COPD continues to emerge as one of our major challenges in the coming years. The impetus in developing new therapies is gathering speed as the pathophysiological processes becomes dissected. The management of the acute and chronic phases of the disease have seen a major awareness of the importance of patient characterization and patient reported outcomes. These aspects are regularly features of all major scientific meetings on respiratory disease but their dissemination throughout busy comprehensive respiratory meetings creates a major challenge to delegates.
For this reason the COPD series was established in Birmingham to gather all key opinion leaders and interested delegates in a single geographically confined site to facilitate interaction discussion and nurture new thoughts and collaboration.
It is now 12 years since the first international, multidisciplinary meeting dedicated to COPD took place in Birmingham, UK. The meeting continues as a biennial event to ensure sufficient new data and thoughts emerge to maintain the interest and enthusiasm of delegates.
COPD7 was no exception and over 600 delegates attended the meeting from countries spread across all 6 continents and included a wide range of health care workers from basic scientists to allied health care professionals delivering patient care. The meeting bought together leading experts from all over the world producing the unique opportunity to see and meet them face to face in a single venue where delegates and speakers mingle at lunch and break times. This interaction once again culminated in an interactive plenary session on the last day entitled ‘Towards excellence in care’ with an enthusiastic and vociferous panel including Professors Klaus Rabe, Jorgen Vestbo, Peter Barnes and Bart Celli, and Dr Mark Britnell and Dr Joan Soriano.
COPD7 included plenary sessions on namely ‘Phenotypes of COPD’, ‘Lung Health’, ‘Managing the COPD Epidemic’ and ‘Treatment Challenges’. There were 12 mini symposia with parallel science, clinical and multidisciplinary care tracks. A total of 9 Meet the Experts sessions covering many aspects of COPD including misinterpreting FEV1, bereavement care, pneumonia and inhaled steroids, chronic disease management, new and emerging diagnostic technologies, common pitfalls in diagnosis, effective partnerships with patients, bronchiectasis and nursing research. All were very well attended and provided a valuable opportunity for delegates to discuss important issues with key opinion leaders.
Professors Nick Anthonisen, Gordon Snider and Gerard Turino were given Lifetime Achievement Awards for their long term and exceptional contributions to the field. Finally, Professor Mike Morgan gave an excellent Tim Griffiths Memorial Lecture in honour of Dr Griffiths who sadly passed away during the COPD5 Conference and continues to be remembered.
The accompanying abstracts were presented as posters at the meeting. 19 other posters describing clinical methodologies were also presented at COPD7.
From a personal point of view, and that of my co-organiser Sue Hill, the success and enjoyment of seeing this meeting come to fruition with continued excellent feedback and enthusiasm of our speakers remains unsurpassed.
We are already making plans for COPD8, to be held in Birmingham from 20–22 June 2012.
The COPD Foundation is planning on sponsoring a similar meeting in the USA on alternate years. Hopefully COPD7USA will come to fruition in 2011.
Professor R A Stockley
SUSTAINED COST REDUCTIONS FROM A NEW HOME OXYGEN SERVICE DURING THE FIRST OPERATING YEAR
M. Fordham, L. Sullivan, P. Hawkins and L. Jongepier
NHS North East Essex Home Oxygen Service, Primary Care Centre, Turner Road, Colchester, CO4 5JR. [email protected]
In June 2003 the Government announced plans to modernise the domiciliary oxygen service and in 2006 the new ‘Integrated Home Oxygen Service’ was launched. To help implement the new guidelines and control the increasing prescribing costs for home oxygen, North East Essex PCT commissioned 2 WTE clinical staff to undertake assessments all patients prescribed oxygen. In the first 12 months 838 patient contact episodes occurred. 609 were face to face (FTF) and 229 telephone (TC) episodes (mean ratio 0.43). The ratio of FTF to TC consultations did not change over the 12 months. Total monthly contacts increased from 54 in month 1 to 95 in month 12. 290 prescriptions (BOC tariff band) were changed. The ratio between number of consultations per month and prescription changes was 0.42 (SD +/−0.32). Total potential full year cost savings were £490,000 and were higher in month 12 (£66,488) compared to month 1 (£32,732). This finding supports the view that home oxygen teams are effective at reducing inappropriate oxygen prescribing and that this produces cost savings that are sustained over at least the first 12 months of operation.
THE PATTERN OF CARDIOVASCULAR DISEASE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
T. G. Romcevic and B. D. S. Sonc
Department of Pneumology, Hospital Sezana, Cankarjeva 4 Sezana, Slovenia, [email protected]
Objectives: To establish the pattern of cardiovascular diseases in COPD patients. Methods: From January 1st 2003 to December 31st 2008, 449 consecutive patients with COPD, attending to out patients clinic (Sezana) were involved in the study. The diagnosis of COPD was made according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Cardiovascular co-morbid diseases at baseline were included in the analysis. Results: 32% patients had mild, 24% had moderate, 21% had severe and 23% had very severe stage of the disease, 45% patients had cardiovascular disease. Among them 49% persons had one, 40% persons had two and 11% persons had three cardiovascular diseases. The most frequent were arterial hypertension in 29%, and ischaemic heart disease in 22% of COPD patients. The prevalence of all cardiovascular manifestations increased with the stage of severity, from 26% among the patients with mild stage to 71% among the patients with very severe stage of the disease. The prevalence of patients with two or three cardiovascular diseases also increased with the stage of severity, from 7% patients with mild stage to 52% patients with very severe stage of the disease. Conclusions: results suggest that cardiovascular co-morbidity occurrence in COPD patients increases with severity of the disease.
THE EFFECT OF METFORMIN THERAPY ON SERUM LACTATE CONCENTRATION IN PATIENTS HOSPITALISED FOR COPD: A RETROSPECTIVE STUDY
A. W. Hitchings, S. Aslam, G. Picton, L. Turner, R. Cull, S. Srivastava, J.R.H. Archer and E.H. Baker
St George's, University of London, Centre for Clinical Pharmacology, Cranmer Terrace, London, SW17 0RE. [email protected]
BACKGROUND: Diabetes mellitus is commonly associated with COPD. Metformin has prognostic benefit in diabetes [UKPDS80. N Engl J Med 2008;359:1577–89], but is often avoided in patients at risk of hypoxia due to a perceived risk of lactic acidosis. Little evidence supports this practice. We investigated the relationship between Metformin use and serum lactate concentrations in patients hospitalised for COPD exacerbations. METHODS: COPD patients with diabetes admitted with exacerbations between 1998 and 2008 were identified using ICD10 codes. The hospital notes were reviewed to confirm diagnoses, and ascertain clinical and biochemical parameters and medication history. RESULTS: 153 patients were identified from coding data. The notes for 142 were reviewed; 108 (76%) met the inclusion criteria. Their mean (±SD) age was 73 ± 10 years; 70 (65%) were male, and 38 (35%) were prescribed Metformin before admission. Haemodynamic parameters, arterial blood gases, creatinine, and APACHE-2 scores were similar in patients prescribed Metformin, versus those not prescribed Metformin. Where measured, the median (interquartile range) lactate concentrations were 1.4(1.1–2.0) mmol/L (n = 23), and 1.1(0.8–1.6) mmol/L (n = 35), respectively (p = 0.11, Mann-Whitney test). CONCLUSION: In this population of patients hospitalised for COPD exacerbations, we found no evidence that serum lactate concentration was affected by concurrent Metformin therapy.
HYPERGLYCAEMIA AND RESPIRATORY RATE AS PROGNOSTIC MARKERS IN NON-INVASIVE VENTILATION FOR DECOMPENSATED COPD: A RETROSPECTIVE VALIDATION STUDY
H. Ahmed, A.I. Ali, E.H. Baker and A.W. Hitchings
St George's, University of London, Centre for Clinical Pharmacology, Cranmer Terrace, London, SW17 0RE. [email protected]
BACKGROUND: At present, our capacity to predict the outcome of non-invasive ventilation (NIV) for acute hypercapnic respiratory failure in COPD is limited. In a single-centre study, Chakrabarti et al (Thorax 2009;64:857–862) found that a baseline respiratory rate <30/min and random glucose <7mmol/L predicted a successful outcome in 97% of patients. We sought to validate this finding in a different population. METHODS: We retrospectively identified patients treated with NIV for decompensated COPD at St George's Hospital, London, between 2006 and 2009. From their case notes, we ascertained their baseline clinical parameters and subsequent outcome. RESULTS: The case notes for 81 patients were reviewed. Seventy-two patients met the inclusion criteria, and 58 had complete data available. Their mean (±SD) age was 75 ± 10 years, 28 (48%) were male, and 32 (55%) had a successful outcome. The combination of a baseline respiratory rate <30/min and random glucose <7mmol/L had a positive predictive value of 50% for NIV success. Its negative predictive value was 44%; sensitivity, 13%; and specificity, 85%. CONCLUSION: In this population, and in contrast to the findings of Chakrabarti et al, we did not find baseline respiratory rate and glucose to be predictive of NIV outcome.
A RETROSPECTIVE EVALUATION OF THE CURB-65 SCORE AS A PROGNOSTIC TOOL IN NON-INVASIVE VENTILATION FOR ACUTE HYPERCAPNIC RESPIRATORY FAILURE IN COPD
A.I. Ali, H. Ahmed, E.H. Baker and A.W. Hitchings
St George's, University of London, Centre for Clinical Pharmacology, Cranmer Terrace, London, SW17 0RE. [email protected]
BACKGROUND: The CURB-65 score (confusion, urea, respiratory rate, blood pressure, and age; score range 0–5), is a valuable prognostic tool in community-acquired pneumonia. As a broad measure of illness severity, we hypothesised that it may also predict the outcome of patients treated with non-invasive ventilation (NIV), for acute hypercapnic respiratory failure complicating COPD exacerbations. METHODS: We retrospectively identified patients admitted for COPD exacerbations, and treated with NIV, at St George's Hospital, London, between 2006 and 2009. From their hospital records, we ascertained their baseline clinical parameters and subsequent outcome. RESULTS: The case notes for 81 patients were reviewed, from which 72 met the inclusion criteria. Their mean (±SD) age was 74 ± 10 years, and 37 (51%) were male. Thirty-eight patients (53%) had a successful outcome. A CURB-65 score greater than or equal to 3, versus less than 3, was associated with a relative risk for NIV failure of 1.94 (95% confidence interval, 1.14–3.29, p = 0.018). Its sensitivity for predicting NIV failure was 65%; specificity, 66%; positive predictive value, 63%; and negative predictive value, 68%. CONCLUSION: The CURB-65 score appears to have value as a prognostic tool for patients treated with NIV for acute hypercapnic respiratory failure complicating COPD exacerbations. This finding requires further exploration in another cohort.
THE EFFECTS OF ELECTRICAL MUSCLE STIMULATION IN A CHRONIC OBSTRUCTIVE PULMONARY DISEASE POPULATION-A PILOT STUDY
É. Hennessy, G.F. Coughlan, B.M. Caulfield, L.M. Crowe, S.D. Perumal and T.J McDonnell
STIM XDP Research Group, The Institute of Sport and Health, University College Dublin, Belfield, Dublin 4, Ireland. [email protected]
Background/Aims: Chronic obstructive pulmonary disease (COPD) patients are frequently physically unable to tolerate conventional exercise training interventions owing to limited cardiopulmonary reserve. Electrical muscle stimulation (EMS) appears to have limited demand on ventilatory requirements and may be a promising alternative in COPD. Our aim was to evaluate the effects of a 6-week EMS training intervention in COPD. Methods: 5 participants (2 males, 3 females, Age: 56.40 ± 4.62 years, Height: 1.61 ± 0.06 metres (m), Weight: 65.80 ± 11.05 kilograms (kg), Body Mass Index: 25.43 ± 3.43 kg/m2), with mild-moderate COPD were recruited. Outcome measures included a 6-minute walk test (6MWT) and maximal isokinetic knee strength pre and post a 6-week training period. Participants trained 5 days per week for 60 minutes (30 minutes aerobic (3 Hertz (Hz) and strength (19 Hz). Results: Quadriceps and hamstrings peak torque improved on average of 4.30% and 13.71% respectively. 6MWTs increased on average 13.65%. Discussion and Conclusions: Initial EMS and COPD studies suggest that this intervention may be most effective in those severely affected by the disease. This pilot study indicates that our novel EMS modality may elicit multiple benefits among a broader spectrum of the population.
LONG-TERM OUTCOME AND PREDICTORS OF SURVIVAL IN PATIENTS HOSPITALIZED FOR AN ACUTE EXACERBATION OF COPD
E. Sen, S. O. Ciloglu, Z. Onen, B. Gulbay, O. A. Yildiz, S. B. Saryal, T. Acican, G. Karabiyikoglu, A. Elhan
Ankara University School of Medicine, Pulmonary Diseases Department, Mamak Cad. 12/A Cebeci Ankara, 06100 Turkey. [email protected]
Objective: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a major cause of hospitalizations, and associated with a greater risk of mortality in subsequent years. This study aimed to determine potential determinants of survival in a group of patients hospitalized for AECOPD. Material and Methods: A retrospective cohort study of 193 patients hospitalized for an AECOPD between the years 2002 and 2004 was performed. Patients demographics, comorbidities, clinical, laboratory data on admission were recorded. In-hospital mortality was determined. Patients were followed-up 4 years after discharge. Results: The mean age was 65.49 ± 8.85, 94.8% of the patients were male. In-hospital mortality rate was 5.2%. Twenty six patients (13.5%) were admitted to the ICU. The mortality rates were 15.5%, 23.8%, 32.1%, and 36.8% at 1st, 2nd, 3rd and 4th years, respectively. Cox regression analysis showed that increased age (HR 1.04; 95% CI, 1.01–1.07), lower BMI (HR 0.89; 95% CI, 0.84–0.94), GOLD stage IV (HR 2.74; 95% CI, 1.31–5.70), cor pulmonale (HR 3.53; 95% CI, 2.15–5.80), ICU admission (HR 3.21; 95% CI, 1.84–5.61) were independently related to mortality. Conclusion: Advanced age, severe COPD, lower BMI, cor pulmonale, and ICU admission were independently associated with mortality after hospitalization for an acute exacerbation. By this regional data from Turkey, it was concluded that it is useful to have the lung function test data for COPD patients and to evaluate the disease stage as the predictors of mortality after acute exacerbations.
DOES A NURSE-LED PALLIATIVE CARE SERVICE FOR CHRONIC LUNG DISEASE HAVE A POSITIVE IMPACT ON QUALITY OF LIFE AND PATIENT SATISFACTION?
K. Carson and K.S. Tan
Wishaw General Hospital, 50 Netherton Street, Wishaw, ML2 0DP. [email protected]
A nurse-led palliative care service for Chronic Lung Disease (CLD) was introduced to promote and maintain the best possible quality of life and end-of-life care for patients with severe disease. Service intervention consists of home visits on a needs-led basis. The following assessments and measurements were carried out: patients needs, pulse oximetry, St. Georges Respiratory Questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS). Subsequent visits consist of symptom control, follow-up SGRQ and HADS questionnaires, psychosocial support, end of life decision making and home exercise where appropriate. The service was evaluated after 15 months by auditing patient admissions, patient outcome measures and patient/carer satisfaction survey. 166 patients with severe CLD have been assessed. At baseline, 39% patients had >11 HADS anxiety score and 11% had >11 HADS depression score. For those with complete HADS assessments there was significant improvement in anxiety scores (p < 0.05) but not for depression. For those with complete SGRQ assessments there was a trend towards a reduction in impact domain scores (p = 0.05). There was a significant reduction in hospital admissions (115 vs 62; p < 0.05). Patient and carer satisfaction survey scored 100% for helpfulness of nurse visits, with 93% of patients and 94% of carers benefiting in coping with the disease. The service has shown a positive impact on quality of life and a reduction in hospital admissions.
AN AUDIT OF THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AGAINST NICE 2004 GUIDELINES USING DATA FROM THE GENERAL PRACTICE RESEARCH DATABASE (GPRD)
R.E. Jordan, K.K. Cheng, R.J. Lancashire, I. Ifesie, M.R. Miller and P.A. Adab
University of Birmingham, Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, UK. [email protected]
New guidelines for COPD were introduced in the UK in 2004 with 188 recommendations. We performed an audit of care of COPD patients in primary care against seven recommendations for diagnosis and management. Data on 29,998 COPD patients aged >35 years, and with a diagnosis of COPD before April 2006 were included. 15,468 (51.6%) were male (mean age 70.8 (SD 10.9)) and 9517 (31.7%) current smokers. We compared recording of recommended measures before and after introduction of NICE guidelines. For newly-diagnosed cases, breathlessness (MRC Dyspnoea scale) was recorded for 2.0% in 2003/4, rising to 8.6% in 2005/6. A confirmatory FEV1 value was recorded for 48.2% in 2003/4, rising to 71.0% in 2005/6. Records of FEV1/FVC were slightly poorer and FEV1% predicted was rarely recorded (7.4% of diagnosed in 2005/6). By 2005/6, 31.8% of newly diagnosed patients had recorded full blood count, 44.3% BMI (44.3%) and 3.5% chest x-ray. An up-to-date smoking status was recorded for 24,701 (82.3%) patients. Of 9517 current smokers, 5800 (60.9%) were offered smoking cessation therapy during 2006/7. 2 years after the introduction of guidelines, records of FEV1 and smoking status had improved but recording of breathlessness and other measures was still poor.
FIVE YEAR SURVIVAL IN PATIENTS REQUIRING ACUTE NIV FOR HYPERCAPNIC RESPIRATORY FAILURE. DO COPD PATIENTS DO WORSE?
C.R.S. Lindesay, B. Barker, A. Thomas, M. Pagaria, D. Banerjee and R. Mukherjee
Heart of England Foundation Trust, Birmingham Heartlands Hospital, Bordesley Green, Birmingham. B9 5ST. [email protected]
Introduction: It is well established that patients with COPD requiring domiciliary NIV for chronic hypercapnic respiratory failure have a worse prognosis than other disease groups with ventilatory failure. (Leger, P. et al. Chest 1994;105 (1):100–5). An exacerbation of COPD requiring acute NIV for hypercapnic respiratory failure is associated with a high inpatient mortality and poor 1 year survival (Plant PK. et al. Thorax 2001;56 (9):708–1). Aims: To compare 5 year mortality after an episode of acute NIV in patients with and without COPD. Methods: We conducted a retrospective, observational study of all patients requiring acute NIV for acidotic, type 2 respiratory failure on a dedicated unit, in a Birmingham teaching hospital between August 2004 and January 2005. Diagnosis was defined on clinical evaluation. Mortality data was assessed from health records. Results: 67 (80.7%) of 83 NIV patients had COPD as a primary diagnosis. After 5 years: 4 of the 67 (6.0%) COPD patients remained alive whereas 10 of the 16 (62.5%) non COPD patients were alive (p = 0.006). Discussion: The data suggests that the 5 year prognosis for patients requiring acute NIV for COPD is worse than that for other causes of acute ventilatory failure.
www.EFFECTIVENESS AND PATIENT SATISFACTION OF A NEW MULTI SITE COMMUNITY PULMONARY REHABILITATION PROGRAMME
L. Jongepier and P. Hawkins
NHS North East Essex COPD Team. [email protected]
Pulmonary rehabilitation (PR) is an effective treatment for symptoms caused by chronic obstructive pulmonary disease (COPD) [1]. Most early PR programmes in the UK were hospital-based but now they are increasingly being developed in line with the ‘Care closer to home’ strategy [2]. In 2008 North East Essex PCT developed a PR programme across several sites within the local catchment area. The scheme was delivered by 2.9 clinical staff. In the first 9 months, 25 groups were run with a capacity of 400 places of which 354 places were filled (86%). Patients were assessed before and after the 6 week programme using the Incremental Shuttle Walk Test (ISWT), Chronic Respiratory Questionnaire (CRQ) score, the Pulmonary Rehabilitation Adapted Self-Efficacy (PRAISE) score, the HAD score and a general patient satisfaction questionnaire (PSQ). Mean (SD) ISWT increased by 67m (±58) and CRQ-D by 4.4. The mean drop out rate was 35 ± 10% and differed between sites (range 17–52%). These data support the view that community PR produces meaningful benefit for patients. Despite sub-optimal uptake of available places, there is a high and variable drop out rate, which need to be taken into account when planning such services. 1. Lacasse Y, Brousseau L, Milne S, Martin S, Wong E, Guyatt GH et al. Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease. (Cochrane Review). The Cochrane Library. Oxford: Update Software 2003; Issue 3. 2. Department of Health (2006) Our health, our say: a new direction for community services. London: Department of Health.
CHANGES IN CASELOAD AND ADMISSION AVOIDANCE IN PATIENTS WITH COPD –THE NORTH EAST ESSEX EXPERIENCE
L. Jongepier, C. Crocker and P. Hawkins
North East Essex PCT COPD Team. Lianne.Jongepier@ northeastessex.nhs.uk
Acute exacerbations of COPD (AECOPD) present a significant challenge for both Acute and Primary Care Trusts [1]. Due to the rising numbers of admissions to the local acute trust for AECOPD, the focus of our community COPD team was shifted from early supported discharge from hospital (EDS) to admission avoidance (AA) in 2006. To explore the effectiveness of this strategy a random case note audit was undertaken. 240 case notes were randomly selected (26% total case load) and data regarding hospital admissions extracted from the patient administration system (PAS). This data was then compared to that from a similar audit in 2006. During this period our caseload increased from 600 to 922 patients. Of the 240 patients, 53 had 1 or more acute medical admission in the 12 months prior to contact with the team (22%) compared to 168 (70%) in 2006. Despite the lower baseline number of admissions a 48% reduction in subsequent admissions was achieved compared to a 42% reduction in 2006 in the 12 months following contact with the team. These results support the view that maintaining admission avoidance is possible despite the increasing and changing caseload for community COPD teams. 1. Buckingham R, Lowe D, Pursey N, Roberts C, Stone R. Report of The National Chronic Obstructive Pulmonary Disease Audit 2008: clinical audit of COPD exacerbations admitted to acute NHS units across the UK: Royal College of Physicians of London, British Thoracic Society, British Lung Foundation; November 2008.
AN EVALUATION OF DO NOT RESUSCITATE ORDERS IN PATIENTS ADMITTED WITH COPD EXACERBATIONS
C.E. Wells, C. Hands, N. Parmar, S.A. Hasso, E.H. Baker
St George's, University of London, Cranmer Terrace, London, SW17 0RE. [email protected]
Introduction: End-of-life care in COPD should include planning for death [Knauft et al, Chest 2005;127:2188–96], but this is seldom addressed until hospital admission. We determined prevalence of ‘Do not attempt resuscitation’ (DNAR) orders in COPD patients and established subsequent survival and patient involvement in decision making. Methods: ICD10 codes identified COPD patients admitted with exacerbations in 2007. Notes were reviewed to confirm diagnoses, identify DNAR orders and retrieve clinical information. Results: 100/120 (83%) patients had confirmed COPD exacerbations (42% female, age 74+/−11years). 16% had DNAR orders. Reasons for DNAR were ‘unlikely to be successful’ (75%) and ‘length/quality of likely survival not in patient's best interests’ (69%). One (6%) was the patient's wish; no patient had a living will. DNAR was discussed with 12.5% of patients and 25% families. Patients with DNAR had increased risk of death at one (odds ratio (OR) 5.5 (95% Confidence Intervals 1.8–16.9) and 2 years (OR 3.5(95% CI 1.2–10.8). Median time from DNAR to death was 247 days, (151–360, interquartile range). Discussion DNAR orders are unilateral decisions about ceiling of care made by physicians that identify patients with reduced survival. Most patients survive for months after DNAR, providing an opportunity for end of life discussions.
EXERCISE PRESCRIPTION FOR COPD PATIENT IN A PULMONARY REHABILITATION PROGRAM: PROTOCOL OR USER ORIENTATION
A. L. Gonçalves da Silva, A. R. de Moura Valim, T. C. Malezan Fleig, V. Mayer, C. Caetano L. Dutra and M. Reckziegel
UNISC and Santa Cruz Hospital, Avenida Independência, 2293, Bairro Universitário, Santa Cruz do Sul/ RS, Brasil CEP: 96815900. [email protected]
Chronic Obstructive pulmonary disease (COPD) by its progressive and irreversible is the case of public health. In addition to pulmonary involvement, extrapulmonary effects occur, nutritional changes and skeletal muscle. Dynamic hyperinflation prevents the patient receives ventilatory demands required for the exercise, favouring the onset of dyspnea, the leading cause of deconditioning due to muscle inactivity. The more severe the disease, the greater the impairment of activities of daily living, and the introduction of monitored exercise is essential to improve the quality of life. The study aimed to develop an exercise protocol based on the experiences of the patient concerning the needs and subjective perception of the disease. The exercise protocol described in the Guide Exercise of COPD, created by students, teachers and patient of the program Cardiopulmonary and Metabolic Rehabilitation, University of Santa Cruz do Sul and Santa Cruz Hospital, southern of Brazil. From the choice of the proposed exercises the subject was submitted to physical training twice a week, for eight weeks. Based on the difficulties of COPD patients, the protocol has helped to improve performance during physical training in a personalized way, minimizing complaints of lower limb fatigue and dyspnea.
EFFICACY OF PROGNOSTIC ASSESSMENT USING ADO INDEX FOR JAPANESE PATIENTS WITH COPD
T. Motegi, R. Wakabayashi, M. Hattori, T. Ishii, K. Kamio, K. Yamada, K. Morii, M. Kurahara, A. Gemma, K. Kida
Department of Respiratory Medicine, Infection and Oncology, Nippon Medical School; Respiratory Care Clinic, Nippon Medical School, Tokyo 102-0074, Japan. mo-dr@ nms.ac.jp
Background: It was previously reported that the ADO index (Puhan MA, et al. Lancet 2009; 374: 704–711) is useful as a prognostic assessment for patients with COPD. Purpose: To test the hypothesis that there is a correlation between the ADO index, exacerbations, and various clinical indicators in Japanese patients with COPD. Methods and patients: Consecutive patients with COPD who lived in Japan were enrolled, and the frequency of exacerbations was studied for one year; we assessed the ADO index, quantitative measures on chest HRCT, and health-related QOL at the first visit. Results: A total of 172 cases (M/F: 161/11) with a mean age of 71 were enrolled. The mean%FEV1 was 58%. Cases with and without exacerbations in one year numbered 47 and 125, respectively. The prediction of exacerbations using the ADO index (cut-off 4) showed a sensitivity, specificity, and area under the receiver-operator curve, of 0.68, 0.51, and 0.65, respectively, suggesting that it was equivalent to the GOLD classification. However, the correlation between the ADO index and LAA% and total SGRQ showed r = 0.37, p < 0.001 and r = 0.55, p < 0.001, respectively. Conclusions: The ADO index poorly predicted exacerbations, but was significantly correlated with the QOL in this cohort.
DOES FEV1 DETERIORATE SIGNIFICANTLY BETWEEN YEARLY FOLLOW-UP ASSESSMENTS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE?
K. Lewis-Jones
Lung Function Chest Clinic, Stepping Hill Hospital, Poplar Grove, Stockport, SK2 7JE. Karen.LewisJones@ stockport.nhs.uk
Background: Management of stable chronic obstructive pulmonary disease (COPD) follows the National Institute for Clinical Excellence (NICE) guidelines (Thorax 2004; 59:39–130). Aim: To determine if the forced expiratory volume in first second (FEV1) deteriorated significantly over 12–18 months between follow-up assessments. This would support or refute the NICE guidelines. Methods: A retrospective study reviewed changes in FEV1 across 52 primary care practices. Sample size was 83 patients (50 male; 33 female; median age 67 yrs, range 42 84 yrs). FEV1 was recorded in millilitres and mean change analysed for total population n = 83 and as a subgroup with FEV1 decline (n = 40). A paired T-test compared the means of baseline FEV1 with follow-up FEV1. Additional information was collected for smoking history, disease classification and age. Summary of Significant Results: Total population n = 83 showed no statistical difference from baseline to follow-up (P = 0.587 mean change −12.2 ml, SD 204). The subgroup (n = 40) showed a highly statistical difference in mean change of FEV1 (p = 0.000, −174.1 ml, SD 147), with 28% deteriorating >200 ml of which 12% was >400 ml. Conclusion: Follow-up assessment at least once per year in accordance with the NICE guidelines would identify the small percentage for whom deterioration occurred at a much faster rate.
PREVALENCE OF OSTEOPOROSIS IN COPD PATIENTS HOSPITALIZED FOR ACUTE EXACERBATION IN INDIAN SUBJECTS
A. Goel, J. Sharad, C. Pankaj, M. Vipul, T. Deepak
Metro Centre for Respiratory Diseases, Metro Multi-speciality Hospital, L-94, Sector 11, Noida, Delhi-201301, India. [email protected]
Study Objective: To study prevalence of osteoporosis by BMD analysis in COPD patients admitted with acute exacerbation to tertiary care respiratory unit in India Design: Retrospective analysis. Setting: Metro Centre for Respiratory Diseases Patients: 476 patients admitted with COPD in acute exacerbation between January 2008 and December 2009. 113 patients underwent DEXA scan for risk factors for osteoporosis and were analyzed retrospectively. Osteoporosis diagnosed by T-score at AP spine < −2.5 was seen in 55/113 (48.6%) patients. Method and measurements: Of 55 patients with osteoporosis, 32 were male (mean age 62.8 ± 9.7), and 23 were females (mean age 62.4 ± 7.1). None of patients were in GOLD stage I, 8 were in stage II (19.5%), 21 stage III (75%), and 26 stage IV (78.8%). 48/55 (87.2%) were smoker. T-score at AP spine of all patients (113) as evaluated by DEXA scan was plotted against post-bronchodilator FEV1 both in males and females. A linear correlation between FEV1and T score and was found in both sexes. Correlation coefficient for males was 0.805 and females was 0.825. Conclusion: In our subset of patients nearly 79% of patients with COPD GOLD stage 4 had osteoporosis. T-score of AP spine by DEXA scan was linearly related to post-bronchodilator FEV1 in COPD patients.
EXACERBATIONS OF COPD AND COGNITIVE IMPAIRMENT: PREVALENCE AND CLINICAL OUTCOMES
S. Chaggar, S. Anpalakhan, C.E. Wells, E.H. Baker, J.W. Dodd
St George's University of London, Cranmer Terrace, Tooting, London, SW17 0RE, UK. [email protected]
Introduction: Cognitive dysfunction has been associated with increased morbidity and mortality in certain COPD populations [Antonelli-Incalzi C Chest 2006;130:1687). We determined the prevalence of cognitive dysfunction in COPD patients admitted to hospital with exacerbations and established the relationship between dysfunction and outcome. Methods: COPD patients admitted with exacerbations in 2007 were identified retrospectively using ICD-10 codes. Clinical information was retrieved from case notes. Cognitive dysfunction was defined as <8 on the 10 point abbreviated mental test score (AMTS). Results: AMTS was documented in 32/100 patients and cognition was impaired in 11/32 (34%). Compared to those with normal cognition (NC), patients with impaired cognition (IC) were older (IC 82 + 9years; NC 74 + 10 years, p = 0.045) and had lower plasma albumin (IC 33 + 6 g/L; NC 37 + 3 g/L, p = 0.038). There were no differences in Charlson (co-morbidities) or APACHE II (acute illness) scores between groups. Mortality one year after admission was greater in patients with impaired cognition (IC 82%; NC 5%, p = 0.000). On logistic regression the effect of impaired cognition on mortality was independent of age. Conclusion: Cognition is poorly documented, but commonly impaired in COPD patients admitted to hospital with exacerbations. The association between impaired cognition and poor outcomes needs further investigation in a larger study.
DOSE RESPONSE OF NVA237, A LONG-ACTING MUSCARINIC ANTAGONIST FOR THE TREATMENT OF COPD
T. Overend1, Y. Lu2, M. Dolker2, D. Banerji2
1Novartis Horsham Research Centre, West Sussex, UK and 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, [email protected]
NVA237 has been shown to provide a dose-related, rapid and sustained 24-hour bronchodilation significantly higher than placebo [1]. A post-hoc analysis of this study was done to compare the efficacy of different NVA237 doses. 83 COPD patients were randomized to receive NVA237 (12.5, 25, 50 μg) or placebo administered once daily for 7 days (n = 49–55). Trough FEV1 was assessed on Days 1 and 7. Responder rates were determined where a patient had an increase of ≥ the minimal clinically important difference (MCID) of 120 mL in trough FEV1 on Day 7 relative to placebo. The improvement in trough FEV1 on Day 7 with 50 μg NVA237 was numerically better than 25 μg and statistically superior (p = 0.0070) to 12.5 μg. On Day 1 it was statistically superior to 25 μg (p = 0.0009) and 12.5 μg (p < 0.0001). However, improvement in trough FEV1 on Day 7 with 25 μg was not statistically superior to 12.5 μg. Trough FEV1 for 50 μg exceeded the MCID on Days 1 and 7. The responder rates for NVA237 50, 25 and 12.5 μg were 61%, 43% and 28%, respectively. Once-daily NVA237 50 μg allowed patients to have superior bronchodilation from Day 1 which was maintained at Day 7. 1. Eur Resp J (2008) 32(Suppl. 52), 430s.
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER, TWO-PERIOD CROSSOVER STUDY TO INVESTIGATE THE BRONCHODILATORY EFFECT OF NVA237 INHALED ONCE DAILY IN PATIENTS WITH (COPD)
T. Overend2, C. Fogarty1, H. Hattersley2, L. Di Scala3, A. Drollman3
1Spartanburg Medical Research, Spartanburg, SC, USA, 2Novartis Horsham Research Centre, West Sussex, UK, 3Novartis Pharma AG, Basel, Switzerland. [email protected]
This randomized, double-blind, placebo-controlled, multi-center, two-period crossover study investigated the 24-h bronchodilatory effect of repeated doses of inhaled NVA237 in patients with mild, moderate or severe stable COPD. 33 patients were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 for 14 days separated by a 7–14 day washout period. The 24-h FEV1 profiles showed a consistent bronchodilator effect on Day 14 with a significant (p < 0.05) increase in FEV1 compared to placebo at all time points (except Hour 8). The mean (95% confidence interval; p-value) FEV1 over 24-h increased by 163 ml (0.079, 0.247; p < 0.001). The mean FEV1 in the first 12h after dosing increased by 165 ml (0.073, 0.257; p = 0.001) and the mean FEV1 12–24h after dosing increased by 161 ml (0.079, 0.234; p < 0.001). Peak FEV1 increased by 208 ml (0.114, 0.303; p < 0.001) and trough FEV1 by 154 ml (0.056, 0.252; p = 0.003). NVA237 was well tolerated and all adverse events were mild and moderate in intensity and not related to study drug. NVA237 50 μg once daily demonstrated a well sustained bronchodilator effect over 24 hours.
CARDIOVASCULAR SAFETY OF QVA149, A NOVEL COMBINATION OF INDACATEROL AND GLYCOPYRRONIUM COMPARED WITH INDACATEROL AND PLACEBO IN PATIENTS WITH COPD
T. Overend3, L. Fabbri1, B. Van de Maele2, C. Martin3, R. Horton3, M. Dolker4
1University of Modena and Reggio Emilia, Italy 2Henri Serruys Hospital, Oostende, Belgium 3Novartis Horsham Research Centre, UK 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. [email protected]
The objective of this study was to assess the cardiovascular safety of QVA149, a dual bronchodilator consisting of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237). This was a randomized, double-blind, placebo-controlled, parallel-group study. Two hundred and fifty seven patients with moderate-to-severe COPD were randomized to receive QVA149 (indacaterol/NVA237)) 600/100, 300/100 or 150/100 μg, indacaterol 300 μg, or placebo once-daily for 14 days. The primary endpoint was change from baseline in 24-h mean heart rate versus placebo on Day 14. Two hundred and fifty five patients were included in the safety analysis (mean age 63.8 years, 76.5% male, post-bronchodilator FEV1 53.2% predicted, mean 24-h heart rate 79.6bpm). There was no difference in the 24-h mean heart rate at Day 14 between QVA149 and placebo (estimated treatment differences vs placebo for QVA149 600/100, 300/100 and 150/100 μg and indacaterol were 0.3, 0.6, 0.4 and 0.1bpm, respectively), nor were there differences between QVA149 and indacaterol. There were no clinically relevant differences in QTc intervals (Fridericia's) observed among treatment groups on Days 1, 7 and 14. Overall AE rates were similar between all groups, including placebo. QVA149 had no significant effect on change in 24-h mean heart rate.
QVA149, A NOVEL COMBINATION OF INDACATEROL AND GLYCOPYRRONIUM DEMONSTRATES SUPERIOR BRONCHODILATION COMPARED WITH INDACATEROL AND PLACEBO IN PATIENTS WITH COPD
T. Overend4, J. A. van Noord1, R. Buhl2, C. LaForce3, C. Martin4, F. Jones4, M. Dolker5
1Department of Respiratory Diseases, Atrium Medisch Centrum, Heerlen, Netherlands, 2Pulmonary Department, Mainz University, Mainz, Germany, 3North Carolina Clinical Research, Raleigh, NC, USA, 4Novartis Horsham Research Centre, West Sussex, UK, 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. [email protected]
The objective of this study was to assess the efficacy and safety of QVA149, a dual bronchodilator consisting of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237). This was a randomized, double-blind, placebo-controlled, 4-period cross-over study. One hundred and fifty four patients with moderate-to-severe COPD were randomized to receive QVA149 (indacaterol/NVA237) 300/50 μg, indacaterol 300 or 600 μg, or placebo once-daily for 7 days, with a 7-day washout between each treatment. The primary endpoint was trough FEV1 at Day 7. One hundred and thirty five (87.7%) patients completed the study (mean age 61.7 years, 61.4% male, post-bronchodilator FEV1 52.2% predicted). The estimated treatment difference for trough FEV1 on Day 7 between QVA149 and placebo was 226 mL (95% CI: 192, 260; p < 0.001). Similarly, the estimated treatment difference between QVA149 and indacaterol 300 μg was 123 mL (95% CI: 89, 157; p < 0.001) and between QVA149 and indacaterol 600 μg the treatment difference was 117 mL (95% CI: 83, 150; p < 0.001). Similar results were observed on Day 1. QVA149 and indacaterol were well tolerated. QVA149 demonstrated significant improvements in bronchodilation at 24 hours compared with placebo and indacaterol.
THE PHARMACOKINETICS OF MULTIPLE INHALED NVA237 DOSES AT FOUR DOSE LEVELS IN COPD PATIENTS
R. Sechaud1, D. Renard1, L. Zhang-Auberson1, S. de la Motte2, A. Drollmann1, G. Kaiser1
1Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland and 2Harrison Clinical Research GmbH, Albrechtstrasse 14, 80636 Munich, Germany. [email protected]
Objective: This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild to moderate COPD patients. Methods: In a double-blind, parallel-group study, 40 patients were randomised to 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. 24 h plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14, trough plasma levels were measured between these days. Results: The median time to reach the maximal plasma concentration (Tmax) was 5 or 6.5 min post-inhalation. At steady-state (Day 14), total and maximum systemic exposure (AUC0–24, Cmax) to NVA237 and amount excreted as unchanged drug into urine (Ae0–24) increased proportionally with dose. Exposure was on average 1.4–1.7 fold higher on Day 14 compared to Day 1. Mean elimination half-life (T1/2) ranged between 13 and 22h. Steady-state plasma concentrations were reached by Day 7. Ae0–24 as fraction of the NVA237 dose ranged from 6.7 to 9.8% on Day 1 and 11.6 to 15.0% on Day 14. Renal clearance (CLr) was similar across doses and after single and repeated dosing. Conclusion: The pharmacokinetics of NVA237 were linear and there was little systemic accumulation at steady-state after repeated once-daily inhalation.
CARDIOVASCULAR ADVERSE EVENTS ACCORDING TO GOLD STAGE IN THE UPLIFT TRIAL
D. Tashkin, B. Celli, S. Kesten, D. Liu and M. Decramer
David Geffen School of Medicine at UCLA, Los Angeles, USA. [email protected]
Background: Previous studies have related COPD severity to cardiovascular (CV) disease. We evaluated whether this relationship is observed in a single large prospective trial. Methods: Evaluation of adverse events (AEs) during the 4-year UPLIFT trial. AE incidence rates(IR) and rate ratios(RR) (tiotropium/placebo) were calculated. Composite CV endpoint included CV deaths + non-fatal MI + non-fatal stroke + sudden death + sudden cardiac death + cardiac death. Results: 5,895 patients: 46% GOLD Stage II, 45% Stage III, 9% Stage IV.%men by stage: 72,76,78; age by stage: 64,65,62 years. IR(per 100 patient-years) for AEs (tiotropium vs. placebo) by stage: cardiac(total) 5.59vs6.21, 7.29vs8.28, 8.65vs10.8 [ischemic heart disease 2.43vs2.63, 2.19vs2.65, 2.15vs1.83; atrial fibrillation/flutter 0.86vs1.15, 1.68vs1.53, 1.50vs1.31; cardiac failure 1.22vs1.82, 2.34vs2.72, 3.66vs4.24; MI 0.72vs0.91, 0.67vs1.07, 0.90vs1.16]; vascular(total) 5.15vs5.98, 6.35vs5.94, 5.30vs5.41; CV endpoint 1.99vs2.67, 2.70vs3.56, 3.93vs4.72. RR(95%CI) (tiotropium/placebo) for CV endpoint by stage: 0.74(0.56,0.98), 0.76(0.59,0.98), 0.83(0.49,1.42). Conclusions: AE reporting during UPLIFT indicated an increased risk of CV events by GOLD stage, although variability was observed among different categories. Potential confounding factors include age, smoking, and small numbers. Tiotropium reduces risk of a CV event regardless of GOLD stage. Clinical implications: Clinical trial data support an association of CV disease with GOLD stage. Study funded by Boehringer Ingelheim/Pfizer.
EFFECTS OF BISOPROLOL AND NEBIVOLOL ON EXERCISE CAPACITY, LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC FUNCTIONS AND PULMONARY FUNCTION IN PATIENTS WITH COEXISTENT CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CHRONIC HEART FAILURE
M.A. Gertsen, E.S. Atroshchenko and A.N. Zuiko
Republican Research and Practical Cardiology Center, Minsk, Belarus. [email protected]
There is growing evidence that chronic obstructive pulmonary disease (COPD) patients (pts) with concomitant chronic heart failure (CHF) tolerate well selective beta-blockade, a cornerstone in the heart failure treatment. The aim of the study was to compare the effects of bisiprolol and nebivolol, supplemented to enalapril, regarding exercise capacity, left ventricular (LV) systolic and diastolic functions and respiratory function in pts with coexistent COPD and CHF. Methods. Forty two men (mean age, 60.01.3 years) with moderate COPD (GOLD stage 2) and past history of myocardial infarction, complicated by CHF New York Heart Association class II symptoms, were randomized to bisoprolol (n = 23) or to nebivolol therapy (n = 19). The treatment period was 1 year. After individual titration, the mean bisoprolol dose was 7.19 mg, the mean nebivolol dose was 8.25 mg. Echocardiographic measurements of LV systolic and diastolic functions, six-minute walk test, and standard pulmonary function tests were performed before the administration of the drugs and 3, 6 and 12 months later. Results. 6-minute walking distance in bisoprolol group has significantly increased by the third month (314.98.5 to 350.1 9.4 m, p = 0,009), in nebivolol group it has significantly increased by the six month (299.2 9.9 to 345.2 10.2 m, p = 0,003). LV ejection fraction increased significantly after 1 year in bisoprolol group (49.0 1.8% before therapy versus 54.8 1.9% after therapy; p < 0.05) and tended to be higher in nebivolol group (47.5 2.2% before therapy versus 51.4 2.1% after therapy; p > 0.05). After 1 year LV diastolic measurements (EA, DT), improved in bisoprolol group and did not change significantly in the nebivolol group. No statistical differences were observed within or between groups in FEV1 and FEV1 to FEV ratio after 12 month of therapy. Conclusion. Administration of bisoprolol as well as nebivolol, in pts with coexistent CHF and COPD is associated with improved exercise capacity, absence of adverse respiratory effects, however with different expressivity extent of effects regarding LV systolic and diastolic functions.
ROFLUMILAST AS AN ADD-ON TO SALMETEROL: EFFICACY IN PATIENTS WITH CHRONIC BRONCHITIS
W. MacNee, M. Brose, U-M. Goehring and K.F. Rabe
Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland. [email protected]
Background: Background: The oral phosphodiesterase 4 inhibitor roflumilast improved lung function and other clinical outcomes in a 6-month, double-blind, randomised, parallel-group study of patients with moderate-to-severe COPD receiving concomitant salmeterol (Fabbri LM, et al. Lancet 2009;347:695–703). This post-hoc analysis assessed the effect of concomitant roflumilast in all patients with pre-bronchodilator FEV1 data available (n = 919) and subgroups with chronic bronchitis (CB, n = 716) or no CB (NCB, n = 203). Methods: After a 4-week baseline period in which patients received salmeterol 50 μg twice daily (bid) and roflumilast placebo once daily (od), patients were randomised and received roflumilast 500 μg (n = 466) or placebo od (n = 467) for 24 weeks with concomitant salmeterol 50 μg bid. Results: The difference between roflumilast+salmeterol versus salmeterol alone in the primary endpoint, pre-bronchodilator FEV1, was significantly greater in CB (55 mL; p < 0.0001) but not in NCB patients (16 mL; p = 0.5350). This treatment difference was 49 mL (p < 0.0001) in all patients. Roflumilast + salmeterol produced a significantly greater reduction in the mean annual rate of moderate or severe exacerbations in CB (−43.4%; p = 0.0234) but not in NCB patients (−0.9%; p = 0.9843); this reduction was also significant in all patients (−36.8%; p = 0.0315). Conclusion: Roflumilast provided additional benefit in patients with COPD with CB already treated with salmeterol compared with salmeterol alone.
WEIGHT LOSS OBSERVED WITH ROFLUMILAST IS NOT ENHANCED IN COPD PATIENTS WITH CONCOMITANT TYPE II DIABETES
D. Shale, E. Wouters and P. Calverley
Section of Respiratory Medicine, Cardiff University School of Medicine, Academic Centre, University Hospital Llandough, Penlan Road, Cardiff, UK. [email protected]
Background: COPD is associated with insulin resistance (Bolton CE, et al. J COPD 2007;4:121–26) and an increased risk of type II diabetes. The oral phosphodiesterase 4 inhibitor roflumilast improved lung function and reduced exacerbations in two 12-month studies in patients with severe-to-very-severe COPD, chronic bronchitis and a history of exacerbations; roflumilast was also associated with a small weight decrease (Calverley PMA, et al. Lancet 2009;347:685–94). Weight change in patients with and without type II diabetes was analysed in pooled data from these studies. Methods: Following a 4-week run-in period, patients were randomised and received roflumilast 500 μg (n = 1537) or placebo (n = 1554) once daily. Body weight was measured at baseline and weeks 4, 8, 12, 20, 28, 36, 44 and 52. Results: Mean (SD) weight change at study end was –2.09(3.98) kg with roflumilast vs 0.08(3.48) kg with placebo (mean difference –2.17 kg, p < 0.0001). In patients with diabetes, least square (LS) mean (SE) weight change was –2.78(0.41) kg with roflumilast and –0.48(0.39) kg with placebo (mean difference −2.3 kg, p < 0.0001) and in patients without diabetes was −2.07(0.11) kg vs 0.08(0.11) kg (mean difference −2.15 kg, p < 0.0001). The incidence of adverse events was slightly higher in the diabetes subgroup, but similar to that in the overall population. Conclusions: Type II diabetes did not enhance weight loss with roflumilast treatment in patients with COPD.
EFFICACY OF ROFLUMILAST IN PATIENTS RECEIVING CONCOMITANT TREATMENTS FOR COPD OVER 12 MONTHS
D. Shale and P. Calverley
Section of Respiratory Medicine, Cardiff University School of Medicine, University Hospital, Llandough, Penlan Road, Cardiff, CF64 2XX. [email protected]
The oral phosphodiesterase 4 inhibitor roflumilast improved lung function and reduced exacerbations in two 12-month studies in patients with severe-to-very-severe COPD, chronic bronchitis and a history of exacerbations (Calverley PMA, et al. Lancet 2009;347:685–94). Pooled data were analysed to investigate whether the effect of roflumilast on the rate of moderate or severe exacerbations is influenced by concomitant maintenance treatment with long-acting beta2 agonists (LABA), short-acting muscarinic antagonists (SAMA), or pre-randomisation treatment with inhaled corticosteroids (ICS). Patients were randomised and received roflumilast 500 μg (n = 1537) or placebo (n = 1554) once daily for 12 months; patients were stratified 1:1 according to LABA use. Regular SAMA use was allowed but ICS was discontinued at randomisation. In the roflumilast and placebo groups, LABAs were used by 49% and 51%, SAMAs by 38% and 40%, and ICS by 42% and 42% of patients, respectively. The change in exacerbation rate with roflumilast over placebo was –16.9% overall (95% confidence interval [CI]: –25, –8). This was not influenced (users vs non-users, respectively) by LABA (–20.7% [95% CI: –31, –9] vs –14.6% [95% CI: –26, –1]), SAMA (–13.1% [95% CI: –24, 0] vs –19.8% [95% CI: –30, –8]) or prior ICS use (–19.3% [95% CI: –30, –7] vs –16.8% [95% CI: –28, –4]). In these two large 12-month studies, roflumilast reduced the frequency of moderate and severe exacerbations independent of concomitant maintenance bronchodilator treatment (LABA or SAMA), or prior ICS treatment.
POTENTIAL OF ROFLUMILAST FOR COPD: WHICH PATIENTS WOULD BENEFIT?
I. Small, D. Freeman and A. Kaplan
Peterhead Health Centre, Scotland. Jon.Weeks@caudex. com
Data from pivotal 1-year (Lancet 2009;347:685–94) and 6-month (Lancet 2009;347:695–703) trials were reviewed to assess which COPD patients would benefit from treatment with the oral phosphodiesterase 4 inhibitor roflumilast 500 μg once daily. The 1-year trials enrolled patients with severe-to-very-severe COPD with chronic bronchitis and a history of exacerbations. Approximately half the patients in both arms used a long-acting beta2-agonist (LABA), and were stratified according to LABA use, and a third used a short-acting muscarinic antagonist (SAMA); inhaled corticosteroids were not allowed after randomisation. The 6-month trials enrolled patients with moderate-to-severe COPD (+ chronic cough and sputum in the tiotropium study); roflumilast was administered concomitantly with salmeterol or tiotropium. In the 1-year studies (n = 3091 randomised and treated), roflumilast improved lung function (48 mL increase in prebronchodilator FEV1; p < 0.0001) and reduced the rate of moderate or severe exacerbations versus placebo, independent of LABA or SAMA usage. In the 6-month studies (n = 1676 randomised and treated), roflumilast improved lung function (49 mL and 80 mL increases in prebronchodilator FEV1, respectively; p < 0.0001) and reduced some exacerbation measures versus salmeterol/tiotropium alone. In all studies, weight loss was more common with roflumilast than placebo. Roflumilast improved lung function and reduced exacerbations regardless of LABA or SAMA use over 1 year and reduced some exacerbation measures regardless of tiotropium use over 6 months in COPD patients.
DEFINING PATIENT POPULATIONS IN COPD: EXPERIENCE WITH ROFLUMILAST
F.J. Martinez1, P.M.A. Calverley2, U-M. Goehring3, S.I. Rennard4
1Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA; 2School of Clinical Sciences, University Hospital Aintree, Liverpool, UK; 3Medical Scientific Strategy & Medical Marketing, Nycomed GmbH, Konstanz, Germany; 4Pulmonary and Critical Care Medicine, Nebraska Medical Center, Omaha, USA. [email protected]
As COPD is a heterogeneous disease, different drugs are likely to benefit different patient subpopulations. We intended to identify a subgroup of patients with moderate and severe COPD who were likely to respond to roflumilast (ROF). Following initial negative results in two replicate, randomised, double-blind, placebo (PBO)-controlled studies (M2–111 and M2–112; oral ROF 500 μg or PBO o.d. for 52 weeks), a post-hoc, pooled analysis was done to identify a responsive subtype. Additionally we studied whether inhaled corticosteroids (ICS) changed the effect of ROF on moderate/severe exacerbations. The pooled analysis included 2686 randomised patients (mean post-bronchodilator FEV1 37% predicted). At 52 weeks, ROF treatment increased mean (SE) pre- (51 [7] mL; p < 0.0001) and post-bronchodilator FEV1 (53 [7] mL; p < 0.0001) vs PBO and decreased exacerbations by 14.3% (p = 0.026). ROF significantly reduced the exacerbation rate by 26.2% vs PBO (p = 0.001) in patients with chronic bronchitis ± emphysema but had no effect on exacerbations in patients with emphysema only (–1.1%; p = 0.93). Patients receiving concomitant ICS also had fewer moderate/severe exacerbations when treated with ROF (ROF + ICS vs ICS: 18.8% decrease [p = 0.014]; ROF + PBO vs PBO: 7.7% decrease [p = 0.55]). Greater reductions were seen for patients with chronic bronchitis: 30.2% (p = 0.001) vs 15.5% (p = 0.31) with or without ICS. There was no indication that ROF increased ICS-associated adverse events. This analysis indicated that a more responsive patient subtype was likely; this finding has now been confirmed in prospective trials. In this subset, ROF treatment remains effective in patients using ICS.
PROFILE PATHOPHYSIOLOGY OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE
A. L. Gonçalves da Silva, T. C. Malezan Fleig, L. G. Possuelo, D. J. de Moura, A. R. de Moura, V. J. A. Pegas Henriques
UNISC and UFRGS, Independence Avenue, n. 2293 Santa Cruz do Sul/ RS, Brazil cep: 96815-900. [email protected]
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disorder with complex pathological features largely unknown. Our aims were to assess and quantify oxidative damage and repair capacity in the DNA of COPD patients, from southern of Brazil. Were used lymphocytes from peripheral blood to perform the alkaline comet assay, neutral and repair oxidative. Activity of antioxidant enzymes such superoxide dismutase (SOD) and catalase (CAT) were performed in the serum of individuals. The levels of oxidative stress were determined by measurement of lipid peroxidation (TBARS). We evaluated 08 individuals (04 cases; 04 controls). The damage index (DI) neutral comet assay (33.25 ± 33.39 cases; 129.90 ± 168.25), and alkaline version DI (22.50 ± 7.72 cases; 117 ± 31.62) were lower in COPD tham in controls. Enzymes used to repair oxidative damage, the results show there is an increase in DI for two enzymes in COPD (Endonuclease III: 131 ± 101.18 cases; 104.33 ± 27.59 / Formamidapirimidina:180 ± 80.45 cases; 144 ± 33.45). Analysis SOD, CAT and TBARS did not identify differential expression. These preliminary data show some differences in the oxidative stress in COPD and reinforce the need to understand the mechanisms by which this happens in the disease process.
EFFECTS OF SUBCHRONIC TOBACCO SMOKE EXPOSURE AND POLYINOSINIC POLYCYTIDYLIC ACID (POLY (I:C)) ADMINISTRATION ON PULMONARY INFLAMMATION IN THE MOUSE
M.S. Freeman, E.L. Hardaker, D.B. Wright, J.A. Dewhurst, K.H. Banner, C.T. Poll
Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham. RH12 5AB. UK, [email protected]
An altered inflammatory response is observed during acute exacerbations of COPD. Our aim was to develop an animal model to mimic this change by exposing mice to a combination of tobacco smoke and a viral mimetic poly (I:C). For 6 weeks Balb/c mice were exposed twice daily to 30 minutes of tobacco smoke (TS; 750 μg/l) or room air. Once a week, one TS exposure was replaced by intranasal poly (I:C) or saline administration. Animals were terminated and a bronchoalveolar lavage (BAL) performed and lung tissue taken. Data is expressed as mean ± SEM. Concentrations of IFNγ in BAL were elevated in the group exposed to both agents (50.8 ± 18.7 pg/ml;p < 0.01) compared to TS (0 ± 0 pg/ml) or poly (I:C) alone (5.0 ± 3.4 pg/ml). Mucus levels in the airways (assessed by UEA1 staining) were also elevated in the group exposed to the dual stimuli, with approximately a 4 fold increase (p < 0.01) compared to groups exposed to the single stimulus. Lymphocytes in the BAL fluid showed a comparable profile, with the highest numbers (81 ± 18 ×103/ml; p < 0.001) observed in animals treated with both agents compared to either TS (19.3 ± 3 ×103/ml) or poly (I:C) (18.3 ± 3 ×103/ml). These results suggest that combining a viral mimetic and TS causes an altered inflammation when compared to TS alone.
PRIMING AND OXIDATIVE BURST INDUCTION IN HUMAN PERIPHERAL BLOOD NEUTROPHILS BY TREATMENT WITH CIGARETTE SMOKE
B. Friedrichs, U. Neumann, J. Schueller
Philip Morris International R&D, Philip Morris Research Laboratories GmbH, Fuggerstrasse 3, 51149 Cologne, Germany. [email protected]
Neutrophils are front-line-defense cells of the innate immune system and a source of reactive oxygen species, inflammatory cytokines, lipid mediators, and tissue-damaging enzymes. They play important roles in both the goblet cell metaplasia in chronic bronchitis and the destruction of lung tissue in emphysema and thus are one of the primary effector cell types in COPD. In order to investigate the mechanism of neutrophil activation by cigarette smoke, neutrophils isolated from peripheral blood of human non-smokers were treated in vitro either directly with cigarette smoke-bubbled phosphate-buffered saline (sbPBS) or indirectly with supernatants from sbPBS-treated Monomac-6 (MM6) cells. Readout parameters were changes in expression of the surface markers CD11b, CD66b, and CD62L; release of the granule proteins matrix metalloproteinase (MMP)-9, MMP-8, and lactoferrin; and oxidative burst induction as measured by N-formyl-methionyl-leucyl-phenylalanine-mediated superoxide release. Direct treatment with sbPBS resulted in the priming of neutrophils as measured by an increase in CD11b and CD66b expression (up to 2.4-fold), a reduction in CD62L expression (down to 46%), and the release of all 3 granule proteins (up to 4.5-fold increase), but no induction of oxidative burst. Indirect treatment with sbPBS resulted in an even stronger priming effect, i.e., an increase in CD11b and CD66b (up to 3-fold), a decrease in CD62L (down to 34%), and a stimulation of granule protein release (up to 13-fold), but with the consequence of an increase in the oxidative burst response (up to 14-fold); p < 0.001 for all changes. These results suggest that cigarette smoking might lead to continuous activation of neutrophils in the lung tissue, which perpetuates the chronic lung inflammation seen in COPD patients.
DISCORDANT LUNG FUNCTION GROUPS IN ALPHA-1-ANTITRYPSIN DEFICIENCY (A1AD)
H. Ward, R.A. Stockley
University Hospitals Birmingham NHS Trust, Birmingham, UK. [email protected]
Introduction: COPD (even due to A1AD) is increasingly recognised as having distinct radiological, physiological and clinical phenotypes. J. Holme et al (Chest, 2007;132:900–915) found that A1AD patients with an isolated KCO abnormality had a predominance of upper zone emphysema and worse quality of life compared to those with normal lung function. We wished to explore the characteristics of these patients compared to those with an isolated FEV1 abnormality and both FEV1 and KCO abnormality. Methods: The Alpha-1-antitrypsin Deficiency Assessment and Programme for treatment (ADAPT) is the UK registry for A1AD patients. Baseline data for 534 PiZZ patients including demographics, full pulmonary function tests, CT imaging and health status (Saint George?s Respiratory Questionnaire(SGRQ)) were analysed. Patients were divided into four groups: Group 1 (Normal FEV1 & KCO), Group 2 (isolated KCO abnormality), Group 3 (isolated FEV1 abnormality) and Group 4 (both FEV & KCO abnormality). The physiological abnormality was defined using standard residuals with a cut off point of −1.645 as the lower limit of normal. Results: The distribution of the patients across each discordant lung function group is represented in figure 1. Group 1 was significantly younger than the other groups (p < 0.007). Group 1 & 2 had a similar pack year history which was less then Group 3 & 4 (p < 0.039). Gender was not distributed evenly with 50%, 30%, 79% & 61% males in Group 1 ? 4 respectively. Body mass index (BMI) was greatest in Groups 1 & 3 compared to Groups 2 & 4 (p < 0.006). Chronic bronchitis most frequented Group 4 compared to Group 1 (p = 0.046). Total SGRQ increased significantly from Group 1 through 4 (p < 0.042). Emphysema was present in all groups but the incidence increased from group 1 ? 4 (25%, 57%, 65% & 79% respectively). Conclusions: These data confirm the presence of distinct physiological phenotypes. Although subjects with normal lung function are younger, the other 3 groups have similar age profile suggesting different progression patterns. This may in part reflect difference in smoking habits but also suggests distinct gene-environment interactions.
IDENTIFICATION OFA 6 kDa PROTEIN AS A POTENTIAL BIOMARKER IN ALPHA-1-ANTITRYPSIN DEFICIENCY
H. Stone, D. Ward, R.A. Stockley
ADAPT Project, Queen Elizabeth Hospital Birmingham, University of Birmingham, UK. [email protected]
Rationale: Alpha one antitrypsin deficiency is a genetic condition which arises from an imbalance between proteases and anti-proteases, predisposing the lungs to protease damage, and resulting in early onset emphysema. Proteomics is an emerging field which is becoming increasingly important to investigate protein-based mechanisms of respiratory disease, identify biomarkers and assist in the detection of new targets for drug development. At present, no single biomarker exists that can predict progression of disease or response to treatment in patients with alpha-1-antitrypsin deficiency, although airways inflammation decreases on treatment (Stockley et al (2002) Am J Respir Crit Care Med; 165:1494–1498). The aim of this study was to use proteomic techniques to look for a peptide or protein that could act as a biomarker. Methods: 23 UK patients undergoing a study of intravenous replacement therapy as part of the EXACTLE Trial (active drug versus placebo) had plasma samples taken at baseline and six months. These samples were analysed using the surface enhanced laser desorption/ionisation time of flight (SELDI-TOF) technique and spectra generated to identify peptides and/or proteins that differed between the active and the control group, which could act as a biomarker of response. Data was analysed using paired T tests. Results: There was a rise in a protein of approximately 50kDa in the patients who received treatment, which is presumed to be alpha-1-antitrypsin, when compared to those who received placebo. During the study, there was a statistically significant reduction in a protein of 6 kDa (p = 0.0006) for those on active treatment. Conclusion: This preliminary study shows that a peptide of 6kDa decreases significantly in patients with alpha-1-antitrypsin deficiency when they receive intravenous replacement therapy. Further studies need to be undertaken to validate the significance of this observation, to identify and characterise the protein and evaluate it as a potential biomarker for augmentation therapy. This work was carried out using an unrestricted educational grant from Talecris Biopharmaceuticals Ltd.
FIBRINOPEPTIDE AA-VAL360: A FOOTPRINT OF NEUTROPHIL ELASTASE ACTIVITY
R. Carter, R. Mumford, K. Treonze, R. Stockley
ADAPT Project, Queen Elizabeth Hospital Birmingham, UK. [email protected]
Introduction: The association between alpha-1-antitrypsin (A1AT) deficiency and emphysema [Eriksson, 1965, Acta Med Scand. 432:1–85.] established the proteinase-antiproteinase theory as a key mechanism in the pathogenesis of emphysema. Subsequent mathematical and in vitro studies by Campbell et al demonstrated the exponential relationship between the distance from the degranulating neutrophil and NE concentration and that, at release, the substantially higher NE concentration exceeds the normal inhibitory capacity of A1AT leading to an area of obligate proteolytic damage [Liou & Campbell, 1995, Biochemistry, 34(49): 16171–7., Liou & Campbell, 1996. J Immunol, 157(6):2624–31]. This hypothesis of quantum proteolysis explains the increased risk of emphysema in subjects with A1AT deficiency, however it has not been confirmed as a mechanism in vivo since the neutrophil micro-environment is difficult to explore. The current study investigates the use of a surrogate marker of NE activity by assessing the Aα360 peptide (a specific NE cleavage product of fibrinogen prior to its inhibition) and its relationship to airflow obstruction in subjects with A1AT deficiency. Methods: The study included 68 individuals with PiZ A1AT deficiency in a stable clinical state and 52 subjects with normal A1AT. Plasma Aα360 levels were measured and related to the A1AT levels and post-bronchodilator spirometry using non-parametric statistical techniques. Results: The A1AT subjects demonstrated a wide range of FEV1 (% predicted) values, with a minimum of 16.1% and maximum of 132.3%. There was an exponential relationship between A1AT and Aα360 concentrations (increasing below 11 μM), and a negative association between Aα360 and FEV1 (p = 0.005), FEV1:VC (p = 0.008) and residual volume (p = 0.013). Conclusion: The Aα360 relates to the A1AT concentration, increasing as expected below 11 μM, supporting the theoretical and in vitro studies published previously. The negative correlation with lung physiology suggests Aα360 is a valid marker of the in vivo destructive activity of NE.