High-risk patients following hospitalisation for an acute exacerbation of COPD (78/90). J. Piquet, J.M. Chavaillon, P. David, F. Martin, F. Blanchon, N. Roche. Eur Respir J. 2013 Jan 24. [Epub ahead of print]
To assess long-term mortality and predictive factors of death after hospital admission for AECOPD.1,824 patients (female: 23.2%; mean age: 70.3+/-11.3 years) consecutively admitted for AECOPD in respiratory medicine departments of 68 general hospitals between October 2006 and June 2007 were prospectively enrolled in a follow-up cohort. Their vital status was documented between October 2010 and April 2011.Vital status was available for 1,750 patients (95.9%), among whom 787 (45%) died during follow-up. Multivariate analysis found that age (80 vs. <60 years: RR = 2.99 [2.31-3.89]), lower BMI (25-30 kg·m(-2) vs. ≤20 kg·m(-2): RR = 0.80 [0.66-0.97]), lung cancer (RR = 2.08 [1.43-3.01]), cardiovascular comorbidity (RR = 1.35 [1.16-1.58]), previous hospital admissions for AECOPD (≥4 admissions vs. 0: RR = 1.91 [1.44-2.53]), use of accessory respiratory muscles (RR = 1.19 [1.01-1.40]) or lower-limb oedema (RR = 1.74 [1.44-2.12]) at admission, and treatment by long-term oxygen therapy at discharge (RR = 2.09 [1.79-2.45]) were independent risk factors of death. Mortality rate during the 4 years following hospital admission for AECOPD was high (45%). Simple clinical information relating to respiratory and general status can help identifying high-risk patients and targeting more intensive follow-up and care. Interestingly, cardiovascular comorbidities and past hospitalizations for AECOPD, but not FEV1, independently predicted the risk of death.
Comments: Reports suggest that individuals with COPD incur significant health care costs, perhaps up to 3.5 times more than individuals without COPD. This may correlate with susceptibility to other ill effects of cigarette smoking including lung and other cancers, cardiovascular disease, cachexia and osteopenia to name a few. It is likely that there is a sub-phenotype of COPD patients that have frequent exacerbations that need more intense interventions perhaps started earlier. This paper provides insights into clinical features that may identify these high-risk patients. Identifying and studying this sub-group's characteristic features may assist in developing interventions to improve their outcomes, quality of life and health care expenditures.
High-Dose N-Acetylcysteine in Stable Chronic Obstructive Pulmonary Disease: the 1-Year, Double-Blind, Randomized, Placebo-Controlled HIACE Study. H.N. Tse, L. Raiteri, K.Y. Wong, K.S. Yee, L.Y. Ng, K.Y. Wai, C.K. Loo, C.M. Houng. Chest. 2013 Jan 24. doi: 10.1378/chest.12-2357. [Epub ahead of print]
ABSTRACT BACKGROUND: N-acetylcysteine's (NAC) mucolytic and antioxidant effects may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used.
OBJECTIVE: to investigate high-dose NAC plus usual therapy in stable Chinese COPD patients.
METHODS: The 1-year HIACE double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible stable COPD patients aged 50-80 yrs to NAC 600mg twice daily (Fluimucil, Zambon SpA, Italy) or placebo after 4 weeks’ run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George Respiratory Questionnaire (SGRQ) scores, 6-minute walking distance (6-MWD), and exacerbation and admission rates, were measured at baseline and every 16 weeks for 1 year.
RESULTS: Of 133 patients screened, 120 were eligible (93.2% male; mean age 70.8 ± 0.74 years;%FEV1 53.9 ± 2.0%). Baseline characteristics were similar in the two groups. At 1-year, there was a significant improvement in Forced Expiratory Flow 25% to 75% (FEF25-75%; P = .037) and forced oscillation technique (FOT), a significant reduction in exacerbation frequency (0.96 vs 1.71 times/year, P = .019) and a tendency towards reduction in admission rate (0.5 vs 0.8 times/year, P = .196) with NAC versus placebo. There were no significant between-group differences in mMRC, SGRQ and 6MWD. No major adverse effects were reported.
CONCLUSION: 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD.
Comments: NAC has several properties that suggest it may have potential to improve outcomes in COPD patients. The patient population in this study could not be on supplemental oxygen and entered trial 4 weeks after having had an exacerbation. Other mucolytic treatments were discontinued but patients were allowed to remain on inhaled corticosteroids, long acting beta agonists and long acting muscarinic antagonists. Between 74 to 83% were on ICS (presumably in some combination with LABA (around 35%) or LAMA (not reported). The mean FEV1 was around 52% predicted and the majority of patients had moderate or severe disease. They had had on average 2 exacerbations in the past year and approximately 23% were non-smokers. This trial demonstrates improvements in small airway function and exacerbations and suggest that NAC may be useful in patients with moderate to severe disease with frequent exacerbations and as a systemically delivered medication may explain the detected improvement in small airway function documented by FEF25-75 and forced oscillation. These results should be validated in a larger sample size to see if results are reproducible.
Chronic obstructive pulmonary disease and lipid core carotid artery plaques in the elderly: the rotterdam study. L. Lahousse, Q.J. Bouwhuijsen, D.W. Loth, G.F. Joos, A. Hofman, J.C. Witteman, A. van der Lugt, G.G. Brusselle, B.H. Stricker. Am J Respir Crit Care Med. 2013 Jan 1;187(1):58-64. doi: 10.1164/rccm.201206-1046OC. Epub 2012 Nov 9.
Rationale: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for ischemic stroke and the risk increases with severity of airflow limitation. Even though vulnerable carotid artery plaque components, such as intra plaque hemorrhage and lipid core, place persons at high risk for ischemic events, the plaque composition in patients with COPD has never been explored.
Objectives: To investigate the prevalence of carotid wall thickening, the different carotid artery plaque components, and their relationship with severity of airflow limitation in elderly patients with COPD.
Methods: This cross-sectional analysis was part of the Rotterdam Study, a prospective population-based cohort study performed in subjects aged 55 years and older. Diagnosis of COPD was confirmed by spirometry. Participants with carotid wall intima-media thickness greater than or equal to 2.5 mm on ultrasonography underwent high-resolution magnetic resonance imaging for characterization of carotid plaques. Data were analyzed using logistic regression.
Measurements and Main Results: COPD cases (n = 253) had a twofold increased risk (odds ratio, 2.0; 95% confidence interval, 1.44-2.85; P < 0.0001) of presentation with carotid wall thickening on ultrasonography compared with control subjects with a normal lung function (n = 920). Moreover, the risk increased significantly with severity of airflow limitation. On magnetic resonance imaging, vulnerable lipid core plaques were more frequent in COPD cases than in control subjects (odds ratio, 2.1; 95% confidence interval, 1.25-3.69; P = 0.0058).
Conclusions: Carotid artery wall thickening is more prevalent in patients with COPD than in control subjects. In elderly subjects with carotid wall thickening, COPD is an independent predictor for the presence of a lipid core, and therefore of vulnerable plaques.
Comments: COPD patients with moderate to severe disease are at a 2 fold increased risk of cardiovascular disease mortality. The use of MRI allows detailed characterization of the plaque and indeed identified that COPD patients have higher incidence of vulnerable plaque noted by an increased lipid content in their core, which portends a higher risk for ischemic events. Further this correlated with the severity of airflow obstruction independent of cigarette smoking although cigarette smoking indeed augmented the risk. Furthermore, while there was a correlation of the extent of such plaque and degree of airflow obstruction, it was shown that this process is present in the patients with even relatively mild airflow obstruction. Hence early identification of COPD patients is key and evaluation for cardiovascular disease should be initiated and treatment started as early as possible to mitigate the potential for significant cardiovascular morbidity in these patients. These findings further our understanding and help generate hypotheses about the mechanisms for the potential benefit of statins in COPD patients considering that many COPD exacerbations are associated with silent or overt coronary ischemic complications.
Six Minute Walk Test in COPD: Minimal Clinically Important Difference for Death or Hospitalization. M I. Polkey, M.A. Spruit, L.D. Edwards, M.L. Watkins, V. Pinto-Plata, J. Vestbo, P.M. Calverley, R. Tal-Singer, A. Agusti, P.S. Bakke, H.O. Coxson, D.A. Lomas, W. Macnee, S. Rennard, E.K. Silverman, B.E. Miller, C. Crim, J. Yates, E.F. Wouters, B. Celli; On behalf of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study investigators. Am J Respir Crit Care Med. 2012 Dec 21. [Epub ahead of print]
Abstract Rationale & OBJECTIVES: Outcomes other than spirometry are required to assess non-bronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the six minute walk distance have been derived from narrow cohorts using non-blinded intervention.
METHODS: Data from the ECLIPSE cohort were used (N = 2112). Death or first hospitalization were index events; we measured change in six minute walk distance in the 12 month period before the event and also related change in six minute walk distance to lung function and St Georges Respiratory Questionnaire (health status).
Measurement and MAIN RESULTS: Of subjects with change in the six minute walk distance data, 94 died and 323 were hospitalized. Six minute walk distance fell by 29.7 (SD = 82.9) m more in those who died than survivors (P < 0.001). A change in distance of more than -30m conferred a hazard ratio of 1.93 (95% confidence interval: 1.29, 2.90; P = 0.001) for death. No significant difference was observed for first hospitalization. Weak relationships only were observed with change in lung function or health status.
CONCLUSIONS: A fall in the six minute walk distance of 30m or more is associated with increased risk of death but not hospitalization due to exacerbation in patients with chronic obstructive pulmonary disease and represents a clinically significant minimally important difference
Comments: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) is an international multicenter longitudinal study with 2112 patients that were studied over 3 years examining the relationship between clinical characteristics and outcomes and a series of biomarkers. Other studies that have evaluated the MCID for 6-minute walk have been designed to look at an intervention and thus typically have exclusions and specific criteria for study entry. The longitudinal observational nature of the ECLIPSE trial provided a relatively unique population of COPD subjects with a broad spectrum of airflow obstruction and comorbidities without selection criteria bias. It is unfortunate that we do not know the cause of death for subjects. Interestingly the -30 meter value that was predictive of mortality parallels the 26–54 meter range that has been reported in previous studies looking at improvements in status after various interventions such as lung volume reduction and pulmonary rehab. How this may translate into something that is clinically applicable remains in question. Future studies may validate this as a surrogate measure of reduced risk of death if an intervention is able to reduce the rate of loss of 6 minute walk distance annually to less than 30 meters.