Pharmacotherapy and Lung Function Decline in Patients with Chronic Obstructive Pulmonary Disease. A Systematic Review.

Rationale: Whether pharmacological therapy alters decline in FEV1 in chronic obstructive pulmonary disease remains controversial. Because pharmacotherapy improves health status, exacerbation rate, and symptoms, it may be unethical to complete placebo-controlled long-term studies aimed at modifying FEV1 decline.Objectives: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline.Methods: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation.Measurements and Main Results: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in nine studies). The active treatment arms demonstrated a 5.0 ml/yr reduction (95% confidence interval, 0.8-9.1 ml/yr; P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of differences reported for health status and for the exacerbation rate in the same studies.Conclusions: In chronic obstructive pulmonary disease, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

Risk factors for exacerbations and pneumonia in patients with chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear. METHODS: This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo. Backward elimination via Cox's proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation. RESULTS: Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216. Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk. BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI <25 kg/m2. The modelled probability of pneumonia varied between 3 and 12% during the first year. Higher exacerbation risk was associated with a history of exacerbations, poorer lung function (GOLD stage), female sex and absence of ICS treatment. The influence of the other exacerbation risk factors was not modified by ICS treatment. Modelled probabilities of an exacerbation varied between 31 and 82% during the first year. CONCLUSIONS: The probability of an exacerbation was considerably higher than for pneumonia. ICS reduced exacerbations but did not influence the effect of risks associated with prior exacerbation history, GOLD stage, or female sex. The only identified risk factor for ICS-induced pneumonia was BMI <25 kg/m2. Analyses of this type may help the development of COPD risk equations.

Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A Post Hoc Cohort Analysis from the SUMMIT Randomized Clinical Trial.

RATIONALE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk. OBJECTIVES: Determine whether AECOPD events are associated with increased risk of subsequent CVD. METHODS: We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD. MEASUREMENTS AND MAIN RESULTS: Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7-5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6-14.9). CONCLUSIONS: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).

Missing data sensitivity analysis for recurrent event data using controlled imputation.

Statistical analyses of recurrent event data have typically been based on the missing at random assumption. One implication of this is that, if data are collected only when patients are on their randomized treatment, the resulting de jure estimator of treatment effect corresponds to the situation in which the patients adhere to this regime throughout the study. For confirmatory analysis of clinical trials, sensitivity analyses are required to investigate alternative de facto estimands that depart from this assumption. Recent publications have described the use of multiple imputation methods based on pattern mixture models for continuous outcomes, where imputation for the missing data for one treatment arm (e.g. the active arm) is based on the statistical behaviour of outcomes in another arm (e.g. the placebo arm). This has been referred to as controlled imputation or reference-based imputation. In this paper, we use the negative multinomial distribution to apply this approach to analyses of recurrent events and other similar outcomes. The methods are illustrated by a trial in severe asthma where the primary endpoint was rate of exacerbations and the primary analysis was based on the negative binomial model.

Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The p38 MAPK pathway seems to be involved in pathogenesis of chronic obstructive pulmonary disease (COPD). Losmapimod is a potent and selective inhibitor of p38 MAPK. We assessed the effect of losmapimod on exercise tolerance in patients with COPD. METHODS: We did this randomised, parallel-group, placebo-controlled trial at 46 secondary care centres in Argentina, Czech Republic, Estonia, Germany, Norway, South Korea, Ukraine, and USA between Nov 4, 2010, and Dec 22, 2011. We enrolled patients aged 40 years or older with moderate-to-severe COPD (6 min walking distance <350 m) who were current or previous smokers. Patients were randomly assigned (1:1:1:1) by a computer generated sequence to one of losmapimod 2·5 mg, 7·5 mg, or 15 mg, or placebo, twice daily for 24 weeks. Randomisation was stratified by country and exacerbation history (block size eight). Patients and investigators were masked to treatment assignment. The primary outcome was change in 6 min walking distance between baseline and week 24, assessed in the intention-to-treat population. This study is registered with ClinicalTrial.gov, number NCT01218126. FINDINGS: We screened 886 patients, of whom 602 were enrolled and received treatment. The difference between the placebo group and the losmapimod groups for mean change of 6 min walk distance was not significant: -6·7 m (95% CI -18·2 to 4·9) for losmapimod 2·5 mg, -4·7 m (-16·1 to 6·8) for losmapimod 7·5 mg, and -3·4 m (-15·1 to 8·2) for losmapimod 15 mg. The safety profile was much the same in each group, although drug-related adverse events were more common with losmapimod 7·5 mg (n=19, 13%) and losmapimod 15 mg (n=20, 13%) than with placebo (n=11, 7%) and losmapimod 2·5 mg (n=13, 9%). The most common serious adverse events were COPD exacerbation resulting in admission to hospital (eight patients [5%] taking placebo, six [4%] taking losmapimod 2·5 mg, two [1%] taking losmapimod 7·5 mg, and three [2%] taking losmapimod 15 mg) and pneumonia (four [3%] vs 0 [0%] vs 1 [1%] vs 4 [3%]). INTERPRETATION: Losmapimod did not cause an improvement in exercise tolerance or lung function, despite being well-tolerated in this COPD population. FUNDING: GlaxoSmithKline.

Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma.

RATIONALE: Measurement of sputum or blood eosinophils may allow identification of a severe eosinophilic asthma population responsive to mepolizumab. OBJECTIVES: The primary objective was assessment of a single blood eosinophil measurement to predict future eosinophil measurements in the following year versus using multiple blood eosinophil measurements. In addition, we examined whether a single sputum or blood eosinophil measurement was a useful biomarker for predicting treatment response to mepolizumab. METHODS: Based on data from placebo subjects (n = 155), we determined whether a blood eosinophil count of 150/µl or greater at screening remained on average above this level during the following year. The rate of exacerbation reduction in the sputum substudy population based on the screening blood eosinophil count and sputum eosinophils was evaluated. MEASUREMENTS AND MAIN RESULTS: Of 115 patients with eosinophils 150/µl or greater at screening, 98 (85%) remained above this level in their post-screening average. Using the average of two, three or four measurements 150/µl or greater, 97 (85%), 103 (90%), and 105 (92%) have postscreening averages above 150/µl. Mepolizumab reduced exacerbations by 69% (95% confidence interval [CI] = 41-83%) in subjects with baseline sputum eosinophils of 3% or greater compared with 66% (95% CI = 7-87%) in subjects with baseline sputum eosinophils under 3%. The reduction was 72% (95% CI = 41-83%) in subjects with blood eosinophils of 150/µl or greater compared with 30% (95% CI = -134 to 79%) in subjects with blood eosinophils under 150/µl. CONCLUSIONS: A single measurement of 150/µl or greater predicted the average of subsequent measurements being 150/µl or greater in 85% of this population. Using an average of multiple measurements only marginally increases the sensitivity. Sputum eosinophils did not predict treatment response with mepolizumab.