Long-acting Anticholinergic Agent Research Articles

The Treatment of Mild and Moderate Asthma in Adults.

Asthma is a chronic inflammatory airway disease that usually causes variable airway obstruction. It affects 5-10% of the German population. This review is based on relevant publications retrieved by a selective search, as well as on national and international guidelines on the treatment of mild and moderate asthma in adults. The goal of treatment is to attain optimal asthma control with a minimal risk of exacerbations and mortality, loss of pulmonary function, and drug side effects. This can be achieved with a combination of pharmacotherapy and non-drug treatment including patient education, exercise, smoking cessation, and rehabilitation. Pharmacohterapy is based on inhaled corticosteroids (ICS) and bronchodilators. It is recommended that mild asthma should be treated only when needed, either with a fixed combination of ICS and formoterol or with short-acting bronchodilators. For moderate asthma, maintenance treatment is recommended, with an inhaled fixed combinations of ICS and long-acting beta-mimetics, possibly supplemented with longacting anticholinergic agents. Allergen immunotherapy, i.e., desensitization treatment, should be considered if the allergic component of asthma is well documented and the patient is not suffering from uncontrolled asthma. Asthma control should be monitored at regular intervals, and the treatment should be adapted accordingly. The treatment of asthma in adults should be individually tailored, with anti-inflammatory treatment as its main component.

A Review of Respiratory Biologic Agents in Severe Asthma.

Asthma is a common but complex chronic inflammatory heterogeneous lung disease, punctuated by the pathophysiological phenomenon of airway narrowing, coupled with symptoms of wheezing and coughing. The mechanism behind these symptoms is due to migration of eosinophils, mast cells, and CD4 T-helper cells into the submucosa of the airway, leading to hyperresponsiveness to common allergens, microorganisms, oxidants, pollutants, and consequently, airway remodeling. There is evidence that this migration is mediated by inflammatory cytokines derived from T-helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2), such as interleukins 4, 5, and 13. These cytokines lead to an increase in immunoglobulin E (IgE) production. Additionally, thymic stromal lymphopoietin (TSLP) released from airway epithelium can activate Th2 cells, innate lymphoid cells, or both. All have proven significant in the promotion of chronic airway inflammation and remodeling. In the past, most treatment strategies for this condition focused on two drug classes: β2 agonists (both short- and long-acting), and inhaled corticosteroids. Other treatments have included maintenance drugs, such as leukotriene receptor antagonists, long-acting anticholinergic agents, and theophylline. None of these, however, directly impact the interleukin or IgE pathways in a meaningful manner. Clinical trials of novel agents impacting these pathways have demonstrated efficacy and improved outcomes in asthma exacerbations, control, and forced expiratory volume in 1 second (FEV1) in patients with severe asthma. Future treatments in asthma will focus on drugs that target these aforementioned cytokines.

Management of Breathlessness in Palliative Care: Inhalers and Dyspnea-A Literature Review.

IntroductionDyspnea is prominently observed in palliative care (PC). Dyspnea can be multifactorial, primarily caused by obstructive or restrictive lung diseases or secondarily induced by various comorbidities. Numerous interventions exist, with route of administration and efficacy requiring further discussion. Despite opioids being the first line of treatment, their adverse effects lead to reluctance on the side of patients to take them, creating limitations in patient management planning.ObjectivesThis paper reviews and highlights the role of inhalers for dyspnea management in PC.MethodsThe CINAHL, CENTRAL, and OVID databases were searched for scholarly articles on the role of inhalers in dyspnea management from 1998 to the present. A grey literature Internet search was also performed via Google, the World Health Organization, and CareSearch. Twenty-five articles relevant to the subject at hand were located and summarized. The Cochrane Systematic Reviews of Health Promotion and Public Health Interventions Handbook was consulted for structuring.ResultIsolated bronchodilators can be effective in dyspnea management. However, combination with opioids leads to a 52% reduction of dyspnea, demonstrating efficacy of their combined use. There is a role for conventional inhalers not only in patients afflicted with chronic obstructive pulmonary disease, but also in those where obstruction is reversible, and in cases of dyspnea not yet diagnosed.ConclusionInhalers can be utilized as adjuvant therapy to opioids, to limit opioid use, augment responses to dyspnea, and/or minimize opioid side effects, especially in opioid-naïve patients. Correct administration can increase the efficacy of short-acting beta-agonists, long-acting beta-agonists, short- and long-acting anticholinergic agents, and inhaled corticosteroids, achieving reduction and alleviation of dyspnea.

The delicate choice of optimal basic therapy for multimorbid older adults: A cross-sectional survey.

Clinical practice guidelines are useful to suggest pharmacological therapies for the treatment of single chronic diseases. However, there is little guidance for multimorbidity, and specific quality measures for people with multimorbidity that can be used at a population level are lacking. To describe what pharmacists and geriatricians consider to be an optimal basic pharmacological therapy for an older individual with type 2 diabetes (DM), chronic obstructive pulmonary disease (COPD) and heart failure (HF). An online cross-sectional survey among 162 pharmacists and geriatricians, in Quebec, Canada, was performed. Participants were invited to choose, from a list of 32 medications or classes, the optimal basic therapy for an individual aged 65-75 years with the 3 chronic diseases. Descriptive statistics were used to calculate the median number of medications chosen and the proportions of participants who chose each medication, according to the participant's specialty. A Kruskall-Wallis test was performed to detect whether there were differences in the median number of medications recommended according to speciality. There was little consensus on the optimal basic pharmacological therapy for this hypothetical multimorbid individual, with 157 different combinations provided by the 162 participants. Nevertheless, 5 classes were chosen by at least 75% of the participants: metformin, long-acting anticholinergic agents, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), beta-blockers, and short-acting beta-agonists. The median number of recommended medications was 10 (interquartile range [IQR]: 6-13). There was a statistically significant difference between specialties (p = 0.0396). Geriatricians recommended the lower median number of medications, 7 (IQR: 5-10). At least half of the participants considered polypharmacy (≥10 medications) inevitable for an optimal basic treatment of DM, COPD and HF. The heterogeneity of responses raises issues when considering quality indicators in population-based studies.

Prophylactic penehyclidine inhalation for prevention of postoperative pulmonary complications in high-risk patients: study protocol of a randomized controlled trial

BackgroundPostoperative pulmonary complications (PPCs) are major causes of morbidity, mortality, and prolonged hospital stay in patients after surgery. Using effective strategies to prevent its occurrence is essential to improve outcome. However, despite various efforts, the incidence of PPCs remains elevated in high-risk patients. Anticholinergic inhalation is used to reduce high airway resistance and improve pulmonary function; it may be helpful to decrease the risk of PPCs. Penehyclidine is a long-acting anticholinergic agent which selectively blocks M1 and M3 receptors. We hypothesize that, in high-risk patients, prophylactic penehyclidine inhalation may decrease the incidence of PPCs.MethodsThis is a randomized, double-blind, placebo-controlled trial with two parallel arms. A total of 864 patients at high risk of PPCs will be enrolled and randomized to receive prophylactic inhalation of either penehyclidine or placebo (water for injection). Study drug inhalation will be administered from the night (7 pm) before surgery until the second day after surgery, in an interval of every 12 hours. The primary outcome is the incidence of PPCs within 30 days after surgery. Secondary outcomes include the time to onset of PPCs (from end of surgery to first diagnosis of PPCs), the number of PPCs (indicates the number of diagnosed individual PPCs), the incidence of postoperative extrapulmonary complications, the length of stay in hospital after surgery, and the 30-day all-cause mortality.DiscussionResults of the present study will provide evidence to guide clinical practice in using prophylactic inhalation of an anticholinergic to prevent PPCs in high-risk patients.Trial registrationThe study was registered prospectively in Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR-IPC-15006603) on 14 May 2015 and retrospectively in ClinicalTrials.gov (NCT02644876) on 30 December 2015.

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.

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抗コリン薬の吸入で肺囊胞が縮小したBirt-Hogg-Dubé症候群の1例

Long-acting Inhaled Bronchodilator and Risk of Vascular Events in Patients With Chronic Obstructive Pulmonary Disease in Taiwan Population.

A combination of long-acting anticholinergic agents (LAACs) and long-acting β2-adrenergic receptor agonist (LABA) is effective in improving lung function in chronic obstructive pulmonary disease (COPD) compared with monotherapy. However, evidence on whether this combination increases the incidence of stroke or other cardiac events remains sparse. The objective of the present study was to investigate the incidence of stroke and other cardiovascular diseases in COPD patients treated with LAAC, LABA, or a combination of the 2.We conducted this population-based study using the Taiwan National Health Insurance Research Database (1997–2008), identifying COPD patients and their prescribed medication from the International Classification of Disease, Ninth Revision codes 490–492 or 496. A multivariate Cox proportional-hazards model was used to compare the risk of stroke and other cardiovascular diseases over the 11-year period after treatment with LAAC or LABA only or in combination.Of the 596 COPD patients (mean age 70 y), 196 were treated with LAAC, 318 with LABA, and 82 were treated with a combination. The overall incidence of stroke (8.53%) significantly increased in the combination group compared with LAAC (2.04%) or LABA (1.26%) only. In the Cox regression analysis, the adjusted hazard ratio over the 11-year survey period for stroke in patients treated with the combination compared with LABA only was 1.04 (95% confidence interval, 1.06–2.99) and for LAAC, it was 0.31 (95% confidence interval, 0.02–2.32).This cohort study using a large health insurance database showed that treating patients with COPD, with a combination of LAAC and LABA, may be associated with an increased hazard of stroke compared with treatment with either agent alone. We should be particularly cautious about comedication of LAAC and LABA in patients with COPD.

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.

Long-acting anticholinergic agents in patients with uncontrolled asthma: a systematic review and meta-analysis.

A novel effective treatment is necessary for severe asthma. To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β₂-agonists. A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included. Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events. The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma.

P231 Once-daily Tiotropium Respimat(R): Safety And Tolerability Results From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Tiotropium Respimat ® , a once-daily long-acting anticholinergic agent, is effective as add-on to inhaled corticosteroids (ICS) ± a long-acting β2-agonist (LABA) in adults with symptomatic asthma. Safety and tolerability are key issues in the development of new therapies or established therapies in new disease areas. We present key safety data from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium Respimat ® versus placebo in adults with symptomatic asthma. Methods: Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results: 3476 patients were treated. Incidence of any adverse events (AEs), serious AEs and investigator-defined drug-related AEs was similar across treatment groups within each trial. AEs reported by ≥5% of patients were similar across all treatment groups within each trial (Table). The number of cardiovascular AEs was small in all five studies and comparable between tiotropium Respimat ® and placebo. No deaths occurred in any trial. Conclusion: Once-daily tiotropium Respimat® is well tolerated and comparable with placebo in adult patients with symptomatic asthma receiving at least low- to high-dose ICS.

Tiotropium Respimat(®) Soft Mist™ inhaler: a review of its use in chronic obstructive pulmonary disease.

The long-acting anticholinergic agent tiotropium bromide (Spiriva(®)) is available as a solution for inhalation via Respimat(®) Soft Mist™ Inhaler in the EU and various other countries for the treatment of chronic obstructive pulmonary disease (COPD). With the Respimat(®) Soft Mist™ Inhaler there is improved lung deposition of drug (allowing a reduced dosage compared with tiotropium HandiHaler(®)), the delivered drug dose is independent of inspiratory effort and the prolonged duration of the aerosol cloud should make the co-ordination of actuation and inhalation easier. In patients with COPD, tiotropium Respimat(®) improved lung function, COPD exacerbations, health-related quality of life and dyspnoea and was at least as effective as tiotropium HandiHaler(®). Tiotropium Respimat(®) was generally well tolerated in patients with COPD, with anticholinergic adverse events among the most commonly reported adverse events. In the TIOSPIR trial, tiotropium Respimat(®) was noninferior to tiotropium HandiHaler(®) in terms of all-cause mortality, and the risk of cardiovascular mortality or major adverse cardiovascular events did not significantly differ between the two treatment groups. In conclusion, tiotropium Respimat(®) Soft Mist™ Inhaler is a useful option for the treatment of patients with COPD.

Determinants of Long-Term Persistence with Tiotropium Bromide for Chronic Obstructive Pulmonary Disease

Tiotropium bromide, a long-acting anticholinergic agent, improves pulmonary function and quality of life of patients suffering from chronic obstructive pulmonary disease (COPD). We retrospectively examined the factors that determine the long-term persistence with tiotropium bromide. Among 6,301 patients who underwent pulmonary function tests in our pulmonary clinic between 2006 and 2009, 644 met the following criteria: 1) age > 40 years, 2) ≥ 20 pack-years smoking history, and 3) forced expiratory volume in 1 sec / forced vital capacity ratio < 0.7. The clinical information, including the prescription of tiotropium, was obtained from the patients’ records. Tiotropium was administered to 255 patients (40%), of whom 48 (19%) discontinued treatment within 1 year, and 65 (25%) discontinued treatment within the median observation period of 32 months. The drug was discontinued because of ineffectiveness in 35 patients (73%), and because of adverse drug effects in 13 patients (27%). Young age, current smoking, absence of respiratory symptoms alleviation, and less severe disease characterized by a) mild airflow limitation, b) mild to moderate emphysema, or c) no exacerbation of COPD during the 1st year of treatment were predictors of drug discontinuation.

Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: A randomised dose-ranging study

Tiotropium, a once-daily long-acting anticholinergic agent, has been shown to be an efficacious and safe add-on treatment for adults with symptomatic asthma, despite treatment with inhaled corticosteroids (ICS). A large proportion of asthmatic adolescents have symptomatic disease despite a wide range of therapeutic options. We investigated the efficacy and safety of three doses of tiotropium, administered in the evening (via Respimat(®) SoftMist™ inhaler), versus placebo in asthmatic adolescents symptomatic despite ICS treatment. This randomised, double-blind, placebo-controlled, incomplete crossover study evaluated once-daily tiotropium 5μg, 2.5μg and 1.25μg versus placebo in three 4-week treatment periods. Primary efficacy end point was change in peak forced expiratory volume in 1swithin 3hpost-dose from baseline (peak FEV1(0-3h)). From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0-3h) response for tiotropium 5μg was significantly greater versus placebo (p=0.0043). Trough FEV1 responses were significantly greater for tiotropium 5μg (p<0.00001) and 1.25μg (p=0.0134) versus placebo, but not for 2.5μg (p=0.0975), while FEV1 area under the curve(0-3h) responses were significant for all doses (p=0.00001-0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose-dependent observations. The majority of adverse events were mild to moderate in intensity. This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. ClinicalTrials.gov identifier; NCT01122680.

Tiotropium in the treatment of patients with asthma.

Asthma is a chronic disease with a significant disease burden, and many patients fail to achieve disease control despite recommended medical therapy. Recent evidence suggests that there may be benefits to the use of the long-acting anticholinergic agent tiotropium in patients with asthma. We performed a systematic review of the literature to determine the role of tiotropium in management of adult patients with asthma. In six studies, 1773 patients were randomized and 1057 received tiotropium as an intervention. The mean prebronchodilator forced expiratory volume in 1 second was 60.1%. All six studies reported a small but statistically significant improvement in spirometry when using tiotropium as compared with the control. Improvement was reported in patients with both moderate and severe asthma, patients uncontrolled on previous regimens, patients treated with low- to high-dose inhaled corticosteroids regimens, and patients treated with and without long-acting β-agonist therapy. Five studies evaluated clinical outcomes with tiotropium with variable success rates. Although a large randomized trial demonstrated a reduction in the frequency of severe asthma exacerbation with tiotropium, there is insufficient evidence to support the argument that tiotropium therapy leads to improvements in asthma symptom measures, asthma control days, asthma-related quality-of-life-scores, or rescue inhaler use. There is strong evidence supporting improvement in spirometry and asthma exacerbations with tiotropium in patients with moderate and severe asthma; therefore, tiotropium may be an effective intervention in patients with asthma.

Impact of theophylline/corticosteroid combination therapy on sputum hydrogen sulfide levels in patients with COPD

To the Editor: Hydrogen sulfide (H2S) has emerged as a new and important endogenous regulator of inflammation in recent years [1] and may also protect from emphysema induced by cigarette smoke exposure [2]. We have also recently shown that H2S can inhibit airway smooth muscle cell proliferation and inflammatory mediator release in vitro [3]. Serum levels of H2S positively correlate with the decline in lung function in chronic obstructive pulmonary disease (COPD) and were significantly lower in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients compared with those in GOLD I [4]. Existing therapies for COPD, such as corticosteroids or long-acting anticholinergic agents, may reduce the exacerbation rate but do not significantly slow disease progression. A previous study has shown that theophylline alone had no impact on serum H2S levels and is of limited value in the management of stable COPD [5]. Interestingly, sputum H2S measured in patients with asthma correlated with sputum neutrophil counts and the degree of airflow obstruction measured by forced expiratory volume in 1 s (FEV1) % predicted [6]. Moreover, combination therapy of an inhaled glucocorticoid with low-dose theophylline has been shown to attenuate airway inflammation in patients with COPD and reverse glucocorticoid resistance [7]. We therefore investigated whether the combination of inhaled corticosteroid and low-dose theophylline, as opposed to …

Bronchodilator combinations for COPD: real hopes or a new Pandora’s box?

Chronic obstructive pulmonary disease (COPD) is a difficult-to-treat condition with multiple outcomes with which to assess new drugs. Most treatments are symptomatic; none, at present, interfere with the natural history of the disease (except smoking cessation) and little is known about the factors able to predict a response. New anti-inflammatory agents able to modify the course of the disease may emerge, but further research is needed to assess their effects [1]. New drugs have to improve lung function and, most importantly, clinical outcomes with a demonstrated long-term safety at a reasonable cost. The crucial issues when combining bronchodilators are to investigate the magnitude of observed effects versus single agents and whether a “responding phenotype” can be identified. These questions are relevant for all the actors in the COPD field, from patients to health authorities, and will allow the definition of whether and how the new treatment approach will integrate with the current treatment guidelines. In this issue of the European Respiratory Journal , Bateman et al. [2] report results of the SHINE study, which assessed QVA149, an association of indacaterol, a long-acting β2-agonist (LABA) and glycopyrronium, a long-acting anticholinergic agent (LAMA), in a dry powder capsule device. This 26-week, large (n = 2144), randomised controlled trial (RCT) in patients with moderate-to-severe COPD compared QVA149 to its monocomponents, open-labelled tiotropium and placebo, all administered once daily. QVA149 improves dyspnoea and health-related quality of life, with statistically significant superiority over placebo and tiotropium, but not over its monocomponents. QVA149 was significantly more effective than its monocomponents, but not tiotropium in terms of lung function (as measured using trough forced expiratory volume in 1 s (FEV1)). These data extend results of RCTs evaluating QVA149 effect on lung function [3, 4], short-term (14 …

Long-acting anticholinergics in the treatment of asthma

The use of anticholinergic medications is well established as maintenance therapy for chronic obstructive pulmonary disease (COPD). There is a growing interest in the use of anticholinergic medications in the treatment of moderate to severe asthma. The purpose of this review is to summarize the scientific evidence for the use of anticholinergic therapy in the management of asthma. Early case reports and small studies evaluated the use of the anticholinergic agent, tiotropium bromide, as maintenance therapy in asthma. Included in this review are several recent clinical trials which provide additional evidence for the use of tiotropium as add-on therapy for asthma. The use of tiotropium was demonstrated to be superior to doubling the dose of an inhaled corticosteroid (ICS) and more effective than placebo based on change in morning peak expiratory flow (PEF). Two large multinational trials provide evidence for the use of tiotropium in a subset of asthmatic patients who have not achieved control using combination therapy with an ICS and a long-acting β2 agonist (LABA). The use of the long-acting anticholinergic agent, tiotropium, as maintenance of therapy in asthma, has been shown to be effective in some patients with moderate to severe asthma who are uncontrolled on combination therapy with ICS and LABA. Further studies are needed to better define which phenotypic subset of patients would benefit from the use of tiotropium.

The Emerging Role of Tiotropium for Patients with Asthma

To review clinical data on the use of the long-acting anticholinergic agent tiotropium in patients with asthma. A literature search was performed via EMBASE and MEDLINE (1966-November 2012). The search was limited to human data published in the English language. Search terms included asthma, tiotropium, and long-acting anticholinergics. Relevant information related to the use of tiotropium in patients with asthma was reviewed. Randomized controlled trials and open-label trials were included. The references of published articles identified in the search were also examined for additional studies appropriate to include in the review. Data were prioritized if they originated from human studies, especially if derived from randomized, placebo-controlled trials. Trials and case reports involving the use of long-acting anticholinergic tiotropium in asthma patients were included; conversely, trials involving ipratropium were not. Two large randomized controlled trials support the safety and efficacy of adding tiotropium to the treatment regimen of select patients with poorly controlled asthma already receiving combination high-dose glucocorticosteroid/long-acting β-agonist (LABA) therapy. Pharmacogenomic studies have shown that patients with polymorphisms of the β2-adrenoreceptor (ADRB2; 16 Arg/Arg and 16 Arg/Gly) are particularly responsive to treatment with tiotropium. Smaller studies indicate that the advantages may be most pronounced in patients with a predominance of sputum neutrophils and that tiotropium can assist with decreasing the inhaled corticosteroid (ICS) dose. An increased risk of cardiovascular events was not identified. Tiotropium should be considered in patients with asthma who remain symptomatic while receiving high-dose ICS and LABA therapy. Specifically, patients with high sputum neutrophil levels or with 16 Arg/Arg or 16 Arg/Gly polymorphism of the ADRB2 gene appear to respond best.

Concomitant Use of Ipratropium and Tiotropium in Chronic Obstructive Pulmonary Disease

To describe the current data evaluating the efficacy and safety of ipratropium used in combination with tiotropium in patients with chronic obstructive pulmonary disease. A literature search using MEDLINE (1966-August 2012) and EMBASE (1973-August 2012) was conducted using the search terms ipratropium, tiotropium, combination drug therapy, and chronic obstructive pulmonary disease. References of identified articles were reviewed for additional relevant citations. All English-language articles regarding the concomitant use of ipratropium and tiotropium were reviewed. Two prospective randomized controlled trials have demonstrated increases in bronchodilation with ipratropium when added to maintenance tiotropium therapy, suggesting potential benefits during short-term, combined use. One study reported significantly higher peak forced expiratory volume in 1 second (FEV(1)) responses with both ipratropium (230 mL) and fenoterol (315 mL) compared to placebo (178 mL) when added to maintenance tiotropium. The peak response with fenoterol was significantly higher than with ipratropium (FEV(1) difference = 84 mL). Another study reported a mean difference in FEV(1) of 81 mL (95% CI 27 to 136) with albuterol versus placebo and a mean difference in FEV(1) of 68 mL (95% CI 3 to 132) with ipratropium versus placebo. The difference between albuterol and ipratropium when added to maintenance tiotropium was not significant. One large observational study reported a significantly higher risk of acute urinary retention in individuals receiving combination therapy with a short- and long-acting anticholinergic agent compared to those receiving monotherapy (OR 1.84; 95% CI 1.25 to 2.71). Individuals at highest risk were men and those with evidence of benign prostatic hypertrophy. While ipratropium may provide spirometric improvements in lung function for patients receiving tiotropium maintenance therapy, the clinical significance of these improvements has not been documented and the risk of anticholinergic adverse effects is increased with combination therapy. Further studies evaluating the safety and efficacy of concomitant ipratropium and tiotropium are warranted before combination use can be recommended for select patients.