Benefit: Risk profile of triple therapy in COPD-hero-image

Benefit: Risk profile of triple therapy in COPD

Inhaled maintenance therapy is a cornerstone of COPD treatment, evident by studies and real-world data showing reductions in exacerbations, symptom burden and mortality.1 While ICS-containing therapies may be associated with pneumonia risk, these risks should be contextualised with the full benefits of therapy when deciding treatment plans.2,3

All-cause mortality in COPD

The risk of all-cause mortality in patients with COPD is significantly increased during severe exacerbations, and in patients with a high symptom burden.3

  n Patients with events (ACM), n(%)‡ Duration at risk (patient-years) Event rate (per 100 patient-years)
Exacerbation-free period Moderate exacerbation* 10,330 70 (0.7) 6280 1.11
During 4397 4 (0.1) 295 1.36
1-90 days post exacerbation 4201 16 (0.4) 1192 1.34
91-365 days post exacerbation 2805 9 (0.3) 881 1.02
Severe exacerbation‡
During 1180 32 (2.7) 65 49.45
1-90 days post exacerbation 980 5 (0.5) 190 2.63
91-365 days post exacerbation 474 2 (0.4) 133 1.51

*Any exacerbation requiring antibiotics and/or oral/systemic corticosteroids; †Any exacerbation leading to hospitalisation or death; ‡Percentage calculated as number of patients with events divided by the total number of patients who spent time in the period.

There was a significant 41-fold increased risk of ACM during a severe exacerbation event, compared with the exacerbation-free period3

*GOLD 2017 subgroups based on spirometry are also used in the 2023 report.1

Effects of single inhaler triple therapy on exacerbations and mortality

Real-world evidence shows that timely initiation of triple therapy with FF/UMEC/VI significantly reduced exacerbation rates compared with delayed initiation. Additionally, the number of inpatient stays and total costs were also reduced with prompt initiation of triple therapy.5,6

Prompt initiation (within 30 days of exacerbation) of FF/UMEC/VI reduced severe exacerbations vs delayed initiation (31–180 days)5

Data from the IMPACT clinical trial show that treatment with ICS-containing triple therapy (FF/UMEC/VI) results in a significant reduction in the risk of all-cause mortality versus dual therapy (UMEC/VI).7 Currently, FF/UMEC/VI is the only triple therapy to demonstrate a statistically significant reduction in all of the following: moderate/severe exacerbations, severe exacerbations, and all-cause mortality versus LAMA/LABA.7,8

On-treatment ACM benefit with both FF-containing regimens vs UMEC/VI7

Relative reduction in risk

FF/UMEC/VI vs UMEC/VI

42%

(95% CI: 12, 62) ; p=0.011

Absolute risk difference = 0.68%

FF/VI vs UMEC/VI

39%

(95% CI: 7, 60); p=0.022

Absolute risk difference = 0.69%

Moreover, all-cause mortality risk increases following stepdown from triple to dual therapy compared with maintenance triple therapy.7

Triple therapy at screening* (n = 4183; 40%) 7

Risk of ACM with FF/UMEC/VI:

vs FF/VI

HR (95% CI)

0.71 (0.46, 1.10)

p value: 0.124 (NS)

vs UMEC/VI

HR (95% CI)

0.62 (0.38, 1.00)

p value: 0.051 (NS)

Maintenance on a triple therapy is associated with a trend towards a lower risk of death than step down to either dual therapy. This supports the benefit of both ICS and LAMA in single-inhaler triple therapy

*In the 3 days prior to and including the screening date; †Calculated as a percentage of the triple therapy at screening* population (FF/UMEC/VI: n=1672; FF/VI: n=1647; UMEC/VI: n=864).

ICS-related pneumonia risk in patients with COPD

Pneumonia rates across ICS/LABA studies show that ICS, commonly used in COPD treatments, is associated with higher rates of pneumonia*,4–9

*Across-study comparisons should be treated with caution due to differences in study design and patient population; †VI is currently not licensed for use as monotherapy in COPD; ‡The licensed dose of FP/SAL in COPD varies by country.

Studies with different SITT showed a higher incidence of pneumonia with all FF-containing regimens8,15,16

ETHOS15

IMPACT8

TRIBUTE16

Pneumonia AESI incidence

Data describing pneumonia risk in patients treated with different therapies show an increase in pneumonia risk associated with ICS use that is generally similar across the different ICS-containing therapies, and as such, can be considered a class effect.8–16 This was confirmed by a report released by the European Medicines Agency, which stated that there was no conclusive evidence of differences in pneumonia risk across different treatments. Furthermore, the report affirmed that the benefits of ICS-containing therapies outweigh the risks.2

Benefits vs risks of triple therapy in COPD

When combining pneumonia risk with the effects of triple therapy on exacerbation risk, there is an overall benefit of therapy with ICS versus without.17–19

Time-to-first severe exacerbation and serious pneumonia AESI17

Risk reduction

Composite of on-treatment severe exacerbation or serious pneumonia AESI*

FF/UMEC/VI vs UMEC/VI

16.9%

(95% CI: 4.2, 27.8); p=0.011

Absolute risk difference = 1.3419

*Serious pneumonia AESI and severe exacerbations were defined as events leading to hospitalisation, prolonged hospitalisation or death.

Using a composite endpoint of severe exacerbation, incidence of serious pneumonia, serious cardiovascular adverse event, and all-cause mortality, risk was lower with triple therapy (FF/UMEC/VI) compared with dual therapy (UMEC/VI).3

Time-to-first on-treatment composite event*,3

*First on-treatment composite event: Severe exacerbation or serious pneumonia or serious CVAESI or ACM

Summary

Exacerbations are associated with increased all-cause mortality in COPD3,4

Treatment with triple therapy is beneficial for all-cause mortality risk7

Increased pneumonia risk observed with triple therapy is a class effect and is generally similar to other ICS-containing therapies2

The composite risk of severe exacerbation and serious pneumonia is lower in patients treated with ICS/LAMA/LABA (FF/UMEC/VI) versus LAMA/LABA dual therapy, demonstrating an overall benefit of triple therapy3

Abbreviations

ACM, all-cause mortality; AE, adverse event; AESI, adverse event of special interest; BDP, beclomethasone dipropionate; BUD, budesonide; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVAESI, cardiovascular adverse events of special interest; FF, fluticasone furoate; FOR, formoterol; FP, fluticasone propionate; GLY, glycopyrrolate; GOLD, Global Initiative for Obstructive Lung Disease; HR, hazard ratio; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β-agonist; LAMA, long-acting muscarinic antagonist; mMRC, Modified Medical Research Council; NS, non-significant; SAL, salmeterol; SITT, single inhaler triple therapy; UMEC, umeclidinium; VI, vilanterol; vs, versus.

References

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  2. European Medicines Agency. PRAC reviews known risk of pneumonia with inhaled corticosteroids for chronic obstructive pulmonary disease. 2016. Available at: https://www.ema.europa.eu/en/documents/press-release/prac-reviews-known-risk-pneumonia-inhaled-corticosteroids-chronic-obstructive-pulmonary-disease_en.pdf Accessed April 2023.
  3. Wells JM, Criner GJ, Halpin DMG, et al. Chronic Obstr Pulm Dis. 2023;10:33–45.
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  11. Wedzicha JA, Singh D, Vestbo J, et al. Respir Med. 2014;108:1153–1162.
  12. Kardos P, Wencker M, Glaab T, et al. Am J Respir Crit Care Med. 2007;175:144–149.
  13. Ferguson GT, Anzueto A, Fei R, et al. Respir Med. 2008;102:1099–1108.
  14. Anzueto A, Ferguson GT, Feldman G, et al. COPD. 2009;6:320–329.
  15. Rabe KF, Martinez FJ, Ferguson GT, et al. N Engl J Med. 2020;383:35–48.
  16. Papi A, Vestbo J, Fabbri L, et al. Lancet 2018:391;1076–1084.
  17. Dransfield MT, Crim C, Criner GJ, et al. Ann Am Thorac Soc. 2021;18:788–798.
  18. Dransfield M, Crim C, Criner G, et al. Presented at: European Respiratory Society International Congress, 15–19 September 2018. Paris, France.
  19. GSK. Data on file. 2020N435647_01.

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NX-GBL-UCV-WCNT-230003 | July 2023