Meta-analysis combining parallel and cross-over clinical trials. III: The issue of carry-over

Stat Med. 2002 Aug 15;21(15):2161-73. doi: 10.1002/sim.1207.


In meta-analysis combining results from parallel and cross-over trials, there is a risk of bias originating from the carry-over effect in cross-over trials. When pooling treatment effects estimated from parallel trials and two-period two-treatment cross-over trials, meta-analytic estimators of treatment effect can be obtained from the combination of parallel trial results either with cross-over trial results based on data of the first period only or with cross-over trial results analysed with data from both periods. Taking data from the first cross-over period protects against carry-over but gives less efficient treatment estimators and may lead to selection bias. This study evaluates in terms of variance reduction and mean square error the cost of calculating meta-analysis estimates with data from the first period instead of data from the two cross-over periods. If the information on cross-over sequence is available, we recommend performing two combined design meta-analyses, one using the first cross-over period data and one based on data from both cross-over periods. To investigate simultaneously the statistical significance of these two estimators as well as the carry-over at meta-analysis level, a method based on a multivariate analysis of the meta-analytic treatment effect and carry-over estimates is proposed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Pressure / physiology
  • Clinical Trials as Topic / methods*
  • Cross-Over Studies*
  • Female
  • Humans
  • Male
  • Meta-Analysis as Topic*
  • Selection Bias
  • Sodium, Dietary
  • Statistics as Topic / methods*


  • Sodium, Dietary