Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis
Jemma Hudson, Moira Cruickshank, Richard Quinton, Lorna Aucott, Magaly Aceves‐Martins, Katie Gillies, Shalender Bhasin, Peter J. Snyder, Susan S. Ellenberg, Mathis Grossmann, Thomas G. Travison, Emily Gianatti, Yvonne T. van der Schouw, Mariëlle H. Emmelot‐Vonk, Erik J. Giltay, Geoff Hackett, Sudarshan Ramachandran, Johan Svartberg, Kerry L. Hildreth, Kristina Groti Antonič, Gerald Brock, J. Lisa Tenover, Hui Meng Tan, Christopher C.K. Ho, Wei Shen Tan, Leonard S. Marks, Richard Ross, Robert S. Schwartz, Paul Manson, Stephen A. Roberts, Marianne Andersen, Line Velling Magnussen, Rodolfo Hernández, Nick Oliver, Frederick C. W. Wu, Waljit S. Dhillo, Siladitya Bhattacharya, Miriam Brazzelli, Channa Jayasena
Abstract
Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.