Articles
Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study

https://doi.org/10.1016/S2213-2600(13)70158-9Get rights and content

Summary

Background

We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months.

Methods

In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 μg) or tiotropium (18 μg) once-daily for 52 weeks. Our 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). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728.

Findings

Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. 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] 1·134 L [SE 0·008] vs tiotropium [n=1467] 1·145 L [0·008]; one-sided 97·5% CI lower limit −0·026 L; p<0·0001). The lower limit of the 97·5% CI was above 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, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718 patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients). 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).

Interpretation

Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines.

Funding

Novartis Pharma AG.

Introduction

Long-acting inhaled bronchodilators used for treatment of stable chronic obstructive pulmonary disease (COPD) include two classes of pharmacological agents: long-acting β2-agonists (LABA; eg, indacaterol) and long-acting muscarinic antagonists (LAMA; eg, tiotropium). Both tiotropium1 and indacaterol2 have shown clinically meaningful bronchodilation, symptomatic benefits, and improved health outcomes in patients with COPD, and both have acceptable safety profiles.

Higher rates of COPD exacerbations have previously been associated with impaired health-related quality of life3, 4 and a more rapid decrease in lung function.5, 6 The mechanical effects of an exacerbation are complex, involving worsening airflow limitation, increases in dynamic hyperinflation, and increased end-expiratory lung volume and residual volume.7 Bronchodilators improve airflow limitation and reduce breathlessness, which might in part explain their effectiveness in preventing exacerbations.8

Findings from three studies comparing once-daily indacaterol (150 μg or 300 μg) with once-daily tiotropium (18 μg), all done in patients with moderate-to-severe airflow limitation (ie, ≥30% and <80% predicted forced expiratory volume in 1 s [FEV1]), have shown a faster onset of bronchodilation at first dose together with non-inferiority or superiority of indacaterol versus tiotropium with regards to trough FEV1.9, 10, 11 Dyspnoea, as measured with the Transition Dyspnoea Index (TDI) total scores at week 12, was improved for once-daily indacaterol (300 μg) versus open-label tiotropium10 in one of these trials, and for indacaterol (150 μg) versus blinded tiotropium in another.9 Once-daily indacaterol (150 μg) improved health status (as shown by improving St George's Respiratory Questionnaire [SGRQ] total scores) at week 12 versus tiotropium in both trials.9, 10

For patients who are at increased risk of exacerbations (eg, patients with greater airflow limitation or those with a history of exacerbations), prevention of exacerbations is a key treatment goal of COPD disease management.12 We therefore assessed the effect of indacaterol on exacerbations in a long-term, blinded study in patients with severe COPD and a history of exacerbations, versus tiotropium, a bronchodilator with long-term efficacy on exacerbations.13, 14

Section snippets

Study design

INVIGORATE (indacaterol: providing opportunity to re-engage patients with life) was a 52 week, international, multicentre (408 centres in 41 countries, appendix), randomised, blinded, double-dummy, parallel group study comparing the effects of once-daily indacaterol maleate (150 μg) and tiotropium bromide (18 μg) on lung function, exacerbations and related outcomes in about 3500 patients with COPD and severe airflow limitation.15

We enrolled both men and women (aged ≥40 years) who had a smoking

Results

Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium (figure 1). Baseline characteristics were much the same between the treatment groups (table 1). Most patients were white men.

We recorded improvements from baseline in trough FEV1 in patients in both groups at week 12 (0·114 L with indacaterol and 0·126 L with tiotropium) and week 52 (0·073 L with indacaterol and 0·092 L with tiotropium).

At week 12, the estimated

Discussion

In this 1-year blinded comparison, once-daily treatment with indacaterol or tiotropium in patients with severe COPD and a history of exacerbations gave equally effective and clinically relevant improvements in lung function, health status, and breathlessness. Patients receiving indacaterol had a 29% higher rate of exacerbations versus patients receiving tiotropium, and a statistically significant 20% increase in the risk of the time to first COPD exacerbation. Compared with patients given

References (30)

  • S Spencer et al.

    Impact of preventing exacerbations on deterioration of health status in COPD

    Eur Respir J

    (2004)
  • BR Celli et al.

    Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study

    Am J Respir Crit Care Med

    (2008)
  • GC Donaldson et al.

    Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

    Thorax

    (2002)
  • DE O'Donnell et al.

    COPD exacerbations. 3: Pathophysiology

    Thorax

    (2006)
  • JA Wedzicha et al.

    The role of bronchodilator tr.eatment in the prevention of exacerbations of COPD

    Eur Respir J

    (2012)
  • Cited by (216)

    • Actualités concernant la prise en charge médicamenteuse de la BPCO

      2022, Revue des Maladies Respiratoires Actualites
    • Pharmacological Management of Asthma and COPD

      2022, Comprehensive Pharmacology
    View all citing articles on Scopus
    View full text