Asthma treatment algorithm. We rule out continuing with the same treatment since the patient is symptomatic.

A patient diagnosed with bronchial asthma who is being treated with low-dose inhaled steroids (200 micrograms of budesonide every 12 hours) and rescue medication (salbutamol on demand) comes for periodic clinical monitoring. The patient reports that in the last 3 months he has had no exacerbations and that he uses salbutamol once a day. He only has dyspnea when climbing stairs and some nights he sleeps irregularly due to coughing. Which of the following therapeutic options should be considered as the treatment of choice?

Increase the dose of inhaled corticosteroids to 800 micrograms/day.

Maintain the same pharmacological regimen.

Switch to ocmbined therapy with low-dose inhaled corticosteroids and long-acting beta2-adrenergics.

The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.

A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies. This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD). This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits. The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms. In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.

Periodic treatment regimens with inhaled steroids in asthma or chronic obstructive pulmonary disease. Is it possible?

To determine whether inhaled corticosteroids can be discontinued in the stable phase of asthma or chronic obstructive pulmonary disease (COPD) or if this therapy should be continued. Nonrandomized open uncontrolled 5-year trial. Prospective study in general practice. Forty-eight patients with steroid-dependent asthma or COPD who had shown a decline in forced expiratory volume in 1 second (FEV1) of at least 80 mL per year and at least one exacerbation per year during the first 2 years of bronchodilator treatment. Subjects were treated additionally with inhaled steroids for another 2 years and were finally given the option to stop using steroids. Sixteen patients were willing to stop using beclomethasone and were studied for another year. No recruitment bias took place in this consecutive sample in the fifth year of follow-up. Two of 16 patients developed carcinomas and dropped out. Two years of bronchodilator treatment alone (400 micrograms of salbutamol or 40 micrograms of ipratropium bromide four times daily), followed by 2 years of additional inhaled corticosteroid treatment (400 micrograms of beclomethasone two times daily), and finally 1 year of bronchodilator treatment alone. Decline in lung function (FEV1), change in bronchial hyperresponsiveness, indicated by a provocative concentration of histamine causing a 20% fall in FEV1 (PC20), morning peak expiratory flow rate (PEFR), diurnal PEFR, week-to-week variation of PEFR, bronchial symptoms, and exacerbations. The course of FEV1 during the year in which beclomethasone was discontinued was not significantly different when compared with the 2-year period of beclomethasone treatment. Neither did the course of PC20, morning PEFR, diurnal PEFR, symptom score, and exacerbation rate change. Only the week-to-week variation of the PEFR increased after discontinuing steroids. Discontinuing inhaled steroids is possible in some patients with asthma or COPD after 2 years of regular treatment. This might indicate that for certain groups of patients with mild asthma or COPD, periodic treatment schedules with inhaled steroids is the treatment policy for the future.

Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma.

In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled ss2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids. To determine the effect of the combination of long-acting ss(2) agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the risk of asthma exacerbations, pulmonary function and on other measures of asthma control, and to look for characteristics associated with greater benefit for either treatment option. We identified randomised controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs, clinical trial registries and correspondence with manufacturers until May 2008. RCTs that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children and adults with asthma. Two authors independently assessed methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the number of patients experiencing one or more asthma exacerbations requiring oral corticosteroids. This review included 48 studies (15,155 participants including 1155 children and 14,000 adults). Participants were inadequately controlled on their current ICS regimen, experiencing ongoing symptoms and with generally moderate (FEV1 60% to 79% of predicted) airway obstruction. The studies tested the combination of salmeterol or formoterol with a median dose of 400 mcg/day of beclomethasone or equivalent (BDP-eq) compared to a median of 1000 mcg/day of BDP-eq, usually for 24 weeks or less. There was a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73 (median study duration: 12 weeks). The study results were dominated by adult studies; trial data from three paediatric studies showed a trend towards increased risk of rescue oral steroids (RR 1.24, 95% CI 0.58 to 2.66) and hospital admission (RR 2.21, 95% CI 0.74 to 6.64) associated with combination therapy. Overall, there was no statistically significant difference in the risk ratios for either hospital admission (RR 1.02, 95% CI 0.67 to 1.56) or serious adverse events (RR 1.12, 95% CI 0.91 to 1.37). The combination of LABA and ICS resulted in significantly greater but modest improvement from baseline in lung function, symptoms and rescue medication use than with higher ICS dose. Despite no significant group difference in the risk of overall adverse events (RR 0.99, 95% CI 0.95 to 1.03), there was an increase in the risk of tremor (RR 1.84, 95% CI 1.20 to 2.82) and a lower risk of oral thrush (RR 0.58, 95% CI 0.40 to 0.86)) in the LABA and ICS compared to the higher ICS group. There was no significant difference in hoarseness or headache between the treatment groups. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS (RR 0.65, 95% CI 0.51 to 0.83). In adolescents and adults with sub-optimal control on low dose ICS monotherapy, the combination of LABA and ICS is modestly more effective in reducing the risk of exacerbations requiring oral corticosteroids than a higher dose of ICS. Combination therapy also led to modestly greater improvement in lung function, symptoms and use of rescue ss(2) agonists and to fewer withdrawals due to poor asthma control than with a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor and less oral candidiasis with combination therapy, the two options appear relatively safe in adults although adverse effects associated with long-term ICS treatment were seldom monitored. In children, combination therapy did not lead to a significant reduction, but rather a trend towards an increased risk, of oral steroid-treated exacerbations and hospital admissions. These trends raised concern about the safety of combination therapy in view of modest improvement in children under the age of 12 years.

Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma.

Patients who continue to experience asthma symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Leukotriene receptor antagonists (LTRA) and long-acting beta(2)-agonists (LABA) agents may both be considered as add-on therapy to inhaled corticosteroids (ICS). We compared the efficacy and safety profile of adding either daily LABA or LTRA in asthmatic patients who remained symptomatic on ICS. The Cochrane Airways Group Specialised Register was searched for randomised controlled trials up to and including March 2006. Reference lists of all included studies and reviews were screened to identify potentially relevant citations. Inquiries regarding other published or unpublished studies supported by the authors of the included studies or pharmaceutical companies who manufacture these agents were made. Conference proceedings of major respiratory meetings were also searched. Only randomised controlled trials conducted in adults or children with recurrent asthma where a LABA (for example, salmeterol or formoterol) or LTRA (for example, montelukast, pranlukast, zafirlukast) was added to ICS for a minimum of 28 days were considered for inclusion. Inhaled short-acting beta(2)-agonists and short courses of oral steroids were permitted as rescue medications. Other daily asthma treatments were permitted, providing the dose remained constant during the intervention period. Two reviewers independently reviewed the literature searches. Data extraction and trial quality assessment were conducted independently by two reviewers. Whenever possible, primary study authors were requested to confirm methodology and data extraction and to provide additional information and clarification when needed. Where necessary, expansion of graphic reproductions and estimation from other data presented in the paper was performed. Fifteen randomised controlled trials met the inclusion criteria; eleven trials including 6,030 participants provided data in sufficient detail to permit aggregation. All eleven trials pertained to adults with moderate airway obstruction (% predicted FEV(1) 66-76%) at baseline. Montelukast (n=9) or Zafirlukast (n=2) was compared to Salmeterol (n=9) or Formoterol (n=2) as add-on therapy to 400-565 mcg of beclomethasone or equivalent. Risk of exacerbations requiring systemic corticosteroids was significantly lower with LABA+ICS when compared to LTRA+ICS (RR= 0.83, 95% Confidence Interval (95%CI): 0.71, 0.97): the number needed to treat with LABA compared to LTRA, to prevent one exacerbation over 48 weeks, was 38 (95% CI: 23 to 247). The following outcomes also improved significantly with the addition of LABA compared to LTRA to inhaled steroids (Weighted Mean Difference; 95%CI): morning PEFR (16 L/min; 13 to 18), evening PEFR (12 L/min; 9 to 15), FEV(1) (80 mL; 60 to 100), rescue-free days (9%; 5% to 13%), symptom-free days (6%; 2 to 11), rescue beta(2)-agonists (-0.5 puffs/day; -0.2 to -1), quality of life (0.1; 0.05 to 0.2), symptom score (Standard Mean Difference -0.2; -0.1 to -0.3), night awakenings (-0.1/week; -0.06 to -0.2) and patient satisfaction (RR 1.12; 1.07 to 1.16). Risk of withdrawals due to any reason was significantly lower with LABA+ICS compared to LTRA+ICS (Risk Ratio 0.83, 95% CI 0.73 to 0.95). Withdrawals due to adverse events or due to poor asthma control, hospitalisation, osteopenia, serious adverse events, overall adverse events, headache or cardiovascular events were not significantly different between the two study groups. In asthmatic adults inadequately controlled on low doses of inhaled steroids, the addition of LABA is superior to LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and the use of rescue beta(2)-agonists.

Patients who continue to experience asthma symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Leukotriene receptor antagonists (LTRA) and long-acting beta2-agonists (LABA) agents may both be considered as add-on therapy to inhaled corticosteroids (ICS). We compare the efficacy and safety profile of adding either daily LABA or LTRA in asthmatic patients with asthma who remained symptomatic on ICS. MEDLINE, EMBASE, CINAHL databases were searched for randomised controlled trials up to and including January 2004. Reference lists of all included studies and reviews were screened to identify potentially relevant citations. Inquiries regarding other published or unpublished studies supported by the authors of the included studies or pharmaceutical companies who manufacture these agents were made. Conference proceedings of major respiratory meetings were also searched. Only randomised controlled trials conducted in adults or children with recurrent asthma where a LABA (for example, salmeterol or formoterol) or LTRA (for example, montelukast, pranlukast, zafirlukast) was added to ICS for a minimum of 28 days were considered for inclusion. Inhaled short-acting beta2-agonists and short courses of oral steroids were permitted as rescue medications. Other daily asthma treatments were permitted, providing the dose remained constant during the intervention period. Two reviewers independently reviewed the literature searches. Data extraction and trial quality assessment were conducted independently by two reviewers. Whenever possible, primary study authors were requested to confirm methodology and data extraction and to provide additional information and clarification when needed. Where necessary, expansion of graphic reproductions and estimation from other data presented in the paper was performed. Twelve randomised controlled trials met the inclusion criteria; only eight trials including 5,895 patients, provided data in sufficient details to allow aggregation. All eight trials pertained to adults with moderate airway obstruction (% predicted FEV1 66-76%) at baseline. Montelukast (n=6) or Zafirlukast (n=2) was compared to Salmeterol (n=7) or Formoterol (n=1) as add-on therapy to 400-565 mcg of beclomethasone or equivalent. Risk of exacerbations requiring systemic corticosteroids was significantly lower with LABA+ICS when compared to LTRA+ICS (RR= 0.83, 95% Confidence Interval (95%CI): 0.71, 0.97): the number needed to treat with LABA compared to LTRA, to prevent one exacerbation over 48 weeks, was 38 (95% CI: 23 to 247). The following outcomes also improved significantly with the addition of LABA compared to LTRA to inhaled steroids (Weighted Mean Difference; 95%CI): morning PEFR (16 L/min; 13 to 18), evening PEFR (12 L/min; 9 to 15), FEV(1) (80 mL; 60 to 100), rescue-free days (9%; 4 to 14), symptom-free days (6%; 2 to 11), rescue beta2-agonists (-0.4 puffs/day; -0.2 to -0.5), quality of life (0.1; 0.05 to 0.2), symptom score (Standard Mean Difference -0.2; -0.1 to -0.3), night awakenings (-0.1/week; -0.06 to -0.2) and patient satisfaction (RR 1.12; 1.07 to 1.16). Risk of withdrawals due to any reason was significantly lower with LABA+ICS compared to LTRA+ICS (Relative Risk 0.84, 95% CI 0.74 to 0.96). Withdrawals due to adverse events or due to poor asthma control, hospitalisation, osteopenia, serious adverse events, overall adverse events, headache or cardiovascular events were not significantly different between the two study groups. In asthmatic adults inadequately controlled on low doses of inhaled steroids, the addition of LABA is superior to LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and use of rescue beta2-agonists.

Tiotropium Respimat®: A Review of Its Use in Asthma Poorly Controlled with Inhaled Corticosteroids and Long-Acting β2-Adrenergic Agonists.

Tiotropium bromide (Spiriva®) solution for inhalation via the Respimat® Soft Mist™ inhaler is a long-acting anticholinergic agent approved in the EU for the add-on maintenance treatment of asthma in adults currently receiving maintenance therapy with an inhaled corticosteroid (ICS) (≥800 µg budesonide per day or equivalent) and a long-acting β2-adrenergic agonist (LABA) and who have experienced at least one severe exacerbation in the previous year. Tiotropium Respimat® added to maintenance ICS/LABA treatment significantly improved lung function after 6 months' treatment and extended the time to the first asthma exacerbation in two well-designed, replicate, phase III trials in patients with poorly controlled asthma despite treatment with an ICS (≥800 µg budesonide/day or equivalent) and a LABA. Tiotropium Respimat® was also associated with a reduced incidence of severe asthma exacerbations and an increase in the median time to asthma worsening. The drug was well tolerated in asthma patients throughout 48 weeks' treatment, with a generally similar incidence of serious adverse events in tiotropium Respimat® and placebo treatment groups. Thus, in patients with poorly controlled asthma despite receiving high-dose ICS and a LABA, tiotropium Respimat® provides a valuable treatment option.

Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children.

Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy). The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler. We last searched the Cochrane Airways Group trials register in September 2008. Randomised controlled trials in adults and children with chronic asthma. Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes. Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run-in for these studies involved withdrawal of long-acting beta(2)-agonists, and patients were recruited who were symptomatic during run-in.One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm].There was no significant difference found in fatal or non-fatal serious adverse events for any of the comparisons. Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long-acting beta(2)-agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.

The use of beta 2-adrenoceptor agonists in the treatment of bronchial asthma.

All guidelines recommend short-acting inhaled beta 2-adrenoceptor agonists as the first-line drugs in acute asthma attacks and inhaled corticosteroids as the drugs of choice when regular daily treatment is needed. Short-acting inhaled beta 2-adrenoceptor agonists are not effective in reducing nocturnal awakenings because of their short duration of action. In addition there has been an intense debate about the regular use of these drugs. This debate is reviewed. They should only be used on "as needed basis". The Swedish guidelines for the treatment of asthma were the first to recommend the new long-acting inhaled beta 2-adrenoceptor agonists at relatively early stage of the illness (800 micrograms daily of inhaled corticosteroids). Two recently completed large multicentre studies with salmeterol in asthmatics support this opinion. Both studies showed a better asthma control with a combination of a low inhaled steroid dose and salmeterol compared to a doubling of the steroid dose. In most asthmatic patients, still symptomatic on inhaled steroids doses 400 to 800 micrograms daily, a test of the addition of inhaled salmeterol is recommended. The steroid dose can be kept low and safe. However, asthmatic patients with either frequent or severe exacerbations should primarily have their steroid dose increased.

Budesonide/formoterol

Use for both maintenance and as needed treatment is also known as single maintenance and reliever therapy ( SMART) and is a well-established treatment. It has been shown to reduce asthma exacerbations that require oral corticosteroids, hospital visits better than maintenance inhaled corticosteroids alone at a higher dose, or inhaled corticosteroid at the same or higher dose with a long acting bronchodilator (LABA)), with a short-acting bronchodilator (SABA) as a reliever. More studies using budesonide/formoterol SMART in children are needed. Side effects Common (up to 1 in 10 people) Mild throat irritation Coughing Hoarseness Oral candidiasis (thrush. significantly less likely if the patient rinses their mouth out with water after inhalations) Headache Often mild, and usually disappear as the medication continues to be used: Heart palpitations Trembling Uncommon (up to 1 in 100 people)

It is the first asthma triple-combination therapy; it consists of a fixed-dose combination of three active substances (indacaterol, glycopyrronium bromide and mometasone furoate) in capsules, to be administered using an inhaler. An optional electronic sensor may also be co-packed with the product. The sensor will be attached to the base of the inhaler to collect data on the use of the inhaler by the patient. The sensor will send the data to an app on a smart phone or other suitable device. It was approved for medical use in the European Union in July 2020. Medical uses Indacaterol/glycopyrronium bromide/mometasone is indicated as a maintenance treatment of asthma in adults not adequately controlled with a maintenance combination of a long acting beta2 agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year.

Comparison between formoterol 12 microg b.i.d. and on-demand salbutamol in moderate persistent asthma.

Inhalation of on-demand salbutamol (ODS) several times daily is sometimes the only beta2-agonist prescribed in moderate persistent asthma, whereas a long-acting beta2-agonist should be added. This trial aimed to compare the efficacy of formoterol dry-powder capsule 12 microg b.i.d. (Foradil) and ODS in patients with moderate persistent asthma treated with inhaled corticosteroids, in the conditions of real practice. Two hundred and fifty-nine patients were randomized (formoterol; 130; ODS: 129) in this open, parallel-group trial. The mean increases in morning peak expiratory flow (PEF primary variable) and evening PEF over the 3-month treatment period were statistically significantly higher with formoterol: +25.7 and +24.1 l min(-1), respectively vs. +4.5 and +0.5 l min(-1) respectively with ODS. The increase in FEV1 was statistically significantly higher with formoterol at months 1 and 3. Formoterol reduced the use of salbutamol as rescue medication by two-thirds. The percentages of symptom-free days and nights statistically significantly increased with formoterol (+20% and +33% respectively), but did not significantly change with ODS. Clinically relevant and statistically significant improvement in the mean total score of the St George's Hospital Respiratory Questionnaire was observed in the formoterol group. Adverse events were similar in the two groups. The results show that treatment with formoterol has significant advantages over ODS in patients with moderate persistent asthma.

Tiotropium bromide

Tiotropium was patented in 1989, and approved for medical use in 2002. It is on the World Health Organization's List of Essential Medicines. In 2019, it was the 132nd most commonly prescribed medication in the United States, with more than 5million prescriptions. Medical uses Tiotropium is used as maintenance treatment of chronic obstructive pulmonary disease (COPD). It may also be used as an add-on therapy in people with moderate-to-severe asthma on medium to high dose inhaled corticosteroids (ICS). It is not however approved for acute exacerbations of COPD or acute worsening of asthma. Tiotropium is also used in a combination inhaler with olodaterol, a long-acting beta-agonist, for the treatment of COPD, under the brand names Stiolto and Spiolto among others. Adverse effects

The use of β2-agonist therapy before hospital attendance for severe asthma exacerbations: a post-hoc analysis.

Patterns of inhaled β2-agonist therapy use during severe asthma exacerbations before hospital attendance are poorly understood. To assess β2-agonist use prior to hospital attendance. We undertook an exploratory post hoc analysis of data from a 6-month clinical trial of 303 patients randomised to combination budesonide/formoterol inhaler according to a Single combination inhaler as Maintenance And Reliever Therapy regimen ('SMART') or fixed-dose budesonide/formoterol with salbutamol as reliever ('Standard'). Patterns of β2-agonist use for 14 days before hospital attendance with a severe asthma exacerbation were determined by electronic monitoring of inhaler use. There were 22 hospital attendances in 16 patients during the study. Seven and nine hospital attendances were eligible for analysis in the SMART and Standard groups, respectively. In both regimens, β2-agonist use increased before hospital attendance, with a median (range) maximum daily number of actuations of 14 (9 to 63) budesonide/formoterol in SMART and 46 (6 to 95) salbutamol in Standard with 4 (0 to 10) budesonide/formoterol actuations on the day of maximal salbutamol use. There was delay in obtaining medical review despite high β2-agonist use, in 9/16 patients. Different patterns of use were observed, including repeated days of no inhaled corticosteroid despite marked salbutamol use, which occurred in 3/9 patients in the Standard group. Delay in obtaining medical review in association with high β2-agonist use is common in patients before hospital presentation with severe exacerbations of asthma. The SMART regimen reduced nonadherence with inhaled corticosteroid therapy during severe exacerbations.

Long-acting beta-adrenoceptor agonist

Long-acting β adrenoceptor agonists (LABAs, more specifically, long-acting β2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β2 agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β2 agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to

Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal.

The use of a combination inhaler containing budesonide and formoterol as both maintenance and quick relief therapy (SMART) has been recommended as an improved method of using inhaled corticosteroid/long-acting beta agonist (ICS/LABA) therapy. Published double-blind trials show that budesonide/formoterol therapy delivered in SMART fashion achieves better asthma outcomes than budesonide monotherapy or lower doses of budesonide/formoterol therapy delivered in constant dosage. Attempts to compare budesonide/formoterol SMART therapy with regular combination ICS/LABA dosing using other compounds have been confounded by a lack of blinding and unspecified dose adjustment strategies. The asthma control outcomes in SMART-treated patients are poor; it has been reported that only 17.1% of SMART-treated patients are controlled. In seven trials of 6-12 months duration, patients using SMART have used quick reliever daily (weighted average 0.92 inhalations/day), have awakened with asthma symptoms once every 7-10 days (weighted average 11.5% of nights), have suffered asthma symptoms more than half of days (weighted average 54.0% of days) and have had a severe exacerbation rate of one in five patients per year (weighted average 0.22 severe exacerbations/patient/year). These poor outcomes may reflect the recruitment of a skewed patient population. Although improvement from baseline has been attributed to these patients receiving additional ICS therapy at pivotal times, electronic monitoring has not been used to test this hypothesis nor the equally plausible hypothesis that patients who are non-compliant with maintenance medication have used budesonide/formoterol as needed for self-treatment of exacerbations. Although the long-term consequences of SMART therapy have not been studied, its use over 1 year has been associated with significant increases in sputum and biopsy eosinophilia. At present, there is no evidence that better asthma treatment outcomes can be obtained by moment-to-moment symptom-driven use of ICS/LABA therapy than conventional physician-monitored and adjusted ICS/LABA therapy.

Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids.

A group of 32 patients with moderately severe, chronic asthma (mean FEV1 55% of predicted), maintained on moderately high doses of inhaled corticosteroids (mean dose 1,100 micrograms/d), participated in this double-blind, placebo-controlled crossover study. The effect on pulmonary function of adding theophylline (U, once daily Uniphyl), inhaled salbutamol (S, 200 micrograms four times per day), and their combination (C) or placebo (P) was assessed on Day 14 of each treatment phase. Patients recorded peak expiratory flow, asthma symptom severity (morning and evening), and use of rescue salbutamol inhaler in daily diaries. Mean FEV1 between 0730 and 1800 h and maximum FEV1 between 0730 and 1300 h were significantly higher on U, S, and C compared with P (p < 0.006). Morning peak flow and FEV1 (0730 h) were significantly higher on U and C compared with S and P (p < 0.01). Evening peak flow was higher on U than P (p < 0.001), and C was higher than S and P (p < 0.01). Rescue salbutamol inhaler use was significantly higher on P than on U, C, or S (p = 0.0001). Patient rating of asthma symptoms during C was significantly better than on S or P (p < 0.05). Patient rating of asthma control and study phase preference was significantly higher on combination and Uniphyl alone than on placebo, the combination also being superior to salbutamol alone. Addition of Uniphyl or a combination of Uniphyl and salbutamol significantly improves pulmonary function and asthma symptoms in patients treated with high doses of inhaled corticosteroids and as-needed beta agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma.

Maintenance treatment with long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) can relieve asthma symptoms and reduce the frequency of exacerbations, but there are limited treatment options for people who do not gain control on combination LABA/ICS. Long-acting muscarinic antagonists (LAMA) are a class of inhaled drug which have been effective for people with chronic obstructive pulmonary disease and are now becoming available for people with asthma to take alongside their LABA/ICS inhaler. To assess the effects of adding a long-acting muscarinic antagonist (LAMA) to combination long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) in adults whose asthma is not well controlled by LABA/ICS. We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to January 2016. We also searched ClinicalTrials.gov, the WHO trials portal, and reference lists of other reviews, and we contacted trial authors for additional information. We included parallel randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies met the inclusion criteria if they compared LAMA as an add-on to LABA/ICS versus LABA/ICS alone for adults with asthma. We included studies reported as full text, those published as abstract only, and unpublished data. Primary outcomes were exacerbations requiring oral corticosteroids (OCS), validated measures of asthma control, and serious adverse events (including mortality). Two review authors screened searches and independently extracted details on risk of bias and numerical data. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MD) using a random-effects model. We rated all outcomes using GRADE. We found four double-blind, double-dummy trials comparing LAMA to placebo, including 1197 people with asthma taking combination LABA/ICS. One of the trials was designed to study glycopyrronium bromide but was withdrawn prior to enrolment, and the other three all studied tiotropium bromide (mostly 5 µg once daily via Respimat) over 48 to 52 weeks. People in the trials had a mean forced expiratory volume in one second (FEV1) of 55% of their predicted value, indicating severe asthma.People randomised to take tiotropium add-on had fewer exacerbations requiring oral corticosteroids than those continuing to take LABA/ICS alone, but the confidence intervals did not rule out no difference (OR 0.76, 95% CI 0.57 to 1.02; moderate quality evidence). Over 48 weeks, 328 out of 1000 people taking their usual LABA/ICS would have to take oral corticosteroids for an exacerbation compared with 271 if they took tiotropium as well (95% CI 218 to 333 per 1000). Analyses comparing the number of exacerbations per patient in each group (rate ratio) and the time until first exacerbation (hazard ratio) were in keeping with the main result. Quality of life, as measured by the Asthma Quality of Life Questionnaire (AQLQ) was no better for those taking tiotropium add-on than for those taking LABA/ICS alone when considered in light of the 0.5 minimal clinically important difference on the scale (MD 0.09, 95% CI - 0.03 to 0.20), and evidence for whether tiotropium increased or decreased serious adverse events in this population was inconsistent (OR 0.60, 95% CI 0.24 to 1.47; I(2) = 76%).Within the secondary outcomes, exacerbations requiring hospital admission were too rare to tell whether tiotropium was beneficial over LABA/ICS alone. There was high quality evidence showing benefits to lung function (trough FEV1 and forced vital capacity (FVC)) and potentially small benefits to asthma control. People taking tiotropium add-on were less likely to experience non-serious adverse events. Tiotropium add-on may have additional benefits over LABA/ICS alone in reducing the need for rescue oral steroids in people with severe asthma. The effect was imprecise, and there was no evidence for other LAMA preparations. Possible benefits on quality of life were negligible, and evidence for the effect on serious adverse events was inconsistent. There are likely to be small added benefits for tiotropium Respimat 5 µg daily on lung function and asthma control over LABA/ICS alone and fewer non-serious adverse events. The benefit of tiotropium add-on on the frequency of hospital admission is still unknown, despite year-long trials.Ongoing and future trials should clearly describe participants' background medications to help clinicians judge how the findings relate to stepwise care. If studies test LAMAs other than tiotropium Respimat for asthma, they should be at least six months long and use accepted and validated outcomes to allow comparisons of the safety and effectiveness between different preparations.

As-needed inhaled beta2-adrenoceptor agonists in moderate-to-severe asthma: current recommendations.

Intermediate-acting inhaled beta2-agonists (e.g. albuterol [salbutamol]), once recommended for round-the-clock bronchodilation, are now recommended to be used exclusively as-needed. Guidelines advise that asthma should be controlled with anti-inflammatory therapeutic strategies so that the as-needed requirement for inhaled beta2-agonists should be infrequent; ideally less than several times per week, up to once a day for exercise, and none at night. These recommendations are based upon the recognition that asthma is primarily an inflammatory condition and that the major thrust of therapy should be anti-inflammatory, including environmental control and administration of inhaled corticosteroids (ICS), leukotriene-receptor antagonists, and possibly oral theophylline and inhaled cromones; the cromones include cromolyn sodium (sodium cromogylcate) and nedocromil. While this is the primary rationale behind the as-needed infrequent prescription of the inhaled beta2-agonist paradigm, there are a number of detrimental effects that can be seen with regularly scheduled (or frequent as-needed) use of inhaled beta2-agonists. These include tolerance to the bronchodilator and particularly the bronchoprotective effects, increased airway responsiveness to allergen, worsened asthma control, and, probably most importantly, over-reliance on an excellent symptom reliever leading to undertreatment. Any or all of these could be responsible for the demonstrated dose-response relationship between inhaled beta2-agonist overuse and death from asthma. Several controlled clinical trials, which have included many patients with at least moderately severe asthma, have failed to demonstrate any obvious advantage to the regular scheduled use of inhaled beta2-agonists compared with as-needed inhaled beta2-agonists. On the other hand, despite no obvious advantage, regular use of albuterol 1000-1200 microg/day appears to be well tolerated and reasonably safe. When asthma is treated using an as-needed, infrequent inhaled beta2-agonist, the requirements for beta2-agonists become a useful marker of whether or not the asthma is adequately controlled. When inhaled beta2-agonists are required inordinately frequently (i.e. when asthma is not adequately controlled), after ensuring compliance with ICS, the most common strategy is to add one of the long-acting inhaled beta2-agonists twice daily. On the basis of the available evidence, the as-needed intermediate-acting inhaled beta2-agonist therapeutic strategy appears appropriate for patients with moderate-to-severe asthma.

Clinical outcome of adding long-acting beta-agonists to inhaled corticosteroids.

Current asthma management guidelines state that where a patient is receiving a low to moderate dose of inhaled corticosteroids and is still experiencing symptoms the dose of corticosteroid should be increased and, if necessary, a long-acting bronchodilator should be added. Many studies have now shown that the addition of a beta2-agonist with long-acting properties is more effective at controlling asthma symptoms than increasing the dose of corticosteroid alone. The Formoterol and Corticosteroid Establishing Therapy (FACET) study was a 12-month study comparing exacerbation rates in patients treated with budesonide (100 microg or 400 microg) twice daily alone vs, treatment with budesonide (100 microg or 400 microg) twice daily plus formoterol 9 microg twice daily (delivered dose). The addition of formoterol reduced the rates of mild and severe exacerbations compared with budesonide alone, with the lowest rates seen in patients receiving high-dose budesonide and formoterol. There was no difference in the profile of exacerbations in any groups, indicating formoterol does not mask any signs of inflammation. The addition of formoterol to budesonide was also shown to result in improved lung function (as measured by peak expiratory flow rate and forced expiratory volume in 1 second), night-time awakenings and the use of as-needed medication when compared with an increase in the dose of budesonide. In all cases, increasing the dose of budesonide and addition of formoterol resulted in the most improvement and a significant increase in quality of life, measured by Asthma Quality of Life Questionnaire (AQLQ), was noted. In conclusion, the addition of formoterol to established treatment with inhaled corticosteroids provides superior asthma control compared with an increase in the dose of corticosteroid alone.

Chronic cough

Treating children who have a non-specific chronic cough with asthma medications such as inhaled beta2-agonists (e.g., salbutamol) or inhaled corticosteroids does not improve the clinical symptoms. Codeine-based cough medications are contraindicated for children under 12 years old due to the risk of respiratory suppression and the potential for opioid toxicity. Leukotriene receptor antagonist-based medications and methylxanthines are not recommended for treating children with persistent non-specific cough.

InternalMed_Harrison

Stepwise Therapy For patients with mild, intermittent asthma, a short-acting β2-agonist is all that is required (Fig. 309-8). However, use of a reliever medication more than twice a week indicates the need for regular controller therapy. The treatment of choice for all patients is an ICS given twice daily. It is usual to start with an intermediate dose (e.g., 200 μg bid of beclomethasone dipropionate [BDP]) or equivalent and to decrease the dose if symptoms are controlled after 3 months. If symptoms are not controlled, a LABA should be added, which is most conveniently given by switching to a combination inhaler. The dose of controller should be adjusted accordingly, as judged by the need for a rescue inhaler. Low doses of theophylline or an antileukotriene may also be considered as an add-on therapy, but these are less effective than LABA. In patients with severe asthma, low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting

[Salmeterol and prolonged treatment of asthma: international clinical data].

Salmeterol is an original molecule with a selective-beta-2-sympathomimetic effect which is intended to a prolonged treatment of asthma. This inhaled preparation has a long duration of action which points to its use on a BID regimen. Results of the phase III development has been assessed in 2,277 subjects. Salmeterol administered at a dose of 50 micrograms morning and evening results in a marked increase in FEV1, which remains superior to 15% by comparison with baseline 12 hours after the last dose in the majority of subjects. In the specific case of more severe asthma (FEV1 less than 50% of predicted), the use of 100 micrograms morning and evening allows for an extra-improvement in FEV1. In the majority of studies, salmeterol has resulted in an almost complete remission of the clinical symptomatology: disappearance or major diminution in the use of inhaled salbutamol administered as a rescue medication on a PRN basis (during the day and at night) and of nocturnal awakenings, global improvement of clinical scores. Daily peak expiratory flow rates (morning and night values) are considerably improved (greater than or equal to 50 l/min) with a significant reduction of daily swings. Lung function tests are also very significantly improved. Salmeterol has proved to be largely superior to the comparison medications, salbutamol taken at a dose of 200 micrograms four times a day, and optimal therapy with theophylline. Clinical acceptability of salmeterol is good and is not different from salbutamol.

Asthma

Humidified Oxygen to alleviate hypoxia if saturations fall below 92%. Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids. Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults intravenous treatment results in a reduction of hospital admissions. Low levels of evidence suggest that inhaled (nebulised) magnesium sulfate may have a small benefit for treating acute asthma in adults. Overall, high quality evidence do not indicate a large benefit for combining magnesium sulfate with standard inhaled treatments for adults with asthma. Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases. Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.

Formoterol. An update of its pharmacological properties and therapeutic efficacy in the management of asthma.

Formoterol, a selective beta 2-adrenoceptor agonist, produces effective dose-proportional bronchodilation, which persists for up to 12 hours, in patients with reversible obstructive respiratory disease. Bronchodilation is significant within minutes of inhalation, maximal within 2 hours, and at therapeutic doses is equivalent to that produced by standard doses of traditional beta 2-agonists. In single-dose studies comparing the two long-acting beta 2-agonists formoterol and salmeterol, significant bronchodilation is achieved more rapidly with formoterol than salmeterol. Duration of bronchodilation is similar with both drugs. The therapeutic efficacy of inhaled formoterol has been equal to or greater than that of salbutamol (albuterol), fenoterol and terbutaline in both short and long term clinical trials. Formoterol reduces symptoms of nocturnal asthma and reduces the need for rescue medication compared with salbutamol. Recent studies have shown that the addition of inhaled formoterol 12 or 24 micrograms twice daily to existing inhaled corticosteroid regimens improves lung function and reduces asthma symptoms compared with placebo. In one well designed study, the frequency of severe exacerbations of asthma over 12 months was decreased by adding formoterol to existing regimens of inhaled corticosteroids. Tolerance to the bronchodilator response of formoterol has not been observed in long term clinical trials. Because of its long duration of action, formoterol offers significant therapeutic advantages over shorter-acting beta 2-agonists in the treatment of nocturnal and exercise-induced asthma. Formoterol is effective in preventing exercise-induced asthma in adults and children and confers significantly more protection than salbutamol when administered 3 and 12 hours before exercise. In general, inhaled formoterol is well tolerated. The most commonly reported adverse effects, tremor and palpitations, are those traditionally associated with the use of beta 2-agonists. Oral formoterol and high doses of inhaled formoterol are associated with more adverse events than are the recommended doses of 6 to 24 micrograms. Formoterol is currently recommended for use as an alternative to increasing inhaled steroid dosage in patients whose symptoms are inadequately controlled despite therapy with low to moderate doses of inhaled steroids and intermittent short-acting beta 2-agonists, and results of recent studies support therapeutic guidelines. Long term clinical studies comparing formoterol and salmeterol have not yet been published. Further studies to evaluate the earlier use of formoterol in patients with mild to moderate asthma are needed to determine the role and long term safety of formoterol in the management of asthma.

Continuous and on demand use of bronchodilators in patients with non-steroid dependent asthma and chronic bronchitis: four-year follow-up randomized controlled study.

A previous two-year study of continuous and on demand bronchodilator therapy in patients with moderate asthma and chronic bronchitis showed a deterioration in lung function in those on continuous therapy. A two-year follow-up study was undertaken of patients who had been shown in the previous study to have non-steroid dependent (mild) asthma and chronic bronchitis, in order to investigate the effect of continuous and on-demand treatment with bronchodilator therapy. Patients for the study were drawn from 29 general practices in the catchment area of the University of Nijmegen, the Netherlands. A total of 83 patients (27 with asthma and 56 with chronic bronchitis) were selected from a group of 160 patients who had completed the previous two-year bronchodilator trial. During these first two years the selected subjects had been shown to be non-steroid dependent (no rapid decline in lung function and a low number of exacerbations of their condition per year), and they were followed up for another two years of treatment with bronchodilator therapy. At the start of the four-year study, patients were randomly assigned to one of two parallel treatment groups: continuous treatment (dry powder inhalations of either salbutamol 1600 micrograms or ipratropium bromide 160 micrograms daily) or treatment on demand (only during exacerbations or periods of dyspnoea). Outcome parameters were the annual decline in lung function, changes in peak flow rate, bronchial hyper-responsiveness, exacerbation rate, respiratory symptoms and reported health. After correction for possibly confounding variables and for regression to the mean, the decline in lung function was 49 ml year in patients taking bronchodilators continuously and 51 ml year in patients using bronchodilators on demand, irrespective of the drug use. Continuously treated patients, whether suffering from asthma or chronic bronchitis, did not differ from patients treated on demand with respect to mean morning peak flow rate, diurnal (and week to week) variation of the peak flow rate, bronchial hyper-responsiveness, exacerbation rate and reported health. There was no difference between the long-term effects of salbutamol and ipratropium. Continuous use of bronchodilators over four years in patients with non-steroid dependent asthma or chronic bronchitis does not increase the decline in lung function which had been observed previously in patients with moderate asthma or chronic bronchitis during two years of continuous treatment with bronchodilators.

Cessation of long-term treatment with inhaled corticosteroid (budesonide) in children with asthma results in deterioration. The Dutch CNSLD Study Group.

Inhaled corticosteroid has been shown to be effective in the management of asthma. However, there is a lack of studies that assess the effect of cessation after long-term treatment with inhaled corticosteroid. This question was addressed in 28 children with stable asthma, aged 11 to 18 yr of age, who had completed 28 to 36 months of treatment with inhaled corticosteroid (budesonide 200 micrograms 3 times/day) and inhaled beta-2-agonist (salbutamol 200 micrograms 3 times/day). The children were randomized in a 1:2 ratio in a double-blind study either to continue budesonide (n = 8) during a period of 6 months or to decrease the dose of budesonide (n = 20) within 2 months, followed by placebo for 4 months. Treatment with salbutamol 600 micrograms daily was continued in both groups. Eight children from the tapering-off group withdrew, mainly due to symptoms of asthma, compared with none in the continuous treatment group. Five patients in the tapering-off group experienced exacerbations for which prednisolone was given, compared with none in the continuous treatment group. After tapering-off, symptoms of asthma and additional bronchodilator use increased, and both FEV1% predicted and PD20 histamine (provocation dose of histamine causing a 20% fall in FEV1) decreased, whereas these all remained unchanged in the group that continued treatment with inhaled corticosteroid. We conclude that in this study long-term treatment with 600 micrograms budesonide daily suppressed underlying mechanisms of asthma, but did not cure the disease.

Add-on tiotropium versus step-up inhaled corticosteroid plus long-acting beta-2-agonist in real-world patients with asthma.

<bBackground:</b A step-up approach (increasing inhaled corticosteroid [ICS] dose and/or add-on treatment) is recommended for asthma that is uncontrolled despite ICS plus long-acting beta-2-agonist (LABA) combination treatment. Understanding the impact of different treatment options on health outcomes can help guide treatment decision-making. <bObjective:</b To compare the effectiveness of add-on tiotropium 1.25 µg (two puffs once daily) versus an increased ICS plus LABA dose in a real-world cohort of patients with asthma initiated on ICS plus LABA. <bMethods:</b De-identified data from patients ages ≥12 years and with asthma who were initiated on ICS plus LABA, and then had tiotropium added (Tio group; index date) or an ICS plus LABA dose increased (inc-ICS group; index date) were collected from two medical and pharmacy claims data bases (2014-2018). To account for population/group differences, propensity score matching was performed. The primary end point was the exacerbation risk after the index date. Secondary end points included exacerbation rates 6 and 12 months postindex, health-care resource utilization, costs, and short-acting beta-2-agonist (SABA) refills 12 months postindex. <bResults:</b Overall, 7857 patients (Tio group, 2619; inc-ICS group, 5238) were included. The exacerbation risk was 35% lower in the Tio group than in the inc-ICS group (hazard ratio 0.65 [95% confidence interval, 0.43-0.99]; p = 0.044). Exacerbation rates in the Tio group also were significantly lower within 6 and 12 months postindex (64% and 73%, respectively). All-cause and asthma-related emergency department (ED) visits were 47% and 74% lower, respectively (p < 0.0001 for both), and all-cause and asthma-related hospitalizations were 48% (p < 0.01) and 76% (p < 0.001) lower, respectively, in the Tio group. Also, significantly fewer patients in the Tio group versus the inc-ICS group required SABA refills (56% versus 67%, p < 0.0001). <bConclusion:</b Add-on tiotropium significantly decreased the risk and rate of exacerbations, decreased all-cause and asthma-related ED visits and hospitalizations, and reduced SABA refills compared with increasing the ICS plus LABA dose. The findings supported the use of add-on tiotropium for patients with uncontrolled asthma taking ICS plus LABA.

Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma.

Long-acting inhaled beta2-adrenergic agonists are recommended as 'add-on' medication to inhaled corticosteroids in the maintenance therapy of asthmatic adults and children aged two years and above. To quantify in asthmatic patients the safety and efficacy of the addition of long-acting beta2-agonists to inhaled corticosteroids on the incidence of asthma exacerbations, pulmonary function and other measures of asthma control. We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers, until April 2004. RCTs were included that compared the addition of inhaled long-acting beta2-agonists to corticosteroids with inhaled corticosteroids alone for asthma therapy in children aged two years and above and in adults. Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of asthma exacerbations requiring systemic corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptom scores, adverse events and withdrawal rates. Of 594 identified citations, 49 trials met the inclusion criteria: 27 full-text publications, one unpublished full-text report and 21 abstracts. Twenty-three citations (21 abstracts and two full-text publications) provided data in insufficient detail, 26 trials contributed to this systematic review. All but three trials were of high methodological quality. Most interventions (N = 26) were of four-month duration or less. Eight trials focused on children and 18 on adults, with participants generally symptomatic with moderate airway obstruction despite their current inhaled steroid regimen. If a trial had more than one intervention or control group, additional control to intervention comparisons were considered separately. Formoterol (N = 17) or salmeterol (N = 14) were most frequently added to low-dose inhaled corticosteroids (200 to 400 microg/day of beclomethasone (BDP) or equivalent). The addition of a daily long-acting beta2-agonist (LABA) reduced the risk of exacerbations requiring systemic steroids by 19% (relative risk (RR) 0.81, 95% CI 0.73 to 0.90). The number needed to treat for one extra patient to be free from exacerbation for one year was 18 (95% CI 13 to 33). The addition of LABA significantly improved FEV1 (weighted mean difference (WMD) 170 mL, 95% CI 110 to 240) using a random-effects model, increased the proportion of symptom-free days (WMD 17%, 95% CI 12 to 22, N = 6 trials) and rescue-free days (WMD 19%, 95% CI 12 to 26, N = 2 trials). The group treated with LABA plus inhaled corticosteroid showed a reduction in the use of rescue short-acting beta2-agonists (WMD -0.7 puffs/day, 95% CI -1.2 to -0.2), experienced less withdrawals due to poor asthma control (RR 0.5, 95% CI 0.4 to 0.7) and less withdrawals due to any reason (RR 0.9, 95% CI 0.8 to 0.98), using a random-effects model. There was no group difference in risk of overall adverse effects (RR 0.98, 95% CI 0.92 to 1.05), withdrawals due to adverse health events (RR 1.29, 95% CI 0.96 to 1.75) or specific adverse health events. In patients who are symptomatic on low to high doses of inhaled corticosteroids, the addition of a long-acting beta2-agonist reduces the rate of exacerbations requiring systemic steroids, improves lung function, symptoms and use of rescue short-acting beta2-agonists. The similar number of serious adverse events and withdrawal rates in both groups provides some indirect evidence of the safety of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids.

Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids.

Current guidelines on asthma management recommend the early use of inhaled corticosteroids. Recent studies of patients with moderate to severe asthma show that the addition of salmeterol is superior to a further increase of the steroids. In this study with adult, mild persistent asthma patients, we compared the effects of adding salmeterol 50 microg b.i.d. versus beclomethasone dipropionate (BDP) 200 microg b.i.d. (both via Diskhaler dry powder inhaler) to the low-dose inhaled steroids. A double-blind, randomized, parallel-group study was conducted with a run-in period of 2 weeks and a treatment period of 12 weeks. Patients (n = 233) were randomized with a peak expiratory flow (PEF) reversibility of 22 +/- 10% (mean +/- SD) in the run-in period. The morning PEF was 84 +/- 17% predicted and the age was 42 +/- 14 years (45% males). The average prestudy inhaled steroid dose was 361 microg daily. Within a week of salmeterol treatment the daily PEF recordings reached maximal levels. At the end of the treatment period the evening PEF remained significantly better in the salmeterol group than in the BDP group (p = 0.036). The PEFs, measured at the general practitioners' (GPs') office, were at least 95% of the predicted values and the post-salbutamol values at the end of both treatments. However, the salmeterol group had already obtained this level after 2 weeks and differed significantly from the beclomethasone group (p = 0.003 for percent predicted and p = 0.0007 for post-salbutamol PEF values). The symptom scores and the use of rescue medication showed a similar profile. Quality of life improved with both treatments, but without significant statistical differences between the groups. The frequency of adverse events, typical for beta2-agonists, was low and showed no differences between the groups. These results showed that the addition of salmeterol is at least as effective as adding beclomethasone in normalizing peak flows and improving asthma control in mild persistent asthma patients. Furthermore, salmeterol has a much faster onset of action.

[Comparative study] of beclomethasone and budesonide, with same posology (400 micrograms every 12 hours), in the control of cortico-dependent intrinsic asthma].

Inhaled steroids have rendered an undoubtful benefit in the control of airway inflammation of the asthmatic patients. Our objective was to compare clinical efficacy between budesonide (BUD) and beclomethasona depropionate (BDP), when administered at equal doses (800 micrograms/24 hours). A two ways crossed open clinical trial was designed. Thirty-three steroid dependent chronic asthmatic patients (18 females, 15 males) were included. Ages ranged from 29 to 73 years (mean = 52.5 +/- 11.7). All subjects suffered a severe asthma, with several years of activity (mean = 11.7 +/- 7.8), insufficiently controlled by inhaled steroids and bronchodilators, who required regular systemic steroids supply. The parameters compared were: the patients subjective symptoms punctuation (cough, expectoration, thoracic noises, exercise induce dyspnea and dyspnea at rest), salbutamol needs (number of inhalations/day), additional prednisone needs, sputum eosinophil counts, FEV1 measurement and inespecific bronchial reactivity control (PD20 methacoline). After a baseline week patients received one of the drugs for 6 weeks and, after a lavage week, the other drug was administered for another 6 weeks. All patients improved with both therapies. We got the following conclusions: 1) a significative decrease in salbutamol (p < 0.05-0.001) and prednisone needs (p < 0.05-0.001); 2) this decrease has been more important during BUD therapy, although without significative differences; 3) no significant variations in sputum eosinophils, FEV1 or bronchial reactivity were observed; 4) both drugs, when administered at equal doses, have probed to be equally effective in severe steroid dependent asthma control.

The effects of long-acting β2-agonists plus inhaled corticosteroids for early reversibility in patients with airway obstruction.

Salbutamol, as a short-acting β2-agonist, was popularly used in the past for detection of reversibility in patients with airway obstruction when it was the only drug available in the treatment of airway obstruction. Today, the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids are the first choice of therapy, with or without the presence of reversibility, in patients with airway obstruction. We aimed to compare the efficacy of salbutamol and long acting β2-agonists plus inhaled glucocorticoids for early reversibility test in patients with airway obstruction. Symptomatic patients (cough, dyspnea, and/or wheezing) with airway obstruction according to pulmonary function testing (FEV1/FVC value less than 70% of expected) who had never used bronchodilators before or had not received short- or long-acting inhaled bronchodilator therapy within the most recent 12 hours were evaluated. Reversibility measurements were made by administering the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids after 15 minutes. A total of 90 patients were evaluated. The mean age of patients was 57.3±17.7 (range, 8-88) years and the male-to-female ratio was 69/21. The baseline pulmonary function test results were mean FVC; 2,747±1,181 mL and 74.7%±21.4%, mean FEV1; 1,716±825 mL and 57.5%±19.0%, mean FEV1/FVC; 61.4%±7.4%. The bronchodilator drugs given before reversibility testing were as salmeterol/fluticasone (FTC/SAL), formoterol/budesonide (BUD/FOR), beclomethasone dipropionate/formoterol (BDP/FOR) and salbutamol (SLB) in 24, 22, 24 and 20 patients, respectively. The reversibility was positive in 33 (36.7%) patients. The absolute change and percentage of change in mean FEV1 were 206±252 mL, 13.2%±16.6% for FTC/SAL group, 273±201 mL, 14%±8% for BUD/FOR group, 240±151 mL, 18.7%±15.9% for BUD/FOR groupand 171±116 mL, 13.3%±11.8% for SLB group. There was no statistically significant for reversibilty results between LABAs/inhaledsteroids and SLB group. And the patients with positivere versibility test were significantly higher in both of BUD/FOR and BDP/FOR groups than SLB group. We think that performance of an early reversibility test using the combination of a LABA and an inhaled corticosteroid for treatment would enhance both the education of the patient in using the device and the reliability of the drug. And, we suggest that: "you should make the reversibility test with Long-Acting β2-Agonists plus Inhaled Corticosteroids which used in treatment of obstructive lung diseases".

Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease.

Spirometry before and after an inhaled beta agonist or a course of oral prednisolone is widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. How many of these patients have a response and how the response to beta agonists relates to the response to corticosteroids is not clear. In 127 outpatients (mean (SD) FEV1 0.92 (0.38) 1) who had a clinical diagnosis of chronic obstructive lung disease (continuous breathlessness for more than six months and an FEV1/forced vital capacity (FVC) ratio less than 60%) and who appeared to be stable, the change in FEV1 was measured after salbutamol 200 micrograms from a metered dose inhaler and 5 mg from a nebuliser. Symptoms and spirometric values were recorded before and after two weeks of oral prednisolone 30 mg. Reversibility was defined as a response in FEV1 of 15% or more from baseline alone and as a 15% change and a minimum increase of at least 200 ml. The latter gave results that showed greater internal consistency between the drug regimens. On the basis of this criterion 56 patients (44%) had no response to salbutamol or prednisolone, 71 responded to salbutamol (including all 27 steroid responders), and 25 patients had a response to salbutamol 5 mg but not to 200 micrograms. In general, the largest increase in FEV1 after salbutamol occurred in the subjects with greatest improvement after prednisolone. Subjects showing a response in FEV1 after two weeks' prednisolone had a fall in total symptom score, unlike those who had no response to any treatment or a response to salbutamol only. These data show that reversibility in response to beta agonists is common in patients diagnosed on clinical grounds as having stable chronic obstructive lung disease, that it can be substantial, and that it is best detected by using a larger dose of salbutamol. Salbutamol responders were those most likely to improve after a trial of oral prednisolone. Allowance should be made for the variability of FEV1 in the calculation of the percentage response at low baseline values (less than 1 litre).