; high-certainty evidence). Triple therapy may result in fewer symptoms measured using the Transition Dyspnoea Index (TDI) (OR 1.33, 95% CI 1.13 to 1.57; n = 3044; moderate-certainty evidence) and improved lung function as measured by change in trough FEV1 (mean difference 38.68 mL, 95% CI 22.58 to 54.77; n = 11,352; low-certainty evidence). However, these benefits fell below MCID thresholds for TDI (1-unit decrease) and trough FEV1 (100 mL), respectively. Triple therapy is probably associated with a higher risk of pneumonia as a serious adverse event compared to combination LABA/LAMA inhalers (3.3% versus 1.9%, OR 1.74, 95% CI 1.39 to 2.18; n = 15,412; moderate-certainty evidence). In contrast, all-cause serious adverse events may be similar between groups (19.7% versus 19.7%, OR 0.95, 95% CI 0.87 to 1.03; n = 15,412; low-certainty evidence). All-cause mortality may be lower with triple therapy (1.4% versus 2.0%, OR 0.70, 95% CI 0.54 to 0.90; n = 15,397; low-certainty evidence). AUTHORS' CONCLUSIONS: The available evidence suggests that triple therapy may reduce rates of COPD exacerbations (low-certainty evidence) and results in an improvement in health-related quality of life (high-certainty evidence) compared to combination LABA/LAMA inhalers, but probably confers an increased pneumonia risk as a serious adverse event (moderate-certainty evidence). Triple therapy probably improves respiratory symptoms and may improve lung function (moderate- and low-certainty evidence, respectively); however, these benefits do not appear to be clinically significant. Triple therapy may reduce the risk of all-cause mortality compared to combination LABA/LAMA inhalers (low-certainty evidence). The certainty of the evidence was downgraded most frequently for inconsistency or indirectness. Across the four included studies, there were important differences in inclusion criteria, trial medications, and duration of follow-up. Investigation of heterogeneity was limited due to the small number of included studies. We found limited data on the effects of triple therapy compared to combination LABA/LAMA inhalers in patients with mild-moderate COPD and those without a recent exacerbation history.

Evaluating the effectiveness of applying aroma seals to masks in reducing stress caused by wearing masks: A randomized controlled trial.

During the COVID-19 pandemic, face masks on patients and healthy people have been recommended to prevent airborne transmission of the virus. This increased the number of people who felt stressed while wearing masks. In this study, we investigated the stress-relieving effects of attaching aroma seals to masks. A double-blind, randomized controlled trial was conducted involving 62 university students. The participants were randomly assigned to two groups and instructed to apply a seal to their masks once a day throughout the study period. The primary measure used was the Depression, Anxiety, and Stress Scale-21 (DASS-21), while the secondary measures included the assessment of breathlessness associated with mask-wearing and the World Health Organization Five Well-Being Index (WHO-5). The intervention group, referred to as the aroma-seal use group, utilized aroma seals infused with orange-lime essential oil with the expectation of experiencing the healing effects of citrus. On the other hand, the non-intervention group, known as the placebo-seal use group, utilized identical seals without any aroma. Results indicated that the aroma-seal use group exhibited significant improvements in both the total DASS-21 scores and depression scores compared to their baseline values by the second week of the intervention. Furthermore, the aroma-seal use group demonstrated a reduced occurrence of breathlessness while wearing masks compared to the placebo-seal group. Additionally, when assessing the item "I have felt calm and relaxed" from the WHO-5 questionnaire, the aroma-seal use group displayed significantly higher scores than the placebo group. Therefore, using aroma seals containing orange-lime essential oil could be beneficial in relieving mental stress and reducing breathlessness while wearing a mask, thus improving mental health.

Monitoring Changes in Oxygen Muscle during Exercise with High-Flow Nasal Cannula Using Wearable NIRS Biosensors.

Exercise increases the cost of breathing (COB) due to increased lung ventilation (V˙E), inducing respiratory muscles deoxygenation (∇SmO2), while the increase in workload implies ∇SmO2 in locomotor muscles. This phenomenon has been proposed as a leading cause of exercise intolerance, especially in clinical contexts. The use of high-flow nasal cannula (HFNC) during exercise routines in rehabilitation programs has gained significant interest because it is proposed as a therapeutic intervention for reducing symptoms associated with exercise intolerance, such as fatigue and dyspnea, assuming that HFNC could reduce exercise-induced ∇SmO2. SmO2 can be detected using optical wearable devices provided by near-infrared spectroscopy (NIRS) technology, which measures the changes in the amount of oxygen bound to chromophores (e.g., hemoglobin, myoglobin, cytochrome oxidase) at the target tissue level. We tested in a study with a cross-over design whether the muscular desaturation of m.vastus lateralis and m.intercostales during a high-intensity constant-load exercise can be reduced when it was supported with HFNC in non-physically active adults. Eighteen participants (nine women; age: 22 ± 2 years, weight: 65.1 ± 11.2 kg, height: 173.0 ± 5.8 cm, BMI: 21.6 ± 2.8 kg·m-2) were evaluated in a cycle ergometer (15 min, 70% maximum watts achieved in ergospirometry (V˙O2-peak)) breathing spontaneously (control, CTRL) or with HFNC support (HFNC; 50 L·min-1, fiO2: 21%, 30 °C), separated by seven days in randomized order. Two-way ANOVA tests analyzed the ∇SmO2 (m.intercostales and m.vastus lateralis), and changes in V˙E and ∇SmO2·V˙E-1. Dyspnea, leg fatigue, and effort level (RPE) were compared between trials by the Wilcoxon matched-paired signed rank test. We found that the interaction of factors (trial × exercise-time) was significant in ∇SmO2-m.intercostales, V˙E, and (∇SmO2-m.intercostales)/V˙E (p < 0.05, all) but not in ∇SmO2-m.vastus lateralis. ∇SmO2-m.intercostales was more pronounced in CTRL during exercise since 5' (p < 0.05). Hyperventilation was higher in CTRL since 10' (p < 0.05). The ∇SmO2·V˙E-1 decreased during exercise, being lowest in CTRL since 5'. Lower dyspnea was reported in HFNC, with no differences in leg fatigue and RPE. We concluded that wearable optical biosensors documented the beneficial effect of HFNC in COB due to lower respiratory ∇SmO2 induced by exercise. We suggest incorporating NIRS devices in rehabilitation programs to monitor physiological changes that can support the clinical impact of the therapeutic intervention implemented.

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del is the commonest CF-causing variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks meaningful CFTR function - faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. Corrective therapy could benefit many pwCF. This review evaluates single correctors (monotherapy) and any combination of correctors (most commonly lumacaftor, tezacaftor, elexacaftor, VX-659, VX-440 or VX-152) and a potentiator (e.g. ivacaftor) (dual and triple therapies). OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022). SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and judged evidence certainty (GRADE); we contacted investigators for additional data. MAIN RESULTS: We included 34 RCTs (4781 participants), lasting between 1 day and 48 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), 16 dual-therapy RCTs (2627 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and 11 triple-therapy RCTs (1804 participants) (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor). Participants in 21 RCTs had the genotype F508del/F508del, in seven RCTs they had F508del/minimal function (MF), in one RCT F508del/gating genotypes, in one RCT either F508del/F508del genotypes or F508del/residual function genotypes, in one RCT either F508del/gating or F508del/residual function genotypes, and in three RCTs either F508del/F508del genotypes or F508del/MF genotypes. Risk of bias judgements varied across different comparisons. Results from 16 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard designs (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically relevant improvements in quality of life (QoL). There was insufficient evidence to determine effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess due to their variety and few participants (all F508del/F508del). Dual therapy In a tezacaftor-ivacaftor group there was one death (deemed unrelated to the study drug). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points (moderate-certainty evidence). At six months, relative change in forced expiratory volume in one second (FEV1) % predicted improved with all dual combination therapies compared to placebo (high- to moderate-certainty evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor (odds ratio (OR) 2.05, 99% confidence interval (CI) 1.10 to 3.83; I2 = 0%; 2 studies, 739 participants; high-certainty evidence). Over 120 weeks (initial study period and follow-up), systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo (all moderate-certainty evidence): lumacaftor 600 mg (hazard ratio (HR) 0.70, 95% CI 0.57 to 0.87; I2 = 0%; 2 studies, 739 participants); lumacaftor 400 mg (HR 0.61, 95% CI 0.49 to 0.76; I2 = 0%; 2 studies, 740 participants); and tezacaftor (HR 0.64, 95% CI 0.46 to 0.89; 1 study, 506 participants). Triple therapy No study reported any deaths (high-certainty evidence). All other evidence was low- to moderate-certainty. QoL respiratory domain scores probably improved with triple therapy compared to control at six months (six studies). There was probably a greater relative and absolute change in FEV1 % predicted with triple therapy (four studies each across all combinations). The absolute change in FEV1 % predicted was probably greater for F508del/MF participants taking elexacaftor-tezacaftor-ivacaftor compared to placebo (mean difference 14.30, 95% CI 12.76 to 15.84; 1 study, 403 participants; moderate-certainty evidence), with similar results for other drug combinations and genotypes. There was little or no difference in adverse events between triple therapy and control (10 studies). No study reported time to next pulmonary exacerbation, but fewer F508del/F508del participants experienced a pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor at four weeks (OR 0.17, 99% CI 0.06 to 0.45; 1 study, 175 participants) and 24 weeks (OR 0.29, 95% CI 0.14 to 0.60; 1 study, 405 participants); similar results were seen across other triple therapy and genotype combinations. AUTHORS' CONCLUSIONS: There is insufficient evidence of clinically important effects from corrector monotherapy in pwCF with F508del/F508del. Additional data in this review reduced the evidence for efficacy of dual therapy; these agents can no longer be considered as standard therapy. Their use may be appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar small improvements in QoL and respiratory function with lower pulmonary exacerbation rates. While the effect sizes for QoL and FEV1 still favour treatment, they have reduced compared to our previous findings. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. Data from triple therapy trials demonstrate improvements in several key outcomes, including FEV1 and QoL. There is probably little or no difference in adverse events for triple therapy (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; VX-152-tezacaftor-ivacaftor) in pwCF with one or two F508del variants aged 12 years or older (moderate-certainty evidence). Further RCTs are required in children under 12 years and those with more severe lung disease.

Overuse of long-acting ß2-agonist/inhaled corticosteroids in patients with chronic obstructive pulmonary disease: time to rethink prescribing patterns.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality globally. In the major revision of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 report, the scientific committee concluded that the use of long-acting ß2-agonist/inhaled corticosteroids (LABA/ICS) is not encouraged in patients with COPD. However, current prescribing patterns reveal significant use of LABA/ICS. In this paper, the evidence behind the current practice and the latest treatment recommendations is reviewed. We compare the efficacy and safety of combination therapy with long-acting muscarinic antagonist (LAMA) and LABA vs LABA/ICS and note that LAMA/LABA combinations have reduced the annual rate of moderate/severe exacerbations, delayed the time to first exacerbation, and increased post-dose FEV1 vs ICS-based regimens. The GOLD 2023 report recommends treatment with LABA and LAMA combination (preferably as a single inhaler) in patients with persistent dyspnea, with initiation of ICS in patients based on the symptoms (dyspnea and exercise intolerance as indicated by modified Medical Research Council [mMRC] score ≥ 2 and COPD Assessment Test [CAT™] > 20), blood eosinophil count (≥ 300 cells/µL), and exacerbation history (history of hospitalizations for exacerbations of COPD and ≥ 2 moderate exacerbations per year despite appropriate long-acting bronchodilator maintenance therapy). We describe practical recommendations for primary care physicians to optimize therapy for their patients and prevent overuse of ICS-based regimens. We advocate adherence to current recommendations and a greater focus on effective treatments to successfully control symptoms, minimize exacerbation risk, preserve lung function, maximize patient outcomes, and reduce the burden of drug-related adverse events.

Chronic obstructive pulmonary disease (COPD) is a common disease of the lungs associated with continued respiratory symptoms and airflow limitation. COPD causes symptoms such as breathlessness, cough, and production of phlegm, and, if not properly managed, these symptoms may get worse and result in flare-ups, also termed exacerbations. COPD management includes controlling symptoms while reducing the risk of exacerbations. COPD treatments include bronchodilators and inhaled corticosteroids (ICS). Bronchodilators help by widening the airways, making it easier to breathe. The two types of bronchodilators are long-acting muscarinic antagonists (LAMAs; these drugs prevent closing of the airways) and long-acting ß₂-agonists (LABAs; these drugs relax the muscles around the airways to help keep the airways open for a longer time). ICS may reduce swelling in the airways in some patients with COPD. However, the use of ICS-based regimens as the first treatment choice has been linked to health risks and is not in keeping with the recent national and international recommendations. In this narrative review, we examine why the use of ICS-based regimens is still growing and explore, based on available evidence, and why this treatment course may not be optimal for most patients with COPD. We discuss how the treatment for COPD has changed over time, and our findings support the use of LAMA and LABA as the first course of therapy in many patients with COPD. We conclude that greater adherence to the treatment guidelines can help to improve treatment outcomes for many patients with COPD.

The clinical outcomes of dapagliflozin in patients with acute heart failure: A randomized controlled trial (DAPA-RESPONSE-AHF).

AIMS: Dapagliflozin may confer additional decongestive and natriuretic benefits to patients with acute heart failure (AHF). Nonetheless, this hypothesis was not clinically examined. This study aimed primarily to investigate the effect of dapagliflozin on symptomatic relief in those patients. METHODS: This was a randomized, double-blind study that included 87 patients with AHF presenting with dyspnea. Within 24 h of admission, patients were randomized to receive either dapagliflozin (10 mg/day, N = 45) or placebo (N = 42) for 30 days. The primary outcome was the difference between the two groups in the area under the curve (AUC) of visual analogue scale (VAS) dyspnea score over the first 4 days. Secondary endpoints included urinary sodium (Na) after 2 h of randomization, percent change in NT-proBNP, cumulative urine output (UOP), and differences in mortality and hospital readmission rates. RESULTS: The results showed that dapagliflozin significantly reduced the AUC of VAS dyspnea score compared to placebo (3192.2 ± 1631.9 mm × h vs 4713.1 ± 1714.9 mm × h, P < 0.001). The relative change of NT-proBNP compared to its baseline was also larger with dapagliflozin (-34.89% vs -10.085%, P = 0.001). Additionally, higher cumulative UOP was found at day 4 (18600 ml in dapagliflozin vs 13700 in placebo, P = 0.031). Dapagliflozin decreased rehospitalization rates within 30 days after discharge, while it did not affect the spot urinary Na concentration, incidence of worsening of heart failure, or mortality rates. CONCLUSION: Dapagliflozin may provide symptomatic relief and improve diuresis in patients with AHF. Further studies are needed to confirm these findings. https://clinicaltrials.gov/study/NCT05406505.

Geriatric Pharmacotherapy Case Series: Chronic Obstructive Pulmonary Disease.

Patient is a 77-year-old female who is a retired teacher living with her husband. Patient presents to the clinic for a post-hospital discharge visit. She was treated for bacterial pneumonia with combination therapy of azithromycin and cefpodoxime. She was diagnosed with COPD seven years ago when she had to be treated for chronic dyspnea, cough, and sputum that kept her breathless and required hospitalization.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention.

BACKGROUND: Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. OBJECTIVES: The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). METHODS: In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. RESULTS: The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). CONCLUSIONS: In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

Effectiveness and safety of opioids on breathlessness and exercise endurance in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Opioids are recommended to treat advanced refractory dyspnoea despite optimal therapy by the American Thoracic Society clinical practice guidelines, while newly published randomised controlled trials of opioids in chronic obstructive pulmonary disease yield conflicting results. AIM: This study aimed to evaluate the effectiveness and safety of opioids for patients with chronic obstructive pulmonary disease. DESIGN: Systematic review and meta-analysis (PROSPERO CRD42021272556). DATA SOURCES: Databases of PubMed, EMBASE and CENTRAL were searched from inception to 2022 for eligible randomised controlled trials. RESULTS: Twenty-four studies including 975 patients, were included. In cross-over studies, opioids improved breathlessness (standardised mean difference, -0.43; 95% CI, -0.55 to -0.30; I2 = 18%) and exercise endurance (standardised mean difference, 0.22; 95% CI, 0.02-0.41; I2 = 70%). However, opioids failed to improve dyspnoea (standardised mean difference, -0.02; 95% CI, -0.22 to 0.19; I2 = 39%) and exercise endurance (standardised mean difference, 0.00; 95% CI, -0.27 to 0.27; I2 = 0%) in parallel control studies that administered sustained-release opioids for more than 1 week. The opioids used in most crossover studies were short-acting and rarely associated with serious adverse effects. Only minor side effects such as dizziness, nausea, constipation and vomiting were identified for short-acting opioids. CONCLUSIONS: Sustained-release opioids did not improve dyspnoea and exercise endurance. Short-acting opioids appeared to be safe, have potential to lessen dyspnoea and improve exercise endurance, supporting benefit in managing episodes of breathlessness and providing prophylactic treatment for exertional dyspnoea.