Effectiveness of Aspirin in COPD: Biases in the Observational Studies

Several observational studies report decreased incidence of mortality and of exacerbations with aspirin use in patients with chronic obstructive pulmonary disease (COPD), with calls for a large randomized trial. Aspirin does have local and systemic pulmonary mechanisms of action that could make this drug beneficial in the treatment of COPD. However, the potential for biases in the observational studies has not been examined. We searched the literature for all observational studies reporting on the effect of aspirin in COPD patients on exacerbation and mortality. We reviewed the studies for the presence of time-related and other biases. We identified eight observational studies reporting an overall reduction in all-cause mortality or exacerbation with aspirin use of 21% (pooled rate ratio (RR) 0.79; 95% CI 0.71-0.86). We found two studies affected by immortal time bias (pooled RR 0.81; 95% CI 0.74-0.89), three studies affected by collider-stratification bias (pooled RR 0.66; 95% CI 0.55-0.79) and three that involved some exposure misclassification (pooled RR 0.85; 95% CI 0.78-0.92). Moreover, while adjusting for cardiovascular factors, six of the eight studies did not adjust for important markers of COPD severity and thus remain susceptible to confounding bias. In conclusion, all observational studies reporting on the effectiveness of aspirin on major outcomes of COPD are affected by biases known to exaggerate the effectiveness of a drug. As these studies cannot be used to support a beneficial effect for aspirin in COPD, it would be premature to consider a randomized trial to investigate this question until methodologically rigorous studies are available.