Changes in lung function and health status in patients with COPD treated with tiotropium or salmeterol plus fluticasone

Background and objective: The effects of tiotropium, a long‐acting anticholinergic drug, were compared with those of the combination of salmeterol, a long‐acting β₂‐agonist, and fluticasone, an inhaled corticosteroid, in patients with COPD. Methods: A 4‐month, randomized, open cross‐over study of tiotropium, 18 µg once daily, versus salmeterol, 50 µg, plus fluticasone, 200 µg, twice daily, was conducted in patients with COPD. Efficacy was assessed by spirometry and responses to the St George's Respiratory Questionnaire (SGRQ). After 4 months, patients were asked to select their subsequent therapy and indicate the reasons for their selection. Results: A total of 78 patients completed the study. There were no significant differences in the improvements in FEV₁ or SGRQ scores between the therapies. Similar numbers of patients selected tiotropium (42.3%) and salmeterol plus fluticasone (57.7%). However, those who preferred one of the therapies demonstrated greater improvements in SGRQ scores with that therapy. One subgroup of patients (30.8%) showed greater improvements in dyspnoea and FEV₁ in response to tiotropium, and the other subgroup of patients (35.9%) showed greater improvements in dyspnoea and FEV₁ in response to salmeterol plus fluticasone. Some patients (14.1%) selected salmeterol plus fluticasone because of positive effects on sputum expectoration. Conclusions: The study was unblinded and the results need to be interpreted with caution. However, tiotropium and salmeterol plus fluticasone had similar overall effects on pulmonary function and SGRQ scores in patients with COPD. Responses to the two therapies were heterogeneous, and the patients who showed greater improvements in FEV₁ or SGRQ scores with one of the therapies preferred it for their subsequent treatment.     

Relationship between polymorphisms in the 5' leader cistron, positions 16 and 27 of the adrenergic β2 receptor gene and asthma in a Han population from southwest China

Background and objective: Adrenergic β2 receptors (ADRB2) play an important role in regulating pulmonary function. Many previous studies have investigated possible associations between polymorphisms in the ADRB2 gene and asthma, but have yielded conflicting results. Furthermore, little is known regarding the possible role of the Arg19Cys polymorphism in susceptibility to asthma among Chinese. Methods: This case–control association study involved 238 patients with asthma and 265 healthy subjects from a Han population in southwest China. For all subjects, the 5′ leader cistron Arg19Cys, Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene were characterized by direct sequencing. Genotype, allele and haplotype frequencies were determined. In addition, to evaluate the association between the ADRB2 polymorphisms and lung function, bronchodilator response to inhaled β2 agonists (400 µg of albuterol) was assessed in the asthmatic patients. Results: There were no significant differences in genotype or allele frequencies for the three ADRB2 polymorphisms between the two cohorts. The Arg19/Arg16/Gln27 haplotype was more frequent among asthmatic patients than control subjects (odds ratio 2.24, 95% confidence interval (CI): 1.05–4.73, P = 0.04). Moreover, the Arg19/Cys19 genotype was associated with a lower FEV₁% (mean difference ?4.5, 95% CI: ?12.5 to 3.6, P = 0.02) and FEV₁/FVC (mean difference 8.9, 95% CI: 8.5–9.4, P = 0.01). The bronchodilator response to albuterol was also marginally lower in individuals who were homozygous for the Arg19 genotype (mean difference 4.2, 95% CI: 3.7–4.8, P = 0.03). Conclusions: The Arg19/Cys19 genotype was an independent risk factor for lower FEV₁% and FEV₁/FVC. Asthmatic patients with the Arg19/Arg19 genotype showed decreased responsiveness to albuterol. Furthermore, the Arg19/Arg16/Gln27 haplotype may contribute to increased susceptibility to asthma in the Chinese population.     

The efficacy and safety of tiotropium in Chinese patients with stable chronic obstructive pulmonary disease: A meta-analysis

Background and objective: Tiotropium is the only long‐acting inhaled anticholinergic bronchodilator currently available in China, but information about its clinical effect in this population is limited. This meta‐analysis assessed the efficacy and safety of tiotropium in Chinese patients with stable COPD. Methods: An electronic search of the literature was undertaken to identify randomized controlled trials (RCTs) of tiotropium in Chinese patients, which were then assessed for inclusion in a meta‐analysis. The efficacy and safety of tiotropium was compared with placebo and ipratropium, using the outcomes of FEV₁, FEV₁%, symptoms, frequency of exacerbations, adverse events and safety. Results: Eleven RCTs recruiting 1006 patients were included in the meta‐analysis. Compared with both placebo and ipratropium, tiotropium significantly improved FEV₁[weighted mean difference (WMD) = 304 mL, 95% CI 271–337], FEV₁% (WMD = 8.35%, 95% CI 5.40–11.31) and symptoms [relative risk (RR) = 2.00, 95% CI 1.61–2.49]. Tiotropium significantly reduced the risk of exacerbations (RR = 0.07, 95% CI 0.01–0.54) compared with placebo, and there was a non‐significant reduction in the risk of exacerbations compared with ipratropium (RR = 0.70, 95% CI 0.13–3.75). Tiotropium was well tolerated with a similar safety profile to placebo and ipratropium (RR = 1.16, 95% CI 0.76–1.77, P = 0.49). Conclusions: Tiotropium improved pulmonary function and symptoms, reduced exacerbations and was well tolerated and safe. On the basis of its efficacy and safety profile, tiotropium appears to be a reasonable first‐line choice for the management of Chinese patients with stable COPD. Additional long‐term RCTs are required to further evaluate the efficacy and safety of tiotropium.     

Polymorphism of the ADRB2 Gene and Response to Inhaled Beta- agonists in Children with Asthma: A Meta-analysis

Background. About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the β₂-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the β₂-adrenergic receptor (β₂AR), induce resistance to the smooth-muscle relaxing effect of β₂-adrenergic agonists. Methods. We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled β₂-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as ≥ 15% improvement in forced expiratory volume in 1 second (FEV₁) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the β₂AR. Individual and summary odds ratios were calculated using a random effects model. Results. We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative β₂-bronchodilator response, defined as < 15% improvement in FEV₁ and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled β₂-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the β₂AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the β₂AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to β₂-agonists and polymorphism at amino acid position 27 of the β₂AR (OR = 1.04; 95% CI [0.76,1.42]). Conclusions. Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the β₂-adrenergic receptor. Genetic typing for β₂AR polymorphism may help identify children with drug-resistant asthma.     

Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4‐year COPD trial. Methods: Subgroup analysis from a randomized, double‐blinded, placebo‐controlled trial of tiotropium 18 µg daily in COPD. Primary end‐point was rate of decline in FEV₁. Secondary end‐points included spirometry at individual time points, health‐related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m²; post‐bronchodilator FEV₁: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV₁ although annual decline was less in Asian patients. Morning pre‐bronchodilator FEV₁ and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57–0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62–1.05) and 0.85 (0.61–1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5–6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. Conclusions: In COPD patients from Asia, tiotropium improves lung function, improves health‐related quality of life and reduces exacerbations over 4 years of treatment.     

Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity

BackgroundGuidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.MethodsA post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.ResultsThe analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.ConclusionsIn patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.     

Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease

Background and objective: Although salmeterol/fluticasone propionate combination (SFC) therapy has been widely used for the treatment of COPD, the relationship between airway dimensions and improvement in pulmonary function remains unknown. The aim of this study was to compare the effects of SFC in combination with tiotropium (Tio) and Tio alone, on airway dimensions and pulmonary function in COPD patients. Methods: Thirty COPD patients were randomized to receive inhaled Tio (18 µg once daily) or inhaled SFC (50/250 µg twice daily) plus Tio for 12 weeks. Spirometry and CT were performed, and the St. George's Respiratory Questionnaire (SGRQ) was completed, before and after the trial. Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage wall area (WA%), absolute wall thickness (T)/√BSA, and luminal area (Ai)/BSA at the right apical segmental bronchus, were measured. Results: Treatment with SFC plus Tio significantly decreased WA/BSA (P < 0.05), WA% (P < 0.01) and T/√BSA (P < 0.01), and increased Ai/BSA (P < 0.01), whereas treatment with Tio alone had no effect. The changes in WA/BSA and Ai/BSA were significantly correlated with increases in FEV₁ (r = 0.48, P < 0.05, and r = 0.36, P < 0.05, respectively). There were significant improvements in SGRQ scores after treatment with SFC plus Tio. Conclusions: Airway wall thickening and airway narrowing decreased after treatment with SFC plus Tio, and the changes in airway dimensions were proportional to the improvements in FEV₁. These results suggest that SFC plus Tio is more effective than Tio alone in the management of COPD patients.     

Pulmonary rehabilitation improves exercise capacity and quality of life in underweight patients with chronic obstructive pulmonary disease

Background and objective: An estimated 20–40% of COPD patients are underweight. We sought to confirm the physiological and psychosocial benefits of pulmonary rehabilitation programmes (PRP) in underweight compared with non‐underweight patients with COPD. Methods: Twenty‐two underweight COPD patients with BMI <20 kg/m², and 22 non‐underweight COPD patients, who were matched for FEV₁ and age, were studied. All patients had moderate‐to‐very severe COPD. All patients participated in 12‐week, hospital‐based outpatient PRP consisting of two sessions per week. Baseline and post‐PRP status were evaluated by spirometry, cardiopulmonary exercise testing, ventilatory muscle strength and the St. George's Respiratory Questionnaire (SGRQ). Results: At baseline, the age distribution and airflow obstruction were similar in underweight and non‐underweight patients with COPD. Baseline exercise capacity, inspiratory muscle strength and SGRQ total and symptoms scores were significantly lower in the underweight patients (all P < 0.05). After the PRP, there was significant weight gain in the underweight COPD patients (mean increase 0.8 kg, P = 0.01). There were also significant improvements in peak oxygen uptake, peak workload and the SGRQ total, symptoms, activity and impact scores in both underweight and non‐underweight patients with COPD (all P < 0.05). Conclusions: Underweight patients with COPD have impaired exercise capacity and health‐related quality of life (HRQL). Exercise training with supplemental oxygen may result in significant weight gains and improvements in exercise capacity and HRQL. Exercise training is indicated for underweight patients with COPD.     

Outcomes in COPD patients receiving tiotropium or salmeterol plus treatment with inhaled corticosteroids

Patients with COPD are frequently prescribed inhaled corticosteroids (ICS); however, it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators. Two 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies of tiotropium 18 μg once daily, compared with salmeterol, 50 μg bid, had been conducted in patients with moderate-to-severe COPD. Efficacy was assessed by spirometry, transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), and exacerbations. Data from both studies were combined to form subgroups with regard to concurrent use of ICS. 796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS. Mean age was 64 years, and pre-bronchodilator FEV₁ was 1.06 L (ICS group) and 1.13 L (non-ICS group). Both bronchodilators increased morning mean ± SE pre-dose FEV₁ compared with placebo (ICS groups: tiotropium 110 ± 20 mL, salmeterol 80 ± 20 mL; non-ICS groups: tiotropium 150 ± 30 mL, salmeterol 110 ± 30 mL; p > 0.05 for tiotropium vs salmeterol). Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium. Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function, irrespective of concurrent use of ICS.     

Long‐acting beta2‐agonists versus long‐acting muscarinic antagonists in patients with stable COPD: A systematic review and meta‐analysis of randomized controlled trials

Several long‐acting bronchodilators have been developed and are widely used as first‐line treatment in patients with stable chronic obstructive pulmonary disease (COPD). However, the initial choice of therapy is still uncertain. The aim of this study was to examine the clinical efficacy and safety of long‐acting muscarinic antagonist (LAMA) and long‐acting beta2‐agonist (LABA) in patients with stable COPD. We searched several databases and manufacturers’ websites to identify relevant randomized clinical trials for meta‐analysis. Outcomes of interest were trough forced expiratory volume in 1 s (FEV₁), acute exacerbations, transitional dyspnoea index (TDI) score, St George's Respiratory Questionnaire (SGRQ) score and adverse events. Sixteen trials with a total of 22 872 patients were included in this study. Compared with LABA, LAMA were associated with a greater reduction in acute exacerbations (OR: 0.84, 95% CI: 0.74–0.94, P = 0.003) and fewer adverse events (OR: 0.92, 95% CI: 0.86–0.97, P = 0.005). There were no significant differences in trough FEV₁, TDI and SGRQ scores. In patients with stable COPD, LAMA were associated with a greater reduction in acute exacerbations and fewer adverse effects compared with LABA.     

Scavenger receptor AI/II truncation, lung function and COPD: a large population-based study

Abstract. Thomsen M, Nordestgaard BG, Tybjærg‐Hansen A, Dahl M (Department of Clinical and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital; The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark) Scavenger receptor AI/II truncation, lung function and COPD: a large population‐based study. J Intern Med 2010; 269 : 340–348. Objectives. The scavenger receptor A‐I/II (SRA‐I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA‐I/II gene, Arg293X, truncates the distal collagen‐like domain, which is essential for ligand recognition. We tested whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population. Methods. We genotyped 48 741 individuals from the adult Danish general population for Arg293X, and recorded lung function and spirometry‐defined COPD. Results. Arg293X homozygotes (n = 5) and heterozygotes (n = 587), compared with noncarriers (n = 48 149), had a 6% and 1% reduction in predicted percentage of forced vital capacity (FVC % predicted) (P = 0.05) and a nonsignificant 7% and 1% reduction in predicted percentage of forced expiratory volume in one second (FEV₁% predicted) (P = 0.06), respectively. The Arg293X genotype interacted with gender (P = 0.004) and α₁‐antitrypsin MZ heterozygosity (P = 0.049), but not with superoxide dismutase‐3 E1I1 heterozygosity (P = 0.11) in determining FEV₁% predicted. Amongst men, FEV₁% predicted and FVC % predicted were both reduced by 4% (P = 0.0004 and P = 0.0003, respectively) in Arg293X heterozygotes compared with noncarriers. Corresponding values were 14% (P = 0.03) and 11% (P = 0.04) amongst MZ heterozygotes, and 9% (P = 0.03) and 8% (P = 0.04) amongst E1I1 heterozygotes, compared with noncarriers. Lung function did not differ between Arg293X heterozygotes and noncarriers amongst females or individuals without MZ and E1I1. Arg293X heterozygosity was associated with spirometry‐defined COPD amongst men [odds ratio (95% confidence interval): 1.7 (1.1–2.4)], but not with COPD in the whole cohort or in any other subgroup. Conclusions. SRAI/II Arg293X heterozygotes have reduced lung function and increased COPD risk amongst men. They also have reduced lung function amongst individuals heterozygous for the α₁‐antitrypsin MZ and superoxide dismutase‐3 E1I1 genotypes.     

Cardio‐selective and non‐selective beta‐blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise

Background: Patients with chronic obstructive pulmonary disease (COPD) often have co‐existing cardiovascular disease and may require beta‐blocker treatment. There are limited data on the effects of beta‐blockers on the response to inhaled β₂‐agonists and exercise capacity in patients with COPD. Objective: To determine the effects of different doses of cardio‐selective and non‐selective beta‐blockers on the acute bronchodilator response to beta‐agonists in COPD, and to assess their effects on exercise capacity. Methods: A double‐blind, randomized, three‐way cross‐over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open‐label high‐dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test. Results: Eleven patients with moderate COPD were recruited. Treatments were well‐tolerated although two did not participate in the high‐dose metoprolol phase. The area under the salbutamol–response curve was lower after propranolol compared with placebo (P = 0.0006). The area under the curve also tended to be lower after high‐dose metoprolol (P = 0.076). The per cent recovery of the methacholine‐induced fall was also lower after high‐dose metoprolol (P = 0.0018). Low‐dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta‐blocker treatments (P = 0.046). Conclusion: Non‐selective beta‐blockers and high doses of cardio‐selective beta‐blockers may inhibit the bronchodilator response to β₂‐agonists in patients with COPD. Beta‐blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta‐blocker treatment for cardiovascular disease.     

Association between β‐adrenoceptor gene polymorphisms and relative response to β2‐agonists and anticholinergic drugs in Japanese asthmatic patients

Background and objective: Whether β₂‐adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to β₂‐agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to β₂‐agonists. Methods: The increases in FEV₁ after inhalation of procaterol hydrochloride (ΔFEV₁ procaterol) or oxitropium bromide (ΔFEV₁ oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5′‐flanking regions of ADRB2 were genotyped by direct sequencing and PCR‐restriction fragment length polymorphism assay. Results: The mean age of the participants was 54 years, and 38 (47%) were smokers. Although ΔFEV₁ procaterol and ΔFEV₁ oxitropium adjusted for predicted FEV₁ were not associated with ADRB2 polymorphisms, the ratio of ΔFEV₁ procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that ΔFEV₁ procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). Conclusions: The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to β₂‐agonists even in elderly asthmatic patients and smokers.     

Effects of tiotropium on lung function in severe asthmatics with or without emphysematous changes

The effects of tiotropium, an inhaled long-acting anti-cholinergic agent, on lung function were investigated in obstructed severe asthmatics with and without emphysematous changes despite maximal recommended treatments with high-dose of inhaled glucocorticoids and inhaled long-acting β₂-agonists.We conducted a double-blind, placebo-controlled study of an inhaled single-dose of tiotropium in 18 asthmatics with emphysema and 18 without emphysema in a crossover manner. The primary efficacy outcome was the relative change in forced expiratory volume in 1 s (FEV₁) from baseline to 60 min, and the secondary outcome was a relative change in FEV₁ from baseline to 12 h. Subsequently, the patients were treated with tiotropium inhaled once daily for 12 weeks in an open label manner, and lung function and symptoms were evaluated.At baseline, patients with or without emphysema had a mean FEV₁ of 55.9% before tiotropium and 56.8% before placebo, or 77.4% before tiotropium and 77.6% before placebo of the predicted value and were taking a mean dose of inhaled glucocorticoids of 1444 or 1422 μg/day. Among patients with emphysema, the increase from baseline FEV₁ was 12.6 percentage points higher at 60 min after tiotropium than after placebo. Among patients without emphysema, the increase from baseline FEV₁ was 5.4 percentage points higher at 60 min after tiotropium than after placebo.Tiotropium resulted in improved lung function and symptoms in asthmatics with and without emphysema. These findings suggest that tiotropium will provide a new strategy for the treatment of bronchial asthma and of overlapping asthma and COPD.     

Validation of the St George’s respiratory questionnaire and risks factors affecting the quality of life of Lebanese COPD and asthma patients

Objective: We aimed to validate the Arabic version of the St George’s Respiratory Questionnaire (SGRQ) for use in Lebanese Chronic obstructive pulmonary disease (COPD) and asthma patients and to identify risk factors that might affect the quality of life in these patients. Methods: COPD (n?=?90) and asthma patients (n?=?124) were recruited from the outpatient clinics of the Pulmonology department of a university hospital and a medical center in Beirut. They filled out a standardized questionnaire. The total SGRQ score and the component scores (symptoms, activity and impacts) were calculated. To confirm the SGRQ validity in the Lebanese population, factor analyses were applied for the whole sample, only asthma and only COPD patients, respectively. The associations between the total SGRQ score and FEV₁% predicted, CCQ score and MRC scale were assessed. Multiple linear regression models were used to evaluate the association between the total SGRQ scores and the socio-demographics and the diseases risk factors. Results: COPD patients had a higher SGRQ total and subscales scores compared to asthma patients. A high Cronbach’s alpha was found for the whole sample (0.802), only COPD patients (0.833) and only asthma patients (0.734). A significant negative correlation was found between FEV₁% predicted and the total SGRQ scores. Occupational exposure, BMI and previous waterpipe smoking were among the factors that significantly and positively influenced a higher SGRQ score. Conclusions: The Lebanese version of the SGRQ emerges as a good health-related quality of life evaluative instrument that is reasonable to be used in COPD and asthma patients in Lebanon.     

Additive benefits of tiotropium in COPD patients treated with long-acting beta agonists and corticosteroids

OBJECTIVE AND BACKGROUND: The addition of an alternative class of long-acting bronchodilator is recommended for COPD patients who do not respond satisfactorily to monotherapy. The aim of this study was to investigate the additive benefit of tiotropium in severe COPD and to establish whether the improvement in lung function in these patients can be predicted from their acute bronchodilator response to ipratropium or salbutamol. METHODOLOGY: Forty-six patients with severe COPD treated with inhaled long-acting beta(2) agonists and corticosteroids (LABA/CS) were enrolled. Their prebronchodilator FEV(1) was less than 50% of the predicted value. Tiotropium (18 microg, once daily) was added via a dry-powder inhaler device. After a month of treatment, tiotropium was stopped but their previous medication was continued. Patients were reassessed a month later. Acute bronchodilator response to ipratropium and salbutamol was assessed prior to tiotropium treatment. Pulmonary function and health status were evaluated. RESULTS: Adding tiotropium significantly improved FVC, FEV(1) and inspiratory capacity (IC). The increase in FVC was significantly associated with an increase in IC (r = 0.36, P = 0.019) and a decrease in residual volume (r =-0.56, P < 0.001). Total scores of St. George Respiratory Questionnaire scores were significantly improved after adding tiotropium treatment (P < 0.001). After tiotropium withdrawal, FVC, FEV(1) and IC decreased markedly. Bronchodilator response to ipratropium did not predict the tiotropium-mediated improvement in FEV(1) or FVC. CONCLUSIONS: Adding tiotropium to inhaled LABA/CS can yield clinical benefits in lung function and improved quality of life in COPD patients, as both drugs act through separate yet complementary pathways to maintain airway calibre.     

Bronchodilator efficacy of tiotropium–formoterol via single pressurized meter dose inhaler (pMDI) versus tiotropium alone in COPD

BackgroundBronchodilators form the main stay of treatment for COPD. When symptoms are not adequately controlled with one bronchodilator, addition of another bronchodilator is recommended. We have recently developed a combination of tiotropium and formoterol in a single pressurized metered dose inhaler (pMDI) (Cipla Ltd., India). The aim of this study was to compare the bronchodilator effects of a single dose of 18 mcg of tiotropium versus a single dose of a combination of 18 mcg tiotropium plus 12 mcg formoterol administered via a pMDI in subjects with moderate-to-severe COPD.Study design44 COPD subjects were enrolled in this randomized, double-blind, multi-centre, cross-over study. 18 mcg tiotropium and 18 mcg tiotropium plus 12 mcg formoterol were administered via pressurized metered dose inhalers on two separate days. FEV₁, FVC and Inspiratory capacity (IC) were measured before, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 h after the study drugs were administered.ResultsCompared with tiotropium alone, a combination of tiotropium plus formoterol showed a faster onset of bronchodilator response (p < 0.01 for FEV1 and FVC), a greater mean maximum change in FEV1 (p = 0.01) and FVC (p = 0.008) and greater AUC_0–24h values for FEV₁, FVC and IC. Trough FEV₁ and FVC values were also greater in the combination group.ConclusionA combination of tiotropium plus formoterol administered via a single inhaler produced a superior bronchodilator response than tiotropium alone over a period of 24 h.     

Role of tiotropium in the treatment of COPD

Tiotropium is a potent, long-acting, selective anticholinergic bronchodilator. Treatment with tiotropium produces sustained improvements in lung function, particularly FEV₁ (peak, trough, average, and area under the curve) compared with either placebo or ipratropium in patients with moderate to severe COPD. Preliminary evidence suggests that treatment with tiotropium may slow the rate of decline in FEV₁, but this finding awaits confirmation. Tiotropium reduces lung hyperinflation, with associated improvements in exercise capacity. Tiotropium, compared with either placebo or ipratropium, improves a variety of patient-centered outcomes, including subjective dyspnea ratings and HRQL scores. Tiotropium reduces the frequency of COPD exacerbations and of hospitalizations due to exacerbations, but has not been shown to reduce all-cause mortality. Compared with the long-acting bronchodilators, tiotropium provides incrementally better bronchodilation, but it is not clearly superior in terms of patient-centered outcomes. Tiotropium has a good safety profile; however patients with severe cardiac disease, bladder outlet obstruction, or narrow angle glaucoma were excluded from all studies. Medico economic analyses suggest that treatment with tiotropium may also be cost-effective, primarily by reducing costs associated with hospitalizations.     

Formoterol

Abstract

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours.Statistically significant and clinically relevant (> 120ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV₁) versus time curve (AUC FEV₁)] were observed with inhaled formoterol 12μg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD).The bronchodilator efficacy of formoterol 12μg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40μg four times daily in a 12-week trial. Improvement in AUC FEV₁ with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12μg twice daily plus ipratropium bromide 40μg four times daily was significantly more effective than albuterol (salbutamol) 200μg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial.Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12μg twice daily was similar to that with placebo and inhaled ipratropium bromide 40μg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range.In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.

Pharmacodynamic Properties

Inhaled formoterol is a long-acting selective β₂-adrenoceptor agonist (β₂-agonist); it has a rapid onset of action (5 minutes in single- and multiple-dose studies) and, like salmeterol, maintains a bronchodilator effect for at least 12 hours. The onset of postdose bronchodilator action was faster with formoterol 12μg than with salmeterol 100μg in a double-blind, randomized, placebo-controlled trial.Formoterol 6 to 24μg improved forced expiratory volume in 1 second (FEV₁) compared with baseline and placebo in single-dose crossover trials in patients with chronic obstructive pulmonary disease (COPD), and was at least as effective as salmeterol 50 or 100μg or albuterol (salbutamol) 400μg at improving FEV₁. Mean peak FEV₁ was reached 1 hour after inhalation of formoterol 12μg; values for this parameter were 1 hour after albuterol 200μg, and 2 to 5 hours after salmeterol 50μg.Formoterol 4.5 to 18μg twice daily for 1 week prolonged the time to exhaustion on a bicycle ergometer test compared with placebo; results were similar to those for ipratropium bromide 80μg three times daily.All β₂-agonists have the potential to increase heart rate and plasma glucose concentrations, and to decrease plasma potassium concentrations, through effects on extrapulmonary β₂ receptors. Dose-dependent increases in heart rate, corrected QT (QTc) interval and plasma glucose concentrations, and dose-dependent decreases in plasma potassium concentrations, were observed with inhaled formoterol 24 to 96μg or salmeterol 100 to 400μg in a double-blind, placebo-controlled, crossover trial in 16 healthy volunteers. In patients with COPD, pre-existing mild to moderate cardiac arrhythmias and hypoxemia [PaO₂ (arterial oxygen pressure) <60mm Hg], formoterol 12μg had similar systemic effects to salmeterol 50μg. Complex ventricular arrhythmias were observed in formoterol 12 and 24μg recipients, but not in salmeterol 50μg or placebo recipients.

Pharmacokinetic Properties

The maximum plasma concentration (92 ng/L) of formoterol was reached within 5 minutes of inhalation of a single supraoptimal dose (120μg) in 12 healthy volunteers. Urinary excretion data suggest that absorption was linear with inhaled formoterol 12 to 96μg in ten healthy volunteers. In vitro plasma protein binding of formoterol was 61 to 64% at concentrations 0.1 to 100 μg/L.Mean plasma concentrations of the drug at 10 minutes to 6 hours postinhalation were 4.0 to 8.8 ng/L and 8.0 to 17.3 ng/L, respectively, after multiple doses of formoterol 12 or 24μg administered twice daily for 12 weeks in patients with COPD, with some evidence of accumulation of formoterol in the plasma (accumulation index 1.19 to 1.38).Formoterol is metabolized primarily in the liver by four cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). These enzymes were not inhibited by the drug at therapeutic concentrations. Following inhalation of formoterol 12 or 24μg by 18 patients with COPD, 7% of the total dose was excreted in the urine as unchanged drug and 6 to 9% of the total dose was eliminated as direct conjugates of formoterol. The mean terminal elimination half-life was determined to be 10 hours (based on plasma concentrations) following inhalation of single-dose formoterol 120μg by 12 healthy volunteers.Currently, there are no pharmacokinetic data for the use of formoterol in patients with hepatic or renal impairment or in elderly individuals.

Therapeutic Efficacy

Inhaled formoterol has been evaluated as monotherapy or combination therapy for the management of patients with COPD. In clinical trials, COPD was diagnosed using the American Thoracic Society guidelines.The bronchodilator effect [measured as normalized area under the FEV₁ versus time curve (AUC FEV₁)] with formoterol 12μg twice daily (n = 194) was significantly greater than that with ipratropium bromide 40μg four times daily (n = 194; p = 0.001) or placebo (n = 200; p < 0.001) in a randomized, double-blind, 12-week trial in patients with COPD. Significant improvements were also observed in mean morning premedication peak expiratory flow (PEF; p < 0.001) and health-related quality of life [all three subsections of the St. George’s Respiratory Questionnaire (SGRQ); p ≤ 0.036], and significant reductions were reported for the use of rescue medication (p ≤ 0.014) and the percentage of ‘bad days’ (days with at least two individual symptom scores of ≥2 and/or a reduction in PEF from baseline of >20%; p < 0.001) in formoterol compared with ipratropium bromide recipients. The differences in health-related quality of life between the two treatments were clinically relevant (exceeding 4 points) for the Activity and the Impacts domains of the SGRQ.Compared with oral slow-release theophylline (individualized dosages targeted at plasma concentrations of 8 to 20 mg/L), formoterol 12μg twice daily significantly increased standardized AUC_12h FEV₁ (primary end-point; p = 0.026) and mean morning premedication PEF (p ≤ 0.020) and reduced the percentage of ‘bad days’ (p ≤ 0.035) in a randomized, double-blind (with the exception of the theophylline arm), 12-month trial. A subgroup analysis in this trial indicated that at 3 (p = 0.007) and 12 months (p = 0.002), formoterol (n = 118), but not oral slow-release theophylline (n = 105), produced significant bronchodilation compared with placebo (n = 117) in patients with irreversible or poorly-reversible airflow obstruction (i.e. patients whose FEV₁ values increased <15% after receiving albuterol). Both formoterol (p ≤ 0.026) and oral slow-release theophylline (p ≤ 0.013) were significantly more effective than placebo at managing COPD during the night (measured as morning premedication FEV₁).In these two monotherapy trials, inhaled formoterol 24μg twice daily did not provide any additional benefit over the 12μg twice daily dosage in patients with COPD.The combined efficacy of inhaled formoterol 12μg twice daily plus inhaled ipratropium bromide 40μg four times daily for 3 weeks has been compared with that of albuterol 200μg four times daily for 3 weeks via a pressurized metered-dose inhaler plus inhaled ipratropium bromide 40μg four times daily in a randomized, double-blind, double-dummy, crossover trial in 172 patients with COPD. Formoterol combination therapy was significantly more effective than albuterol combination therapy at increasing mean morning premedication PEF (primary endpoint; p = 0.0003). Combination therapy with formoterol was also more effective according to secondary endpoints, significantly increasing postmedication FEV₁ to 6 hours (p< 0.0001), peak postmedication FEV₁ (p < 0.0001) and AUC FEV₁ (p < 0.0001) and improving symptoms of COPD (measured as mean total symptoms score, p = 0.0042) and the SGRQ symptoms score (p = 0.0408) relative to albuterol combination therapy.

Tolerability

Inhaled formoterol was well tolerated in clinical trials in patients with COPD. The percentage of patients experiencing at least one adverse event with inhaled formoterol 12μg twice daily was similar to that with placebo, inhaled ipratropium bromide 40μg four times daily or oral slow-release theophylline (individualized dosages targeted at plasma concentrations of the drug of 8 to 20 mg/L) in randomized, double-blind, comparative trials of 12 weeks’ and 12 months’ duration. Viral infection, exacerbation of COPD, bronchitis, upper respiratory tract infection, dyspnea and headache were the most commonly reported adverse events (i.e. occurring in >5% of formoterol 12μg twice daily recipients); however, the incidence of these events was not significantly different compared with oral slow-release theophylline or placebo.Drug-related adverse events, serious adverse events and events leading to withdrawal from the study occurred with a similar incidence with inhaled formoterol, placebo or ipratropium bromide. In contrast, drug-related adverse events and withdrawal because of adverse events occurred with a higher incidence in patients receiving oral slow-release theophylline in the 12-month trial.There were no significant differences in the incidence of cardiovascular adverse events with inhaled formoterol (0.5% of patients) compared with inhaled placebo (2.5%) or ipratropium bromide (2.6%) after 12 weeks’ treatment or in the incidence of serious cardiovascular adverse events with inhaled formoterol (2.4% of patients) compared with placebo (0.9%) or oral slow-release theophylline (2.4%) after 12 months’ treatment in patients with COPD and QTc interval values within the normal range; heart rate and rhythm disorders were infrequent. The incidences of QTc interval prolongation (>0.46s), ECG abnormalities or clinically relevant changes in serum potassium or fasting plasma glucose concentrations were similar with inhaled formoterol 12μg twice daily compared with placebo, inhaled ipratropium bromide or oral slow-release theophylline in clinical trials.

Dosage and Administration

Formoterol, inhaled orally using an Aerolizer?1 inhaler, is indicated in the US for the long-term maintenance treatment of bronchoconstriction associated with COPD (including chronic bronchitis and emphysema). The recommended dosage of formoterol in this patient group is 12μg twice daily approximately 12 hours apart; the total daily dose should not exceed 24μg.Formoterol should be used with caution in patients with cardiovascular disorders (especially coronary insufficiency, cardiac arrhythmias or hypertension), convulsive disorders or thyrotoxicosis, or hypersensitivity to sympathomimetic amines. Extreme caution is advised if formoterol is used concomitantly with monoamine oxidase inhibitors, tricyclic antidepressants or drugs that are known to prolong the QTc interval, and caution is recommended with the concomitant use of formoterol and non-potassium-sparing diuretics.