Lorna McKinlay

Fluticasone/Salmeterol Combination Confers Benefits in People With Asthma Who Smoke

BACKGROUND Smoking induces airway inflammation and relative resistance to inhaled steroids. The objective of this study was to evaluate the effects on airway hyperresponsiveness of adding salmeterol to fluticasone vs doubling the dose of fluticasone in patients with asthma who smoked and patients with asthma who did not smoke. METHODS Sixteen patients with mild to moderate persistent asthma who did not smoke and 15 such patients who smoked completed a double-blind, randomized, placebo-controlled crossover study. They received either a fluticasone/salmeterol combination (FP/SM) (125/25 μg) two puffs bid (plus fluticasone placebo), or active fluticasone (250 μg) two puffs bid (plus FP/SM placebo), for 2 weeks each, with baselines after 1-week to 2-week run-in and washout periods. The primary outcome was the change from baseline in the provocative concentration of methacholine required to produce a 20% fall in FEV(1) (PC(20)). RESULTS In the patients who did not smoke, there were similar improvements in the methacholine PC(20) with the use of fluticasone and FP/SM. The patients who smoked gained a benefit from FP/SM but not fluticasone, amounting to a PC(20) difference of 1.6 doubling dilutions (95% CI, 1.0-2.2), P < .01. The provocative dose of mannitol required to produce a 15% fall in FEV(1) (PD(15)) showed greater improvements with FP/SM than fluticasone in both patients who smoked and did not smoke. Similar differences in airway caliber between those who smoked and did not smoke were observed in FEV(1) and airway resistance. CONCLUSIONS FP/SM confers greater improvements in airway hyperresponsiveness and airway caliber in patients with asthma who smoke compared with double the dose of fluticasone. We hypothesize that in the presence of relative steroid resistance, the smooth muscle stabilization conferred by salmeterol is of greater clinical importance in patients who smoke than in those who do not smoke. TRIAL REGISTRY ClinicalTrials.gov: No.: NCT00830505; URL: www.clinicaltrials.gov.

Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers

PurposeThis study compares the in vivo relative lung bioavailability of Hydrofluoroalkane (HFA) Seretide delivered via unprimed and unwashed Aerochamber Plus (AP) or Volumatic (VM) spacers, a integrated breath-actuated vortex Synchro-Breathe (SB) device and an Evohaler pMDI (EH) device using adrenal suppression and early fall in serum potassium (K) as surrogates for respirable dose.MethodsSeventeen healthy volunteers completed this randomised double-blind, double-dummy crossover study. Single doses of placebo/Seretide 250 (total dose ex valve fluticasone 2000 mcg/salmeterol 200 mcg) were administered via the devices. Overnight urinary cortisol/creatinine (OUCC) and serum K were measured at baseline and after each dose.ResultsSignificant suppression of OUCC and K occurred from baseline with the SB, AP and VM but not with the EH devices. The geometric mean fold suppression (95% confidence interval, p) was: EH, 1.59 (0.80–3.14, p = 0.40); AP, 4.26 (3.01–6.02, p < 0.001); VM, 3.11 (1.99–4.78, p < 0. 001); SB, 3.29 (2.04–5.24, p < 0.001). For K, the arithmetic mean fall (mmol/l) (95% confidence interval; p) was: EH, −0.10 (−0.25–0.05, p = 0.18); AP, −0.23 (−0.41 to −0.04, p = 0.02); VM, −0.22 (−0.44 to −0.01, p = 0.04); SB, −0.28 (−0.42 to −0.13, p = 0.001).ConclusionsThe breath-actuated SB device was comparable to ‘out of the box’ small and large volume spacers and produced similar improvements in relative systemic lung bioavailability for fluticasone and salmeterol.

Proof of concept study to evaluate step-down therapy with inhaled corticosteroid alone or additive therapy on surrogate inflammatory markers in asthma

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Much of the focus of inflammatory surrogates and airway challenges in asthma has been directed towards success of therapy and diagnosis. Few have considered them in the context of guiding dose reduction once sufficient control has been achieved. WHAT THIS STUDY ADDS Adenosine monophosphate (AMP) as an indirect bronchial airway challenge, together with non invasive inflammatory surrogate measures were not found to be clinically useful when guiding therapy in a group of asthmatic patients through step 3-4 in British Thoracic Society asthma guidelines. However, they may still play a role in predicting failure of individual step-down. AIM The aim of the study was to evaluate the usefulness of inflammatory surrogates in determining step-down therapy in asthma. METHODS AMP challenge, serum eosinophil cationic protein (ECP), exhaled nitric oxide (eNO) and pulmonary function tests were recorded. Subjects were divided into two groups following high dose inhaled corticosteroids (ICS): Group A fixed dose ICS vs. Group B ICS alone and in combination with add on therapies. RESULTS No differences were seen in inflammatory measures between fixed dose ICS and reduced dose ICS alone or with combination therapies. CONCLUSIONS AMP challenge conferred no additional benefit in guiding step-down therapy. The role of inflammatory surrogates may still play a role in predicting failed step-down on an individual basis.

P172 Fluticasone/salmeterol combination confers significant benefits in smoking asthmatics

Rationale Smoking is known to increase airway inflammation and induce relative resistance to of inhaled steroids. Objectives This study aimed to evaluate the effects of adding salmeterol to fluticasone (FPSM) versus doubling the dose of fluticasone (FP) in smoking and non-smoking asthmatics. Methods 16 non-smoking and 15 smoking asthmatics were randomised to completion in a double blind, placebo-controlled crossover study. They received either FP/SM pMDI (125/25 mg) two puffs bid (+FP placebo) or active FP 250 mg pMDI two puffs bid (+FPSM placebo), for 2 weeks each, with baselines after 1–2 week run-in and wash-out periods. The primary outcome was change from baseline in methacholine PC20. Results In non-smokers there were similar improvements with FP and FPSM. Smokers demonstrated no change in methacholine PC20 following treatment with FP, however FPSM conferred significant benefit: 1.6 doubling dilution (95% CI 1.0 to 2.2), p<0.01. Smokers gained proportionally greater benefit from FPSM minus FP compared to smokers: 1.4dd (95% CI 0.01 to 2.8), p=0.047. Similar changes were observed in FEV1 and IOS, and a similar but non-significant trend was seen with AHR to mannitol. Conclusion Combination FPSM confers greater improvements in AHR and airway caliber in smoking asthmatics, as compared to double the dose of FP alone. It is likely that in the face of the relative steroid resistance, the smooth muscle stabilisation conferred by SM becomes of greater clinical importance.

β-agonist safety and the elephant in the room?

We read with interest the recent paper by Weatherall et al who presented data from a meta-analysis of the relative safety of long-acting β-agonists (LABAs).1 In 2008 the FDA reported on the safety of LABAs and concluded that the nature and magnitude of risk needs to be confirmed. When adverse outcomes are reported relatively infrequently in clinical trials, it is difficult to interpret the value of such analysis and a more thorough examination of these index cases may yield …