Relationship between risk, cumulative burden of exacerbations and mortality in patients with COPD: modelling analysis using data from the ETHOS study

BMC Med Res Methodol. 2022 May 25;22(1):150. doi: 10.1186/s12874-022-01616-7.


Background: The major drivers of cost-effectiveness for chronic obstructive pulmonary disease (COPD) therapies are the occurrence of exacerbations and deaths. Exacerbations, including acute and long-term events, can cause worsening of COPD and lead to an increased risk of further exacerbations, and ultimately may elevate the risk of death. In contrast to this, health economic models are based on COPD severity progression. In this post hoc analysis of the ETHOS study, we focus on the progression of COPD due to exacerbations and deaths.

Methods: We fitted semi-parametric and fully parametric multi-state Markov models with the following five progressive states: State 1, no exacerbation; State 2, 1 moderate exacerbation; State 3, ≥ 2 moderate exacerbations; State 4, ≥ 1 severe exacerbations; State 5, death. The models only allowed a patient to transition to a worsened health state, and transitions did not necessarily have to be to the next adjacent state. We used the multi-state models to analyse data from ETHOS, a phase III, 52-week study assessing the efficacy and safety of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate in moderate-to-very severe COPD.

Results: The Weibull multi-state Markov model showed good fit of the data. In line with clinical evidence, we found a higher mortality risk after a severe exacerbation (11.4-fold relative ratio increase [95% CI, 7.7-17.0], 6.4-fold increase [95% CI, 3.8-10.8] and 5.4-fold increase [95% CI, 2.9-10.3] relative to no exacerbations, 1 moderate exacerbation or ≥ 2 moderate exacerbations, respectively). One moderate exacerbation increased mortality risk 1.8-fold (95% CI, 1.1-2.9) vs no exacerbations. We also found a higher risk of severe exacerbation and mortality following ≥ 2 moderate exacerbations.

Conclusion: Multi-state modelling of patients with COPD in ETHOS found an acute and chronic effect of severe exacerbations on mortality risk. Risk was also increased after a moderate exacerbation. Clinical management with effective pharmacotherapies should be optimised to avoid even moderate exacerbations. Modelling with exacerbations could be an alternative to current COPD models focused on disease progression.

Trial registration: NCT02465567.

Keywords: Chronic obstructive pulmonary disease; Cost of illness; Disease progression; Incidence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchodilator Agents* / adverse effects
  • Clinical Trials, Phase III as Topic
  • Disease Progression
  • Drug Therapy, Combination / adverse effects
  • Humans
  • Models, Statistical
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Pulmonary Disease, Chronic Obstructive* / mortality
  • Pulmonary Disease, Chronic Obstructive* / pathology
  • Risk


  • Bronchodilator Agents

Associated data