Beta-Blockers in COPD: A Methodological Review of the Observational Studies

The use of beta-blockers in patients with chronic obstructive pulmonary disease (COPD) has received much attention. Several observational studies reported important reductions in mortality and exacerbations with these drugs, but the extent of bias in these studies is unclear. Nevertheless, the large ongoing randomized trial (βLOCK-COPD) was initiated specifically to evaluate these effects. We searched the literature to identify all observational studies investigating the effectiveness of beta-blockers in COPD patients on major outcomes, including death and COPD exacerbation. We identified 18 observational studies, with 10 studies affected by confounding bias and six by immortal time bias, while two addressed these biases. Reductions in all-cause mortality with beta-blocker use were observed among the studies with confounding bias (pooled rate ratio 0.72; 95% CI 0.59-0.88) and those with immortal time bias (pooled rate ratio 0.64; 95% CI 0.53-0.77). A large five-database study that addressed these two biases reported hazard ratios of 0.90 (95% CI: 0.78-1.02) for death and 0.54 (95% CI: 0.47-0.61) for COPD hospitalization. However, this latter estimate was the same as for the first 30 days after treatment initiation, thus indicating that important residual confounding cannot be ruled out. Observational studies, important to provide evidence from real-world data on medication effects, are unsupportive for beta-blockers in COPD. Even if immortal time bias is properly avoided, confounding bias cannot be fully controlled due to their relative contraindication in COPD. In the case of beta-blockers, randomized trials such as βLOCK-COPD are necessary to eliminate the uncertainty from residual confounding bias.