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Research

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

BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2445 (Published 27 May 2015) Cite this as: BMJ 2015;350:h2445
  1. Iosief Abraha , researcher 1,
  2. Antonio Cherubini , director 2,
  3. Francesco Cozzolino , researcher 1,
  4. Rita De Florio , researcher 3,
  5. Maria Laura Luchetta , researcher 4,
  6. Joseph M Rimland , researcher 2,
  7. Ilenia Folletti , researcher 6,
  8. Mauro Marchesi , director 5,
  9. Antonella Germani , researcher 5,
  10. Massimiliano Orso , researcher 1,
  11. Paolo Eusebi , researcher 1,
  12. Alessandro Montedori , researcher 1
  1. 1Health Planning Service, Regional Health Authority of Umbria, Department of Epidemiology, 06124 Perugia, Italy
  2. 2Geriatrics and Geriatric Emergency Care, Italian National Research Centre on Aging Ancona, Italy
  3. 3General Medicine, Azienda USL Umbria 2, Terni, Italy
  4. 4General Medicine, Azienda USL Umbria 1, Perugia
  5. 5Transfusion Medicine Service, Azienda Ospedaliera di Perugia, Perugia
  6. 6Department of Clinical and Experimental Medicine, University of Perugia, Perugia
  1. Correspondence to I Abraha iosief_a{at}yahoo.it
  • Accepted 25 March 2015

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 τ2=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; τ2=0.08). After exclusion of five influential studies, results remained consistent (0.85 (0.75 to 0.98); τ2=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); τ2=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.

Footnotes

  • We thank Tom Jefferson, Mark Jones, and Ian Shrier for their comments and suggestions; Kathy Mahan for assistance in editing; Marcello Catanelli, Emilio Duca, and Gianni Giovannini for their support; IA is indebted to Albano Del Favero.

  • Contributors: IA, AM, AG, FC, RDF, MLL, and MO conceived the study. IA, AM, AC, JMR, IF, MM, and PE designed the study. MLL, RDF, MO, FC, JMR, AG, and IF acquired the data. IA, AC, MM, PE, and AM analysed the data. IA and AM drafted the manuscript. All authors critically revised the manuscript and approved the final version. IA is guarantor.

  • Funding: This study was funded by the Ministry of Health, Italy (RF-2009-1549561). The study sponsor was not involved in the study design and collection, analysis, and interpretation of data, or the writing of the article or the decision to submit it for publication. The authors were independent from study sponsors.

  • 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.

  • Ethical approval: Not required.

  • Data sharing: The dataset is available from the corresponding author.

  • The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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