Proportion attributable to contextual effects in general medicine: a meta-epidemiological study based on Cochrane reviews

OBJECTIVES: Our objectives were to examine the magnitude of the proportion attributable to contextual effects (PCE), which shows what proportion of the treatment arm response can be achieved by the placebo arm across various interventions, and to examine PCE variability by outcome type and condition. DESIGN: We conducted a meta-epidemiological study. SETTING: We searched the Cochrane Database of Systematic Reviews with the keyword ‘placebo’ in titles, abstracts and keywords on 1 January 2020. PARTICIPANTS: We included reviews that showed statistically significant beneficial effects of the intervention over placebo for the first primary outcome. MAIN OUTCOME MEASURES: We performed a random-effects meta-analysis to calculate PCEs based on the pooled result of each included review, grouped by outcome type and condition. The PCE quantifies how much of the observed treatment response can be achieved by the contextual effects. PUBLIC AND PATIENT INVOLVEMENT STATEMENT: No patient or member of the public was involved in conducting this research. RESULTS: We included 328 out of 3175 Cochrane systematic reviews. The results of meta-analyses showed that PCEs varied greatly depending on outcome type (I(2)=98%) or condition (I(2)=98%), but mostly lie between 0.40 and 0.95. Overall, the PCEs were 0.65 (95% CI 0.59 to 0.72) on average. Subjective outcomes were 0.50 (95% CI 0.41 to 0.59), which was significantly smaller than those of semiobjective (PCE 0.78; 95% CI 0.72 to 0.85) or objective outcomes (PCE 0.94; 95% CI 0.91 to 0.97). CONCLUSIONS: The results suggest that much of the observed benefit is not just due to the specific effect of the interventions. The specific effects of interventions may be larger for subjective outcomes than for objective or semiobjective outcomes. However, PCEs were exceptionally variable. When we evaluate the magnitude of PCEs, we should consider each PCE individually, for each condition, intervention and outcome in its context, to assess the importance of an intervention for each specific clinical setting.