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#238 In COPD puffers, does three-of-kind beat a pair?

In Chronic Obstructive Pulmonary Disease (COPD) patients on Long-Acting Muscarinic Antagonist (LAMA) and Long-Acting Beta-Agonist (LABA) dual therapy, does adding inhaled corticosteroids (ICS) improve outcomes?

In COPD patients with ≥1 exacerbation per year, triple therapy reduces the risk of having ≥1 exacerbations/year compared to LAMA/LABA dual therapy (one less patient for every 36) but increases the risk of pneumonia (one more patient for every 34) and costs. It is possible that higher blood eosinophil counts (>150-300 cells/µL) may help target adding ICS.     

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  • 2019 systematic review: 4 randomized, controlled trials (RCTs) comparing triple versus LAMA/LABA dual therapy in 9310 patients for 24-52 weeks, usually in patients with ≥1 exacerbation/year.1 
    • Less exacerbations with triple therapy, Rate Ratio 0.71 (0.60-0.84). 
    • Clinically important quality of life improvement (2 RCTs): 
      • 50% versus 44% (dual therapy), number needed to treat (NNT)=17. 
    • Serious adverse events or discontinuation due to adverse events similar. 
      • Patients with ≥1 pneumonia: 6.4% versus 3.9% (dual therapy), statistically significant. 
  • Largest RCT of above systematic review, 6221 patients on umeclidinium/vilanterol/fluticasone (triple therapy) or umeclidinium/vilanterol (LAMA/LABA dual therapy). [Vilanterol/fluticasone arm not reported here].2 At 1 year: 
    • Exacerbation rate and quality of life similar to above systematic review.   
    • Patients with ≥1 exacerbation (data from sponsor, statistics by TFP authors): 
      • Triple 47% versus dual therapy 50% (statistically significant, NNT=36). 
    • Patients with ≥1 pneumonia: triple 7.6% versus dual therapy 4.7% (statistically significant, number needed to harm=34). 
    • Other systematic reviews found similar.3,4
  • Exacerbations in RCTs defined as moderate (needing oral steroids and/or antibiotics) or severe (leading to hospitalization or death). 
  • Subgroup analyses suggest individuals with higher blood eosinophil counts (>150-300 cells/µL) benefit more from triple therapy, but amount of benefit is not quantifiable.4,5 
    • Targeting treatment by eosinophils has not specifically been tested in large RCTs. 
  • Newest guideline suggests adding ICS in patients who develop further exacerbations on LABA/LAMA therapy (and have blood eosinophil counts ≥100cells/µL).6 
  • When withdrawing ICS from triple, there is a small (6-8% relative), but not statistically different, increase in exacerbations.7,8 
  • Average annual cost: ~$1100 for dual versus ~$1700 for triple therapy.9 

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  • Nicolas Dugré PharmD MSc BCPAC
  • William Tenaglia McInnis
  • G. Michael Allan MD CCFP

1. Zayed Y, Barbarawi M, Kheiri B, et al. Clin Respir J. 2019 Apr 4. doi: 10.1111/crj.13026. [Epub ahead of print].

2. Lipson DA, Barnhart F, Brealey N, et al. N Engl J Med. 2018; 378(18):1671-1680.

3. Zheng Y, Zhu J, Liu Y, et al. BMJ. 2018; 363: k4388.

4. Cazzola M, Rogliani P, Calzetta L, et al. Eur Respir J. 2018; 52:1801586.

5. Ferguson GT, Rabe KF, Martinez FJ, et al. Lancet Respir. 2018; 6(10):747-58.

6. Global Initiative for Chronic Obstructive Lung Disease. (2019). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Available at Accessed: May 11, 2019.

7. Magnussen H, Disse B, Rodriguez-Roisin R, et al. N Engl J Med. 2014; 371: 1285-94.

8. Chapman KR, Hurst JR, Frent SM, et al. Am J Respir Crit Care Med. 2018; 198(3): 329-39.

9. Alberta College of Family Physicians. (2018). Price Comparison of Commonly Prescribed Pharmaceuticals in Alberta 2018. Available at Accessed: May 11, 2019.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.