To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist.

DESIGN: Observational retrospective pairwise cohort study matched (1:1) for propensity score.

SETTING: Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.
PARTICIPANTS: Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.
MAIN OUTCOME MEASURES: Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.

RESULTS: 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).

CONCLUSIONS: There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.

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Noninvasive ventilation (NIV) is contraindicated or at least not recommended in patients with altered consciousness syndrome (ACS) given to the poor compliance of confused/agitated patients, difficult management of accumulated secretion in depressed cough reflex, and risk of aspirative pneumonia in absence of airways protection.

Conventional mechanical ventilation (CMV) via endotracheal intubation (ETI) has been usually considered as the "golden standard" ventilator treatment in ACS. However, the possibility of avoiding ETI-related life-threatening complications by means of NIV, especially in fragile, older patients with multiple comorbidities, is an appealing option.

The available published data dealing with the use of NIV in ACS were obtained in patients with hypercapnic encephalopathy complicating severe exacerbations of COPD. In this clinical scenario, an initial cautious NIV trial may be attempted as long as there are no other contraindications and the technique is provided by experienced caregivers in a closely monitored setting where ETI is always readily available. The concomitant use of techniques for removing secretion and/or controlled analgo-sedation performed by expert teams may be considered in highly selected cases.

The purpose of this paper is to review rationale, clinical feasibility, advantages and risks correlated with the use of NIV in ACS.

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The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.

OBJECTIVE: The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration-time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.

METHODS: The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0-24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (E max) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM(®).

RESULTS: Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an E max model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C 0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.

CONCLUSION: A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.

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Cardiovascular disease (CVD) is common among patients with chronic obstructive pulmonary disease (COPD). However, it is not clear whether this is due to shared risk factors or if COPD increases the risk for CVD independently.

This study aimed to provide a systematic review of studies that investigated the association between COPD and CVD outcomes, assessing any effect of confounding by common risk factors.

METHODS: A search was conducted in Medline (via PubMed) for observational studies published between January-1990 and March-2012 reporting cardiovascular comorbidity in COPD patients (or vice versa).

RESULTS: Of the 7322 citations identified, 25 studies were found relevant for this systematic review. Twenty-two studies provided an estimate for CVD risk in COPD, whereas four studies provided estimates of COPD risk in CVD. The crude prevalence rate for aggregate CVD category ranged from 28% to 70%, likely due to differences in populations studied and CVD definitions; unadjusted relative risk (RR) estimates of unspecified CVD among patients with COPD compared to patients without COPD ranged from 2.1 to 5.0. The association between COPD and CVD persisted after adjustment for shared risk factors in the majority of the studies. Two studies found a relationship between the severity of airflow limitation and CVD risk. Increased RRs were observed for individual CVD types, but their estimates varied considerably for congestive heart failure, coronary heart disease, arrhythmias, stroke, arterial hypertension, and peripheral arterial disease.

CONCLUSIONS: Available observational data supports the hypothesis that COPD is associated with an increased risk of CVD.

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