Cumulative meta-analysis

by Harri Hemilä 

This text is based on p 32 of Hemilä (2006)
These documents have up to date links to documents that are available via the net.
Harri Hemilä
Department of Public Health
University of Helsinki, Helsinki, Finland
harri.hemila@helsinki.fi

Home: http://www.mv.helsinki.fi/home/hemila

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Version May 29, 2012


The various potential limitations of the experimental data should make a meta-analyst cautious in drawing conclusions, but sometimes the conclusions are extraordinarily comprehensive considering the kind of small trials on which they are based.

A particularly bold general proposal related to drawing conclusions from meta-analyses made by the Chalmers group was that meta-analyses should be updated with each new trial so that when, or if, the combined P-value becomes statistically significant at a chosen level, the treatment should be considered proven efficacious, and further trials may be considered even unethical. This approach was called ‘cumulative meta-analysis’ (Antman et al. 1992; Lau et al. 1992), a concept considered to be among the most important contributions to medicine by Thomas Chalmers (Ian Chalmers 1996; Liberati 1996). Using cumulative meta-analysis, the Chalmers group showed that the effect of administering intravenous magnesium in acute myocardial infarction reached P[2-t] < 0.05 in 1989, and P[2-t] < 0.001 in 1990 with a cumulative OR of 0.44 (95% CI: 0.27 – 0.71), and they concluded that the evidence for the benefit of magnesium was persuasive (Antman et al. 1992; Lau et al. 1992). However, a large trial with 58,050 patients carried out thereafter showed that mortality in the first 5 weeks after myocardial infarction was, paradoxically, slightly higher in the magnesium group (+6%; 95% CI: 0% to +12%) (ISIS-4 1995; Egger & Smith 1995). The ‘cumulative meta-analysis’ thus led to a completely false conclusion.

Nevertheless, it is of interest that, following the reasoning of ‘cumulative meta-analysis’, if Chalmers (1975; pp 36-8 of Hemilä 2006) had restricted his meta-analysis of vitamin C and the common cold to double-blind placebo-controlled trials in which ≥2 g/day of vitamin C was regularly administered to participants, he might have found powerful evidence by 1975 from 5 trials that vitamin C alleviates the symptoms and/or reduces the duration of colds during supplementation (P = 0.000,002; Hemilä 1996a). Using the approach of Chalmers’ ‘cumulative meta-analysis,’ the addition of 3 trials that were carried out after 1975 led to P = 0.000,000,02 by 1996 (Hemilä 1996a). No trials with this selection criterion have been published since 1996.

References

Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC (1992) A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. JAMA 268:240-8

Chalmers I (1996) Thomas Chalmers. BMJ 312:118

Chalmers TC (1975) Effects of ascorbic acid on the common cold: an evaluation of the evidence. Am J Med 58:532-6  ***  SEE PROBLEMS OF CHALMERS' REVIEW

Egger M, Smith GD (1995) Misleading meta-analysis: lessons from “an effective, safe, simple” intervention that wasn’t. BMJ 310:752-4

Hemilä H (1996a) Vitamin C supplementation and common cold symptoms: problems with inaccurate reviews. Nutrition 12:804-9   HH 1996a 

ISIS-4 [Fourth International Study of Infarct Survival Collaborative Group] (1995) A randomised factorial trial assessing early oral capropril, oral mononitrate, intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 345:669-85

Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC (1992) Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 327:248-54 * comments in: (1992);327:273-4, 1316

Liberati A (1996) Thomas C Chalmers. Lancet 347:188



Copyright: © 2006-2009 Harri Hemilä. This text is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  

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Vitamin C and infections in animals by Harri Hemilä is licensed under a Creative Commons Attribution 1.0 Finland License.
Based on a work at www.mv.helsinki.fi/home/hemila/metaanalysis



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