The association between previous and future severe exacerbations of chronic obstructive pulmonary disease: Updating the literature using robust statistical methodology

Abstract

Background: There is minimal evidence on the extent to which the occurrence of a severe acute exacerbation of COPD that results in hospitalization affects the subsequent disease course. Previous studies on this topic did not generate causally-interpretable estimates. Our aim was to use corrected methodology to update previously reported estimates of the associations between previous and future exacerbations in these patients.

Methods: Using administrative health data in British Columbia, Canada (1997-2012), we constructed a cohort of patients with at least one severe exacerbation, defined as an episode of inpatient care with the main diagnosis of COPD based on international classification of diseases (ICD) codes. We applied a random-effects 'joint frailty' survival model that is particularly developed for the analysis of recurrent events in the presence of competing risk of death and heterogeneity among individuals in their rate of events. Previous severe exacerbations entered the model as dummy-coded time-dependent covariates, and the model was adjusted for several observable patient and disease characteristics.

Results: 35,994 individuals (mean age at baseline 73.7, 49.8% female, average follow-up 3.21 years) contributed 34,271 severe exacerbations during follow-up. The first event was associated with a hazard ratio (HR) of 1.75 (95%CI 1.69-1.82) for the risk of future severe exacerbations. This risk decreased to HR = 1.36 (95%CI 1.30-1.42) for the second event and to 1.18 (95%CI 1.12-1.25) for the third event. The first two severe exacerbations that occurred during follow-up were also significantly associated with increased risk of all-cause mortality. There was substantial heterogeneity in the individual-specific rate of severe exacerbations. Even after adjusting for observable characteristics, individuals in the 97.5th percentile of exacerbation rate had 5.6 times higher rate of severe exacerbations than those in the 2.5th percentile.

Conclusions: Using robust statistical methodology that controlled for heterogeneity in exacerbation rates among individuals, we demonstrated potential causal associations among past and future severe exacerbations, albeit the magnitude of association was noticeably lower than previously reported. The prevention of severe exacerbations has the potential to modify the disease trajectory.

Fig 1. Regression coefficients relating the occurrence of each follow-up severe exacerbations to subsequent severe exacerbations (green circles) or death (black squares).

Footnote: Regression coefficients for all variables are provided in S2 Table. For each exacerbation, the reference (baseline) hazard for the reported HR is the period between the immediately previous and the current exacerbation.

Fig 2. Individualized hazard ratios* of severe exacerbations after removing the effects of observed patient characteristics†.

Footnote: * Individual-specific HRs represent the tendency of individuals to exacerbate or die that exceeds the effects of the independent variables included in the model. † 0.8% of individuals had HRs of greater than 5 and were not shown in this graph.