Missing data in randomized controlled trials testing palliative interventions pose a significant risk of bias and loss of power: a systematic review and meta-analyses

Abstract

Objectives: To assess the risk posed by missing data (MD) to the power and validity of trials evaluating palliative interventions.

Study design and setting: A systematic review of MD in published randomized controlled trials (RCTs) of palliative interventions in participants with life-limiting illnesses was conducted, and random-effects meta-analyses and metaregression were performed. CENTRAL, MEDLINE, and EMBASE (2009-2014) were searched with no language restrictions.

Results: One hundred and eight RCTs representing 15,560 patients were included. The weighted estimate for MD at the primary endpoint was 23.1% (95% confidence interval [CI] 19.3, 27.4). Larger MD proportions were associated with increasing numbers of questions/tests requested (odds ratio [OR], 1.19; 95% CI 1.05, 1.35) and with longer study duration (OR, 1.09; 95% CI 1.02, 1.17). Meta-analysis found evidence of differential rates of MD between trial arms, which varied in direction (OR, 1.04; 95% CI 0.90, 1.20; I(2) 35.9, P = 0.001). Despite randomization, MD in the intervention arms (vs. control) were more likely to be attributed to disease progression unrelated to the intervention (OR, 1.31; 95% CI 1.02, 1.69). This was not the case for MD due to death (OR, 0.92; 95% CI 0.78, 1.08).

Conclusion: The overall proportion and differential rates and reasons for MD reduce the power and potentially introduce bias to palliative care trials.

Keywords: Differential mortality; Meta-analysis; Missing data; Palliative care; Randomized controlled trials; Systematic review.