Primary Care Corner with Geoffrey Modest MD: COPD – Superiority of LABA and LAMA Combo Treatment

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By Dr. Geoffrey Modest

A recently released report, presented at the American Thoracic Society, found that patients with COPD benefited more from the combination of a long-acting b-agonist (LABA) plus a long-acting anti-muscarinic (LAMA), as opposed to a LABA plus inhaled steroid (see DOI: 10.1056/NEJMoa1516385). Details of the FLAME trial (drug company sponsored trial), a double-blind, double-dummy, parallel-group, non-inferiority trial:

  • 3354 patients with COPD, from 356 centers in 43 countries. Inclusion criteria: >40 yo, grade 2 or greater in modified MRC dyspnea scale (patient describing shortness of breath as “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”), post-bronchodilator FEV1 25-60% of predicted value with FEV1/FVC <70%, and documentation of at least one COPD exacerbation in past year prescribed either systemic steroids, antibiotics or both
  • Mean age 65, 76% male, 78% white/most of rest Asian, duration of COPD 7 years, 56% on inhaled steroids, 40% current smokers, predicted post-bronchodilator FEV1 44%, post-bronchodilator FEV1/FVC 42%
  • GOLD stage:24% Group B (low risk/high symptom burden), 75% Group D (high risk/high symptom burden)
  • Assigned to LABA-LAMA combination (indacaterol 110 mg plus glycopyrronium 50 mg) once daily, vs LABA-steroid (salmeterol 50 mg plus fluticasone 500 mg) bid, followed 52 weeks.
  • Results, comparing LABA-LAMA to LABA-steroid:
    • >99% adherence to each of the treatment groups
    • Rate of COPD exacerbations: 3.59 vs 4.03, 11% lower [RR 0.89 (0.83-0.96, p=0.003]
    • Longer time to first exacerbation: 71 vs 51 days [HR 0.84 (0.78-0.91, p<0.001]
    • Rate of moderate or severe exacerbations: 0.98 vs 1.19, 17% lower [RR 0.83 (0.75-0.91, p<0.001], as well as time to the first severe exacerbation
    • The effect of LABA-LAMA was independent of baseline blood eosinophil count (comparing >2% vs <2%)
    • Subgroup analysis: all showed superiority for LABA-LAMA, though some did not reach statistical significance. Subgroups included race, smoking status at screening, severity of airflow limitation, severity of COPD (where those with high risk/high symptoms had the most improvement), number of COPD exacerbations in past year, or type of med use at screening for study)
    • Change from baseline throughFEV1 was 62 ml more in the LABA-LAMA group at week 52 (p<0.001), and the standard area under the curve for FEV1 was 110 ml more (p<0.001)
    • There was a small but not clinically significant improvement in the patients’ perception of their health status with LABA-LAMA, as measured by the St George’s Respiratory Questionnaire
    • There was a decrease in the use of rescue medications in the LABA-LAMA group
    • Incidence of adverse events was similar, though incidence of pneumonia was 3.2% with LABA-LAMA vs 4.8% LABA-steroid (p=0.02). Rates of discontinuation of treatment were 16.6% in LABA-LAMA and 19.0% with LABA-steroids

So, this trial showed actual superiority of the LABA-LAMA combination, not just non-inferiority

  • The combination LABA-LAMA was approved by the FDA last year, under the brand name: ultibro. (Neither drug nor price are available yet, though it may be cheaper to use the individual combo of tiotropium, a tried-and-true LAMA, with salmeterol or formoterol)
  • Prior trials have shown rough equivalence of tiotropium (a LAMA) by itself and the combination LABA-steroid for prevention of COPD exacerbations, leading to the GOLD guidelines recommending either of these therapies. Also, another study found that a LAMA-LABA combination was superior to a LAMA alone.
  • There are some data suggesting that the LABA-steroid combo works better in those with high blood eosinophil counts. The FLAME study, however, found that even in this subgroup (examined prospectively in the trial) still found superiority of LABA-LAMA

So, this study will change my practice, and for a few reasons. My prior approach for those with symptomatic COPD was to use a LAMA first (specifically tiotropium). If that were insufficient, I added a combo LABA-steroid med. Now, I will still start with tiotropium, but now add a LABA as a single agent, if clinically necessary (though, I should note, no study compares LABA-LAMA to triple therapy with LABA-LAMA-steroid, though I will reserve this triple hit as my third string). And I am concerned about the consistent association of inhaled steroids with pneumonia, as was also the case in this trial and the last blog I sent (see https://stg-blogs.bmj.com/bmjebmspotlight/2016/05/17/primary-care-corner-with-geoffrey-modest-md-copd-safety-of-labas/, the SUMMIT trial, which demonstrated the safety of giving a LABA as sole treatment for COPD). And, the FLAME trial showed superiority for the LABA-LAMA is many realms: decreasing COPD exacerbations in those with even severe COPD as well as decreasing the time to a first exacerbation, improving some parameters of lung function (e.g. FEV1), improving (though not to the point of clinical significance) the patients’ perception of their health status, and a trend to overall fewer adverse events (and actually lower pneumonia events).

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