O1.2 Long-acting bronchodilators

Long-acting bronchodilators produce significant improvements in lung function, symptoms and quality of life (Braido 2013), as well as decreasing exacerbations.  These benefits come at a cost of increased adverse effects, which are generally of mild to moderate severity.

O1.2.1 Long-acting muscarinic antagonists (LAMA)

Long-acting muscarinic antagonists (formerly known as anticholinergics) e.g. tiotropium, glycopyrronium bromide and umeclidinium cause bronchodilation with a duration of action of over 24 hours and are used once daily (Maltais 2011, Trivedi 2014). Aclidinium bromide is another long-acting muscarinic antagonist used twice daily (Karabis 2013). A systematic review (Karner 2014) found that tiotropium improved mean quality of life, increased the number of patients with a clinically significant improvement, and reduced the number of patients with a clinically significant deterioration in quality of life [evidence level I]. Tiotropium reduced the number of patients with an exacerbation (OR 0.78; 95% CI 0.70 to 0.87), corresponding to a number needed to treat (NNT) of 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations. Lung function improved with tiotropium, compared to placebo (trough FEV1 mean difference 119 mL; 95% CI 113 to 125). There was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Karner 2014). Refer Section P5.1 for further information on tiotropium mortality. Systematic reviews (Barr 2006, Barr 2005) found tiotropium produced a significant increase in FEV1 of the order of 130mls compared to placebo. A 2011 meta-analysis (Yohannes 2011b) comparing tiotropium with placebo, ipratropium and the long-acting beta2-agonist, salmeterol, included a larger number of patients (16,301) and found superior efficacy for quality of life, dyspnoea and exacerbation rates compared with placebo and ipratropium. The number of patients needed to treat with tiotropium was 22 (95% CI 13 to 65) to prevent one exacerbation compared to placebo. No significant differences between tiotropium and salmeterol were found for any outcome. Dry mouth was the most common adverse event reported and the proportion of patients experiencing a dry mouth was higher in those using tiotropium than any of placebo, ipratropium or salmeterol (NNH compared to placebo =  25, 95%CI 12 to 66). Pneumonia rates were not analysed. Use of 18 micrograms per day of tiotropium (by HandiHaler) in mild to moderate (FEV1 50-80% of predicted) COPD over 7 months was associated with an 85ml advantage in FEV1, which is of uncertain clinical benefit, and inconsistent benefits in other outcomes, without assessment of quality of life or health service utilisations (Troosters 2014)[evidence level II].

Many of these effects have been confirmed in a large four-year randomised-controlled trial, whose primary outcome was the effect of tiotropium on the rate of decline in lung function (Tashkin 2008). Tiotropium produced no effect on the rate of decline of FEV1 or FVC, but both measurements were significantly higher in the tiotropium group when compared to placebo at all time points following randomisation (mean pre-bronchodilator difference in FEV1 = 87 to 103 mls).  Tiotropium was associated with improved HRQL at all time points (mean difference in total SGRQ for all time points = 2.7, 95% CI 2.0 to 3.3) and a delay to time of first exacerbation (tiotropium = 16.7 months vs. placebo = 12.5 months).

In an international, multi-centre, double blind placebo controlled trial, Vogelmeier et al randomised 7,376 patients with moderate to severe COPD and a history of exacerbations to either salmeterol or tiotropium (Vogelmeier 2011). Tiotropium increased the time to first exacerbation by 42 days compared to salmeterol (187 vs. 145 days) corresponding to a reduction in risk by 17% (hazard ratio, 0.83; 95% CI, 0.77 to 0.90) [evidence level II].

The beneficial effects come at a cost of increased adverse drug effects.  A pooled safety analysis of data from 35 Phase III and IV tiotropium clinical trials completed as of July 2012 was carried out (Halpin 2015). This analysis of 24,555 patients adds to the previous comprehensive safety review by Kesten et al (Kesten 2006). Of these, 28 trials (n=9,647) used tiotropium bromide dry powder (delivered via HandiHaler® 18 μg once daily), and 7 trials (n=3,282) used tiotropium bromide solution (delivered via Respimat® 5 μg once daily). All placebo-controlled, double-blind, and parallel-group COPD trials of ≥4 weeks’ duration were included in the analysis. Patients who had a diagnosis of COPD with FEV1≤70% of FVC, who were aged ≥40 years and had ≥10 pack-years of smoking history were eligible for inclusion. Exclusion criteria included a diagnosis of asthma, symptomatic prostatic hypertrophy or bladder neck obstruction, narrow-angle glaucoma, and known hypersensitivity to trial medication or components. Patients with significant disease other than COPD that could significantly confound the trial results or preclude trial completion were also excluded. Dry mouth (RR 2.35, 95% CI 1.99 to 2.77), constipation (RR 1.28, 95% CI 1.06 to 1.54), and urinary retention (RR 1.56, 95% CI 1.03 to 2.36) occurred more frequently with tiotropium versus placebo, with dry mouth and dyspepsia being the most common adverse events, occurring in 4% of patients each, in the tiotropium group. Gastrointestinal obstruction (RR 1.76, 95% CI 1.16 to 2.69), dyspepsia (RR 1.21,  95% CI 1.06 to 1.38), dysuria (RR 2.07, 95% CI 1.26 to 3.39) and gastroesophageal reflux (RR 1.25, 95% CI 1.06 to 1.46) also increased with tiotropium use.  A population based nested case control study of COPD patients found that if 514 (95% CI 336 to 905) men with benign prostatic hypertrophy were commenced on inhaled antimuscarinics, one would develop acute urinary retention (Stephenson 2011) [evidence level III-2]. These effects have been confirmed in a large four-year randomised-controlled trial (Tashkin 2008) which found no increase in death from any cause, RR 0.89 (95% CI 0.79 to 1.02) [evidence level II]. There was a decreased rate of serious adverse cardiac events in patients randomised to tiotropium compared to placebo. However, it is important to note that patients with unstable arrhythmias, a history of heart failure or heart attack within the previous 6 months were excluded from this trial (Singh 2013).

42 double-blind, randomised, active or placebo-controlled trials of ≥6 months (52,516 patients, 64 years of age, 73% men, 37% current smokers, and 44% of predicted value in FEV1) that evaluated the effects of tiotropium Soft Mist Inhaler, tiotropium HandiHaler, long-acting beta agonists (LABA), inhaled corticosteroids (ICS) or a combination of LABA and ICS in patients with COPD of any severity were included in the systematic review by Dong et al (Dong 2013). The primary outcome of interest of the systematic review was all-cause death and the secondary outcome was death from cardiovascular causes. Patients using tiotropium Soft Mist Inhaler had universally increased risks compared with those receiving placebo (OR 1.51; 95% CI 1.06 to 2.19) or those using tiotropium HandiHaler (OR 1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to 2.44) and LABA-ICS (OR 1.90; 95% CI 1.28 to 2.86). In contrast, LABA-ICS demonstrated a beneficial profile versus placebo (OR 0.80; 95% CI 0.67 to 0.94) or ICS (OR 0.77; 95% CI 0.64 to 0.93). For cardiovascular death, tiotropium Soft Mist Inhaler had a more apparent risk compared with placebo (OR 2.07; 95% CI 1.09 to 4.16), tiotropium HandiHaler (OR 2.38; 95% CI 1.20 to 4.99), LABA (OR 3.04; 95% CI 1.48 to 6.55), LABA-ICS (OR 2.79; 95% CI 1.37 to 6.02) and ICS (OR 2.39; 95% CI 1.18 to 5.12). In contrast, LABA had a decreased risk versus placebo (OR 0.68; 95% CI 0.50 to 0.93). Use of 10 μg/day tiotropium Soft Mist Inhaler tended to be associated with a higher risk of overall death against all comparators.

A prospective study (Wise 2013) has allayed concerns regarding use of lower doses of tiotropium delivered by Soft Mist Respimat Inhaler and the risk of death in COPD. In a large prospective double blind parallel group RCT of tiotropium delivered via Respimat Misthaler 2.5 or 5μg or via HandiHaler 18μg there was no increased risk of death in either of the two Respimat arms compared with the HandiHaler arm [HR for Respimat 5 μg v HandiHaler was 0.96 (95% CI 0.84 to 1.09); for Respimat 2.5 μg v HandiHaler HR 1.00 (95% CI 0.87 to 1.14)]. The study included patients with concomitant heart disease but excluded patients with myocardial infarction in the previous six months or who had been hospitalised for Class 3 or 4 heart failure or had had an unstable or life-threatening arrythmia requiring new treatment within the previous 12 months. Also excluded were pateints with moderate or severe renal impairment. Death from any cause in the groups was just over 7% in each arm and cardiovascular death just on 2% in each. Rates of exacerbation were similar in all three groups. This study suggests that tiotropium delivered in doses no higher than 5ug via the Soft Mist Respimat Inhaler device appears to be as safe and efficacious as that delivered via HandiHaler, but prescribers should be aware of the exclusion crtieria for such trials and use caution in patients with characteristics which would have excluded them from this trial.

Glycopyrronium bromide (NVA237) is another inhaled, once daily, long-acting muscarinic antagonist. In a non-inferiority, double blind randomised, controlled clinical trial, Chapman et al compared glycopyrronium to tiotropium (Chapman 2014). The trial was only 12 weeks in duration. No difference was found with respect to trough FEV1, dyspnoea, quality of life, exacerbations or side effects. Two randomised controlled trials have demonstrated significant improvement in spirometry and a reduction in moderate to severe exacerbations compared with placebo; there was no difference in quality of life (D’Urzo 2011, Kerwin 2012). One of these trials also randomised patients to tiotropium and found that glycopyrronium was not inferior with regards to spirometry, quality of life and moderate to severe exacerbations (Kerwin 2012) [evidence level II].

Aclidinium is a long-acting muscarinic antagonist used twice daily. A Cochrane systematic review which included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD to either aclidinium bromide or control for 4 to 52 weeks found that aclidinium resulted in marginal improvements in quality of life and FEV1 when compared to placebo. Compared to placebo, aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 13 per 1,000 over 4 to 52 weeks (NNT = 77, 95% CI 51 to 233) (Ni 2014) and reduced the rate of moderate-severe exacebrations (OR 0.80) (Wedzicha 2016a) [evidence level I].

A network meta-analysis of clinical trials of at least 12 weeks duration comparing the efficacy of LAMAs versus placebo in preventing moderate-to-severe and severe COPD exacerbations suggested that there were no statistically significant differences among LAMAs. Tiotropium dry powder inhaler was the only LAMA formulation which reduced severe exacerbations (HR 0.73; 95% CrI 0.60– 0.86) (Oba 2015) [evidence level I]. Another network meta-analysis showed that all current LAMAs have similar efficacy in terms of change in FEV1, SGRQ, dyspnoea index and rescue medications (Ismaila 2015) [evidence level I]. However, direct head to head double-blind comparisons of the different LAMAs are not available, meaning that choice of LAMA inhaler depends on patient and clinician preferences.

Umeclidinium is a once daily LAMA approved for the treatment of COPD. A 12-week, multicentre, randomized, blinded, double-dummy, parallel-group, non-inferiority study of umeclidinium 62.5 μg plus placebo or tiotropium 18 μg plus placebo in patients with symptomatic moderate-to-severe COPD showed that the least squares (LS) mean changes from baseline in trough FEV1 at day 85 was greater with umeclidinium (difference 53 mL, 95% CI: 25–81; P<0.001). Both treatments showed clinically meaningful improvements, but no significant differences between groups for transition dyspnoea index (TDI), SGRQ, and CAT scores. Tolerability and safety profiles were also similar (Feldman 2016) [evidence level II].