Treatment algorithms for chronic obstructive pulmonary disease (COPD) have generally recommended the use of long-acting bronchodilators (long-acting β-agonists [LABA] and long-acting antimuscarinics [LAMA]) on an interchangeable basis since few head-to-head comparisons of agents in these classes exist.
In The Lancet Respiratory Medicine, researchers provide additional insight into use of these agents. Their 52 week study compared the efficacy and safety of indacaterol 150mcg (n= 1723) and tiotropium 18mcg (n=1721) in 3444 patients with severe COPD and a history of at least one moderate to severe exacerbation in the previous 12 months. The primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Inhaled corticosteroids were allowed during the study and used by more than 70% of patients in each treatment group.
The primary and key secondary endpoints were analysed in the per-protocol sets and the safety set included all patients who received at least one dose of study drug. The following findings were reported:
• At week 12, the estimated least squares mean trough FEV1 difference between the groups was −0.011 L (least squares mean with indacaterol [n=1450] 1.34 L vs. tiotropium [n=1467] 1.145 L; p<0.0001). The 97.5% CI lower limit of −0.026 L was within the prespecified non-inferiority margin of −0.055 L, suggesting that indacaterol was non-inferior to tiotropium.
• Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44).
• In the safety set, there were no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 vs. tiotropium 1065 [62%] of 1718) or serious adverse events (indacaterol, 263 [15%] vs. tiotropium, 255 [15%]).
• Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 [43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147 [9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients).
The researchers conclude indacaterol was non-inferior to tiotropium for trough FEV1 at week 12 with a comparable safety profile; thus these data offer evidence consistent with current guidelines.
An accompanying Comment discusses the differences between these current trial findings and those from previous studies which reported more favourable findings with indacaterol. It was noted that though, in the current study, the overall exacerbation rate was less than anticipated, tiotropium provided better protection for exacerbations in a prespecified, superiority analysis (rate ratio indacaterol vs. tiotropium 1.24, 95% CI 1.12—1.37, p<0.0001); rates favouring tiotropium were also noted for exacerbations requiring corticosteroids or antibiotics, or admissions to hospital or emergency department visits. Similarly, the time to the first moderate or severe exacerbation was longer with tiotropium (HR 1.20, 95% CI 1.073—1.332, p=0.0012). In addition, the POET-COPD investigators confirmed that tiotropium was more effective than salmeterol in preventing exacerbations in patients with COPD with moderately severe airflow obstruction (mean FEV1 49%). The author of the comment infers from these evolving data that long-acting bronchodilators might differ in their ability to affect exacerbation rates in patients with COPD. It is hoped that further high-quality, randomised trials comparing active therapeutic approaches will help in guiding recommendations in future revisions of the GOLD guidelines or the development of new therapeutic guidelines.
NICE guidance on COPD issued in 2010 makes the following recommendations on use of long acting bronchodilators:
• In people with stable COPD who remain breathless or have exacerbations despite using short-acting bronchodilators as required, offer the following as maintenance therapy: if FEV1 ≥ 50% predicted: either long-acting beta2 agonist (LABA) or LAMA; if FEV1 < 50% predicted: either LABA with an inhaled corticosteroid (ICS) in a combination inhaler, or LAMA.
• In people with stable COPD and an FEV1 ≥ 50% who remain breathless or have exacerbations despite maintenance therapy with a LABA: consider LABA+ICS in a combination inhaler or consider LAMA in addition to LABA where ICS is declined or not tolerated.
• Offer LAMA in addition to LABA+ICS to people with COPD who remain breathless or have exacerbations despite taking LABA+ICS, irrespective of their FEV1.
• The choice of drug(s) should take into account the person's symptomatic response and preference, and the drug's potential to reduce exacerbations, its side effects and cost.