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

Eriksson, Göran LU ; Calverley, Peter M; Jenkins, Christine R; Anzueto, Antonio R.; Make, Barry J; Lindberg, Magnus; Fagerås, Malin and Postma, Dirkje S (2017) In International Journal of COPD 12. p.1457-1468
Abstract

Background: 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. Methods: 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.... (More)

Background: 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. Methods: 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. Results: 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 treatmentrelated 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. Conclusions: 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Disease severity, Early differential dropout, Exacerbation outcomes, Healthy survivor effect, RCT
in
International Journal of COPD
volume
12
pages
12 pages
publisher
Dove Press
external identifiers
  • scopus:85019764980
  • wos:000401272800001
ISSN
1176-9106
DOI
10.2147/COPD.S130713
language
English
LU publication?
yes
id
67d8ec95-7fb4-40e2-8fac-ebb015d865c6
date added to LUP
2017-07-03 16:20:21
date last changed
2017-09-18 11:37:19
@article{67d8ec95-7fb4-40e2-8fac-ebb015d865c6,
  abstract     = {<p>Background: 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. Methods: 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. Results: 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 treatmentrelated 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. Conclusions: 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.</p>},
  author       = {Eriksson, Göran and Calverley, Peter M and Jenkins, Christine R and Anzueto, Antonio R. and Make, Barry J and Lindberg, Magnus and Fagerås, Malin and Postma, Dirkje S},
  issn         = {1176-9106},
  keyword      = {Disease severity,Early differential dropout,Exacerbation outcomes,Healthy survivor effect,RCT},
  language     = {eng},
  month        = {05},
  pages        = {1457--1468},
  publisher    = {Dove Press},
  series       = {International Journal of COPD},
  title        = {The effect of COPD severity and study duration on exacerbation outcome in randomized controlled trials},
  url          = {http://dx.doi.org/10.2147/COPD.S130713},
  volume       = {12},
  year         = {2017},
}