Soft Mist Inhaler Research Articles

Tiotropium formulations and safety: a network meta-analysis.

Tiotropium is now delivered via two different inhaler devices: the original Handihaler 18 μg once daily, which uses a powder formulation; and the newer Respimat Soft Mist Inhaler (SMI) 5 μg once daily. It has been questioned whether the two devices can be assumed to have the same safety profile, although the TIOSPIR trial showed that tiotropium when administered via Respimat SMI 5 μg is not less safe than Handihaler 18 μg. Therefore, we have carried out a safety evaluation of tiotropium Handihaler 18 µg versus tiotropium Respimat SMI 5 µg and 2.5 µg, via systematic review and network meta-analysis of the currently available clinical evidence. The results of our meta-analysis with an extremely large number of patients analysed demonstrate that the safety profile of tiotropium HandiHaler is generally superior to that of tiotropium Respimat SMI, although no statistical difference was detected between these two devices. However, the SUCRA analysis favoured tiotropium Respimat SMI with regards to serious adverse events (AEs). We do not believe that using Respimat SMI rather that HandiHaler exposes patients to higher risks of real AEs. Rather, we believe that there may be a different cardiovascular (CV) response to muscarinic receptors blockage in individual patients. Therefore, it will be essential to make all possible efforts to proactively identify patients at increased risk of CV AEs when treated with tiotropium or another antimuscarinic drug.

Asthma and chronic obstructive pulmonary disease inhalers: Techniques for proper use.

Asthma and chronic obstructive pulmonary disease (COPD) affect millions of Americans. Inhalers are necessary to manage these diseases, but physicians and patients often struggle to use them correctly. To simplify inhaler use for patients and physicians. This article compares the various inhalers used to treat asthma and COPD, their techniques for use, and the steps necessary to prime the inhaler if required. The authors provide a suggested standardized technique for the use of metered-dose inhalers, dry powder inhalers, and soft-mist inhalers to provide for a more universal approach for the use of these medications and summarizes how each product is to be used per the U.S. Food and Drug Administration approved package insert. The simplified techniques proposed in this article for the use of metered-dose inhalers, dry powder inhalers, and soft mist inhalers used to treat asthma and COPD may limit inhaler misuse and aid in proper medication delivery and treatment.

The economic impact of educational training assessed by the Handling Questionnaire with three inhalation devices in asthma and Chronic Obstructive Pulmonary Disease patients.

BackgroundThe usability of inhalation devices depends on several factors, eg, the drug to inhale, device handling, and patients’ training. Usability is then presumed to have economic consequences.AimTo assess and compare the cost of patients’ training for proper usability of Breezhaler and Genuair (both dry powder inhalers) and Respimat (a soft mist inhaler) in asthma and chronic obstructive pulmonary disease (COPD) outpatients.MethodsThe acceptance and handling of the three devices were investigated by means of the Handling Questionnaire. The time spent in specific training for ensuring a proper actuation and the corresponding costs were also calculated. Linear and logistic regressions were used in order to investigate the factors influencing proper handling of the devices. A significance level of P<0.05 was accepted.ResultsAccording to both the patients’ and the nurse’s judgments, Genuair and Respimat were perceived as the easiest devices to use, while Breezhaler required the highest number of attempts for achieving the first proper actuation (2.6 vs 1.6; P<0.0001). The total training cost per patient (including the nurse’s time for demonstration and that for attending the patients’ maneuvers) was €1.38±€1.21. Breezhaler was found to be the most expensive as the cost per patient was €2.35±€1.26, which was three to four times higher than that of Genuair and Respimat (both devices involved a cost of <€1 per patient, with negligible differences between each other). Asthma and COPD patients showed a similar trend, with better outcomes reported for asthma patients probably due to lower age.ConclusionSubstantial differences were found to exist in patients’ acceptability and handling of the three devices. The economic impact of specific training was also different and strictly related to the comprehension of the procedure for actuation of each device. Respimat as a soft mist inhaler and Genuair as an metered-dose inhaler proved to be the most convenient in economic terms also.

Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function.

PurposeIn two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled β2-agonist for treatment of COPD, were investigated.Subjects and methodsThe first trial included eight subjects with mild hepatic function impairment (Child–Pugh A), eight subjects with moderate impairment (Child–Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min−1) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 μg olodaterol administered with the Respimat Soft Mist inhaler.ResultsOlodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0–4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%–125%) and 105% (79%–140%), respectively. Corresponding values for dose-normalized maximum concentration (Cmax) were 112% (84%–151%) (mild impairment) and 99% (73%–135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0–4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%–195%), and for Cmax was 137% (84%–222%). There was no significant relationship between creatinine clearance and AUC0–4 or Cmax. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment.ConclusionMild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.

Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma?

Asthma is a chronic inflammatory disorder of the airways that is a major global burden on both individuals and healthcare systems. Despite guideline-directed treatment, a significant proportion of patients with asthma do not achieve control. This review focuses on the potential use of long-acting anticholinergics as bronchodilators in the treatment of asthma, with results published from clinical trials of glycopyrrolate, umeclidinium and tiotropium. The tiotropium clinical trial programme is the most advanced, with data available from a number of phase II and III studies of tiotropium as an add-on to inhaled corticosteroid maintenance therapy, with or without a long-acting β2-agonist, in patients across asthma severities. Recent studies using the Respimat Soft Mist inhaler have identified 5 µg once daily as the preferred dosing regimen, which has shown promising results in adults, adolescents and children with asthma. Tiotropium Respimat has recently been incorporated into the Global Initiative for Asthma 2015 treatment strategy as a recommended alternative therapy at steps 4 and 5 in adult patients with a history of exacerbations. The increasing availability of evidence from ongoing and future clinical trials will be beneficial in determining where long-acting anticholinergic agents fit in future treatment guidelines across a variety of patient populations and disease severities.

Acceptability and preference of three inhalation devices assessed by the Handling Questionnaire in asthma and COPD patients

Background: The patients’ criteria of preference for inhalation devices can affect the extent of their adherence to treatment and outcomes. Aim of this study was to assess and compare the patients’ preference and acceptability (PPA) for Breezhaler and Genuair (both Dry Powder Inhalers), and for Respimat (a Soft Mist Inhaler) in asthma and COPD out-patients by means of the Handling Questionnaire. Methods: The Handling Questionnaire is a validated instrument which allows the investigation of different domains of PPA; it also takes into account the patients’ age and gender, together with their previous experience with the inhalation devices and their previous education approach to them. Differences in terms of preference, acceptance and usability were assessed by linear and logistic regressions in order to evaluate factors influencing the proper actuation. Results and Discussion: Data from 333 patients were collected: Genuair and Respimat were the most liked and perceived as the easiest to use at glance by patients, but also as the least problematic according to the patients’ and nurse’s judgments. Mean number of attempts for achieving the first effective actuation was the highest with Breezhaler (2.6 vs 1.6; p &lt;0.0001). Linear regressions showed that longer the explanation, higher was the number of attempts to the first proper actuation (0.58 additional attempts every 10 s increase in the first explanation, p &lt;0.0001). Devices requiring less manoeuvres for the actuation were used properly after less attempts (0.38 increase in the number of attempts every additional manoeuvres, p &lt;0.0001). Respimat proved to be the most indicated in COPD patients since it was the most liked and its successful rate at first attempt was the highest. Logistic regressions confirmed these data. Previous experience with DPIs and/or MDIs did not affect the patient preference and acceptability, independently whether suffering from asthma or COPD. Conclusions: Substantial differences are existing in patient’s preference and acceptability for inhalation devices, mainly related to the handling and the understanding of the different devices.

Acceptability and preference of three inhalation devices assessed by the Handling Questionnaire in asthma and COPD patients.

BackgroundThe patients’ criteria of preference for inhalation devices can affect the extent of their adherence to treatment and outcomes.Aim of this study was to assess and compare the patients’ preference and acceptability (PPA) for Breezhaler and Genuair (both Dry Powder Inhalers), and for Respimat (a Soft Mist Inhaler) in asthma and COPD out-patients by means of the Handling Questionnaire.MethodsThe Handling Questionnaire is a validated instrument which allows the investigation of different domains of PPA; it also takes into account the patients’ age and gender, together with their previous experience with the inhalation devices and their previous education approach to them. Differences in terms of preference, acceptance and usability were assessed by linear and logistic regressions in order to evaluate factors influencing the proper actuation.Results and DiscussionData from 333 patients were collected: Genuair and Respimat were the most liked and perceived as the easiest to use at glance by patients, but also as the least problematic according to the patients’ and nurse’s judgments. Mean number of attempts for achieving the first effective actuation was the highest with Breezhaler (2.6 vs 1.6; p <0.0001). Linear regressions showed that longer the explanation, higher was the number of attempts to the first proper actuation (0.58 additional attempts every 10 s increase in the first explanation, p <0.0001). Devices requiring less manoeuvres for the actuation were used properly after less attempts (0.38 increase in the number of attempts every additional manoeuvres, p <0.0001). Respimat proved to be the most indicated in COPD patients since it was the most liked and its successful rate at first attempt was the highest. Logistic regressions confirmed these data. Previous experience with DPIs and/or MDIs did not affect the patient preference and acceptability, independently whether suffering from asthma or COPD.ConclusionsSubstantial differences are existing in patient’s preference and acceptability for inhalation devices, mainly related to the handling and the understanding of the different devices.

Differential pharmacology and clinical utility of long-acting bronchodilators in COPD - focus on olodaterol.

Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 μg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy.

Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis.

ObjectiveTo compare the safety and effectiveness of long-acting β-antagonists (LABA), long-acting antimuscarinic agents (LAMA) and inhaled corticosteroids (ICS) for managing chronic obstructive pulmonary disease (COPD).SettingSystematic review and network meta-analysis (NMA).Participants208 randomised clinical trials (RCTs) including 134 692 adults with COPD.InterventionsLABA, LAMA and/or ICS, alone or in combination, versus each other or placebo.Primary and secondary outcomesThe proportion of patients with moderate-to-severe exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia and cardiovascular-related mortality (CVM) were secondary outcomes.ResultsNMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 26 141 patients with an exacerbation in the past year. 32 treatments were effective versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol and tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% probability of being the most effective according to the Surface Under the Cumulative RAnking (SUCRA) curve). NMA was conducted on mortality (88 RCTs, 97 526 patients); fluticasone/salmeterol was more effective in reducing mortality than placebo, formoterol and fluticasone alone, and was the most effective (SUCRA=71%). NMA was conducted on CVM (37 RCTs, 55 156 patients) and the following were safest: salmeterol versus each OF placebo, tiotropium and tiotropium (Soft Mist Inhaler (SMR)); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful (SUCRA=81%). NMA was conducted on pneumonia occurrence (54 RCTs, 61 551 patients). 24 treatments were more harmful, including 2 that increased risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol (SUCRA=89%). NMA was conducted for arrhythmia; no statistically significant differences between agents were identified.ConclusionsMany inhaled agents are available for COPD, some are safer and more effective than others. Our results can be used by patients and physicians to tailor administration of these agents.Protocol registration numberPROSPERO # CRD42013006725.

Efficacy and safety of the long-acting β2-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease.

BackgroundOlodaterol is a novel long-acting β2-agonist with proven ≥24-hour duration of action in preclinical and clinical studies.ObjectiveThis randomized, double-blind, placebo-controlled, parallel-group study evaluated the dose response of once-daily (QD) olodaterol based on bronchodilator efficacy, safety, and pharmacokinetics over 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD).MethodsAll eligible patients were randomized to receive 2 µg, 5 µg, or 10 µg of olodaterol or placebo for 4 weeks via the Respimat® Soft Mist™ inhaler. The primary end point was the change from baseline in trough forced expiratory volume in 1 second (FEV1) after 4 weeks of olodaterol treatment. Secondary end points included trough FEV1 after 1 week and 2 weeks of treatment, FEV1 area under the curve from 0 hour to 3 hours (AUC0–3), peak FEV1 from 0 hour to 3 hours (peak FEV1), and corresponding forced vital capacity (FVC) responses. Rescue medication use, COPD symptoms, physician global evaluation, pharmacokinetics, and safety were also assessed.ResultsA total of 328 patients with COPD were randomized to receive treatment. All olodaterol doses assessed in the study showed statistically significant increases in trough FEV1 compared to placebo at Day 29 (P<0.0001). Mean increases in peak FEV1 and FEV1 AUC0–3 compared to placebo were also significant (P<0.0001). A clear dose–response relationship was observed across all treatment groups. FVC responses (trough and FVC AUC0–3) supported FEV1 outcomes. All doses of olodaterol were well tolerated, and no safety concerns were identified.ConclusionQD olodaterol demonstrated 24-hour bronchodilator efficacy and was well tolerated in Japanese patients with COPD.Trial registrationClinicalTrials.gov: NCT00824382.

Validating CFD Predictions of Pharmaceutical Aerosol Deposition with In Vivo Data

CFD provides a powerful approach to evaluate the deposition of pharmaceutical aerosols; however, previous studies have not compared CFD results of deposition throughout the lungs with in vivo data. The in vivo datasets selected for comparison with CFD predictions included fast and slow clearance of monodisperse aerosols as well as 2D gamma scintigraphy measurements for a dry powder inhaler (DPI) and softmist inhaler (SMI). The CFD model included the inhaler, a characteristic model of the mouth-throat (MT) and upper tracheobronchial (TB) airways, stochastic individual pathways (SIPs) representing the remaining TB region, and recent CFD-based correlations to predict pharmaceutical aerosol deposition in the alveolar airways. For the monodisperse aerosol, CFD predictions of total lung deposition agreed with in vivo data providing a percent relative error of 6% averaged across aerosol sizes of 1-7 μm. With the DPI and SMI, deposition was evaluated in the MT, central airways (bifurcations B1-B7), and intermediate plus peripheral airways (B8 through alveoli). Across these regions, CFD predictions produced an average relative error <10% for each inhaler. CFD simulations with the SIP modeling approach were shown to accurately predict regional deposition throughout the lungs for multiple aerosol types and different in vivo assessment methods.

Drug Inhalation Devices and Delivery Systems

•Inhalation drug therapy is one of the most popular ways to deliver medication locally to the lungs. •There are many inhalation devices available including metered dose inhalers; dry powder inhalers; nebulizers; and, more recently, soft mist inhalers. •Advances in inhalation devices have enhanced drug delivery and improved adherence. Shalonda Williams, PharmD, BCACP, is an assistant professor of pharmacy practice at LIU Pharmacy in Brooklyn, NY, and can be reached at [email protected].

A Handling Study to Assess Use of the Respimat(®) Soft Mist™ Inhaler in Children Under 5 Years Old.

Background: Respimat® Soft Mist™ Inhaler (SMI) is a hand-held device that generates an aerosol with a high, fine-particle fraction, enabling efficient lung deposition. The study objective was to assess inhalation success among children using Respimat SMI, and the requirement for assistance by the parent/caregiver and/or a valved holding chamber (VHC).Methods: This open-label study enrolled patients aged <5 years with respiratory disease and history of coughing and/or recurrent wheezing. Patients inhaled from the Respimat SMI (air only; no aerosol) using a stepwise configuration: “1” (dose released by child); “2” (dose released by parent/caregiver), and “3” (Respimat SMI with VHC, facemask, and parent/caregiver help). Co-primary endpoints included the ability to perform successful inhalation as assessed by the investigators using a standardized handling questionnaire and evaluation of the reasons for success. Inhalation profile in the successful handling configuration was verified with a pneumotachograph. Patient satisfaction and preferences were investigated in a questionnaire.Results: Of the children aged 4 to <5 years (n=27) and 3 to <4 years (n=30), 55.6% and 30.0%, respectively, achieved success without a VHC or help; with assistance, another 29.6% and 10.0%, respectively, achieved success, and the remaining children were successful with VHC. All children aged 2 to <3 years (n=20) achieved success with the Respimat SMI and VHC. Of those aged <2 years (n=22), 95.5% had successful handling of the Respimat SMI with VHC and parent/caregiver help. Inhalation flow profiles generally confirmed the outcome of the handling assessment by the investigators. Most parent/caregiver and/or child respondents were satisfied with operation, instructions for use, handling, and ease of holding the Respimat SMI with or without a VHC.Conclusions: The Respimat SMI is suitable for children aged <5 years; however, children aged <5 years are advised to add a VHC to complement its use.

Safety of once-daily tiotropium and olodaterol fixed-dose combination via the Respimat in chronic obstructive pulmonary disease in two 1-year studies

Introduction: The fixed-dose combination (FDC) of tiotropium (T), a once-daily long-acting muscarinic antagonist, and olodaterol (O), a once-daily long-acting ß2-agonist, is currently being evaluated in chronic obstructive pulmonary disease (COPD). Two 52-week, Phase III replicate pivotal studies were conducted to assess the efficacy and safety of FDCs of T and O (T+O) delivered via Respimat Soft Mist inhaler in patients (pts) with GOLD Stage 2 – 4 COPD. Pooled safety data from the two studies are presented here.

Once-daily tiotropium and olodaterol fixed-dose combination via the Respimat improves outcomes vs mono-components in COPD in two 1-year studies

Introduction: Tiotropium (T), a once-daily long-acting muscarinic antagonist, is a well-established first-line maintenance treatment in chronic obstructive pulmonary disease (COPD); olodaterol (O) is a once-daily long-acting ß2-agonist that has recently gained approval in several countries. Two Phase III replicate pivotal studies assessed the efficacy and safety of fixed-dose combinations of T and O (T+O) delivered via Respimat Soft Mist inhaler in patients with GOLD Stage 2 – 4 COPD.

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

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. 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. 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). 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.

Modern inhalation drug delivery devices for treatment of chronic obstructive pulmonary disease

This review includes history of development of devices for drug delivery to the airways. Currently, there is a large diversity of different drug delivery devices for inhalation therapy of chronic obstructive pulmonary disease (COPD): pressurized metered dosing aerosol inhalers (activated or not activated by breath), dry powder nhalers (single dose or multiple dose), jet nebulizers, ultrasound nebulizers and soft mist inhalers. This wide spectrum of different inhalation drug delivery devices provides an improvement in treatment of various respiratory diseases, primarily COPD, due to individual choice of an inhaler considering the patient's age, comorbidity and severity of the disease.

Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials.

BackgroundTiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat® Soft Mist™ Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy.MethodsCombined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler® 18 μg and/or tiotropium Respimat® (1.25-, 2.5-, 5.0- and 10-μg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days.ResultsFour trials (n = 727) were included in the analysis. Respimat® (1.25–10 μg) or HandiHaler® (18 μg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure–effect relationship.ConclusionsIn this analysis, tiotropium maintenance therapy administered using Respimat® (1.25–10 μg) or HandiHaler® (18 μg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.

Tiotropium versus placebo for chronic obstructive pulmonary disease.

Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease (COPD). In the past few years there have been several systematic reviews of the efficacy of tiotropium, however, several new trials have compared tiotropium treatment with placebo, including those of a soft mist inhaler, making an update necessary. To evaluate data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints. We searched the Cochrane Airways Group's Specialised Register of Trials (CAGR) and ClinicalTrials.gov up to February 2012. We included parallel group RCTs of three months or longer comparing treatment with tiotropium against placebo for patients with COPD. Two review authors independently assessed studies for inclusion and then extracted data on study quality and the outcome results. We contacted study authors and trial sponsors for additional information, and collected information on adverse effects from all trials. We analysed the data using Cochrane Review Manager 5, RevMan 5.2. This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung function at the end of the study compared with those on placebo (trough forced expiratory volume in one second (FEV1) MD 118.92 mL; 95% CI 113.07 to 124.77). This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.

Feasibility of aerosol drug delivery to sleeping infants: a prospective observational study

ObjectivesDelivery of inhaled medications to infants is usually very demanding and is often associated with crying and mask rejection. It has been suggested that aerosol administration during sleep may be...