The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials.



Eriksson, Göran, Calverley, Peter M, Jenkins, Christine R, Anzueto, Antonio R, Make, Barry J, Lindberg, Magnus, Fagerås, Malin and Postma, Dirkje S
(2017) The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials. International journal of chronic obstructive pulmonary disease, 12. 1457 - 1468.

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Abstract

When discontinuation in COPD randomized controlled trials (RCTs) is unevenly distributed between treatments (differential dropout), the capacity to demonstrate treatment effects may be reduced. We investigated the impact of the time of differential dropout on exacerbation outcomes in RCTs, in relation to study duration and COPD severity.A post hoc analysis of 2,345 patients from three RCTs of 6- and 12-month duration was performed to compare budesonide/formoterol and formoterol in moderate, severe, and very severe COPD. Outcomes were exacerbation rate, time-to-first exacerbation, or discontinuation; patients were stratified by disease severity. Outcomes were studied by censoring data monthly from 1 to 12 months.In patients treated with budesonide/formoterol, annualized exacerbation rates (AERs) were comparable for each study duration (rate ratio [RR] =0.6). With formoterol, the AER decreased with study duration (RR =1.20 at 1 month to RR =0.86 at 12 months). There was a treatment-related difference in exacerbation rates of 45%-48% for shorter study durations (≤4 months) and 27% for 12-month duration. This treatment-related difference in exacerbation rates was comparable for the three disease severities in studies ≤4 months (range: 39%-51%), but this difference decreased with longer study durations, especially in more severe groups (22% and 29% at 12 months). There were fewer discontinuations with budesonide/formoterol; the treatment-related difference in time-to-first discontinuation decreased by study duration (35%, 30%, 26%, and 22% at 3, 6, 9, and 12 months, respectively). Numbers of differential dropouts increased with increasing disease severity, being greatest during second, third, and fourth months.COPD severity and study duration impact exacerbation as an outcome in double-blind RCTs. This effect is most obvious in patients with severe/very severe COPD and in studies that are longer than 4 months. Early differential dropout particularly impacts study outcome, producing a "healthy survivor effect," which reduces estimations of treatment impact on exacerbations.

Item Type: Article
Uncontrolled Keywords: Lung, Humans, Pulmonary Disease, Chronic Obstructive, Disease Progression, Bronchodilator Agents, Glucocorticoids, Treatment Outcome, Endpoint Determination, Severity of Illness Index, Double-Blind Method, Research Design, Time Factors, Aged, Middle Aged, Patient Dropouts, Female, Male, Randomized Controlled Trials as Topic, Adrenergic beta-2 Receptor Agonists, Formoterol Fumarate, Budesonide, Formoterol Fumarate Drug Combination
Depositing User: Symplectic Admin
Date Deposited: 13 Aug 2019 09:10
Last Modified: 17 Mar 2020 10:01
DOI: 10.2147/COPD.S130713
URI: http://livrepository.liverpool.ac.uk/id/eprint/3051531