Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone.

BACKGROUND: The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS: In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS: Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). CONCLUSIONS: Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.

BACKGROUND: Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. METHODS: We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. RESULTS: Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). CONCLUSIONS: In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

Fluticasone propionate/salmeterol 250/50 µg versus salmeterol 50 µg after chronic obstructive pulmonary disease exacerbation.

BACKGROUND: Inhaled long-acting beta2 agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone. METHODS: Patients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 µg or SAL 50 µg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed. RESULTS: There was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV1 change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort. CONCLUSIONS: No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV1 ≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment. TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).

An evaluation of asthma medication utilization for risk evaluation and mitigation strategies (REMS) in the United States: 2005-2011.

PURPOSE: The purpose of this study was to assess drug utilization patterns of fluticasone propionate (FP)/salmeterol (SAL) combination (FSC) and SAL over the 7-year period of 2005-2011 in patients with asthma as part of the Risk Evaluation and Mitigation Strategies (REMS). METHODS: A descriptive, retrospective observational study utilizing national pharmacy data and employer-based claims data to characterize drug utilization patterns. RESULTS: For patients with asthma, the total number of FSC and SAL dispensings and users of FSC and SAL has declined between 2005 and 2011. During this period, FSC and SAL dispensing for asthma decreased 24% and 76%, respectively, with a more pronounced decline between 2010 and 2011 relative to other years. The total number of patients with asthma who were dispensed FSC has decreased by 10% among adults and by 40% in children and adolescents. While SAL-containing medications decreased, dispensing of FP monotherapy increased 39% during the same 7-year period. The number of patients dispensed FP for asthma has increased 47% in children 4-11 years of age, 72% in adolescents 12-17 years of age, and 6% in adults. SAL use without a controller was infrequent and decreasing, reported by 1.7% and 0.5% of patients with asthma in 2005 and 2011, respectively. CONCLUSIONS: In patients with asthma, use of FSC and SAL decreased between 2005 and 2011, while the use of FP increased. Use of SAL monotherapy was infrequent and declined during the study period. The data suggest that the substantial communication activities have encouraged appropriate prescribing of long-acting ß2-adrenergic agonist (LABA).

Seasonal variation in asthma exacerbations in the AUSTRI and VESTRI studies.

Seasonal variation in the benefit of LABA/ICS versus ICS on asthma exacerbation rate is observed in children. http://ow.ly/pcZF30o8hHk.

Patient Comprehension of Medication Guides for Asthma and Chronic Obstructive Pulmonary Disease Medications.

PURPOSE: This study assessed patients' comprehension of the Advair and Serevent medication guides (MGs) and MG reading behaviors with the goal to improve risk communication. METHODS: After reading their assigned MGs, 452 adults with asthma or chronic obstructive pulmonary disease participated in structured interviews to assess comprehension of safety risks in the Advair MG (asthma, n = 150; chronic obstructive pulmonary disease, n = 153) and Serevent MG (asthma, n = 149). Generalized estimating equations for correlated binary data were used to identify factors associated with correct responses. RESULTS: For 10 of 12 individual risk questions, ≥75% of patients reported correct responses. After adjusting for patient characteristics, health literacy was significantly associated with correct responses (odds ratio = 1.03, 95% confidence interval = 1.02-1.05 per 1-point increase in the Rapid Estimate of Adult Literacy in Medicine). MG reading behaviors were inconsistent, with many patients reading MGs only once (40%) despite multiple prescriptions. CONCLUSIONS: Comprehension of safety risks in the Advair and Serevent MGs was adequate for most patients in the study but decreased with health literacy. Initiatives to improve patient-directed risk communication should consider health literacy and reasons for inconsistent reading behaviors.

Prevalence of airway obstruction assessed by lung function questionnaire.

OBJECTIVE: To estimate the prevalence of unidentified chronic obstructive pulmonary disease (COPD) and determine the screening accuracy of the Lung Function Questionnaire (LFQ). PATIENTS AND METHODS: Cigarette smokers who had a smoking history of 10 or more pack-years and were aged 30 years or older were recruited from 36 centers from February 18, 2009, to May 29, 2009. A total of 1575 patients completed a Web-based survey including the 5-item LFQ. Spirometry was performed on patients with an LFQ total score of 18 or less and on a subset scoring more than 18. The primary outcome was the proportion of patients at risk of airflow obstruction as measured by the LFQ (score, ≤ 18) in whom an airflow obstruction was confirmed by spirometry. RESULTS: Of the patients who completed the LFQ, 849 (54%) had standardized spirometry data available. On the basis of LFQ and spirometry results, the estimated prevalence of possible COPD was 17.9% (95% confidence interval, 15.3%-20.6%). At a cut point of 18 or less, sensitivity, specificity, positive predictive value, and negative predictive value of the LFQ were 88%, 25%, 21%, and 90%, respectively. Approximately 1 in 5 patients (21%) aged 30 years or older and 1 in 4 (26%) aged 50 years or older scored 18 or less on the LFQ and had a ratio of forced expiratory volume in the first second of expiration to forced vital capacity less than 0.70. CONCLUSION: On the basis of postbronchodilator spirometry results using weighted estimates, approximately 1 in 5 patients (21%) aged 30 years or older with a smoking history of 10 or more pack-years seen in a primary care setting is likely to have COPD. The LFQ could be a helpful COPD case-finding tool for clinicians to identify patients who need further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01013948.

The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD.

Exacerbations contribute significantly to the morbidity of COPD, leading to an accelerated decline in lung function, reduced functional status, reduced health status and quality of life, poorer prognosis and increased mortality. Prevention of exacerbations is thus an important goal of COPD management. In patients with COPD, treatment with a combination of the inhaled corticosteroid fluticasone propionate (250 microg) and the long-acting beta(2)-agonist salmeterol (50 microg) in a single inhaler (250/50 microg) is an effective therapy option that has been shown to reduce the frequency of exacerbations, to improve lung function, dyspnea and health status, and to be relatively cost-effective as a COPD maintenance therapy. Importantly, results of various studies suggest that fluticasone propionate and salmeterol have synergistic effects when administered together that improve their efficacy in controlling symptoms and reducing exacerbations. The present non-systematic review summarizes the role of fluticasone propionate/salmeterol combination therapy in the prevention of exacerbations of COPD and its related effects on lung function, survival, health status, and healthcare costs.

Prevalence of COPD among symptomatic patients in a primary care setting.

OBJECTIVE: Spirometry is recognized as the gold standard assessment for the diagnosis of COPD. However, spirometry continues to be underused, perpetuating the underdiagnosis of COPD. The aim of this study was to evaluate the prevalence of COPD in a primary care setting in patients with a smoking history and self-reported chronic bronchitis symptoms. RESEARCH DESIGN AND METHODS: This was a multi-center, cross-sectional study. The primary assessment was the percentage of patients with airway obstruction (post-bronchodilator FEV(1)/FVC ratio < or = 0.70) compared to those without obstruction (post-bronchodilator FEV(1)/FVC ratio > 0.70). RESULTS: Airflow obstruction consistent with COPD was confirmed in 26% of patients (mean age 52.9 years, FEV(1) 81.4% predicted and smoking history 39.8 pack-years) that reported chronic bronchitis symptoms. Airflow obstruction increased with age and smoking history. Slight or moderate dyspnea was reported by 68% of patients and the majority had not talked to their doctor about cough and continued to smoke. LIMITATIONS: Patients were evaluated at a single visit. The definition of airway obstruction used may have lead to overdiagnosis in patients aged 70 and older. CONCLUSION: This study confirms that many patients with COPD remain undiagnosed in the primary care setting. Evaluation of spirometry in patients with a smoking history and chronic bronchitis symptoms can aid in the diagnosis of COPD, allowing earlier treatment thereby reducing the burden of this debilitating disease. CLINICAL TRIAL REGISTRATION: Study code ADC109043; clinicaltrials.gov #NCT00442468.

Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol.

OBJECTIVE: Pulmonary arterial hypertension (PAH) remains challenging to treat, especially in association with scleroderma. We examined survival rates among patients with PAH in association with scleroderma who received epoprostenol (Flolan) through continuous intravenous (i.v.) infusion in an uncontrolled open-label 3-year extension study following an initial randomized, controlled 12-week study. METHODS: One hundred two patients diagnosed with PAH in association with scleroderma who received epoprostenol were included in the analyses. This included 51 PAH patients from a subject population of 56 who received epoprostenol in the randomized controlled study, and 46 patients from an initial population of 55 subjects on conventional therapy in the randomized controlled study, who received epoprostenol in the extension study. All patients in this extension study received open-label epoprostenol. Adverse events, survival, and dosing information were collected throughout the study. RESULTS: The probabilities of survival during the first and second years for all subjects who received epoprostenol during the initial randomized controlled study or during the extension study were 0.71 and 0.52, respectively. This measure remained constant at 0.48 during the third and fourth years. CONCLUSION: This study reports longterm survival rates for patients with scleroderma-associated PAH treated with i.v. epoprostenol. Although comparisons to historical data should be made with caution, this study reports a better survival outcome than natural history data on patients with scleroderma-associated PAH.

Methylation and expression of the lactoferrin gene in human tissues and cancer cells.

The lactoferrin gene promoter contains GC-rich regions that harbor consensus sequences for a variety of transcription factors. Previous work in our laboratory has demonstrated a link between methylation at the CpG sites of the mouse lactoferrin gene promoter and the level of its expression. The current work investigates the methylation profile in three regions of the human lactoferrin gene by bisulfite genomic sequencing. In addition, the methylation profiles of normal leukocyte DNA, and leukemia cell line and patient DNA were compared. The three regions are located at the -504/-190, which includes the estrogen response element, the -282/+271 which contains the lactoferrin promoter and the +1087/+1476, a region within the first intron that has the alternative delta lactoferrin promoter. Differential methylations were found within all the regions. Increased methylation at the CpG sites and the presence of non-CpG methylation of the lactoferrin promoters were found in the cancer samples.