Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey

Abstract

Objective: To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question.

Design: Meta-epidemiological survey.

Data sources: PubMed searched up to November 2014.

Methods: Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results.

Results: The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17,275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I(2)=0%)).

Conclusions: Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

Fig 1 Study flow diagram. RCT=randomized controlled trial

Fig 2 Meta-analyses of comparative effects of medical interventions on mortality reported in randomized controlled trials published after the same clinical question was investigated in RCD studies (part one). For each clinical question investigated in a RCD study, the trials published subsequently are shown. Diamonds=result of meta-analyses combining these subsequent trials as summary odds ratios (using random effects models)

Fig 3 Meta-analyses of comparative effects of medical interventions on mortality reported in randomized controlled trials published after the same clinical question was investigated in RCD studies (part two). For each clinical question investigated in a RCD study, the trials published subsequently are shown. Diamonds=result of meta-analyses combining these subsequent trials as summary odds ratios (using random effects models)

Fig 4 Treatment effects on mortality in RCD studies and randomized controlled trials. Left panel shows comparative effects of medical interventions on mortality reported in RCD studies and results of subsequently published trials on the same treatment comparisons. White circles=effect estimates reported in RCD studies; blue circles=pooled summary effects from subsequent trials (corresponding meta-analyses are shown in fig 2 and fig 3); lines=95% confidence intervals. Right panel shows for each clinical question the ratio of mortality effects reported in trial evidence versus RCD study effects (as relative odds ratios). Blue squares (lines)=relative odds ratio (95% confidence intervals); blue diamond=pooled summary relative odds ratio (meta-analysis of relative odds ratio) across all clinical questions. A relative odds ratio greater than 1 indicates more favorable mortality outcomes in RCD studies than in subsequent trials