ReviewAssociation between exogenous testosterone and cardiovascular events: an overview of systematic reviews
Introduction
During the past decade, the use of exogenous testosterone among middle-aged and elderly men in the USA has greatly increased.1, 2 However, some evidence has suggested that use of exogenous testosterone is associated with potential cardiovascular risks. For example, in 2010, the randomised, placebo-controlled Testosterone in Older Men with Mobility Limitations (TOM) trial3 of a transdermal gel containing high-dose testosterone was stopped early after an excess of adverse events—including atrial fibrillation, exacerbation of congestive heart failure, myocardial infarction, and acute coronary syndrome—was reported among treated participants.3 The trial was not powered to assess cardiovascular outcomes, and since then results of observational studies have both supported4, 5 and refuted6, 7 an association between exogenous testosterone and potential cardiovascular risks. To complicate matters further, previous observational studies have also shown endogenously low testosterone concentrations to be associated with increased cardiovascular mortality.8, 9, 10
Regulatory authorities such as the US Food and Drug Administration (FDA), Health Canada,11 and the European Medicines Agency have reviewed the evidence for the safety of testosterone. In July, 2014, Health Canada identified a possible association between testosterone-replacement therapies and cardiovascular risk.11 In September, 2014, an FDA advisory committee meeting was held,12 and subsequently a Drug Safety Communication was released recommending that clinicians “should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests”.13 In March, 2015, the FDA required labelling changes for all prescription testosterone products to reflect the possible increased risk of stroke and myocardial infarction associated with use of these medicines.
Systematic reviews and meta-analyses of randomised controlled trials are regarded as the highest standard of scientific evidence and are a highly efficient way to pool together data from several clinical studies and generate evidence-based clinical practice. Since 2005, at least seven systematic reviews14, 15, 16, 17, 18, 19, 20 of randomised controlled trials have been published on the association between exogenous testosterone and cardiovascular risk.14, 15, 16, 17, 18, 19, 20 Although the results of each of these meta-analyses appeared to be pointing in the direction of a positive association between testosterone exposure and cardiovascular events, only three had significant results,17, 18, 20 and two18, 20 of these three had significant results only for subgroup analyses and not for their overall estimates.
We did an overview of published systematic reviews of randomised controlled trials21 and qualitatively assessed the association between exogenous testosterone and cardiovascular risks.22 In addition to investigating the direction and magnitude of the primary association of interest, we compared and contrasted study characteristics, analytic methods, included trials, key findings, and methodological quality of each synthesis.
Section snippets
Study selection and definitions
We prepared this overview paper in conjunction with work on our own systematic review of randomised controlled trials on the same topic (unpublished). We used the same search strategy for both investigations. We determined screening criteria a priori, with the aim of identifying published systematic reviews that assessed the effects of any formulation of exogenous testosterone on any cardiovascular outcome among men aged 18 years or older (appendix). We defined systematic review as any review
Characteristics of included reviews
The results from our combined search totalled 29 335 citations—21 909 abstracts from the initial search (Aug 28, 2015) and additional 7426 citations from the update (July 19, 2016). We identified 954 articles for full text review, which included reports of systematic reviews, randomised controlled trials, and observational studies. After full text screening of these articles, we included seven eligible systematic reviews of randomised controlled trials in which the effects of any formulation of
Discussion
Available data, including evidence syntheses, provide conflicting evidence about the association between exogenous testosterone and cardiovascular events. We systematically assessed evidence of an association between exogenous testosterone and cardiovascular events among published systematic reviews of randomised controlled trials and identified substantial variations in study characteristics, the randomised controlled trials included in each review, analytic methods, and methodological quality.
Conclusions
These data from systematic reviews of randomised controlled trials suggest a small increase in the risk of serious cardiovascular events associated with exogenous testosterone. A meta-analysis of individual patient data that takes into account time to event and in which appropriate analytic approaches for sparse data are used would be informative. An FDA communication13 emphasised that testosterone products are FDA approved for disorders of the testicles, pituitary gland, or brain that cause
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