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Meta-Analysis
. 2015 May 27:350:h2445.
doi: 10.1136/bmj.h2445.

Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study

Iosief Abraha  1 , Antonio Cherubini  2 , Francesco Cozzolino  3 , Rita De Florio  4 , Maria Laura Luchetta  5 , Joseph M Rimland  2 , Ilenia Folletti  6 , Mauro Marchesi  7 , Antonella Germani  7 , Massimiliano Orso  3 , Paolo Eusebi  3 , Alessandro Montedori  3
Affiliations
Meta-Analysis

Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study

Iosief Abraha et al. BMJ. .

Abstract

Objective: To examine whether deviation from the standard intention to treat analysis has an influence on treatment effect estimates of randomised trials.

Design: Meta-epidemiological study.

Data sources: Medline, via PubMed, searched between 2006 and 2010; 43 systematic reviews of interventions and 310 randomised trials were included.

Eligibility criteria for selecting studies: From each year searched, random selection of 5% of intervention reviews with a meta-analysis that included at least one trial that deviated from the standard intention to treat approach. Basic characteristics of the systematic reviews and randomised trials were extracted. Information on the reporting of intention to treat analysis, outcome data, risk of bias items, post-randomisation exclusions, and funding were extracted from each trial. Trials were classified as: ITT (reporting the standard intention to treat approach), mITT (reporting a deviation from the standard approach), and no ITT (reporting no approach). Within each meta-analysis, treatment effects were compared between mITT and ITT trials, and between mITT and no ITT trials. The ratio of odds ratios was calculated (value <1 indicated larger treatment effects in mITT trials than in other trial categories).

Results: 50 meta-analyses and 322 comparisons of randomised trials (from 84 ITT trials, 118 mITT trials, and 108 no ITT trials; 12 trials contributed twice to the analysis) were examined. Compared with ITT trials, mITT trials showed a larger intervention effect (pooled ratio of odds ratios 0.83 (95% confidence interval 0.71 to 0.96), P=0.01; between meta-analyses variance τ(2)=0.13). Adjustments for sample size, type of centre, funding, items of risk of bias, post-randomisation exclusions, and variance of log odds ratio yielded consistent results (0.80 (0.69 to 0.94), P=0.005; τ(2)=0.08). After exclusion of five influential studies, results remained consistent (0.85 (0.75 to 0.98); τ(2)=0.08). The comparison between mITT trials and no ITT trials showed no statistical difference between the two groups (adjusted ratio of odds ratios 0.92 (0.70 to 1.23); τ(2)=0.57).

Conclusions: Trials that deviated from the intention to treat analysis showed larger intervention effects than trials that reported the standard approach. Where an intention to treat analysis is impossible to perform, authors should clearly report who is included in the analysis and attempt to perform multiple imputations.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Ministry of Health, Italy, for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

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Fig 1 Study screening process
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Fig 2 Differences in intervention effect estimates between mITT trials and ITT or no ITT trials. Unadjusted and adjusted analyses are shown
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Fig 3 Influence of meta-analyses contributing most heterogeneity in mITT v ITT and mITT v no ITT trial comparisons
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Fig 4 Differences in treatment effect between mITT trials and ITT trials using the two step meta-epidemiological approach
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Fig 5 Differences in treatment effect between mITT trials and ITT/no ITT trials combined using the two step meta-epidemiological approach
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Fig 6 Influence of meta-analyses contributing most heterogeneity in mITT v ITT/no ITT trial comparison
See this image and copyright information in PMC

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