Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis.

BACKGROUND: Inhaled corticosteroids (ICS) are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA) or doubling the dose of ICS. OBJECTIVES: To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD)-ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov, and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022. SELECTION CRITERIA: We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD)-ICS, ICS/LAMA, or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe). MAIN RESULTS: We included 38,276 participants from 35 studies (median duration 24 weeks (range 12 to 78); mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 litres and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio (HR) 0.70, 95% credible interval (CrI) 0.59 to 0.82; moderate certainty; HR 0.59, 95% CrI 0.46 to 0.76; moderate certainty; and HR 0.56, 95% CrI 0.38 to 0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70 to 1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio (OR) 1.47, 95% CrI 1.23 to 1.76; high certainty; and OR 1.59, 95% CrI 1.31 to 1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22 to 2.13; moderate certainty and OR 1.55, 95% CrI 1.20 to 2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11 to 1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or qualify of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.77 to 0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26 to 0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity. AUTHORS' CONCLUSIONS: The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA, or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than medium-dose ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was six months.

A case of acute non-typeable Hemophilus influenza infective endocarditis in a patient with hypocomplementemia.

Hemophilus influenzae is a gram-negative bacteria responsible for significant cases of invasive infections, especially in the pediatric population and in immunosuppressed adult patients. Before vaccination, most cases were frequently caused by capsulated or typeable variants. Due to the absence of effective vaccination against the nontypeable variant, it is now responsible for most invasive infections. Predisposing risk factors in adults include asplenia, hypocomplementemia, cancer, human immunodeficiency virus infection, and chronic cardiopulmonary disease. Immunity to the nontypeable variants causing disease is perplexing and not yet wholly described as they are genetically diverse. Infective endocarditis (IE) is a cardiac infection with devastating consequences if not detected earlier and treated appropriately. Gram-positive bacteria are the primary cause of IE overall, followed by gram-negative bacteria. Hemophilus species belong to the HACEK group of gram-negative bacteria responsible for causing IE in the pediatric population more than in adults. Hemophilus species, especially the nontypeable variant, is a rare cause of IE in adults. Here we present a case of IE due to Nontypeable Hemophilus influenzae in a 49-year-old caucasian male with hypocomplementemia.

Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis.

BACKGROUND: Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy. OBJECTIVES: To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma. SEARCH METHODS: We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022. SELECTION CRITERIA: We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to the previously published protocol. We used Cochrane's Screen4ME workflow to assess search results and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome was steroid-requiring asthma exacerbations and asthma-related hospitalisations (moderate to severe and severe exacerbations). MAIN RESULTS: We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without. High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty). The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA. AUTHORS' CONCLUSIONS: Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs. High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD- ICS remains to be demonstrated given the median duration of included studies was six months. The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.

Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis.

BACKGROUND: Long-acting bronchodilators such as long-acting ß-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class. OBJECTIVES: To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA). SEARCH METHODS: We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers' websites. The most recent searches were conducted on 6 April 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups. DATA COLLECTION AND ANALYSIS: We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta-analyses. MAIN RESULTS: We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good.The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations.There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively).There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies.The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events.None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population. AUTHORS' CONCLUSIONS: The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia.Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines.

Long-acting Muscarinic Antagonist Versus Inhaled Corticosteroid when Added to Long-acting ß-agonist for COPD: A Meta-analysis.

The purpose of this study was to systematically review the efficacy and safety of long-acting ß-agonist/long-acting muscarinic antagonist (LABA/LAMA) and LABA/inhaled corticosteroid (ICS) combinations in patients with advanced chronic obstructive pulmonary disease (COPD). Randomized clinical trials of at least 12 weeks of duration comparing LABA/LAMA and LABA/ICS combinations were included. We chose forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) score, Transitional Dyspnea Index (TDI), COPD Assessment Test (CAT) score, COPD exacerbations, mortality, and other safety parameters as outcome assessment criteria. We included six randomized controlled trials with a total of 4,319 patients. Most patients did not have a history of exacerbation. LABA/LAMA was associated with greater improvement in FEV1 than LABA/ICS (mean difference (MD) 0.09L, 95%confidence interval (CI) 0.07 to 0.11L; high certainty). Two treatments appeared clinically equivalent in improving SGRQ (MD -0.12, 95%CI -1.16 to 0.92; high certainty), TDI (MD 0.15, 95%CI -0.05 to 0.35; high certainty), and CAT scores (MD 0.28 95%CI -0.29 to 0.85; moderate certainty). LABA/LAMA was associated with an absolute reduction of approximately 8% in the incidence of pneumonia compared with LABA/ICS (risk ratio 0.41, 95%CI 0.18 to 0.94; moderate certainty). There was no significant difference in safety and exacerbation outcomes. However, equivalence of two treatments could not be concluded due to imprecision especially for mortality, cardiac serious adverse events, and severe exacerbations. Our findings support the use of dual long-acting bronchodilators for patients with advanced COPD but without frequent exacerbations given the excess risk of pneumonia with LABA/ICS.

Efficacy and safety of long-acting ß-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis.

BACKGROUND: The place of long-acting ß agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations in stable patients with COPD is not well defined. The purpose of this study was to systematically review the efficacy and safety of LABA/LAMA combinations. METHODS: Several databases and manufacturers' websites were searched for relevant clinical trials. Randomised control trials, at least 12 weeks duration, comparing a LABA/LAMA combination with placebo and/or monotherapy were included. The data were pooled using a network as well as a traditional direct comparison meta-analysis. RESULTS: Twenty-three trials with a total of 27 172 patients were included in the analysis. LABA/LAMA combinations were associated with a greater improvement in lung function, St. George's Respiratory Questionnaire (SGRQ) score, and Transitional Dyspnoea Index (TDI) than monotherapies. LABA/LAMA combinations were associated with a significantly greater proportion of SGRQ and TDI responders than monotherapies (OR 1.23 (95% credible interval (CrI) 1.06-1.39), OR 1.34 (95% CrI 1.19-1.50) versus LABAs and OR 1.24 (95% CrI 1.11-1.36), OR 1.31 (95% CrI 1.18-1.46) versus LAMAs, respectively) and fewer moderate-to-severe exacerbations compared with LABAs (HR 0.82 (95% CrI 0.73-0.93)), but not when compared with LAMAs (HR 0.92 (95% CrI 0.84-1.00)). There were no statistically significant differences associated with LABA/LAMA combinations compared with monotherapies in safety outcomes as well as in severe exacerbations. CONCLUSIONS: The combination therapy was the most effective strategy in improving lung function, quality of life, symptom scores and moderate-to-severe exacerbation rates, and had similar effects on safety outcomes and severe exacerbations as compared with monotherapies.

Comparative efficacy of long-acting muscarinic antagonists in preventing COPD exacerbations: a network meta-analysis and meta-regression.

BACKGROUND: We hypothesized a class effect of currently available long-acting muscarinic antagonists (LAMAs; i.e., tiotropium as a dry powder inhaler or a soft mist inhaler, aclidinium bromide, and glycopyrronium) in preventing chronic obstructive pulmonary disease (COPD) exacerbations. The hypothesis was tested with a network meta-analysis. METHODS: Several databases and manufacturer's websites were searched for relevant clinical trials. Randomized, controlled trials, of at least 12 weeks duration, comparing a LAMA with placebo or another LAMA were included. Moderate-to-severe and severe exacerbations were chosen as the outcome assessment criteria. The data were pooled using network meta-analysis. RESULTS: A total of 27 studies with 48,140 subjects were included. All LAMAs reduced moderate-to-severe exacerbations compared with placebo. However, there were no statistically significant differences in preventing moderate-to-severe or severe exacerbations among LABAs. In a subgroup analysis restricting studies to those that had a minimum of 6 months of treatment, glycopyrronium was associated with the least-effective strategy and aclidinium was associated with the greatest probability of being the best therapy in preventing severe exacerbations. Our meta-regression analysis suggested that the prevention of COPD exacerbations were less effective in studies which allowed concomitant use of a long-acting beta agonist (LABA). CONCLUSION: All LAMAs were equally effective in preventing moderate-to-severe exacerbations. Aclidinium was associated with the lowest risk for severe exacerbations when treatment duration was 6 months or longer. The concomitant use of LABA may not enhance the efficacy of LAMAs in preventing COPD exacerbations. More studies are needed to further examine above findings.

Mortality benefit of vasopressor and inotropic agents in septic shock: a Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVE: The choice of vasopressor in septic shock has been a matter of debate. The purpose of this study was to systematically review overall evidence of vasopressor and inotropic agents in septic shock using a Bayesian network meta-analysis. METHODS: Databases, including Medline, Scopus, CINAHL, and Google Scholar were searched to identify relevant studies. Eligible studies were randomized controlled trials that reported mortality rates on the use of vasopressors and inotropes in patients with septic shock. We chose to use 28-day mortality as the outcome assessment criterion. RESULTS: Fourteen studies with a total of 2811 patients were included in the analysis. Norepinephrine (NE) and NE + low-dose vasopressin but not epinephrine (EPI) were associated with significantly reduced mortality compared with dopamine. (Odds ratio, 0.80 [95% credibility interval, 0.65-0.99], 0.69 [0.48-0.98], and 0.56 [0.26-1.18], respectively). The addition of an inotropic agent such as dobutamine or dopexamine did not reduce mortality compared with EPI or NE alone. CONCLUSIONS: Our results support the use of NE with or without low-dose vasopressin as the first-line vasopressor therapy in septic shock. No concrete evidence exists to support the use of EPI over dopamine as the second-line agent or the addition of an inotropic agent.

Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis.

BACKGROUND: A combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations. Currently, there are five ICS/LABA combination products available on the market. The purpose of this study was to systematically review the efficacy of various ICS/LABA combinations with a network meta-analysis. METHODS: Several databases and manufacturer's websites were searched for relevant clinical trials. Randomized control trials, at least 12 weeks duration, comparing an ICS/LABA combination with active control or placebo were included. Moderate and severe exacerbations were chosen as the outcome assessment criteria. The primary analyses were conducted with a Bayesian Markov chain Monte Carlo method. RESULTS: Most of the ICS/LABA combinations reduced moderate-to-severe exacerbations as compared with placebo and LABA, but none of them reduced severe exacerbations. However, many studies excluded patients receiving long-term oxygen therapy. Moderate-dose ICS was as effective as high-dose ICS in reducing exacerbations when combined with LABA. CONCLUSION: ICS/LABA combinations had a class effect with regard to the prevention of COPD exacerbations. Moderate-dose ICS/LABA combination therapy would be sufficient for COPD patients when indicated. The efficacy of ICS/LABA combination therapy appeared modest and had no impact in reducing severe exacerbations. Further studies are needed to evaluate the efficacy of ICS/LABA combination therapy in severely affected COPD patients requiring long-term oxygen therapy.

Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

BACKGROUND: Roflumilast, a phosphodiesterase 4 inhibitor, has been shown to improve lung function and reduce exacerbation rates, but is associated with adverse events (AEs). The purpose of this study was to systematically review the clinical effectiveness and safety of roflumilast. METHODS: A systematic search was made of MEDLINE, Cochrane trials database, DARE and CINAHL. Randomized, controlled trials of more than 12 weeks' duration comparing roflumilast with placebo were reviewed. Studies were pooled to yield relative risk (RR), incident rate difference or weighted mean differences with 95% confidence intervals (CIs). RESULTS: Eight trials (8698 patients) met the inclusion criteria. Roflumilast significantly reduced moderate to severe exacerbations (RR 0.85; 95% CI 0.80-0.91) compared with placebo, but not severe exacerbations (RR 0.83; 95% CI 0.68-1.01) or mortality (RR 0.90; 95% CI 0.63-1.28). Roflumilast significantly improved lung function relative to placebo, but not quality of life measures. AEs (RR 1.11; 95% CI 1.03-1.19) and discontinuations of treatment due to AEs (RR 1.63; 95% CI 1.45-1.84) were significantly more frequent with roflumilast than placebo. In the chronic obstructive pulmonary disease (COPD) Safety Pool (12,054 patients), the overall incidence of serious AEs did not differ between groups. However, atrial fibrillation (0.4% versus 0.2%; p = 0.02) and suicidality (0.08% versus 0%) were more frequent with roflumilast than placebo. CONCLUSIONS: The efficacy of roflumilast appears modest compared with other available therapies for COPD. Further studies are needed to investigate the risk-benefit ratio and long-term safety of roflumilast before its wider use.

The prevalence and diagnostic significance of eosinophilic pleural effusions: a meta-analysis and systematic review.

BACKGROUND: Eosinophilic pleural effusion (EPE) is defined by an eosinophil count of ≥10% in the pleural fluid and often caused by air or blood in the pleural space. The diagnostic significance of EPEs is still a matter of debate. OBJECTIVE: The objective of this study was to systematically review the medical literature to evaluate the diagnostic significance of EPEs. METHODS: Electronic databases were searched from 1950 to April 2010 to perform a meta-analysis. Data were extracted using standardized forms, and pooled odds ratios with 95% confidence intervals were calculated. A logistic regression analysis was also performed to evaluate the association between the pleural eosinophil counts and the likelihood of underlying causes of EPEs. RESULTS: We identified a total of 687 cases of EPE. The most common cause of EPEs was malignancy (26%) followed by idiopathic (25%) and parapneumonic (13%) effusions. The likelihood of malignancy or tuberculosis was somehow lower in EPEs than in non-EPEs, but the differences were not statistically significant. The prevalence of malignancy was significantly lower in the group of patients that required a pathologic confirmation (21 vs. 30%; p = 0.01). The likelihood of malignancy was inversely correlated with the pleural fluid eosinophil counts. The likelihood of idiopathic effusion was significantly higher in EPEs than in non-EPEs. CONCLUSIONS: Malignancy was the most common cause of EPEs. EPEs appeared to be a negative predictor of malignancy when a pleural fluid eosinophil count was extremely high. EPEs were more likely to be idiopathic as compared with non-EPEs.

Abandoning daily routine chest radiography in the intensive care unit: meta-analysis.

PURPOSE: To systematically examine whether abandoning daily routine chest radiography would adversely affect outcomes, such as mortality and length of stay (LOS), and identify a subgroup in which daily routine chest radiography might be beneficial. MATERIALS AND METHODS: This was a meta-analysis of clinical trials that examined the effect of abandoning daily routine chest radiography in adults in intensive care units (ICUs). Studies were identified through searches of MEDLINE, Cochrane Database, Database of Abstracts of Reviews of Effects, Biological Abstracts, and CINAHL. The results were expressed as odds ratios (ORs) or weighted mean difference (WMD) along with their 95% confidence intervals (CIs). RESULTS: Eight studies with a total of 7078 patients were identified. A pooled analysis revealed that the elimination of daily routine chest radiography did not affect either hospital or ICU mortality (OR, 1.02;[95% CI: 0.89, 1.17; P = .78 and OR, 0.92; 95% CI: 0.76, 1.11; P = .4, respectively). There was no significant difference in ICU LOS (WMD = 0.19 days; 95% CI: -0.13, 0.51; P = .25), hospital LOS (WMD = -0.29 days; 95% CI: -0.71, 0.13; P = .18), and ventilator days (WMD = 0.33 days; 95% CI: -0.12, 0.78; P = .15) between the on-demand and daily routine groups. Regression analyses failed to identify any subgroup in which performing daily routine chest radiography was beneficial. CONCLUSION: Systematic but unselective daily routine chest radiography can likely be eliminated without increasing adverse outcomes in adult patients in ICUs. Further studies are necessary to identify the specific patient population that would benefit from daily routine chest radiographs.

Cost-effectiveness of salmeterol, fluticasone, and combination therapy for COPD.

OBJECTIVE: To assess the incremental cost-effectiveness of inhaled medication use in chronic obstructive pulmonary disease (COPD). STUDY DESIGN: A Markov model was constructed to estimate the incremental quality-adjusted life-years (QALYs) gained of the alternative treatment arms used in the Towards a Revolution in COPD Health (TORCH) study (ie, salmeterol-fluticasone propionate combination [SFC], salmeterol, fluticasone, and placebo). METHODS: The cycle length for the model was set to 3 months, and the maximum time horizon was set to 3 years. The cost-effective analysis was conducted from a third-party payer's perspective in the US healthcare system. Future costs and effects were discounted at 3%. Multiple 1-way sensitivity analyses and a probabilistic sensitivity analysis using Monte Carlo simulation were performed to handle uncertainty. RESULTS: The most cost-effective strategies are placebo (as-needed short-acting bronchodilator use with no maintenance therapy) when willingness to pay (WTP) is less than $52,800/QALY gained and SFC when WTP exceeds that threshold. When no maintenance therapy is not an acceptable option, the most cost-effective strategies are treatment with salmeterol when WTP is less than $49,500/QALY gained and treatment with SFC when WTP exceeds that threshold. The base-case analysis showed that incremental cost-effectiveness ratios of salmeterol, fluticasone, and SFC relative to placebo were $56,519, $62,833, and $52,046/QALY gained, respectively. CONCLUSIONS: The most cost-effective strategy in moderate-to-severe COPD depends on how much society is willing to pay to achieve health improvements. When treatment with as-needed short-acting bronchodilator use does not provide adequate control, salmeterol or SFC would be the drug of choice depending on WTP.

Cost-effectiveness of long-term oxygen therapy for chronic obstructive disease.

OBJECTIVES: To assess the cost-effectiveness of long-term oxygen therapy to facilitate proper resource allocation. STUDY DESIGN: Markov process. METHODS: A Markov model was developed to estimate the incremental cost-effectiveness ratios (ICERs) for continuous and nocturnal oxygen therapies. The maximum time horizon was set to 5 years. Efficacy variables were obtained from pertinent clinical studies. Cost variables were based on the current Medicare reimbursement rate and on appropriate sources. Multiple 1-way and probabilistic sensitivity analyses were performed to examine the robustness of base-case results. RESULTS: The ICER for continuous oxygen therapy ($16,124 per quality-adjusted life-year [QALY]) was within bounds considered to be cost-effective, while that of nocturnal oxygen therapy was not ($306,356/QALY). The estimated ICER for continuous oxygen therapy was robust (95% confidence interval, $13,153-$24,658/QALY) and was more favorable than the ICERs for commonly used medical and surgical therapies for chronic obstructive pulmonary disease. The ICER for nocturnal oxygen therapy was sensitive to variation in the mortality rate; it could be as low as $18,267/QALY gained. At the other end, nocturnal oxygen therapy could be less effective than no oxygen therapy, despite additional costs. CONCLUSIONS: There is substantial room for improvement in the current Medicare policies regarding long-term oxygen therapy. Medicare coverage can be improved by prescribing long-term oxygen therapy to patients who will receive substantial benefit and by providing adequate support for services and maintenance.

High levels of PEEP may improve survival in acute respiratory distress syndrome: A meta-analysis.

OBJECTIVE: Positive end-expiratory pressure (PEEP) has been viewed as an essential component of mechanical ventilation in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). However, clinical trials have not yet convincingly demonstrated that high PEEP levels improve survival. The object of this study was to test a priori hypotheses that a small but clinically important mortality benefit of high PEEP did exist, especially in patients with greater overall severity of illness and differences in PEEP protocols might have affected the study results. METHODS: Meta-analysis of randomized controlled trials comparing high versus low PEEP in ARDS/ALI. Studies were identified by search of MEDLINE (1950-2008) and other sources. MEASUREMENTS AND MAIN RESULTS: Five studies including 2447 patients were identified. A pooled analysis showed a significant reduction in hospital mortality in favor of high PEEP (RR=0.89; 95% CI, 0.80-0.99; p=0.03). However, significant statistical and clinical heterogeneities such as differences in disease severity and ventilator protocols were found. The differences in PEEP protocols were not associated with differences in mortality rates. A logistic analysis suggested that the beneficial effect of high PEEP was greater in patients with higher ICU severity scores. CONCLUSIONS: The statistical and clinical heterogeneities make proper interpretation of the results difficult. However, a small, but significant mortality benefit of high PEEP may exist. In addition, our analysis suggests the effects of high PEEP are greater in patients with higher ICU severity scores.