Sex differences in mortality and clinical expressions of patients with chronic obstructive pulmonary disease. The TORCH experience.

RATIONALE: There is limited knowledge regarding sex differences and outcomes in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: Determine sex differences in survival, causes of death, and patient-centered outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study. METHODS: A total of 1,481 women and 4,631 men with COPD were enrolled in TORCH, a trial comparing salmeterol, 50 µg, plus fluticasone propionate, 500 µg, twice a day and each component individually. Causes of death were determined by an endpoint committee. Sex differences in survival were explored using a Cox proportional hazards model adjusted for other baseline factors. Exacerbation rate was compared using a negative binomial model. Dyspnea was evaluated using the Medical Research Council scale and health status using the St. George's Respiratory Questionnaire. MEASUREMENTS AND MAIN RESULTS: At baseline, women were younger (63 vs. 66 yr), had higher FEV(1) (47% vs. 44% predicted), and worse St. George's Respiratory Questionnaire (51.3 vs. 48.7) and Medical Research Council score. During the study, 707 (15.3%) men and 168 (11.3%) women died. After adjusting for differences in baseline factors, the risk of dying was 16% higher in men than in women; however, this was not statistically significant (hazard ratio 1.16 [95% CI, 0.98-1.39]). Causes of death were similar in women and men. Exacerbation rate was 25% higher in women than in men. CONCLUSIONS: Women enrolled in TORCH had a lower mortality rate than men but similar causes of death. The risk of dying was similar in women and men after adjusting for important baseline variables. Women reported more exacerbations, and worse dyspnea and health status scores than men. Clinical trial registered with www.clinicaltrials.gov (NCT00268216).

Reported pneumonia in patients with COPD: findings from the INSPIRE study.

BACKGROUND: Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids (ICSs). Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD. We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study. METHODS: This was a 2-year, double-blind, double-dummy parallel study of 1,323 patients randomized to salmeterol/fluticasone propionate 50/500 µg bid (SFC) or tiotropium 18 µg once daily (Tio). Baseline demographics, including serum C-reactive protein (CRP) levels, were measured, and daily record cards (DRCs) were completed. RESULTS: We identified 87 pneumonia reports from adverse event records (SFC=62; Tio=25) in 74 patients (SFC=50; Tio=24), compared with 2,255 exacerbations (SFC=1,185; Tio=1,070). Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level>10 mg/L. Numbers of de novo pneumonias (events that were not preceded by symptoms of an exacerbation) were similar between treatment groups, but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs (SFC=32; Tio=7). Similar results were seen when analysis was confined to radiologically confirmed events. CONCLUSIONS: Pneumonia is much less frequent than exacerbation in COPD. The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations. Earlier identification and treatment of these events to prevent pneumonia merits further investigation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00361959; Study No.: SC040036; URL: clinicaltrials.gov.

Cardiovascular events in patients with COPD: TORCH study results.

BACKGROUND: Previous studies have suggested that long-term use of beta agonists to treat chronic obstructive pulmonary disease (COPD) may increase the risk of cardiovascular adverse events. In this post hoc analysis, data from the TOwards a Revolution in COPD Health (TORCH) study were used to investigate whether use of the long-acting beta(2) agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD. METHODS: TORCH was a randomised, double-blind, placebo controlled study conducted at 444 centres in 42 countries. Patients (n=6184; safety population) received twice daily combined salmeterol 50 microg plus fluticasone propionate 500 microg (SFC), either component alone, or placebo. Adverse events were recorded every 12 weeks for 3 years. RESULTS: The probability of having a cardiovascular adverse event by 3 years was 24.2% for placebo, 22.7% for salmeterol, 24.3% for fluticasone propionate and 20.8% for SFC. Although a history of myocardial infarction doubled the probability of cardiovascular adverse events, the event rates remained similar across treatment groups. CONCLUSION: Post hoc analysis of the 3-year TORCH dataset showed that salmeterol alone or in combination (SFC) did not increase the risk of cardiovascular events in patients with moderate to severe COPD.

Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study.

BACKGROUND: The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease. METHODS: TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV1, 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: >or= 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937). RESULTS: Compared with placebo, SFC improved post-bronchodilator FEV1: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages. CONCLUSION: In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV1 across GOLD stages. Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease. The effects were similar to those reported for the study as a whole. Thus, SFC is an effective treatment option for patients with GOLD stage II COPD. TRIAL REGISTRATION: Clinicaltrial.gov registration NCT00268216; Study number: SCO30003.

Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study.

BACKGROUND: Osteoporosis is common in patients with COPD, but its prevalence and progression are not well characterized. Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids (ICSs) on bone density in this population. Here, we investigated the long-term effects of therapy with fluticasone propionate (FP) alone, salmeterol (SAL) alone, and a SAL/FP combination (SFC) on bone mineral density (BMD) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health (TORCH) study. METHODS: A randomized, double-blind, parallel-group, placebo-controlled study conducted at 88 US centers involving 658 patients (a subset of 6,184 international subjects in TORCH). Therapy with placebo, SAL (50 microg), FP (500 microg), or SFC (SAL 50 microg/FP 500 microg) twice daily was administered for 3 years. Baseline and yearly measurements of BMD at the hip and lumbar spine were performed. The incidence of traumatic and nontraumatic bone fractures was recorded. RESULTS: At baseline, 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia based on BMD assessments. Forty-three percent of subjects completed all testing. The changes in BMD at the hip and lumbar spine over 3 years were small. No significant differences were observed between treatment arms (adjusted mean percent change from baseline at hip was -3.1% for placebo, -1.7% for SAL, -2.9% for FP, and -3.2% for SFC therapy, respectively; while, the corresponding changes for the lumbar spine were 0, 1.5%, -0.3%, and -0.3% for placebo, respectively, SAL, FP, and SFC therapy). The incidence of fractures was low and was similar for all treatments (5.1% to 6.3%). CONCLUSIONS: Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. In the TORCH study, no significant effect on BMD was detected for ICS therapy compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NTC00268216.