The present meta-analyses combined data from existing randomized placebo-controlled trials, using number of patients achieving the minimum clinically important difference (MCID) for TDI score ≥1 as an outcome measure, and evaluated the efficacy of once-daily indacaterol on TDI scores in patients with stable COPD. A favorable effect was consistently obtained for indacaterol over placebo: 75 μg od OR 1.784 (95% CI 1.282 to 2.482); 150 μg od OR 2.149 (95% CI 1.746 to 2.645); and 300 μg od OR 2.458 (95% CI 2.010 to 3.006). A trend of increasing patient benefit was observed as indacaterol doses increased.
Recent guidelines recommend regular use of bronchodilators, such as indacaterol, as a long-term maintenance treatment of airflow limitation in COPD [1
]. The extent to which indacaterol improves airflow in patients with COPD is well studied [4
]. In these phase III studies, indacaterol provided 24-h bronchodilation on once-daily dosing with an effect that was sustained during treatment for up to one year. However, from the patients’ viewpoint, it may be more important to know whether this therapy improves dyspnea associated with daily activities, and these meta-analyses of available randomized placebo-controlled trials comparing indacaterol with placebo allows us to examine the efficacy of indacaterol on this important patient outcome. In all trials included in the meta-analyses, dyspnea was assessed using validated multidimensional instruments of BDI and TDI that are widely used to measure treatment effects in COPD [13
]. When data were analyzed for a pre-determined outcome, i.e. the number of patients responding with a change of TDI equal to or greater than the minimum clinically important difference MCID (a ‘responder analysis’), a favorable effect was obtained for all three doses of indacaterol. The overall OR estimates of the meta-analyses are largely consistent with the results from the individual studies, in which the ORs for patients achieving a MCID in the indacaterol group compared with the placebo group varied from 1.582 to 2.015 for the 75 μg dose (Figure
], 1.950 to 2.303 for the 150 μg dose (Figure
], and 2.520 to 2.626 for the 300 μg dose (Figure
], with a exception of the Asian study [9
]. It becomes apparent that patients receiving indacaterol had clinically significant improvements in symptoms of dyspnea compared to placebo over 12 weeks of treatment.
The overall odds ratio for response in TDI appeared to vary depending on indacaterol doses, and tended to increase with increasing indacaterol doses. Additionally, the percentage of patients who exceeded the one unit of the MCID in TDI varied in different indacaterol doses. The percentage in the analysis of indacaterol 75 μg once daily was 48%, compared with 34% in placebo. Compared to placebo, a higher percentage of patients achieved the MCID with the indacaterol 150 μg (60% versus 41%) and indacaterol 300 μg doses (63% versus 41%). Renard and his colleagues recently performed a model based analysis of the bronchodilatory dose response to indacaterol in patients with COPD [25
]. The analysis demonstrated that indacaterol dosages of 75 μg once daily and above achieved minimal clinically important improvements in predicted trough FEV1
response, although dosages of 150 μg and 300 μg once daily provided optimum bronchodilation. The analysis also demonstrated that disease severity, as determined by FEV1
, significantly affected dose response, suggesting that higher doses may be required in patients with more severe COPD to achieve optimal reduction of dyspnea.
In six trials included in the meta-analysis (n=5405), patients with COPD who received indacaterol 75 μg, or 150 μg, or 300 μg od had a significantly higher trough FEV1
than placebo after at least 12 weeks, with indacaterol increasing trough FEV1
by 120ml to 200 ml over placebo at week 12 [5
]. The overall improvement in FEV1
, though modest, may be sufficient to decrease the extent of hyperinflation which contributes to the sensation of dyspnea [26
]. A better indicator of the effect of a bronchodilator on hyperinflation (and therefore the sensation of dyspnea) is perhaps inspiratory capacity. One could hypothesize that the prolonged bronchodilation observed with indacaterol would be associated with reductions of air trapping, and therefore reductions in hyperinflation, which would then be reflected in improvements in the sensation of dyspnea. There are relatively few indacaterol studies that included both an assessment of inspiratory capacity and of dyspnea, however, two short-term exercise studies comparing the 300 μg dose of indacaterol with placebo have been published [30
]. The BDI/TDI was included in one of the studies, an improvement of 182 ml in resting inspiratory capacity after 14 days (p<0.05 vs. placebo) was associated with a change of TDI total score of +3.33 (p<0.01 vs. placebo) [31
], providing indirect evidence to support the hypothesis.