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

Abstract

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.

Conflict of interest statement

KR, MJ, MA and MO are all employees and shareholders of AstraZeneca. EdN was an employee of AstraZeneca at the time of the analysis.

© 2022. The Author(s).

Figures

Fig. 1

a Description of the multi-state model using the Markov assumption; and b Paths for four hypothetical patients through the model. All patients were in the ‘no exacerbation’ state at randomisation. The model only allowed transition to a worsened health state. Transitions did not have to be to the next adjacent state; however, transitions directly from no exacerbations to ≥ 2 moderate exacerbations were not permitted. Markov assumption: transition to future states depends only on the current state at time t and not previously occupied states. Panel b shows paths for four hypothetical patients: for example, patient 1 (overlapping with patient 2 up to week 20) was in State 1 (no exacerbations) up to week 8, then transitioned to State 2 (1 moderate exacerbation) and stayed there up to week 20. At week 24, the patient transitioned to State 3 (≥ 1 moderate exacerbations) then to State 4 (≥ 1 severe exacerbations) at week 28. The patient remained in State 4 until week 36 and died at week 40. exac exacerbation, mod moderate, sev severe

Fig. 2

Kaplan–Meier curves for time to death (cumulative incidence) from time of entry to four progressive exacerbation states arising post-randomisation (mITT population). Since time is measured from state entry, and the majority of patients are in the state of no exacerbation at study entry, the number at risk is much higher at 12 months for the no exacerbation state compared with the other exacerbation states. exac exacerbation, mITT modified intent-to-treat, mod moderate, sev severe

Fig. 3

Estimated probabilities of occupying states of a death, b ≥ 1 severe exacerbations or death, c ≥ 2 moderate exacerbations, ≥ 1 severe exacerbations or death, and d 1 moderate exacerbation, ≥ 2 moderate exacerbations, ≥ 1 severe exacerbations or death, estimated for eight patient profiles, based on patient age, FEV1% predicted and exacerbation history, given the patients occupied the state of no exacerbation at study entry (time 0). exac exacerbation, FEV1 forced expiratory volume in 1 s, mITT modified intent-to-treat, mod moderate, pred predicted, sev severe