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INTRODUCTION: Chronic discogenic low back pain (CD-LBP) is caused by degeneration of the disc due to trauma to the annulus or by unprovoked degeneration, resulting in chronic pain. Spinal cord stimulation (SCS) employing the BurstDR™ waveform has been shown to be an effective treatment in a variety of chronic pain conditions. The aim of this prospective case study was to determine the effect of BurstDR™ SCS on pain relief, disability, and patient satisfaction in a population with CD-LBP.METHODS: Seventeen subjects with CD-LBP received a SCS trial with BurstDR™ stimulation. Patients with >50% pain relief after a trial period of 2 weeks were permanently implanted (n = 15). Patients then rated LBP and leg pain using the numeric rating scale (NRS), Oswestry disability index (ODI), patient global impression of change (PGIC), EQ-5D quality of life, and painDETECT for neuropathic pain at baseline following trial, 3, 6, and 12 months after permanent implantation.RESULTS: Treatment with BurstDR™ SCS resulted in significant reduction of LBP as the NRS was reduced from 71.7 ± 7.3 at baseline to 42.5 ± 18.1 at 12 months. Average pain relief at 12 months was 42.5%. In patients with leg pain (n = 8), pain was significantly reduced from 66.9 ± 8.2 to 11.7 ± 10.4 at 12 months. PainDETECT scores for neuropathic pain significantly reduced from 18.9 ± 4.8 at baseline, and 14.8 ± 3.2 at 12 months. Baseline ODI score significantly reduced from 41.2 ± 12.8 to 25.8 ± 8.6 at 12 months. PGIC scores remained low from 2.6 ± 1.6 at 3 months, 2.5 ± 1.0 at 6 months, and 2.5 ± 1.3 at 12 months. EQ-5D-5L rates remained constant from baseline 56.10 ± 23.9 to 68.6 ± 12.9 at 12 months.CONCLUSION: BurstDR™ SCS resulted in significant reduction of back pain, leg pain, and quality of life in patients with CD-LBP and decreased the level of disability and generated positive patient satisfaction scores.

Contains fulltext : 286719.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Spinal cord stimulation (SCS) can provide long-term pain relief for various chronic pain conditions, but some patients have no relief with trial stimulation or lose efficacy over time. To "salvage" relief in patients who do not respond or have lost efficacy, alternative stimulation paradigms or anatomical targets can be considered. Dorsal root ganglion stimulation (DRG-S) has a different mechanism of action and anatomical target than SCS. OBJECTIVES: We assessed DRG-S salvage therapy outcomes in patients who did not respond to SCS or had lost SCS efficacy. MATERIALS AND METHODS: We retrospectively included consecutive patients from 2016 to 2020 who were salvaged with DRG-S after failed SCS trials (

Background: A novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL. Methods: Patients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%–75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 μg), high-dose MF/IND (320/150 μg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 μg). Results: Of the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%–75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively. Conclusions: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

Background: The relationship between symptom burden and physical activity (PA) in chronic obstructive pulmonary disease (COPD) remains poorly understood with limited data on undiagnosed individuals and those with mild to moderate disease. Objective: The primary objective was to evaluate the relationship between symptom burden and moderate-to-vigorous intensity PA (MVPA) in individuals from a random population-based sampling mirroring the population at large. Methods: Baseline participants of the Canadian Cohort Obstructive Lung Disease (n=1558) were selected for this cross-sectional sub-study. Participants with mild COPD (n=406) and moderate COPD (n=331), healthy individuals (n=347), and those at risk of developing COPD (n=474) were included. The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire was used to estimate MVPA in terms of energy expenditure. High symptom burden was classified using the COPD Assessment Test ([CAT] ≥10). Results: Significant associations were demonstrated between high symptom burden and lower MVPA levels in the overall COPD sample (β=-717.09; 95% confidence interval [CI]=-1079.78, -354.40; p

Background: Chronic pain patients implanted with a neurostimulation device typically require follow-up and device programming visits to address changes in symptoms or treatment. Follow-up visits require access to specialty care and necessitate patients to take time off work, commute long distances, arrange for travel, and/or work with a caregiver's schedule. Telemedicine was adopted for some patient management as a result of the Sars-Cov-2 pandemic; however, remote optimization for neuromodulation still required an in-person visit to adjust device parameters. An FDA-approved digital platform enables remote programming of an implanted neuromodulation device using a real-time audio-video link from the clinical programmer to the patient controller. The Remote Optimization, Adjustment, and Measurement for Chronic Pain Therapy (ROAM-CPT) is a multi-center, prospective study that is currently underway to access the effectiveness of the teleprogramming system in fulfilling patients' clinical demands. Methods: This pilot study surveyed 16 patients to determine the ability of the teleprogramming platform to provide a rapid solution safely and effectively for patient's chronic pain. Data were collected using a questionnaire that asked 6 clinician-centric questions and 5 patient-centric questions. Results: 4/4 surveyed physicians were able to address patients' needs. 16/16 surveyed patients reported a quick resolution to pain and 15/16 did not require additional follow-up. Data curated from this pilot study show that the teleprogramming application greatly improves patient care, is preferred by both clinicians and patients with minimal disruptions to patients' everyday lives. Conclusion: Teleprogramming provides real-time virtual programming capabilities and optimizes patients' therapy. Perspective: This article describes remote device programming and analysis as an alternative to in-person programming/treatment sessions for neuromodulation patients. This remote option gives patients access to timely and clinically appropriate device management when in-person care may not be available.

Background A pre-specified meta-analysis of individual patient data from the 52-week METREX and METREO trials, which investigated mepolizumab for chronic obstructive pulmonary disease (COPD) in patients with blood eosinophil counts ≥150 cells/µL (screening) or ≥300 cells/µL (prior year) and frequent exacerbations, enables more robust characterization of mepolizumab efficacy in COPD and exploration of the relationship between blood eosinophil count and treatment responses. Methods In METREX (117106/NCT02105948) and METREO (117113/NCT02105961), randomized patients received mepolizumab or placebo added to existing inhaled corticosteroid (ICS)–based triple maintenance therapy. The annual rate of moderate/severe exacerbations (primary endpoint) was compared between subcutaneous (SC) mepolizumab 100 mg versus placebo (primary comparison of interest) and all doses (100 mg and 300 mg SC) versus placebo in patients with blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the prior year. Secondary/other endpoints included time to first moderate/severe exacerbation, exacerbations leading to emergency department visit/hospitalization and health-related quality of life (HRQoL). A predictive model of the relationship between screening blood eosinophil counts and exacerbation rates included data from all randomized patients. Results In total, 1510 patients were randomized in METREX and METREO and 1136 patients were included in the pre-specified meta-analysis. From the meta-analysis, mepolizumab 100 mg SC significantly reduced annual moderate/severe exacerbation rates versus placebo by 18% (rate ratio: 0.82; 95% confidence interval: 0.71, 0.95; p=0.006) and delayed time to first moderate/severe exacerbation (hazard ratio: 0.80 [0.68, 0.94]; p=0.006). Mepolizumab 100 mg SC versus placebo numerically reduced exacerbations leading to ED visits/hospitalization and improved HRQoL. A modelling approach demonstrated increasing efficacy for moderate/severe exacerbations with increasing screening blood eosinophil count; this relationship was more pronounced for exacerbations requiring oral corticosteroids (post hoc). The all-doses comparison had similar results. Conclusion Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD. Results suggest that blood eosinophil counts (≥150 cells/µL at screening or ≥300 cells/µL in the prior year) allow for identification of patients with COPD who experience exacerbations while treated with maximal ICS-based triple maintenance therapy who are likely to benefit from mepolizumab., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/YCq1mqQ5Xl4

Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail rwise@jhmi.eduPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.Results: Of 3589 patients, 2156 (60.1%) had ≥ 1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥ 1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54– 1.16; none: HR 1.27, 95% CI: 0.65– 2.47; interaction P=0.233) or all-cause mortality (≥ 1: HR 1.08, 95% CI: 0.81– 1.43; none: HR 0.66, 95% CI: 0.36– 1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥ 1: rate ratio [RR] 0.80, 95% CI: 0.68– 0.94; none: RR 0.69, 95% CI: 0.54– 0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).Conclusion: In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.Keywords: COPD, COPD exacerbation, aclidinium, MACE, mortality

Contains fulltext : 235081.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dorsal root ganglion neurostimulation (DRG-S) is effective in treating various refractory chronic pain syndromes. In preclinical studies, DRG-S at very low frequencies (

Background: Patients with asthma who are inadequately controlled on inhaled corticosteroid–long-acting β2-adrenoceptor agonist (ICS–LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF–IND–GLY) versus ICS–LABA in patients with inadequately controlled asthma. Methods: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS–LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF–IND–GLY (80 μg, 150 μg, 50 μg; 160 μg, 150 μg, 50 μg) or MF–IND (160 μg, 150 μg; 320 μg, 150 μg) once daily via Breezhaler, or high-dose fluticasone–salmeterol (FLU–SAL; 500 μg, 50 μg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF–IND–GLY versus MF–IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. Findings: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF–IND–GLY, n=620; high-dose MF–IND–GLY, n=619; medium-dose MF–IND, n=617; high-dose MF–IND, n=618; high-dose FLU–SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF–IND–GLY (treatment difference [Δ] 76 mL [95% CI 41–111]; p1 versus corresponding doses of MF–IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF–IND–GLY (99 mL [64–133]; p

Background: Radiofrequency ablation (RFA) of the medial branches of the dorsal rami has been reported to relieve facet joint–related back pain for 6 months to 1 year in 60% of patients. Although providing benefit in a significant proportion of patients, there remains a group of patients who do not experience any pain relief from RFA or experience only benefit from the ablation for a short period. Failure of RFA has been attributed to technical failure of coagulating the nerve or coagulation of a minimal section of the nerve, allowing for early reinnervation. Increasing the success rate and duration of relief may require techniques that increase the likelihood of successful nerve ablation over a relevant distance by maximizing lesion size. Objectives: The aim of this technical note is to detail a modification to the current commonly used lumbar medial branch radiofrequency (RF) denervation approach to increase lesion size. Study Design: This is a technical report describing a novel two-needle approach to lumbar RF medial branch denervation. Setting: Large private interventional pain management institute. Methods: A dual needle placement of two 10-mm active tip RF cannulas separated by 6 mm is used to optimally contact the superior articular process (SAP) from its ventral to dorsal borders, which encompasses the anticipated course of the medial branch nerves. Results: The described technique creates a lesion that we estimate to be 11.0-mm wide and 11.6-mm long along the course of the medial branch adjacent to the SAP ensuring adequate coverage and treatment. Limitations: This report does not encompass a systematic evaluation of the clinical safety and efficacy of the two-needle RFA approach. Future studies will have to assess the longterm efficacy and safety of the approach. Conclusions: The detailed two-needle approach to lumbar RF medial branch denervation appears to be promising in terms of projected treatment success by coagulating a large volume of tissue, in a cost- and time-efficient manner. Key words: Radiofrequency ablation, RFA, lumbar, medial branch, facet joint, pain, rhizotomy

With the rapid rise in cases of COVID-19 across the world, health systems face unprecedented challenges in the delivery of patient care. This includes constrained capacity for intensive care unit (...

ObjectiveTo conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain.DesignGrade the evidence for DRG stimulation.MethodsAn international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsDRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies.ConclusionsModerate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

Introduction: Bromhexine is a potential therapeutic option in COVID-19, but no data from a randomized clinical trial has been available. The present study aimed to evaluate the efficacy of bromhexine in intensive care unit (ICU) admission, mechanical ventilation, and mortality in patients with COVID-19. Methods: An open-label randomized clinical trial study was performed in Tabriz, North-West of Iran. They were randomized to either the treatment with the bromhexine group or the control group, in a 1:1 ratio with 39 patients in each arm. Standard therapy was used in both groups and those patients in the treatment group received oral bromhexine 8 mg three times a day additionally. The primary outcome was a decrease in the rate of ICU admissions, intubation/mechanical ventilation, and mortality. Results: A total of 78 patients with similar demographic and disease characteristics were enrolled. There was a significant reduction in ICU admissions (2 out of 39 vs. 11 out of 39, P = 0.006), intubation (1 out of 39 vs. 9 out of 39, P = 0.007) and death (0 vs. 5, P = 0.027) in the bromhexine treated group compared to the standard group. No patients were withdrawn from the study because of adverse effects. Conclusion: The early administration of oral bromhexine reduces the ICU transfer, intubation, and the mortality rate in patients with COVID-19. This affordable medication can easily be administered everywhere with a huge positive impact(s) on public health and the world economy. Altogether, the verification of our results on a larger scale and different medical centers is strongly recommended. Trial Registration: IRCT202003117046797N4; https://irct.ir/trial/46969.

Xiaoshu Cao,1,2 Cristina de Oliveira Francisco,2 T Douglas Bradley,2– 4 Nasim Montazeri Ghahjaverestan,1,2 Susan M Tarlo,3,5,6 Matthew B Stanbrook,3,5 Kenneth R Chapman,3,5 Mark Inman,7 Azadeh Yadollahi1,2 1Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; 2KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, Canada; 3Department of Medicine, University of Toronto, Toronto, ON, Canada; 4Department of Medicine, University Health Network Toronto General Hospital, Toronto, ON, Canada; 5Department of Medicine, University Health Network Toronto Western Hospital, Toronto, ON, Canada; 6Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; 7Faculty of Medicine (Respirology), McMaster University, Hamilton, ON, CanadaCorrespondence: Azadeh Yadollahi, KITE, Toronto Rehabilitation Institute - University Health Network, Room 12-106, 550 University Avenue, Toronto, ON, M5G 2A2, Canada, Email azadeh.yadollahi@uhn.caRationale: Obstructive sleep apnea (OSA) is highly prevalent among patients with asthma, suggesting a pathophysiological link between the two, but a mechanism for this has not been identified.Hypothesis: Among patients with asthma, those with OSA will have greater overnight increases in thoracic fluid volume and small airways narrowing than those without OSA.Methods: We enrolled 19 participants with asthma: 9 with OSA (apnea-hypopnea index (AHI) ≥ 10) and 10 without OSA (AHI < 10). All participants underwent overnight polysomnography. Before and after sleep, thoracic fluid volume was measured by bioelectrical impedance and small airways narrowing was primarily assessed by respiratory system reactance at 5Hz using oscillometry.Results: Patients with asthma and OSA (OSA group) had a greater overnight increase in thoracic fluid volume by 120.5 mL than patients without OSA (non-OSA group) (164.4 ± 44.0 vs 43.9 ± 47.3 mL, p=0.006). Compared to the non-OSA group, the OSA group had greater overnight decrease in reactance at 5Hz (− 1.08 ± 0.75 vs 0.21 ± 0.27 cmH2O/L/s, p=0.02), and overnight increase in reactance area (14.81 ± 11.09 vs − 1.20 ± 2.46 cmH2O/L, p=0.04), frequency dependence of resistance (1.02 ± 0.68 vs 0.05 ± 0.18 cmH2O/L/s, p=0.04), and resonance frequency (2.80 ± 4.14 vs − 1.42 ± 2.13 cmH2O/L/s, p=0.04).Conclusion: Patients with asthma and co-existing OSA had greater overnight accumulation of fluid in the thorax in association with greater small airways narrowing than those without OSA. This suggests OSA could contribute to worsening of asthma at night by increasing fluid accumulation in the thorax.Keywords: asthma, obstructive sleep apnea, small airway narrowing, thoracic fluid volume

IntroductionAlthough most asthma is mild to moderate, severe asthma accounts for disproportionate personal and societal costs. Poor co-ordination of care between primary care and specialist settings is recognised as a barrier to achieving optimal outcomes. The Primary Care Severe Asthma Registry and Education (PCSAR-EDU) project aims to address these gaps through the interdisciplinary development and evaluation of both a ‘real-world’ severe asthma registry and an educational programme for primary care providers. This manuscript describes phase 1 of PCSAR-EDU which involves establishing interdisciplinary consensus on criteria for the: (1) definition of severe asthma; (2) generation of a severe asthma registry and (3) definition of an electronic-medical record data-based Clinician Behaviour Index (CBI).Methods and analysisIn phase 1, a modified e-Delphi activity will be conducted. Delphi panellists (n≥13) will be invited to complete a 30 min online survey on three separate occasions (i.e., three separate e-Delphi ‘rounds’) over a 3-month period. Expert opinion will be collected via an open-ended survey (‘Open’ round 1) and 5-point Likert scale and ranking surveys (‘Closed’ round 2 and 3). A fourth and final Delphi round will occur via synchronous meeting, whereby panellists approve a finalised ideal ‘core criteria list’, CBI and corresponding item weighting.Ethics and disseminationEthical approval has been obtained for the activities involved in phase 1 from the University of Toronto’s Human Research Ethics Programme (approval number 39695). Future ethics approvals will depend on information gathered in the proceeding phase; thus, ethical approval for phase 2 and 3 of this study will be sought sequentially. Findings will be disseminated through conference presentations, peer-reviewed publications and knowledge translation tools.

Objective A heightened and organized understanding of sacral anatomy could potentially lead to a more effective and safe method of dorsal root ganglion stimulation (DRG-S) lead placement. The aim of this technical note is to describe a standardized access method for S1 DRG-S lead placement. Design Technical note. Methods The described approach utilizes alignment of the lumbosacral prominence and is measurement-based, allowing for standardized sacral access, even when visualization is suboptimal. The medial-to-lateral needle trajectory is designed to limit interaction with the sensitive neural structures and allows for a more parallel orientation of the lead to the DRG and nerve root. Conclusions The described technique potentially improves the safety of S1 DRG-S lead placement. The parallel lead orientation to the DRG may also increase efficacy while lowering energy requirements.

Background Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users. Methods ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year. Results Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041). Conclusions This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity. Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107.

Summary Background Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available. Methods TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12–84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV1, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov , NCT02134028 . Findings Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5–25·9%), injection-site erythema (2·2–23·4%), and bronchitis (9·3–19·0%). Serious asthma exacerbations (0·5–3·6%) and pneumonia (0·7–2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277–0·327) across parent study and treatment groups, pre-bronchodilator FEV1 improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV1 and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks. Interpretation Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population. Funding Sanofi and Regeneron Pharmaceuticals.