Peter A. Williamson

The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-Agonist Therapy in COPD

BACKGROUND Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting β-agonists (LABAs). METHODS We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index. RESULTS A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively. CONCLUSIONS The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

BACKGROUND We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. METHODS One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. RESULTS One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). CONCLUSIONS Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

The minimal clinically important difference in allergic rhinitis

Background When presented with results from clinical measurements or research findings, clinicians must first make an interpretation of their importance, not only in statistical terms, but also the ‘clinical importance’ given the size of the change observed. To do this, they require an understanding of the relationship between their outcome measures, and the patients perception of change. The minimal clinically important difference (MCID) illustrates this relationship by calculating the smallest change in a given outcome that is meaningful to a patient. There are few reports of calculated MCIDs in the Rhinology literature.

Response to salbutamol in patients with mild asthma treated with nadolol

To the Editors: β-blockers (inverse agonists) have an exactly opposite effect to β2-adrenoceptor (β2-ADR) agonists and are currently contraindicated in asthma. This results from the fact that the acute administration of these drugs can produce bronchoconstriction by blocking the bronchodilating effects of endogenous adrenaline, or by inactivating constitutively active β2-ADRs, and can worsen asthma symptoms 1. In fact, published accounts have shown that acute β-blocker use can, but will not always, precipitate airway constriction in patients with asthma 2. Nevertheless, there are compelling uses of β-blockers in asthmatics, such as in heart failure and after myocardial infarction. The effect of chronic administration of β-blockers in asthma has remained unknown until recently, when studies on a murine model of asthma showed that, while acute (single-dose) administration of β-blockers increased airway hyperresponsiveness (AHR), their chronic (28-day) administration had an opposite effect and decreased AHR 3. Furthermore, recent data demonstrate that chronic β-blocker treatment produces broad anti-inflammatory effects, and especially dramatic effects on airway epithelium and mucous metaplasia 4, 5. More recently, our group has further confirmed the pivotal role that β2-ADR has on mucous metaplasia using a β2-ADR null mouse 6. Based on these findings in the murine asthma model, …

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.

Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease?

Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents an interesting model to investigate the existence of a non‐allergic unified airway. The factors associated with airway dysfunction in CRSwNP are not fully understood.

Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers

To cite this article: Clearie KL, Vaidyanathan S, Williamson PA, Goudie A, Short P, Schembri S, Lipworth BJ. Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

AIMS A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

Supervised step-down of inhaled corticosteroids in the community – An observational study

INTRODUCTION Current asthma guidelines recommend step-down of inhaled corticosteroids (ICS) to the minimum dose required for control of symptoms. AIM To determine if supervised step-down of (ICS) in the community has any effect on asthmatic inflammation. METHODS 119 Community based asthmatics underwent progressive step-down of therapy until they became unstable or reached an (ICS) dose of ≤200 μg beclomethasone dipropionate (BDP) or equivalent. Once unstable, participants stepped back up to the last stable dose of ICS. Exhaled nitric oxide (NO) and mannitol challenge were performed at the start and end of step-down. Asthma Quality of Life Questionnaire (AQLQ) and spirometry were recorded at each step-down visit. RESULTS The median (interquartile range) BDP equivalent dose was significantly higher pre vs. post step-down: 400 μg (400-800) and 250 μg (200-400) per day respectively (P < 0.05). Examination of change in PD(10) in individual patients revealed that 34% had an improvement (>+1 dd), 47% had no change (±-1 dd), and 19% had a worsening (<-1 dd). The geometric mean fold ratio in NO for pre vs. post was 0.96 (95% CI 0.87 to 1.06, P = 0.43). Mean (SEM) values for FEV(1) were 86.2% (1.51) vs. 84.5% (1.46) (P = 0.04). There was a significant improvement in AQLQ. CONCLUSIONS We have demonstrated that a significant reduction in ICS dose may be achieved in a community setting without any worsening of airways inflammation or lung function, and with an associated improvement quality of life in the majority of patients. This apparent disconnect may reflect enhanced adherence due to supervision of step-down.

Think the impossible: β-blockers for treating asthma

Asthma was originally thought to be associated with an intrinsic defect in beta2ADR (beta2-adrenoceptor) function, tipping the balance towards parasympathetic bronchoconstriction. Hence beta-blocking drugs (such as beta2ADR antagonists and inverse agonists) may cause acute bronchoconstriction which, in turn, may be attenuated by anti-cholinergic agents. Although beta2-agonists are highly effective for the acute relief of bronchoconstriction, their chronic use is accompanied by an adaptive reduction in beta2ADR numbers and associated desensitization of response, resulting in increased exacerbations and rare cases of death. The hypothesis examined in the present article is that, while single dosing with a beta-blocker may cause acute bronchoconstriction, chronic dosing may afford putative beneficial effects including attenuated airway hyperresponsiveness.