Department of General Practice, University Medical Centre Nijmegen, 229 HAG, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
* Corresponding author. Tel.: +31-24-3614411; fax: +31-24-3541862
E-mail address: f.vandelaar{at}hag.umcn.nl
With great interest we read the article of Hanefeld et al., in which a meta-analysis of seven randomised controlled trials was presented. This meta-analysis compared acarbose with placebo in patients with type 2 diabetes with respect to the incidence of cardiovascular events.1 The conclusion that acarbose can prevent myocardial infarctions surprised us because, currently finishing a Cochrane systematic review on the topic,2 we found only scarce outcomes regarding diabetes-related morbidity so far. Moreover, we were very disappointed that the design and conduct of this study was not critically discussed at all, even more so because they suggest major flaws that seriously undermine the conclusions.
The criteria for the selection of these seven long-term randomised controlled trials are not clear. Studies that are included in meta-analyses should be the result of an extensive and systematic search strategy. Failing to do so could result in selection bias, affecting the outcome significantly, usually in the direction of the desired outcome.3 Also, the results from the largest included study were never published as a journal article and thus not subject to the peer-review process, and two studies were not published at all. The inclusion of unpublished studies is a virtue, but the reasons why a study has not been published should be made clear because this might reflect methodological flaws or conflicting interests.
Heterogeneity should not be investigated solely by statistical methods, but firstly with a visual inspection of the main study characteristics of each trial. In this meta-analysis clinical heterogeneity is obvious. For example, different kinds of co-interventions were used. We also have concerns about the way the main outcome data were collected and handled. The authors use the so-called safety data from the original studies, an idea that is creative in a fashion. However, safety-data were not collected following the rigorous methods as required in controlled trials.
Possible other causes for a reduction of myocardial infarctions should be investigated carefully. First, it should be made clear which study contributes most to the results. This might lead to possible other factors related to study design that also might explain the results. Secondly, special attention should be paid to the possible contribution in each study of additional medication and life-style factors. And thirdly, the data should be analysed accounting for the intervention that was actually received. Since the authors used data from the safety group, an unknown number of patients did not actually use acarbose. Usually, dropouts receive some other form of anti-diabetic treatment and thus it cannot be excluded that the measured effect on cardiovascular events is merely the result of anti-diabetic treatment in general, rather than the effect of acarbose.
Finally, we wonder if the outcome `any cardiovascular event' would still be significant if myocardial infarctions were excluded. If so, the conclusion that acarbose has shown preventive effects on `any cardiovascular event' is not logical.
In summary, this meta-analysis is subject to publication bias, heterogeneity, detection bias and confounding factors. The conclusion that there is evidence for a reduction of myocardial infarctions by acarbose is not justified.
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