Comparison of Indacaterol With Tiotropium or Twice-Daily Long-Acting β-Agonists for Stable COPD
A Systematic Review
Gustavo J. Rodrigo, MD; and Hugo Neffen, MD
Background: Bronchodilators are central to the symptomatic management of patients with COPD. Previous data have shown that inhaled indacaterol improved numerous clinical outcomes over placebo.
Methods: This systematic review explored the efficacy and safety of indacaterol in comparison with tiotropium or bid long-acting β2-agonists (TD-LABAs) for treatment of moderate to severe COPD. Randomized controlled trials were identifi ed after a search of different databases of published and unpublished trials.
Results: Five trials (5,920 participants) were included. Compared with tiotropium, indacaterol showed statistically and clinically signifi cant reductions in the use of rescue medication and dyspnea (43% greater likelihood of achieving a minimal clinically important difference [MCID] in the transitional dyspnea index [TDI]; number needed to treat for benefi t [NNTB] = 10). Additionally, the MCID in health status was more likely to be achieved with indacaterol than with tiotropium (OR = 1.43; 95% CI, 1.22–1.68; P = .00001; NNTB = 0). Trough FEV 1 was significantly higher at the end of treatment with indacaterol than with TD-LABAs (80 mL, P = .00001). Similarly, indacaterol signifi cantly improved dyspnea (61% greater likelihood of achieving an MCID in TDI, P = .008) and health status (21% greater likelihood of achieving an MCID in St. George’s Respiratory Questionnaire, P = .04) than TD-LABA. Indacaterol showed similar levels of safety and tolerability to both comparators.
Conclusions: Available evidence suggests that indacaterol may prove useful as an alternative to tiotropium or TD-LABA due to its effects on health status, dyspnea, and pulmonary function.
CHEST 2012; 142(5):1104–1110
Abbreviations: AE 5 adverse effect; LABA 5 long-acting β2 -agonist; MCID 5 minimal clinically important difference; NNTB 5 number needed to treat for benefi t; SAE 5 severe adverse effect; SGRQ 5 St. George’s Respiratory Questionnaire; TDI 5 transitional dyspnea index; TD-LABA 5 bid long-acting b 2 -agonist; WMD 5 weighted mean difference.
Bronchodilators are central to the symptomatic management of patients with COPD. Current management guidelines recommend the use of monotherapy using either long-acting inhaled muscarinic antagonists or long-acting inhaled β2-agonists (LABAs) for patients with moderate or more severe disease on the basis of long-term improvements that can be achieved in clinical outcomes, such as dyspnea, health status, and exacerbations. 1 Currently available longacting inhaled bronchodilators include once-daily tiotropium and the bid LABA (TD-LABA) formoterol and salmeterol. Tiotropium is widely used and has generally been shown to provide better bronchodilation and clinical outcomes than TD-LABA. 2,3 More recently, indacaterol, an inhaled ultra-LABA (24 h) with a rapid onset of action, was approved in many countries at different doses (75 to 300 μg once daily ) for the treatment of patients with COPD. A once-daily LABA could not only simplify disease managementbut has the potential to improve adherence and compliance. Accordingly, a published study found that adherence was strongly correlated with dosing frequency. 4 Additionally, randomized, controlled phase 3 COPD trials have shown that indacaterol improved numerous clinical outcomes over placebo, including FEV 1, symptom control, health status, and exacerbations, with a safety and tolerability profi le similar to placebo. 5,6 The objective of this system atic review was to explore the effi cacy and safety of inhaled indacaterol in comparison with tiotropium or TD-LABA in moderate to severe COPD.
Materials and Methods
We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform this systematic review. 7 A protocol was prospectively developed detailing the study objectives, primary and secondary outcomes, criteria for study selection, approach to assessing study quality, data synthesis, and statistical analysis. This study was registered with the International Prospective Register of Systematic Reviews (www.crd. york.ac.uk/PROSPERO) as CRD42011001539.
Search and Selection Criteria
We identifi ed published studies from MEDLINE, EMBASE (December 2011), and the Cochrane Controlled Trials Register (CENTRAL) (December 2011) database using the terms “indacaterol,” “QAB-149,” “long-acting β2-agonists,” “salmeterol,” “formoterol,” “long-acting antimuscarinic agents,” “tiotropium,” and “chronic obstructive pulmonary disease.” Also, we performed a search of relevant fi les from the Novartis Pharma AG (http://www.novctrd.com/ctrdWebApp/clinicaltrialrepository/public/login.jsp) and US Food and Drug Administration (www.fda.gov) databases. Trials published solely in abstract form were excluded because the meth ods and results could not be fully analyzed.
To be included, studies had to meet all the following criteria: (1) randomized (parallel group or crossover) controlled tri als without language restriction of > 4 weeks of duration; (2) inclusion of adult patients aged > 40 years with stable moderate to severe COPD satisfying American Thoracic Society/European Respiratory Society 8 or GOLD (Global Initiative for Chronic Obstructive Lung Disease) diagnostic criteria 9 ; (3) comparison of inhaled inda caterol with tiotropium, salmeterol, or formoterol monotherapy; and (4) report at least one of the following outcomes: trough (24-h postdose) FEV 1 at the end of treatment (primary variable), use of rescue medications, health status assessed with the St. George’s Respiratory Questionnaire (SGRQ), 10 dyspnea assessed with the transitional dyspnea index (TDI), 11 COPD exacerbations, all-cause mortality, withdrawals during treatment period, adverse effects (AEs) and severe adverse effects (SAEs), ECG data including Fridericia correction of QT interval (QTc interval), and the incidence of clinically notable laboratory values, including reduced serum potassium level ( < 3.0 mmol/L) and elevated blood glucose level ( > 9.99 mmol/L) (secondary variables). A serious adverse event was defi ned as any untoward medical occurrence that sometimes results in death, is life-threatening, requires inpatient hospitalization, or results in persistent or sig nifi cant disability/incapacity. 12
Data Abstraction and Assessment of Risk of Bias
Titles, abstracts, and citations were independently analyzed by the two authors (G. J. R. and H. N.). From full text, they independently assessed all studies for inclusion based on the criteria for population intervention, study design, and outcomes. After obtaining full reports about potentially relevant trials, they assessed eligibility. The authors were independently involved in all stages of study selection, data extraction, and risk of bias assessment. The latter was assessed according to recommendations outlined in the Cochrane Handbook 13 for the following items: (1) adequacy of sequence generation, (2) allocation concealment, (3) blinding of participants and investigators, (4) reporting of withdrawals and loss to follow up, and (5) reporting of adverse outcomes. Disagreements were resolved by group consensus (G. J. R. and H. N.). In case of multiple published or unpublished reports, data from the most recent version were extracted.
Data Analysis
Analysis was by intention to treat and included all participants to minimize bias. Outcomes were pooled using weighted mean differences (WMDs) or Mantel-Haenszel ORs. The precision of the mean estimates was quantifi ed by the 95% CIs. When effect estimates were signifi cantly different between groups, the number needed to treat for benefi t (NNTB) or for harm was obtained. Heterogeneity was measured by the I 2 test 14 ( < 40%, unimportant; 40%-60%, moderate; and 60%-100%, substantial). Because selected studies differed in the mixes of participants and interventions, a random-effects meta-analysis was performed to address this vari ation across studies for all outcomes. 15 Publication bias of pri mary outcomes was evaluated by visual inspection of funnel plots. 16 In trials that had more than two intervention groups, we preserved randomization but collapsed the multiple intervention arms (eg, indacaterol 150 μg and 300 μg once daily) into single treatment arms. As a priori subgroup analysis, we explored the influence of the type of TD-LABA (formoterol or salmeterol vs indacaterol) and length of treatment ( < 24 weeks vs ≥ 24 weeks). Subgroups were compared using the interaction test. 17 P ≤ 05 (two-tailed test) was considered signifi cant. Predefi ned sensitivity analysis was done to explore the infl uence of the statistical model (fi xed vs random effects) on the effect size. Meta-analysis was performed with the Review Manager 5.1.6 software (2011; Cochrane IMS).
Results
Five randomized controlled trials 18-22 enrolling 5,920 subjects (3,377 in the indacaterol arms and 2,543 in the comparators arms) met the entry criteria ( Fig 1 ). Participants were symptomatic at baseline with moderate to severe airway obstruction. All studies were multicenter, randomized, parallel groups and were sponsored by a single pharmaceutical company ( Table 1 ). Two studies compared indacaterol with tiotropium, 18,19 and three compared indacaterol with a TD-LABA (salmeterol or formoterol). 20-22 All medications were administered via dry powder inhalers. Two studies included two indacaterol arms. 18,20 The mean age of patients was 63 years (71% were men).
Figure 1. Flowchart for identifi cation of studies used. TD-LABA = bid long-acting β2-agonist.
The duration of treatment ranged from 12 weeks to 52 weeks. Overall, the fi ve studies were judged to have a low risk of bias. All studies presented adequate sequence generation and concealment. One study had an open-label design for tiotropium. 18 Finally, all trials reported complete outcome data and information on the AEs.
Primary Outcome
The analysis of two studies 18,19 comparing indacaterol with tiotropium showed no statistical difference in mean trough FEV 1 (at the end of treatment or in change from baseline) ( Table 2 ). The fi rst outcome showed statistical heterogeneity. In contrast, data from three studies 19-21 showed that mean trough FEV 1 at the end of treatment was 70 mL higher with indacaterol than TD-LABA ( P < .0001) ( Table 3 ). Also, as change from baseline, trough FEV 1 signifi cantly increased by 80 mL with indacaterol compared with TD-LABA ( P < .0001). Sensitivity analyses showed similar results to those of the primary analysis. Post hoc subgroup analysis was not performed due to the small number of trials.
Table 1— Characteristics of Included Studies
Secondary Outcomes
On the basis of two trials 18,19 including 2,840 subjects with COPD (1,626 in the indacaterol arm and 1,214 in the tiotropium arm), signifi cant reductions in the use of rescue medication ( – 0.57 puffs/d, P < .0001) ( Table 2 ) and dyspnea were reported with inhaled indacaterol therapy.
Compared with tiotropium, indacaterol arm subjects showed a 43% greater likelihood of experiencing a minimal clinically important difference (MCID) in TDI ( ≥ 1 point) 23 (62% of indacaterol arm patients vs 52% of tiotropium arm patients, P < .0001). The NNTB was 10 (95% CI, 7-16) ( Fig 2 ). Also, the fi nal mean SGRQ total score was signifi cantly lower with indacaterol than tiotropium ( 2 2.02 units, P < .0008). Most impor tantly, the percentage of patients receiving indacaterol with an MCID in the SGRQ ( ≥ 4 units of total score) 23 was signifi cantly higher compared with those receiv ing tiotropium (57% vs 46%, P < .0001) ( Fig 2 ). The NNTB was 10 (95% CI, 7-15). On the other hand, there were nonsignifi cant differences in the rate of COPD exacerbations (15.1% vs 14.6%), withdrawals (14.2% vs 12.3%), AEs (53% vs 48%), SAEs (5.4% vs 5.2%), all-cause mortality (0.06% vs 0.32%), percent of patients with blood glucose level > 9.99 mmol/L (6.0% vs 4.2%), and serum potassium level < 3.0 mmol/L (0.24% vs 0.16%). The rate of nonacute cough as an adverse event did not differ across the treatment groups (4.6% vs 3.3%). However, in one study, 18 investigators recorded any instances of acute cough occurring within 5 min of drug administration, finding in an average of 16.6% and 21.3% of patients per visit in the indacaterol 150- and 300- μg groups and in 0.8% of the tiotropium group. This cough typically started within 15 s of inhalation and had a median duration of 6 s. It was not associated with bronchospasm or with increased study discontinuation rates.
Table 2 - Effect of Indacaterol vs Tiotropium Monotherapy on Different COPD Outcomes
The assessment of three trials 20-22 with 3,080 patients (1,449 in the indacaterol arms and 1,329 in TD-LABA arms) showed that indacaterol signifi cantly improved clinical outcomes and health status more than did therapy with TD-LABA. It reported signifi cant reductions in the use of rescue medication ( – 0.22 puffs/d, P = .03) ( Table 3 ) and dyspnea (a signifi cant improvement in mean TDI score and a signifi cant increase in the percentage of patients achieving an MCID in TDI, [63% of patients receiving indacaterol vs 53% TD-LABA, P = .008]) ( Fig 3 ). The NNTB was 10 (95% CI, 7-15). Also, indacaterol signifi cantly increased the percentage of patients achieving an MCID in the SGRQ total score (53% vs 48%, P = .03) ( Fig 3 ), with an NNTB of 20 (95% CI, 11-345). Finally, there were nonsignifi cant differences between groups in the rate of COPD exacerbations (19.0% vs 16.1%), withdrawals (16.7% vs 15.1%), AEs (57% vs 49%), SAEs (9.3% vs 7.9%), all-cause mortality (0.22% vs 0.30%), percent of patients with blood glucose level > 9.99 mmol/L (6.1% vs 6.5%), serum potassium level < 3.0 mmol/L (0.22% vs 0.15%), and nonacute cough (5.6% vs 3.3%). In addition, investigators from two studies 20,21 recorded instances of acute cough occurring within 5 min of drug administration during clinic visits. They observed an average of 18% in the indacaterol groups against 0.9% in the TD-LABA groups. This cough of short duration (few seconds) was not associated with bronchospasm or withdrawals.
Effect of Indacaterol vs bid Long-Acting β-Agonist Monotherapy on Different COPD Outcomes
Figure 2. Studies comparing indacaterol with tiotropium. A, Pooled OR (with 95% CI) for the number of subjects with a minimally clinically important difference for transitional dyspnea index ( ≥ 1 point). B, Pooled OR (with 95% CI) for the number of subjects with a minimally clinically important difference for St. George’s Respiratory Questionnaire ( ≥ 4 units). df 5 degrees of freedom; M-H = Mantel-Haenszel.
Discussion
Indacaterol is a novel inhaled LABA providing 24-h bronchodilation on once-daily dosing recently approved in many countries for the treatment of patients with COPD. Previous data have shown that inhaled indacaterol improved numerous clinical outcomes over placebo, with a similar safety and tolerability profile. 5 This review has found a similar efficacy between indacaterol (150-300 μg/d) and tiotropium (18 μg/d) on trough FEV 1 after 12 to 26 weeks of treatment. Since the relationship between spirometry, symptoms, and health status appears to be poor, measures of lung physiology alone may not adequately describe both the social impact of COPD and the effectiveness of therapeutic interventions. 23 Thus, indacaterol produced statistically signifi cantly better results in clinical outcomes of dyspnea, use of as-needed salbutamol, and health status, compared with tiotropium. Dyspnea is the primary reason for patients seek ing medical care, and its measure may provide an insight into the practical effects of treatment on every day life, refl ecting whether patients perceive an improvement in this primary symptom of COPD. Patients treated with indacaterol had a greater likelihood of experiencing an MCID in TDI 23 compared with those receiving tiotropium. The NNTB was 10, indicating that one of every 10 patients treated with indacaterol obtained this benefi t. Additionally, we found statistically signifi cant improvements in total SGRQ score; however, the clinical relevance of these fi ndings remains unclear, because they did not reach the MCID of 4 units. However, the interpretation of this remains unclear, because MCID differences were derived on the basis of differences vs placebo or changes from baseline rather than differences between two active treatments. 23 Even so, compared with tiotro pium, indacaterol-treated patients had a greater likelihood of achieving an MCID improvement in health status with an NNTB = 10. In addition, patients tak ing indacaterol required significantly less rescue med ication (more than one-half puff per day) refl ecting the effectiveness of treatment in achiev ing clinical control. Finally, indacaterol-related and tiotropium-related events, like COPD exacerbations and withdrawals, did not differ from each other.
Figure 3. Studies comparing indacaterol with TD-LABA. A, Pooled OR (with 95% CI) for the number of subjects with a minimally clinically important difference for transitional dyspnea index ( ≥ 1 point). B, Pooled OR (with 95% CI) for the number of subjects with a minimally clinically important difference for St. George’s Respiratory Questionnaire ( ≥ 4 units). LABA = long-acting β2 -agonist. See Figure 2 legend for expansion of other abbreviations.
Our data also indicated that indacaterol (150-600 μg) was more effective than TD-LABA (salmeterol 50 μg bid or formoterol 12 μg bid) for several outcomes. Thus, trough FEV 1 was signifi cantly higher with indacaterol than TD-LABA ( P < .0001), after 12 to 52 weeks of treatment. The difference in trough effect with indacaterol of 70 to 80 mL relative to TD-LABA did not exceed the prespecifi ed 100-mL MCID. However, the clinical interpretation is unclear, since reported MCID differences were derived on the basis of differences vs placebo. 23 This bronchodilator effect of indacaterol was accompanied by signifi cant improvements in dyspnea and health status. Once-daily indacaterol was statistically superior to TD-LABA (salmeterol and formoterol) in terms of the percentage of patients exceeding the MCID in TDI compared with those receiving LABA, with an NNTB of 10. Indacaterol also allowed the use of fewer puffs per day of rescue salbutamol. Additionally, patients receiving indacaterol had a greater likelihood of achieving an MCID in health status, with an NNTB of 20. Also, the use of inda caterol was associated with a signifi cant but small reduction in the rescue medication use compared with LABA treatment, although probably without clinical signifi cance. Finally, the rate of COPD exacerbations and withdrawals was equivalent in both groups.
In both comparisons, safety and tolerability of indacaterol were similar to comparators. The overall incidence of AEs and SAEs did not differ between groups. The greater efficacy of indacaterol was not reflected in any increase in β2 -mediated effects relative to tiotropium and TD-LABA. Thus, the class-related side effects of β2 -agonists (hyperglycemia, hypokalemia, or prolonged QTc interval) were low. Although the rate of nonacute cough did not differ across the treatment groups, different studies have reported acute cough immediately following indacaterol inhalation. Although these events occurred with some frequency (15%-20% of subjects), they did not decrease the effectiveness of indacaterol and did not produce bronchoconstriction or study withdrawal.
This study met most of the methodologic criteria suggested for systematic reviews. 7 Inclusion criteria were clearly defi ned. Several relevant databases were searched for published and unpublished articles in any language. Attempts were made to minimize error and bias in the process of study selection, data extraction and quality assessment. Trial quality was formally assessed, and the results were clearly reported. Its assessment showed a high methodologic quality of studies. Overall, the effect sizes were consistent, and only 10% of outcomes explored showed evidence of substantial heterogeneity. Although the small number of included trials can be considered a limitation of this review, they included a signifi cant sample of nearly 6,000 subjects.
In November 2009, indacaterol was approved for the maintenance treatment of COPD in the European Union at a recommended dose of 150 μg once daily and a maximum dose of 300 μg once daily. Although the same doses of indacaterol are used almost worldwide, the Federal Drug Administration decreed a few months ago that the only available dosage for US physicians would be 75 μg per day. Although the use of indacaterol 75 μg per day in patients with COPD shows statistical and clinical benefi ts compared with placebo, 24,25 most studies have used 150 to 300 μg per day. In fact, all the studies included in this review used a dose of ≥ 150 μg per day.
In summary, this systematic review suggests that indacaterol has better effects than once-daily tiotropium or TD-LABA, with a favorable safety profi le. This evidence from a limited number of studies suggests that patients with moderate to severe COPD treated with indacaterol have better clinical outcomes (dyspnea and health status) than those treated with tiotropium. Similarly, indacaterol may be a useful alternative to TD-LABA due to its effects on pulmonary function, health status, and dyspnea. These effects are statistically and clinically signifi cant in both comparisons.
Acknowledgments
Author contributions: Dr Rodrigo: contributed to study conception and design; acquisition, analysis, and interpretation of data; drafting the submitted article and revising it critically for important intellectual content; and providing fi nal approval of the version to be published.
Dr Neffen: contributed to study conception and design, interpretation of data, revising the article critically for important intellectual content, and providing fi nal approval of the version to be published.
Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Rodrigo has participated as a lecturer and speaker in scientifi c meetings and courses under the sponsorship of Boehringer Ingelheim GmbH, GlaxoSmithKline plc, AstraZeneca, Dr. Esteve SA, Merck Sharp & Dohme Corp, and Admiral. Dr Neffen has participated as a lecturer and speaker in scientifi c meetings and courses under the sponsorship of Merck & Co, Inc; GlaxoSmithKline plc; Novartis AG; and AstraZeneca .
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript .
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