Adverse cardiovascular events and mortality in men during testosterone treatment: An individual patient and aggregate data meta-analysis

Hudson, Jemma and Cruickshank, Moira and Quinton, Richard and Aucott, Lorna and Aceves-Martins, Magaly and Gillies, Katie and Bhasin, Shalender and Snyder, Peter J and Ellenberg, Susan S and Grossmann, Mathis and Travison, Thomas G and Gianatti, Emily J and van der Schouw, Yvonne T and Emmelot-Vonk, Marielle H and Giltay, Erik J and Hackett, Geoff and Ramachandran, Sudarshan and Svartberg, Johan and Hildreth, Kerry L and Groti Antonic, Kristina and Brock, Gerald B and Tenover, J Lisa and Tan, Hui Meng and Kong, Christopher Ho Chee and Tan, Wei Shen and Marks, Leonard S and Ross, Richard J and Schwartz, Robert S and Manson, Paul and Roberts, Stephen and Andersen, Marianne Skovsager and Magnussen, Line Velling and Hernández, Rodolfo and Oliver, Nick and Wu, Frederick and Dhillo, Waljit S and Bhattacharya, Siladitya and Brazzelli, Miriam and Jayasena, Channa N (2022) Adverse cardiovascular events and mortality in men during testosterone treatment: An individual patient and aggregate data meta-analysis. The Lancet Healthy Longevity, 3 (6). e381 -e393. ISSN 2666-7568, DOI

Full text not available from this repository.


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: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, SD 11) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six 0·4% of 1621) than placebo (12 0·8% of 1537) without significant differences between groups (odds ratio OR 0·46 95% CI 0·17–1·24; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 7·5% of 1601 events) and placebo treatment (110 7·2% of 1519 events; OR 1·07 95% CI 0·81–1·42; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 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. © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

Item Type: Article
Funders: National Institutes of Health Research (NIHR) [Grant No: 17/68/01], Chief Scientist Office of the Scottish Government Health and Social Care Directorates, UK Research & Innovation (UKRI) Medical Research Council UK (MRC), UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC), Integrative Mammalian Biology Capacity Building Award, EuroCHIP grant [Grant No: FP7-HEALTH-2009-241592], NIHR Research Professorship, United States Department of Health & Human Services National Institutes of Health (NIH) - USA
Uncontrolled Keywords: Placebo; Testosterone; Article; Cardiovascular disease; Cardiovascular risk; Clinical evaluation; Diabetes mellitus; Drug dose regimen; Drug formulation; Drug safety; Follow up; Groups by age; Heart arrhythmia; Heart failure; Heart infarction
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 27 Oct 2023 07:04
Last Modified: 27 Oct 2023 07:04

Actions (login required)

View Item View Item