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In patients with severe COPD receiving inhaled glucocorticoids and two classes of long-acting bronchodilators, glucocorticoid withdrawal was noninferior to continuation with respect to exacerbations but was associated with a slight worsening in lung function and symptoms. Exacerbations of chronic obstructive pulmonary disease (COPD) are symptomatically defined, acute events that lead to a change in treatment 1 , 2 and are associated with an accelerated decline in lung function and health status. 3 Treatment with inhaled glucocorticoids reduces the exacerbation rate, especially when the drugs are used in combination with a long-acting β-agonist (LABA). 4 , 5 Consequently, combination therapy with an inhaled glucocorticoid and a LABA is recommended in patients with severe COPD or a history of frequent exacerbations. 2 Long-acting muscarinic antagonists (LAMAs) have also been shown to prevent exacerbations. 6 – 8 However, in patients with severe or very severe COPD and . . .

An important goal in the treatment of COPD is the prevention of exacerbations. In this trial, the investigators found that treatment with tiotropium, as compared with salmeterol, prolonged the time to the first exacerbation of COPD and decreased the number of exacerbations. Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death worldwide. 1 – 3 Exacerbations of COPD indicate instability or worsening of the patient's clinical status and progression of the disease and have been associated with the development of complications, an increased risk of subsequent exacerbations, a worsening of coexisting conditions, reduced health status and physical activity, deterioration of lung function, and an increased risk of death. 4 – 7 The prevention of exacerbations therefore constitutes a major goal of treatment. 1 , 2 Therapy with a long-acting anticholinergic drug or a long-acting β 2 -agonist is recommended as first-line maintenance therapy in . . .

In this trial involving adults with asthma that was poorly controlled by a low-dose inhaled glucocorticoid, the addition of inhaled tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid and was not inferior to the addition of inhaled salmeterol. Many adults with asthma have inadequate control of symptoms when receiving a low-to-medium dose of an inhaled glucocorticoid. 1 , 2 Treatment options include the addition of a leukotriene modifier, 2 the addition of a long-acting beta-agonist (LABA), 2 – 4 or an increased dose of an inhaled glucocorticoid. 2 Current guidelines of the National Asthma Education and Prevention Program favor the last two options. 2 In recent communications, however, the Food and Drug Administration (FDA) 5 and asthma experts 6 , 7 have questioned the safety of LABA therapy and suggested strategies to minimize the use of these drugs. Because of such concerns and the heterogeneity of patients with . . .

This trial involving more than 6000 patients with chronic obstructive pulmonary disease (COPD) compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate; this fell short of the study's prespecified goals. There were improved clinical outcomes among patients treated with the combination regimen. This trial involving more than 6000 patients with COPD compared the effects on all-cause mortality of treatment with an inhaler containing both salmeterol and fluticasone, salmeterol or fluticasone alone, or placebo. After 3 years, the study showed a reduction of 2.6 percentage points in the mortality rate, which fell short of the prespecified goal. Chronic obstructive pulmonary disease (COPD) is a major cause of illness, death, and the use of health care resources globally. 1 – 3 The disease causes approximately 2.75 million deaths annually, and the number is projected to increase. 2 Treatment for COPD is focused on minimizing risk factors, improving symptoms, and preventing exacerbations. 3 With the exception of smoking-cessation programs for patients with early disease, 4 home oxygen treatment for persistent hypoxemia, 5 , 6 and lung-reduction surgery for selected patients with emphysema, 7 no treatment has been shown to reduce mortality. Pulmonary inflammation is prominent in COPD. 8 Antiinflammatory drugs such as inhaled corticosteroids have little or no . . .

Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease (COPD). We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination (salmeterol/fluticasone propionate) 50/500 microg twice daily and the long-acting bronchodilator (tiotropium) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD. A total of 1,323 patients (mean age, 64 yr, post-bronchodilator FEV1, 39% predicted) were randomized in this 2-year, double-blind, double-dummy parallel study. Primary endpoint was health care utilization exacerbation rate. Other endpoints included health status measured by St. George's Respiratory Questionnaire (SGRQ), mortality, adverse events, and study withdrawal. Probability of withdrawing from the study was 29% greater with tiotropium than salmeterol/fluticasone propionate (P = 0.005). The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio, 0.967; 95% confidence interval [CI], 0.836-1.119]; P = 0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium (difference 2.1 units; 95% CI, 0.1-4.0; P = 0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3%) of patients in this group died compared with 38 (6%) in the tiotropium group (P = 0.032). More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (P = 0.008). We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium. More patients failed to complete the study while receiving tiotropium. A small statistically significant beneficial effect was found on health status, with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00361959).

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 μg + fluticasone propionate 500 μg 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.

To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. A 28-week, randomized, double-blind, placebo-controlled, observational study. Study subjects were seen once in the study physician's office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting beta2-agonist use were excluded. Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI. Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo. For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.

For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.

Many children have uncontrolled asthma symptoms when treated with low-dose inhaled corticosteroids (ICS). In this three-way crossover trial, the investigators asked whether doubling the dose of ICS, adding a leukotriene-receptor antagonist to the ICS, or adding a long-acting beta-agonist to the ICS would result in better asthma control. Most children had a best response to the long-acting beta-agonist, but some children had a best response to an increased dose of ICS or a leukotriene-receptor antagonist. In this crossover trial comparing three step-up treatments, most children had a best response to the long-acting beta-agonist, but some children had a best response to an increased dose of inhaled corticosteroids or a leukotriene-receptor antagonist. Uncontrolled asthma occurs in many children who receive treatment with low-dose inhaled corticosteroids. In the Pediatric Asthma Controller Trial (PACT), 1 administration of 100 μg of fluticasone twice daily was the most effective therapy, but uncontrolled asthma occurred in more than 50% of the children, and 39% of the children had at least one asthma exacerbation that was treated with oral corticosteroids during a 48-week period. The few data that are available to guide practitioners about how to treat children whose asthma is poorly controlled while they are receiving low-dose inhaled corticosteroids 2 – 8 are inconsistent. The discrepancies may be related to . . .

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. Objectives In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 μg plus fluticasone propionate 500 μg, either component alone or placebo, on the rate of post-bronchodilator FEV1 decline in patients with moderate or severe COPD. Methods A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. Measurements and Main Results Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV1 was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV1 decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7–25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5–22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV1 declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV1 decline. Conclusions Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV1 in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216).