  BACKGROUND: An important goal of chronic obstructive pulmonary disease (COPD)
treatment is to reduce the frequency of exacerbations. Some observations
suggest a decline in exacerbation rates in clinical trials over time. A more
systematic understanding would help to improve the design and interpretation of
COPD trials.
  METHODS: We performed a systematic review and meta-regression of the placebo
groups in published randomized controlled trials reporting exacerbations as an
outcome. A Bayesian negative binomial model was developed to accommodate
results that are reported in different formats; results are reported with
credible intervals (CI) and posterior tail probabilities ($p_B$).
  RESULTS: Of 1114 studies identified by our search, 55 were ultimately
included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); $p_B$ <
0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available
study and baseline characteristics such as forced expiratory volume in 1 s
(FEV1) did not alter the observed trend considerably. Two subsets of studies,
one using a true placebo group and the other allowing inhaled corticosteroids
in the "placebo" group, also yielded consistent results.
  CONCLUSIONS: In conclusion, this meta-regression indicates that the rate of
COPD exacerbations decreased over the past two decades to a clinically relevant
extent independent of important prognostic factors. This suggests that care is
needed in the design of new trials or when comparing results from older trials
with more recent ones. Also a considerable effect of adjunct therapy on COPD
exacerbations can be assumed.
