Definitions of exacerbations: does it really matter in clinical trials on COPD?
Many definitions of COPD exacerbations are reported. The choice for a definition determines the number of exacerbations observed. However, the effect of different definitions on the effect sizes of randomized controlled trials is unclear. This article provides an overview of the large variation of definitions of COPD exacerbations from the literature. Furthermore, the effect of using different definitions on effect sizes (relative risk and hazard ratio) was investigated in a randomized controlled discontinuation trial of inhaled corticosteroids. The following definitions were applied: (1) unscheduled medical attention, (2) a course of oral corticosteroids/antibiotics, (3) deterioration in two major or one major and one minor symptom according to Anthonisen (referenced later), (4) a change in one or more symptoms, (5) a change in two or more symptoms, and (6) a combination of numbers 2 and 4. Relative risks for the exacerbation rate ranged from 1.19 to 1.49, and hazard ratios for time to first exacerbation ranged from 1.36 to 1.84 for the various definitions, varying from nonsignificant to significant. Because the definition of a COPD exacerbation has an impact on the effect size of interventions, there is an urgent need for concerted attempts to reach agreement on a definition of an exacerbation. Also, the exact definition to be used in a study should be specified in the protocol.
Effing
Tanja W
TW
Department of Pulmonology, Medisch Spectrum Twente, Enschede, the Netherlands. Electronic address: tanjaeffing@gmail.com.
Kerstjens
Huib A M
HAM
University Medical Center Groningen and the Department of Pulmonology, University of Groningen, Groningen, the Netherlands.
Monninkhof
Evelyn M
EM
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
van der Valk
Paul D L P M
PDLPM
Department of Pulmonology, Medisch Spectrum Twente, Enschede, the Netherlands.
Wouters
Emiel F M
EFM
Department of Respiratory Medicine, University Hospital Maastricht, Maastricht, the Netherlands.
Postma
Dirkje S
DS
University Medical Center Groningen and the Department of Pulmonology, University of Groningen, Groningen, the Netherlands.
Zielhuis
Gerhard A
GA
Department of Epidemiology, Biostatistics, and HTA, Radboud University Nijmegen, Nijmegen, the Netherlands.
van der Palen
Job
J
Department of Pulmonology, Medisch Spectrum Twente, Enschede, the Netherlands; Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, the Netherlands.
D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D009626:Terminology as Topic