Tiotropium treatment for bronchiectasis: a randomised, placebo-controlled, crossover trial

Tiotropium via HandiHaler® is an established long-acting, anticholinergic bronchodilator that prevents exacerbations and improves lung function in patients with COPD. We hypothesized that tiotropium would reduce pulmonary exacerbations and improve lung function in patients with stable bronchiectasis and airflow limitation, and assessed the effect of tiotropium on these outcomes. In a randomised, double-blind, 2-period crossover trial, we recruited adult patients from 3 hospitals in New Zealand. Patients were excluded if they had a smoking history of more than 20 pack years. Patients were assigned to either the tiotropium-placebo or placebo-tiotropium sequence in a 1:1 ratio, using randomly permuted blocks stratified by centre. Participants and investigators were masked to treatment allocation. Eligible patients received tiotropium 18mcg via the HandiHaler® device daily for 6 months followed by 6 months of placebo, or vice versa, with a washout period of 4 weeks. The primary endpoint was rate of event-based exacerbations during the 6-month period. Primary analyses were carried out in an intention-to-treat set. Ninety patients were randomly assigned and 85 completed both treatment cycles. The rate of exacerbations under the tiotropium treatment was 2.17 y−1 and 2.27 y−1 under placebo (rate ratio 0.96, 95% CI 0.72–1.27; p=0.77). Tiotropium, as compared with placebo, improved FEV1 by 58 mL (95% CI 23–92; p=0.002). Adverse events were similar under both treatments. Tiotropium via HandiHaler® over 6 months significantly improved lung function but not frequency of exacerbations. Further research is required to understand the clinical context and significance of these findings.

Evidencia de Tiotropio en asma.

Asthma is a chronic disease with a significant disease burden and many patients fail to control the disease despite recommended medical therapy.19 The long-term goals of asthma management include achieving good control of symptoms, minimizing risk asthma exacerbations, reduce hospitalizations, use of rescue medication, airflow limitation and side effects, as well as allow normal levels of activity.29 According to the Global Initiative for Asthma (GINA) guidelines , asthma management is based on a cornerstone of inhaled corticosteroid therapy (ICS), supplemented with complementary therapies for those with poor or deteriorating disease control.1 Tiotropium, a long-acting anticholinergic bronchodilator that is administered once a day, it is indicated for the treatment of chronic obstructive pulmonary disease (COPD) for more than a decade and has recently been approved in several countries for the treatment of asthma.18 In this review, we summarized the significant effect of tiotropium for the treatment of moderate-to-severe asthma, mainly in increasing morning PEF, evening PEF, peak FEV and trough FEV based on high-quality RCTs. Nevertheless, no significant difference in peak FVC, trough FVC, AE and serious AE was found between the 2 groups. A close comparison of the 2 groups revealed that more high-quality larger-sample RCTs are needed to gather more strong evidence on the therapeutic efficacy and safety of tiotropium for clinical practice.

Comparison of Combined Nebulization of Salbutamol-Ipratropium Bromide with Salbutamol Alone in Children with Mild and Moderate Acute Asthma

ntroduction: The β2 agonists are potent bronchodilators but their repeated and high doses are related to adrenergic side effects. While ipratropium bromide, an anticholinergic bronchodilator has less adverse effects. Objective: To compare the efficacy of combined nebulization of salbutamol-ipratropium bromide with salbutamol alone in children with mild and moderate acute asthma. Materials and Methods: This randomised control trial was done on 80 children aged 5 to 12 years who presented with mild to moderate acute asthma in the emergency department of Children Hospital of Pakistan Institute of Medical Sciences (PIMS) from July 2014 to June 2016 and randomized into 2 groups. In the experimental group each child received 2 nebulizations of combined salbutamol (5mg) and ipratropium Bromide (0.25mg) at presentation and 20 minutes later. Similarly, each child of the control group received 2 nebulizations of 5mg Salbutamol and 2 ml of Normal saline. Asthma clinical score (ACS) was assessed at baseline and then after every 20 minutes up to one hour after the presentation. Results: In the experimental group, the mean + SD ACS at presentation and 60 minutes were 3.50±1.8 and 3.45±1.7 respectively with mean + SD change in ACS of 0.05 ± 0.1. In the control group, the mean + SD ACS at presentation and 60 minutes were 3.70 ± 1.2 and 3.60 ± 1.9, respectively with mean + SD change in ACS of 0.1 ± 0.7. This difference in mean + SD change in ACS between 2 groups was not statistically significant (P=0.6560). Conclusion: There is no statistically significant benefit of adding ipratropium bromide with salbutamol nebulization as compared to salbutamol alone for the management of children with mild to moderate asthma attacks.

Tiotropium in COPD: clinical outcomes and economic evidence

Tiotropium bromide is a once-daily anticholinergic bronchodilator with duration of action of at least 24 hours. In clinical trials, tiotropium has been compared with placebo, ipratropium or salmeterol, the most frequently used long-acting β2 agonist. When compared with ipratropium or placebo in COPD management, tiotropium resulted associated with FEV1, dyspnoea and health-related quality of life (QoL) improvement, along with reduced exacerbation and hospitalisation rates. In comparison to salmeterol, it proved to be superior in terms of lung function improvement and exacerbation risk reduction. Recently, the randomised, double-blind trial UPLIFT showed that 4 years of therapy with tiotropium were associated with improvements in lung function, QoL, and exacerbations, and with an effective reduction of mortality compared with control group in 5,993 patients with moderate to very-severe COPD. These encouraging clinical effects are to be traded against the pharmaceutical cost increase induced by the inclusion of tiotropium in routine care. However, published work indicates that this pharmaceutical cost increase may be totally or partially offset by the reduction in costs needed for exacerbations management and hospitalisations. Depending on the setting analysed, tiotropium is estimated to dominate ipratropium and salmeterol or to be associated with an incremental cost of less than € 2,500 per exacerbation avoided. An Italian model based on UPLIFT data shows that therapy including tiotropium induces an incremental cost of € 6,700 for year of life and of € 7,916 for Quality-adjusted Life Year gained, with respect to routine care alone. These values are much lower than commonly accepted thresholds and than cost/effectiveness results estimated for other long-acting bronchodilators. In conclusion, available evidence suggests that tiotropium may prove an appropriate therapeutic option with a largely affordable cost.

Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD

During constant-work-rate exercise in chronic obstructive pulmonary disease, dyspnea increases steeply once inspiratory reserve volume (IRV) falls to a critical level that prevents further expansion of tidal volume (Vt). We studied the effects of this mechanical restriction on the quality and intensity of exertional dyspnea and examined the impact of an anticholinergic bronchodilator. In a randomized, double-blind, crossover study, 18 patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 s = 40 ± 3%predicted; mean ± SE) inhaled tiotropium 18 μg or placebo once daily for 7–10 days each. Pulmonary function tests and symptom-limited cycle exercise at 75% of each patient’s maximal work capacity were performed 2 h after dosing. Dyspnea intensity (Borg scale), operating lung volumes, breathing pattern, and esophageal pressure ( n = 11) were measured during exercise. Dynamic hyperinflation reached its maximal value early in exercise and was associated with only mild increases in dyspnea intensity and the effort-displacement ratio, which is defined as the ratio between tidal swings of esophageal pressure (expressed relative to maximum inspiratory pressure) and Vt (expressed relative to predicted vital capacity). After a minimal IRV of 0.5 ± 0.1 liter was reached, both dyspnea and the effort-displacement ratio rose steeply until an intolerable level was reached. Tiotropium did not alter dyspnea-IRV relationships, but the increase in resting and exercise inspiratory capacity was associated with an improved effort-displacement ratio throughout exercise. Once a critically low IRV was reached during exercise, dyspnea rose with the disparity between respiratory effort and the Vt response. Changes in dyspnea intensity after tiotropium were positively correlated with changes in this index of neuromechanical coupling.