Publications
265 results found
Wedzicha JA, Chapman KR, Vogelmeier CF, et al., 2017, Improvement In Sgrq Component Score With Indacaterol/glycopyrronium Versus Salmeterol/fluticasone: Results From The Flame Study, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Roche N, Wedzicha JA, Donohue JF, et al., 2017, Indacaterol/glycopyrronium Improves Lung Function And Health Status Versus Salmeterol/fluticasone In Moderate-To-Very Severe COPD Patients Irrespective Of Prior Ics/laba/lama Therapy: The Flame Study, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Wedzicha JA, 2017, Rate Of Deterioration In Sgrq Is Independently Predictive Of Mortality In COPD, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Parkin JM, Vaz M, Orford C, et al., 2017, Designing An Acute Intervention Trial In Patients Hospitalised For AeCOPD: Experience From The Ph2 Aether Study Of Acumapimod (bct197) P38 Map Kinase Inhibitor, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Allinson JP, Finney L, et al., 2017, Not All Treated COPD Exacerbations Are Associated With A Raised C-Reactive Protein, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Allinson JP, Donaldson GC, Wedzicha JA, 2017, Is The Absence Of Purulence Sputum At Exacerbation Useful For Guiding Long-Term Therapy?, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Allinson JP, Hardy R, Donaldsonl GC, et al., 2017, Combined Impact Of Early Life Factors And Smoking On Adult Fev1 trajectory - A Prospective 64 Year National Birth Cohort Study, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Wedzicha JA, 2017, Rise In Blood Neutrophils, And Falls In Eosinophils, Over Time Is Associated With Mortality In COPD: A Joint Model Analysis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Chapman KR, Wedzicha JA, Roche N, et al., 2017, Improvement In Lung Function And Health Status With Indacaterol/glycopyrronium Versus Salmeterol/fluticasone In A Subgroup Of Patients With ≥2 Exacerbations In The Previous Year: Results From The Flame Study, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Smith JA, McGarvey L, Morice AH, et al., 2017, The Effect Of Aclidinium Bromide 400 μg On The Relief Of Daily Symptoms Associated With Chronic Obstructive Pulmonary Disease, Including Cough, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Smith JA, McGarvey L, Morice AH, et al., 2017, Efficacy Of Aclidinium Bromide 400 μg On The Relief Of Cough Symptoms In Symptomatic Patients With Chronic Obstructive Pulmonary Disease: A Cough Severity Subgroup Analysis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Law M, Sweeting MJ, Donaldson GC, et al., 2016, Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: the resultant bias in treatment effect estimation, Pharmaceutical Statistics, Vol: 16, Pages: 201-209, ISSN: 1539-1604
In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol.
Beeh KM, Burgel P-R, Franssen FME, et al., 2016, How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 139-149, ISSN: 1073-449X
Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease. Several studies have documented that long-acting bronchodilators can reduce exacerbation rate and/or severity, and others have shown that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroid combinations in patients at low and high risk for these events. In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single long-acting bronchodilators or LABA/inhaled corticosteroids in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary clearance, and symptom severity may all contribute to decreasing exacerbations. Although preclinical studies suggest LABAs and LAMAs have antiinflammatory effects, such effects have not been demonstrated yet in patients with chronic obstructive pulmonary disease.
Allinson JP, Hardy R, Donaldson GC, et al., 2016, EARLY-LIFE RESPIRATORY TRACT INFECTION AND ADULT SUSCEPTIBILITY TO CHRONIC MUCUS HYPERSECRETION - A PROSPECTIVE 64 YEAR NATIONAL BIRTH COHORT STUDY, THORAX, Vol: 71, Pages: A1-A2, ISSN: 0040-6376
Finney LJ, Belchamber KBR, Mallia P, et al., 2016, HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MONOCYTE DERIVED MACROPHAGES FROM PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A2, ISSN: 0040-6376
Wedzicha JA, Vogelmeier C, Larbig M, et al., 2016, EFFECT OF INDACATEROL/GLYCOPYRRONIUM ON THE TIME TO FIRST MODERATE OR SEVERE COPD EXACERBATION VERSUS SALMETEROL/FLUTICASONE BY BASELINE BLOOD EOSINOPHIL LEVELS: FINDINGS FROM THE FLAME STUDY, Publisher: WILEY-BLACKWELL, Pages: 117-117, ISSN: 1323-7799
Wedzicha JA, Chapman KR, Larbig M, et al., 2016, ONCE-DAILY INDACATEROL/GLYCOPYRRONIUM (IND/GLY) IS MORE EFFECTIVE THAN TWICE-DAILY SALMETEROL/FLUTICASONE (SFC) IN REDUCING EXACERBATIONS IN COPD PATIENTS AT A HIGH RISK OF EXACERBATIONS: THE FLAME STUDY, Publisher: WILEY-BLACKWELL, Pages: 116-116, ISSN: 1323-7799
Wedzicha JA, Zhong N, Ichinose M, et al., 2016, INDACATEROL/GLYCOPYRRONIUM (IND/GLY) IS SUPERIOR TO SALMETEROL/FLUTICASONE (SFC) IN ASIAN PATIENTS WITH MODERATE-TO-VERY SEVERE COPD AT A HIGH RISK OF EXACERBATIONS: FLAME STUDY RESULTS, Publisher: WILEY-BLACKWELL, Pages: 180-180, ISSN: 1323-7799
Wedzicha JA, Roche N, Larbig M, et al., 2016, INDACATEROL/GLYCOPYRRONIUM SHOWS CONSISTENT IMPROVEMENT IN LUNG FUNCTION AND HEALTH-RELATED QUALITY OF LIFE VERSUS SALMETEROL/FLUTICASONE IN MODERATE-TO-VERY SEVERE COPD PATIENTS: THE FLAME STUDY, Publisher: WILEY-BLACKWELL, Pages: 116-116, ISSN: 1323-7799
Westwood JP, Mackay AJ, Donaldson G, et al., 2016, The role of complement activation in COPD exacerbation recovery., ERJ Open Research, Vol: 2, ISSN: 2312-0541
Bewley M, Belchamber K, Chana K, et al., 2016, Differential effects of p38, MAPK, PI3K or Rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in COPD, PLOS One, Vol: 11, ISSN: 1932-6203
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.
Rodriguez-Roisin R, Han MK, Vestbo J, et al., 2016, Chronic respiratory symptoms with normal spirometry: a reliable clinical entity?, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 17-22, ISSN: 1535-4970
The 2001 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report defined five stages of spirometric severity (post-bronchodilator FEV1/FVC≥0.7): 0, and 1 (mild) to 4 (very severe). GOLD Stage 0 was defined by chronic cough and sputum production or chronic mucus hypersecretion (CMH) alone with preserved FEV1/FVC. Subsequently, GOLD 0 was discarded as further evidence of COPD development in subjects with GOLD 0 was not more likely to develop. When expanding symptomatic burden in GOLD 0 to include other chronic respiratory symptoms, such as dyspnea, wheeze, poor quality of life, limited physical activity, and ‘COPD exacerbations-like’ events needing health resources, symptomatic smokers with normal FEV1 resulted in larger risk of death. We review the evidence supporting a relationship between an increased symptom burden, long-term FEV1 decline and development of COPD. We also address the evidence for the presence of respiratory symptoms with normal FEV1 in smokers as a potential clinical entity. This subset of symptomatic patients encompasses a compelling category of smokers with normal spirometry but increased risk for poor outcomes. What exactly these symptomatic patients with intact FEV1 represent remains unclear. Whether they exemplify smoking-induced just a broadening of respiratory abnormalities or a distinct clinical entity that precedes the development of COPD or both remains unknown. Other aims, such as providing information on pathogenesis and future areas of research, are just as vital. What ultimately prevails however is the importance of the public health message to the frightening presence of chronic respiratory symptoms in the whole population.
Singh D, Roche N, Halpin D, et al., 2016, Current controversies in the pharmacological treatment of chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 541-549, ISSN: 1535-4970
Clinical phenotyping is currently used to guide pharmacologicaltreatment decisions in chronic obstructive pulmonary disease(COPD), a personalized approach to care. Precision medicineintegrates biological (endotype) and clinical (phenotype)information for a more individualized approach topharmacotherapy, to maximize the benefit versus risk ratio.Biomarkers can be used to identify endotypes. To evolve towardprecision medicine in COPD, the most appropriate biomarkers andclinical characteristics that reliably predict treatment responses needto be identified. FEV1 is a marker of COPD severity and hashistorically been used to guide pharmacotherapy choices. However,we now understand that the trajectory of FEV1 change, as anindicator of disease activity, is more important than a single FEV1measurement. There is a need to develop biomarkers of diseaseactivity to enable a more targeted and individualized approach topharmacotherapy. Recent clinical trials testing commonly usedCOPD treatments have provided new information that is likely toinfluence pharmacological treatment decisions both at initialpresentation and at follow up. In this Perspective, we considerthe impact of recent clinical trials on current COPD treatmentrecommendations. We also focus on the movement towardprecision medicine and propose how this field needs to evolvein terms of using clinical characteristics and biomarkers toidentify the most appropriate patients for a given pharmacologicaltreatment.
Wedzicha JA, Banerji D, Vogelmeier CF, 2016, Indacaterol-Glycopyrronium for COPD REPLY, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 375, Pages: 899-900, ISSN: 0028-4793
Patalano F, Wedzicha JA, Vestbo J, et al., 2016, Indacaterol/glycopyrronium (IND/GLY) reduces exacerbation and improves lung function versus salmeterol/fluticasone (SFC) in patients with and without prior ICS use: The FLAME study, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wedzicha JA, 2016, Oral Phosphodiesterase-4 Inhibitors for Chronic Obstructive Pulmonary Disease "Super Exacerbators", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 194, Pages: 527-528, ISSN: 1073-449X
Al-Ahmari A, Kowlessar BS, Patel ARC, et al., 2016, Physical activity and exercise capacity in patients with moderate COPD exacerbations, European Respiratory Journal, Vol: 48, Pages: 340-349, ISSN: 1399-3003
Introduction: Little is known about changes in physical activity during moderate (out-patient managed) exacerbations. Methods: Six minute walking distance (6MWD) was measured during 50 exacerbations when the patients were stable, and at 3 and 7 days post exacerbation presentation. At similar time points, quadriceps maximum voluntary contraction (QMVC) was measured during 47 different exacerbations. Physical activity (SenseWear) was recorded over two consecutive week periods post presentation. Results: 6MWD fell from a median 422 metres when stable to 373 metres on day 3 (p=0.001). Similarly, QMVC fell from 32.6 vs. 29.7 kg (p=0.026). Falls in 6MWD were associated with rise in C-Reactive Protein (r=-0.364; p=0.041) and increased FACIT fatigue (r=-0.44; p=0.013). Light physical activity was 2.18 hours/day during the first week post exacerbation and was less over week 2, 1.98 hours/day (p=0.009). Patients who had attended pulmonary rehabilitation (PR) had smaller changes in 6MWD than those who had not attended (-35.0 vs. -114.9 meters; p=0.013). Falls in physical activity were correlated with higher depression scores (rho=-0.51; p=0.006).Conclusion: These findings indicate that exercise capacity and muscle strength falls at exacerbation in COPD patients treated at home and free to maintain normal activity.
Rothnie K, Smeeth L, Pearce N, et al., 2016, Predicting mortality after acute coronary syndromes in people with chronic obstructive pulmonary disease, Heart, Vol: 102, Pages: 1442-1448, ISSN: 1468-201X
ObjectiveTo assess the accuracy of Global Registry of Acute Coronary Events (GRACE) scores in predicting mortality at 6 months for people with COPD and to investigate how it might be improved. Methods Data were obtained on 481,849 patients with acute coronary syndrome (ACS) admitted to UK hospitals between January 2003-June 2013 from the myocardial ischaemia national audit project (MINAP) database. We compared risk of death between chronic obstructive pulmonary disease (COPD) and non-COPD patients at 6 months, adjusting for predicted risk of death. We then assessed whether several modifications improved the accuracy of the GRACE score for people with COPD. ResultsThe risk of death after adjusting for GRACE score predicted risk of death was higher for COPD patients than for other patients (RR 1.29, 95% CI 1.28-1.33). Adding smoking into the GRACE score model did not improve accuracy for COPD patients. Either adding COPD into the model (RR 1.00, 0.94-1.02) or multiplying the GRACE score by 1.3 resulted in better performance (RR 0.99, 0.96-1.01). ConclusionGRACE scores underestimate risk of death for people with COPD. A more accurate prediction of risk of death can be obtained by adding COPD into the GRACE score equation, or by multiplying the GRACE score predicted risk of death by 1.3 for people with COPD. This means that one third of COPD patients currently classified as low risk should be classified as moderate risk, and could be considered for more aggressive early treatment after non-ST-elevation myocardial infarction or unstable angina.
Wedzicha JA, Donaldson G, Augusti A, et al., 2016, Effect of aclidinium bromide on exacerbations in patients with moderate-to-severe COPD: a pooled analysis of five phase III, randomized, placebo-controlled studies, COPD: Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 669-676, ISSN: 1541-2555
We investigated the effect of the long-acting muscarinic antagonist aclidinium bromide on chronic obstructive pulmonary disease (COPD) exacerbations by pooling data from five randomized, placebo-controlled, parallel-group Phase III studies of 3–6 months’ duration. Data were pooled from the aclidinium 400 μg twice-daily (BID) and placebo arms (N = 2,521) and stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) group (A, B, C and D). Results showed that fewer patients experienced ≥1 exacerbation with aclidinium (any severity: 12.5%; moderate to severe: 10.9%) compared with placebo (any severity: 15.7%; moderate to severe: 13.3%) and the odds of experiencing ≥1 exacerbation of any severity were reduced in patients receiving aclidinium (odds ratio = 0.78, p = 0.039). Furthermore, aclidinium reduced the rate of exacerbations compared with placebo (any severity: rate ratio = 0.79, p = 0.026; moderate to severe: 0.80, p = 0.044). The time to first exacerbation of any severity was delayed with aclidinium compared with placebo (hazard ratio = 0.79, p = 0.026) and there was a numerical delay in time to first moderate-to-severe exacerbation. Finally, the effects of aclidinium on exacerbations versus placebo were greater in patients in GOLD Groups B and D; however, it is of note that only 10.7% of patients were classified in Group A or C. In summary, the results indicate that aclidinium 400 μg BID reduces the frequency of COPD exacerbations compared with placebo and that these effects are greater in symptomatic patients.
Wedzicha JA, 2016, Eosinophils as Biomarkers of Chronic Obstructive Pulmonary Disease Exacerbation Risk. Maybe Just for Some, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 937-938, ISSN: 1535-4970
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