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variety of causes, relating to clinical heterogeneity (differences in patient mix, setting, etc.) or differences in methods. The degree of statistical heterogeneity can be measured to see if it is greater than is compatible with the play of chance. 34 Such a statistical tool may lack statistical power; consequently, results that do not show significant heterogeneity do not necessarily mean that the trials are truly homogeneous and one must look beyond them to assess the degree of heterogeneity.
     
    ‘Meta-analysis is on the strongest ground when the methods employed in the primary studies are sufficiently similar that any differences in their results are due to the play of chance.’ 30
    Figure 1.1 An example of a meta-analysis of 19 randomised controlled trials investigating the use of endoscopic sclerotherapy to reduce mortality from oesophageal varices in the primary treatment of cirrhotic patients. Reproduced from Chalmer I, Altman DG. Systematic reviews. London: BMJ Publishing, 1995; p. 119. With permission from Blackwell Publishing Ltd.
    Views on the usefulness of meta-analyses are divided. On the one hand, they may provide conclusions that could not be reached from other trials because of the small numbers involved. However, on the other hand, they have some limitations and cannot produce a single simple answer to all complex clinical problems. They may give misleading results if used inappropriately where there is a biased body of literature or clinical or methodological heterogeneity. If used with caution, however, they may be a useful tool in providing information to help in decision-making.
    Figure 1.2 shows a funnel plot of a meta-analysis relating to the use of magnesium following myocardial infarction. 35 The result of each study in the analysis is represented by a circle plotting the odds ratio (with the vertical line being at 1, the ‘line of no effect’) against the trial size. The diamond represents the overall results of the meta-analysis with its pooled data from all the smaller studies shown. This study 36 was published in 1993 and showed that it was beneficial and safe to give intravenous magnesium in patients with acute myocardial infarction. The majority of the studies involved show a positive effect of the treatment, as does the meta-analysis. However, the results from this study were contradicted in 1995 by ISIS-4, a very large RCT involving 58 050 patients. 37 It had three arms, in one of which intravenous magnesium was given to patients suspected of an acute myocardial infarction. The results are marked on the funnel plot and show that there is no clear benefit for this treatment, contrary to the results of the earlier meta-analysis.
    Figure 1.2 A funnel plot of a meta-analysis relating to the use of magnesium following myocardial infarction. Points indicate values from small and medium-sized trials; the diamond is the combined odds ratio with 95% confidence interval from the meta-analysis of these trials and the square is that for a mega trial. Reproduced from Egger M, Smith GD. Misleading meta-analysis. Br Med J 1995; 310:752–4. With permission from the BMJ Publishing Group Ltd.
    Some would say that this is one of the major problems with using statistical synthesis. An alternative viewpoint is that it is an example of the importance of ensuring that the material fed into a meta-analysis from a systematic review is researched and critically appraised to the highest possible standard. Explanations for the contradictory findings in this review have been given as: 32 , 35
    • publication bias, since only trials with positive results were included (see funnel plot);
    • methodological weakness in the small trials;
    • clinical heterogeneity.
    Clinical guidelines
     
    Clinical guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances. 38
    EBM is increasingly advocated in healthcare, and