Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis
Hudson, Jemma; Cruickshank, Moira; Quinton, Richard; Aucott, Lorna; Aceves-Martins, Magaly; Gillies, Katie; Bhasin, Shalender; Snyder, Peter J.; Ellenberg, Susan S.; Grossmann, Mathis; Travison, Thomas G.; Gianatti, Emily J.; van der Schouw, Yvonne T.; Emmelot-Vonk, Marielle H.; Giltay, Erik J.; Hackett, Geoff; Ramachandran, Sudarshan; Svartberg, Johan; Hildreth, Kerry L.; Groti Antonic, Kristina; Brock, Gerald B.; Tenover, J. Lisa; Tan, Hui Meng; Kong, Christopher Ho Chee; Tan, Wei Shen; Marks, Leonard S.; Ross, Richard J.; Schwartz, Robert S.; Manson, Paul; Roberts, Stephen; Andersen, Marianne Skovsager; Magnussen, Line Velling; Hernández, Rodolfo; Oliver, Nick; Wu, Frederick; Dhillo, Waljit S.; Bhattacharya, Siladitya; Brazzelli, Miriam; Jayasena, Channa N.
(2022) The Lancet Healthy Longevity, volume 3, issue 6, pp. e381 - e393
(Article)
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
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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.
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Keywords: Aged, Heart Failure, Humans, Hypogonadism, Male, Myocardial Infarction, Systematic Reviews as Topic, Testosterone, Geriatrics and Gerontology, Health(social science), Psychiatry and Mental health, Family Practice, Research Support, Non-U.S. Gov't, Meta-Analysis, Journal Article
ISSN: 2666-7568
Publisher: Elsevier
Note: Funding Information: This work was supported by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project no 17/68/01). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR HTA Programme, or the Department of Health and Social Care, UK. The funders were not actively involved in the research process at any stage. The study design; collection, analysis, and interpretation of data; writing of the manuscript; and decision to submit for publication were performed independent of the funders. The Health Services Research Unit at the University of Aberdeen is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The Section of Endocrinology and Investigative Medicine at Imperial College London is funded by grants from the Medical Research Council, Biotechnology and Biological Sciences Research Council, NIHR, an Integrative Mammalian Biology Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The following authors are also funded as follows: NIHR Research Professorship (WSD), NIHR post-doctoral fellowship (CNJ). SBhasin receives National Institutes of Health research grant funding. The authors are grateful to Prakash Abraham, Alison Avenell, Craig Ramsay, Graham Scotland, Neil Scott, and Finlay MacKenzie for their advice; and to the many individuals from academia and industry who helped in the conduct of this study. Funding Information: CNJ reports research grants from Logixx Pharma. SBhas reports research grants from AbbVie and National Institutes of Health; consulting fees from Aditum; participation on the Data Safety Monitoring board of OKPO; a leadership or fiduciary role in the Endocrine Society; and a patent (free T calculator based on the ensemble allosteric model, reference 20200174026). SSE reports research grants from AbbVie. MG reports research grants from Otsuka, Bayer, Lilly, Weight Watchers, Novartis, National Health and the Medical Research Council Australia; speaker honoraria from Besins Healthcare, Bayer, and Otsuka; consulting fees from Bayer; and Royalties from Walter and Eliza Hall Institute Melbourne Australia. KLH reports research grants from NIA K23 Career Development Award; a leadership or fiduciary role from Kavod Senior Life Board of Directors, Executive Committee; and stock or stock options from Medaware Systems. NO reports research grants from Dexcom, Roche Diabetes, and Medtronic Diabetes; speaker honoraria from Roche Diabetes; consulting fees from Roche Diabetes and Medtronic Diabetes; payment for expert testimony from London law firm Wilmer Hale; and an issued patent for automatic closed loop glucose control with an adaptive meal bolus calculator. SR reports research grants from North Staffordshire Medical Institute and support for attending meetings or travel from Besins Healthcare. PJS reports research grants from Abbvie and payment for expert testimony from Teva. RQ reports speaker honoraria and support for attending meetings or travel from Bayer. SBhat reports speaker honoraria from Obstetrical & Gynaecological Society of Singapore, Merck SMART Masterclass, and Merck FERRING Forum; leadership or fiduciary role at National Health Service Grampian; editorial role (Editor in Chief of Human Reproduction Open, Special Senior Editor of Cochrane Gynaecology and Fertility); membership of NHS Grampian Board; other financial or non-financial interests from Oxford University Press; and Royalties from Cambridge University Press (Royalties for book Reproductive Medicine for the MRCOG, Cambridge University Press). GBB reports speaker honoraria and consulting fees from Acerus Pharmaceutical. HMT reports consulting fees from Besin Healthcare. EJGil reports provision of study materials from Bayer. All other authors declare no competing interests. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.
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