ArticlesAnalysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study
Introduction
Chronic obstructive pulmonary disease (COPD) is associated with a progressive and accelerated reduction in lung function and worsening dyspnoea, punctuated by episodes of acute worsening of symptoms needing additional specific drug treatment and, possibly, emergency or hospital care. Such exacerbations are associated with a poor prognosis in terms of accelerated lung function decline;1, 2 and increased risk of death,3, 4 as well as reduced physical activity and poor health status.5, 6, 7 Prevention of exacerbations is an important management strategy8 and a key objective for new drug treatments for COPD.
Longacting inhaled bronchodilators feature prominently in the recommended management strategy for COPD.8 Both longacting β2-agonists (LABAs) and longacting muscarinic antagonists (LAMAs) have shown efficacy in preventing exacerbations of COPD.9, 10, 11, 12, 13 Although these agents are effective in the treatment of COPD, significant deterioration in health status can persist and hence a need remains for increased disease control. QVA149, a once-daily dual bronchodilator in development for treatment of patients with COPD, contains a fixed dose of the LABA indacaterol and the LAMA glycopyrronium (NVA237). Both these components provide 24-h bronchodilation with once-daily dosing and have an established profile of efficacy and safety in patients with moderate-to-severe COPD.14, 15, 16, 17, 18
The hypothesis for the present study was that the potent bronchodilator effect of a fixed-dose combination of a LABA and a LAMA would translate into better patient-reported outcomes than single bronchodilator therapy, particularly in terms of prevention of COPD exacerbations. We also expected that a greater bronchodilator effect would be associated with an improvement in health status.19 The SPARK study was designed to evaluate the effect of once-daily QVA149 on exacerbations of COPD, using rigorous methods to detect events, including mild exacerbations. The study was conducted in patients with severe or very severe airflow limitation who had experienced at least one exacerbation in the past year and who were therefore at high risk of future adverse outcomes.8 The effect of QVA149 was compared with the once-daily LAMAs glycopyrronium and tiotropium.
Section snippets
Study design
SPARK was a multicentre study (international investigators by country are listed in the appendix pp 2–3) consisting of a pre-randomisation period and a double-blind, parallel-group treatment period (64 weeks). The double-blind treatment period could be extended to a total of 76 weeks; this extension period was designed to increase the number of exacerbation events to ensure the study achieved the exacerbation rate prespecified for analysis (further details provided in statistical analysis
Results
The study was undertaken at 362 centres across 27 countries (appendix p 11). The first patient was enrolled on April 27, 2010; the last patient completed on July 11, 2012. Patient disposition is shown in figure 1. Of 3865 patients screened, 2224 were randomly assigned to treatment groups. The most frequent reasons for screening failure were unacceptable test procedure result and not meeting criteria for diagnosis or COPD severity. Overall, 75% of patients completed the study treatment period.
Discussion
To our knowledge, this is the first report of the efficacy of dual long-acting bronchodilator treatment in a population of patients with severe and very severe COPD at high risk of COPD exacerbations (panel). The study met its primary endpoint, the dual LABA/LAMA bronchodilator QVA149 significantly reduced the rate of moderate to severe exacerbations by 12% compared with the LAMA glycopyrronium, one of its components, and a 10% reduction was seen versus the LAMA tiotropium; however, this
References (46)
- et al.
Physical activity and hospitalization for exacerbation of COPD
Chest
(2006) - et al.
The costs of exacerbations in chronic obstructive pulmonary disease (COPD)
Respir Med
(2002) - et al.
Alternative mechanisms for long-acting beta(2)-adrenergic agonists in COPD
Chest
(2001) - et al.
Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study
Respir Med
(2008) - et al.
Combining tiotropium and salmeterol in COPD: effects on airflow obstruction and symptoms
Respir Med
(2010) - et al.
Adherence to treatment by patients with asthma or COPD: comparison between inhaled drugs and transdermal patch
Respir Med
(2007) - et al.
Enhanced persistence with tiotropium compared with other respiratory drugs in COPD
Respir Med
(2007) - et al.
Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study
Am J Respir Crit Care Med
(2001) - et al.
Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease
Thorax
(2002) - et al.
Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease
Thorax
(2005)
Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments)
Am J Respir Crit Care Med
Exacerbations and time spent outdoors in chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease
Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial
Ann Intern Med
The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide
Am J Respir Crit Care Med
Tiotropium versus salmeterol for the prevention of exacerbations of COPD
N Engl J Med
Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease
N Engl J Med
A 4-year trial of tiotropium in chronic obstructive pulmonary disease
N Engl J Med
Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium
Am J Respir Crit Care Med
Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD
Eur Respir J
Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD
Thorax
Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial
Respir Res
Cited by (464)
COPD treatment – a conceptual review based on critical endpoints
2023, PulmonologycAMP-PDE signaling in COPD: Review of cellular, molecular and clinical features
2023, Biochemistry and Biophysics ReportsSpanish COPD Guidelines (GesEPOC) 2021: Updated Pharmacological treatment of stable COPD
2022, Archivos de Bronconeumologia