Steve Yancey

Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone

ABSTRACT Objective: This long-term prospective study was conducted in African Americans with persistent asthma to examine the safety and effectiveness of the combination of the inhaled corticosteroid, fluticasone propionate (FP), and the long-acting beta-agonist, salmeterol, compared with FP alone. Research and design methods: This was a randomized, double-blind, parallel group, multi-center trial in adolescent and adult subjects ≥12 years of age symptomatic on a low dose of an inhaled corticosteroid (ICS). The study consisted of a 2-week screening period on low dose ICS; a 4-week open-label FP 250u2009mcg twice daily (BID) run-in; a 52-week double-blind period (FP/salmeterol [FSC] 100/50u2009mcg [n = 239] or FP 100u2009mcg [n = 236] BID), and a 4-week FP 250u2009mcg BID run-out period. Annualized exacerbation rate was the primary outcome for comparing the two treatments. Other measures of asthma control included peak expiratory flow, asthma symptoms, and albuterol use. Safety was assessed through adverse events. Results: Exacerbation rates were not significantly different in those treated with FSC 100/50u2009mcg (0.449 per year) compared with FP 100u2009mcg (0.529 per year, p = 0.169). When the per-protocol analysis was applied, the rates were 0.465 and 0.769 per year for FSC 100/50u2009mcg and FP 100u2009mcg, respectively. Treatment with FSC 100/50u2009mcg provided statistically greater improvements in lung function measures and nighttime awakenings (p ≤ 0.050) and demonstrated numerically lower daily symptoms (p = 0.216) and albuterol use (p = 0.122). Two subjects treated with FSC 100/50u2009mcg were hospitalized for an asthma exacerbation compared to three treated with FP 100u2009mcg. The overall incidence of adverse effects during double-blind treatment was similar between the FSC 100/50u2009mcg and FP 100u2009mcg treatment groups (61u2009%u2009and 68u2009%u2009, respectively). Frequent study visits were required of subjects during this long-term study, and it remains unknown whether this intervention may affect generalizability. Conclusion: In this large, prospective study among African Americans with asthma, the addition of salmeterol to FP resulted in a similar low rate of exacerbations and improved other markers of asthma control. Both FSC 100/50u2009mcg and FP 100u2009mcg were well-tolerated, and the overall safety-profiles were similar over 1 year of treatment.

Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma

RATIONALEnLittle is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR.nnnMETHODSnAfter a 2-week run-in period, subjects (> or = 12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSC(BHR) group) or fluticasone propionate (FP(BHR) group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FP(REF) group; n=154). All treatments were administered via Diskus. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subjects derived severity class, which was based on clinical measures of asthma control with or without BHR.nnnRESULTSnThe mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSC(BHR) group compared with the FP(BHR) group (a difference of -42.9 mcg; p=0.07). Compared with the FP(REF) group, the mean total daily ICS dose was higher in the FSC(BHR) group (a difference of 85.2 mcg) and was significantly higher in the FP(BHR) group (a difference of 131.2 mcg, p=0.037).nnnCONCLUSIONnThis study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol.

Ecologic analysis of asthma-related events and dispensing of inhaled corticosteroid- and salmeterol-containing products

BACKGROUNDnAn association between salmeterol use and serious asthma episodes or asthma-related mortality has been noted in 2 clinical trials; however, a causal relationship has not been established. To date, observational studies have not replicated this finding.nnnOBJECTIVEnTo examine the relationship between number of prescriptions dispensed of salmeterol-containing products and inhaled corticosteroid (ICS)-containing products and the rates of asthma-related hospitalizations and mortality in the United States.nnnMETHODSnIn this ecologic study, annual age-adjusted rates of asthma-related hospitalization and asthma-related mortality from US population-based sources were graphed alongside annual number of prescriptions dispensed of salmeterol- and ICS-containing products by year from 1991 to 2004. We computed the Spearman rank correlations between number of prescriptions dispensed and serious events (asthma-related hospitalization rate, number of hospitalizations, asthma-related mortality rate, and number of asthma deaths).nnnRESULTSnDuring more than 14 years, while number of prescriptions dispensed of salmeterol-containing and ICS-containing products increased, age-adjusted asthma-related mortality rates declined and asthma-related hospitalization rates remained relatively stable. The number of asthma-related deaths has decreased steadily since the mid-1990s.nnnCONCLUSIONnThis study provides population-level evidence that asthma-related death rates declined and asthma-related hospitalization rates remained relatively constant for more than 14 years during a period of improvements in asthma management per treatment guidelines, including increased use of maintenance medications, such as ICSs and salmeterol.

Controller medications and their effects on asthma exacerbations temporally associated with upper respiratory infections

BACKGROUNDnExacerbations are a major risk and a cause of asthma morbidity and healthcare utilization. Viral-induced upper respiratory tract infections are the most frequent trigger of asthma-related exacerbations. Studies have traditionally assessed exacerbations without documentation regarding exacerbation etiology. Therefore, it remains unknown whether asthma medications can alter exacerbation susceptibility based on a specific etiology.nnnOBJECTIVEnTo examine whether treatment with inhaled corticosteroids plus long-acting beta(2)-agonists reduced the number of exacerbations associated with upper respiratory tract infections versus inhaled corticosteroids alone.nnnMETHODSnTwo large datasets comparing treatment with fluticasone propionate and fluticasone propionate plus salmeterol were analyzed, including the number of clinically reported upper respiratory tract infections, asthma-related exacerbations, and the presence of an exacerbation and concurrent report of an upper respiratory tract infection.nnnRESULTSnBoth treatment groups had similar incidences of upper respiratory tract infections. Of those reporting an upper respiratory tract infection, statistically significantly fewer reported an asthma-related exacerbation comparing fluticasone propionate plus salmeterol with fluticasone propionate (p=0.0057).nnnDISCUSSIONnThis retrospective analysis suggests that therapy with fluticasone propionate plus salmeterol provides protection against asthma exacerbations temporally associated with upper respiratory tract infections. This retrospective analysis supports the hypothesis that specific therapeutic approaches to mitigate virus-associated exacerbations may benefit asthma care. Well-controlled prospective studies are warranted.

Pharmacokinetics and absolute bioavailability of mepolizumab following administration at subcutaneous and intramuscular sites

This study characterized the pharmacokinetics (PK) of mepolizumab, after a single intravenous (IV), subcutaneous (SC), or intramuscular (IM) dose in healthy adults and determined the absolute bioavailability of SC and IM mepolizumab delivered at different anatomical regions. Sixty healthy subjects were randomly assigned to receive a single dose of either mepolizumab 250u2009mg by IV, SC injection (upper arm, abdomen, or thigh); or IM injection (thigh). Following IV administration, the mean maximum observed plasma mepolizumab concentration (Cmax) and the mean area under the concentration versus time curves from time zero to infinity (AUC(0‐∞)) were 109u2009±u200917u2009µg/mL and 1,557u2009±u2009250u2009µgu2009d/mL, respectively. After SC administration, the mean (±SD) values of Cmax and AUC(0‐∞) were 34.1–38.2u2009±u20097.3–12.1u2009µg/mL and 1,110–1,238u2009±u2009228–372u2009µgu2009d/mL, respectively. Following IM administration, the mean values of Cmax and AUC(0‐∞) were 46.9u2009±u200910.6u2009µg/mL and 1,395u2009±u2009348u2009µgu2009d/mL. The median terminal half‐life was similar for SC, IM and IV administration (17.9–20.4, 19.2, and 18.5 days, respectively). The overall mean bioavailability of SC mepolizumab was 64–75%, and absorption was relatively similar for the three SC injection sites. Mepolizumab 250u2009mg was generally well tolerated in this study. These results support flexibility in the SC injection site for mepolizumab.