Compared to the conventional rescue-therapy involving steroids, the LABA-LAMA regimen (long acting β2-agonist-long-acting muscarinic antagonist), has shown superior efficacy in reducing annual rates of chronic obstructive pulmonary disease (COPD) exacerbations in patients. According to a FLAME trial, published in the New England Journal of Medicine (NEJM) on May 15th, 2016, the regimen will help prevent side-effects associated with the long-term use of glucocorticoids.
Glucocorticoid therapy is the gold standard in controlling symptoms of COPD and reducing the frequency of exacerbations in COPD. Treatment guidelines recommend using a long-acting beta-agonist plus an inhaled glucocorticoid agent, or a solitary long-acting muscarinic agent in high-risk patients. However, the long-term use of steroid therapy is associated with a number of side-effects, one of which is pneumonia.
In an attempt to provide a better alternative to the hitherto indispensable steroid therapy, the FLAME trial investigated whether the LABA (indacaterol) + the LAMA (glycopyrronium) regimen would be better, or at least as effective as the conventional LABA (salmeterol) + inhaled glucocorticoid (fluticasone) regimen in preventing COPD exacerbations. The results were encouraging and showed not only non-inferiority but also superiority of the former over the latter in reducing the annual rate of all COPD exacerbations.
The trial involved 3,362 patients; all of whom were 40 years of age or older and had the following symptoms.
- COPD of grade 2 or higher (Modified Medical Research Council scale range: 0-4, where 0 indicates minimal symptoms, and 4 indicates severe breathing distress called dyspnea).
- A post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 25%-60% of the predicted value
- A post-bronchodilator ratio of FEV1 to forced vital capacity (FVC) of less than 0.70
All patients had a documented history of at least one COPD exacerbation during the previous year. They were noted to receive treatment with systemic glucocorticoids, antibiotic agents, or both.
The trial was multicenter, randomized and double-blind.
A double-blind trial is one in which neither the investigator nor the patient knows whether they are getting the experimental drug or placebo. Such a trial bequeaths the rigor and strength to the study and produces more objective results.
The patients, enrolled in 356 centers in 43 countries, were randomized into two groups – the LABA-LAMA group receiving indacaterol (110 μg) + glycopyrronium (50 μg) once daily (n=1680); and the LABA-Steroid group receiving salmeterol (50 μg) + fluticasone (500 μg) twice daily (n=1682).
The 52-week, Novartis-sponsored study asked patients to record their daily symptoms and their usage of rescue medication in an electronic diary.
The primary objective of this trial was to investigate whether indacaterol–glycopyrronium showed efficacy equivalent or better than salmeterol–fluticasone, in reducing the primary outcome. The primary outcome was the annual rate of all COPD exacerbations regardless of whether the exacerbations were mild, moderate, or severe.
In terms of a reduction in the annual rate of COPD exacerbations, the indacaterol–glycopyrronium regimen showed itself to be superior to the conventional LABA-steriod regimen The rate of exacerbation was 11% lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group.
Patients in the indacaterol–glycopyrronium group also showed a relatively longer time to the first exacerbation c patients in the salmeterol–fluticasone group i.e., 71 days vs. 51 days.
Moreover, the indacaterol–glycopyrronium group showed a lower annual rate of moderate or severe exacerbations than salmeterol–fluticasone group i.e., 0.98 vs. 1.19.
In terms of secondary outcomes, indacaterol–glycopyrronium provided a longer relief for the first moderate or severe exacerbation than the salmeterol–fluticasone group.
Despite the incidence of adverse events and deaths being similar in both groups, the incidence of pneumonia was lower in the indacaterol–glycopyrronium group than in the salmeterol–fluticasone group i.e., 3.2% vs 4.8%.
Strengths And Weaknesses Of The Study
The study was randomized and double-blind which reduced the margin of error and increased not only the margin of safety, but also the authenticity and supremacy of the study.
The multicenter approach of the study allowed the analysis of the drug effect in combination with various differing factors such nationality, race and ethnicity.
The only limitation of the study was that patients who were on a LABA–inhaled
glucocorticoid regimen before enrollment and were later randomized to the indacaterol–glycopyrronium group, may have experienced withdrawal effects from the long-term use of the regimen, which could account for an increase in the exacerbations.
In conclusion, the clinical trial established that indacaterol–glycopyrronium showed a superior effectiveness than salmeterol–fluticasone among patients with COPD having a history of exacerbation during one previous year.
By statistically showing the superiority of the LABA-LAMA regimen, the study results are expected to influence the clinical guidelines and recommendations that press the use of LABA plus an inhaled glucocorticoid, or LAMA as the first-line therapy for COPD in high-risk patients.