Adherence to inhaled therapy, mortality and hospital admission in COPD.

BACKGROUND: Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity. METHODS: Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study. RESULTS: Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence. CONCLUSION: Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE).

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and not well understood. The forced expiratory volume in one second is used for the diagnosis and staging of COPD, but there is wide acceptance that it is a crude measure and insensitive to change over shorter periods of time. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) is a 3-yr longitudinal study with four specific aims: 1) definition of clinically relevant COPD subtypes; 2) identification of parameters that predict disease progression in these subtypes; 3) examination of biomarkers that correlate with COPD subtypes and may predict disease progression; and 4) identification of novel genetic factors and/or biomarkers that both correlate with clinically relevant COPD subtypes and predict disease progression. ECLIPSE plans to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II-IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter. Assessments include pulmonary function measurements (spirometry, impulse oscillometry and plethysmography), chest computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better describe the subtypes of chronic obstructive pulmonary disease, as well as defining predictive markers of its progression.

Dyspnea in a patient years after severe poliomyelitis. The role of cardiopulmonary exercise testing.

Dyspnea after polio can occur for a variety of reasons, including neuromuscular disease and upper airway abnormalities resulting from prolonged intubation, including tracheal stenosis, tracheomalacia, and vocal cord paralysis. Routine studies such as spirometry and maximum voluntary ventilation (MVV) measurements can give similar results in these conditions. We present a 50-year-old woman who as a child developed poliomyelitis that required tracheostomy and negative pressure ventilation. Thirty-nine years later, she developed breathlessness with normal spirometry but decreased MVV. The flow volume loop showed flattening of the inspiratory and expiratory limbs, consistent with a fixed upper airway obstruction or neuromuscular weakness. Exercise testing with measurement of exercise flow volume loops and respiratory pressures was performed. The patient was ventilatory limited with increasing end-expiratory lung volume through exercise. Flow volume loops confirmed flow limitation. Respiratory pressures did not change after maximal exercise. Further evaluation confirmed left vocal cord paralysis and tracheomalacia. This patient demonstrates that the causes of dyspnea after poliomyelitis can be multifactorial, and that routine evaluation may fail to elucidate the limiting factor. In this case, exercise testing provided valuable insight into the limiting factor for this patient and provided useful data for counseling and for further management.

Salmeterol plus theophylline combination therapy in the treatment of COPD.

BACKGROUND: Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. OBJECTIVES: To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. METHODS: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 microg/mL), patients were randomly assigned to receive salmeterol (42 microg bid) plus theophylline, salmeterol (42 microg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. RESULTS: All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p < or = 0.045) greater improvements in pulmonary function; significantly (p < or = 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p < or = 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. CONCLUSION: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

The bronchodilator response to salmeterol is maintained with regular, long-term use in patients with COPD.

Long-acting beta(2)-agonists (LABAs) are recommended in the management of patients with chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated that the LABA, salmeterol, improves lung function, symptoms and quality of life in patients with COPD. In this study, we have performed additional analyses of the combined data from two previous double-blind, placebo-controlled, parallel studies of salmeterol (50 microg, b.i.d) in patients with COPD. The new analyses reveal that the significant improvements seen in pre-dose and 2-h post-dose forced expiratory volume in 1 s (FEV(1)) compared to placebo, occur early in the treatment period, and are sustained for at least 24 weeks. Moreover, improvements in peak expiratory flow rate occur as early as Day 1, and are sustained throughout the 24-week period. Additional analyses of 12-h FEV(1) data also show that salmeterol is associated with an increase in the area under the curve at Week 12 compared with Day 1, adding further support to evidence that it results in a sustained bronchodilator response, with no evidence of tolerance.

Oxidant stress responses in influenza virus pneumonia: gene expression and transcription factor activation.

The pathogenesis of influenza virus infections of the lungs is in part mediated by oxidative stress. Such infections might therefore be expected to induce expression of stress-response genes and genes encoding antioxidant enzymes and to activate transcriptional regulatory proteins. Mice (C57B1/6 and C3H/HeJ) were infected intranasally with influenza virus A/PR/8/34 (H1N1). Expression of the genes encoding the antioxidant enzymes manganese superoxide dismutase (Mn- SOD), indoleamine-2, 3-dioxygenase (IDO), heme oxygenase-1, and glutathione peroxidase were increased in the lungs of virus-infected animals. Cu/ZnSOD and catalase mRNA were not induced by viral infection. Activation of the transcriptional regulatory proteins AP-1, C/EBP, and NF-kappa B (which are known to be affected by oxidant stress) was demonstrated by electrophoretic mobility shift assay after viral infection. In the case of MnSOD, despite increased gene expression enzyme activity was not increased. In contrast, for heme oxygenase-1 both mRNA and activity were increased. C3H/ HeJ and C57B1/6 mice, which are known to have different responses to other types of oxidant stress, also differed in their responses to viral infection. Induction of heme oxygenase-1 expression was greater in C57B1/6 mice than in C3H/ HeJ mice, although inhibiting this enzyme did not alter virus-induced mortality. In contrast, IDO was more strongly induced in C3H/HeJ mice. Activation of NF-kappa B was much more marked in C57B1/6 mice than in C3H/HeJ mice. Although virus replication and inflammatory responses were equivalent in the two strains, lung injury (as measured by wet-to-dry wt ratios) and mortality were greater in C3H/HeJ mice than in C57B1/6 mice, a difference that may be related to differing oxidant stress responses. Thus influenza pneumonia causes an oxidant stress response in the lungs, the nature of which is determined in part by the genetic background of the host.

Role of oxidants in influenza virus-induced gene expression.

Influenza virus-induced epithelial damage may be mediated, in part, by reactive oxygen intermediates (ROIs). In this study, we investigated the role of ROIs in the influenza virus-induced gene expression of antioxidant enzymes and in the activation of nuclear factor-kappa B (NF-kappa B), an oxidant-sensitive transcriptional factor. Influenza virus infection increased production of intracellular ROIs in A549 pulmonary epithelial cells. Induction of manganese superoxide dismutase (MnSOD) mRNA correlated with increased MnSOD protein and enzyme activity. Influenza virus infection also activated NF-kappa B binding as determined by an electrophoretic mobility shift assay. Pretreatment of A549 cells with N-acetyl-L-cysteine attenuated virus-induced NF-kappa B activation and interleukin (IL)-8 mRNA induction but did not block induction of MnSOD mRNA. In contrast, pyrrolidine dithiocarbamate blocked activation of NF-kappa B and induction of MnSOD and IL-8 mRNAs. Treatment with pyrrolidine dithiocarbamate also markedly decreased virus-induced cell death. Thus oxidants are involved in influenza virus-induced activation of NF-kappa B, in the expression of IL-8 and MnSOD, and in virus-induced cell death.

Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast.

BACKGROUND: Asthma is a disease of chronic inflammation and bronchoconstriction. Inhaled corticosteroids (ICSs) provide important anti-inflammatory treatment but may not provide optimal control of asthma when taken alone. Two therapeutic alternatives for enhanced asthma control are to substitute the combination of fluticasone propionate (FP) and salmeterol (FP/Salm Combo) through the Diskus inhaler or to add montelukast to existing ICS therapy. OBJECTIVE: We compared the efficacy and safety of FP/Salm Combo through the Diskus inhaler versus montelukast added to FP (FP + montelukast) in patients whose symptoms were suboptimally controlled with ICS therapy. METHODS: We performed a multicenter, double-blind, double-dummy, parallel-group, 12-week study in 447 patients with asthma who were symptomatic at baseline while receiving low-dose FP. Patients were treated for 12 weeks with one of the following: (1) combination of FP 100 microg plus salmeterol 50 microg twice daily through the Diskus inhaler, or (2) FP 100 microg twice daily through the Diskus inhaler plus oral montelukast 10 mg once daily. RESULTS: FP/Salm Combo treatment provided better overall asthma control than FP + montelukast with significantly greater improvements in morning peak expiratory flow (+24.9 L/min vs +13.0 L/min, P <.001), evening peak expiratory flow (+18.9 L/min vs +9.6 L/min, P <.001), and forced expiratory volume in 1 second (+0.34 L vs +0.20 L, P <.001), as well as a change in the percentage of days with no albuterol use (+26.3% vs +19.1%, P =.032) and the shortness of breath symptom score (-0.56 vs -0.40, P =.017). The groups had comparable improvements in chest tightness, wheeze, and overall symptom scores. Asthma exacerbation rates were significantly lower (P =.031) in the FP/Salm Combo group (4 patients, 2%) than in the FP + montelukast group (13 patients, 6%). Adverse event profiles were comparable. CONCLUSION: Symptomatic patients on low-dose ICS therapy had significantly greater improvement in asthma control when switched to the FP/Salm Combo than when montelukast was added to ICS therapy.

Time to onset of effect of fluticasone propionate in patients with asthma.

BACKGROUND: The effectiveness of inhaled glucocorticoids in the treatment of asthma is well documented; however, times to onset and maximal treatment effects of these agents have been poorly described. OBJECTIVE: We sought to determine the time to onset of effect and the time to the best observed effect of inhaled fluticasone propionate (FP) in patients with asthma. METHODS: Data from 8 randomized, double-blind, placebo-controlled clinical trials of at least 8 weeks' duration were analyzed. Corticosteroid-naive patients (n = 1461) were treated with either FP (25 micrograms to 500 micrograms) or placebo twice daily. Efficacy evaluations included morning peak expiratory flow (PEF), asthma symptom scores, supplemental albuterol use, and FEV1. RESULTS: Statistically significant improvements in PEF, asthma symptom scores, and supplemental albuterol use were observed beginning on day 1 of treatment in the FP group versus the placebo group (P <.001); significant increases in FEV1 were observed at the first measurement at week 1 (P <.001). The best observed effect occurred within 3 weeks of the start of FP treatment for PEF (+36 L/min) and FEV1 (+0.52 L) and within 2 weeks for reduction in supplemental albuterol use and asthma symptom scores. Patients with the most severe airflow obstruction had the greatest change in PEF (+56 L/min) and fastest time to 50% of best observed effect (3 days) compared with patients with mild or moderate airflow obstruction; however, time to best observed effect was similar in the 3 groups (20 to 27 days). CONCLUSION: In patients with asthma, the onset of significant benefit of FP on PEF, symptoms, and rescue albuterol use occurred within 1 day of the start of therapy. FEV1 improved within 1 week of the start of therapy (the first measurement after randomization). There was no effect of sex, age, or dose of FP on the time to response. The best observed response in PEF varies with the degree of baseline airflow obstruction; however, the degree of airflow obstruction has no effect on the time to best observed response.