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

Hudson J 1 , Cruickshank M 1 , Quinton R 2 , Aucott L 1 , Aceves-Martins M 1 , Gillies K 1 Show all authors , Bhasin S 3 , Snyder PJ 4 , Ellenberg SS 4 , Grossmann M 5 , Travison TG 6 , Gianatti EJ 7 , van der Schouw YT 8 , Emmelot-Vonk MH 9 , Giltay EJ 10 , Hackett G 11 , Ramachandran S 12 , Svartberg J 13 , Hildreth KL 14 , Groti Antonic K 15 , Brock GB 16 , Tenover JL 17 , Tan HM 4 , Kong CHC 18 , Tan WS 19 , Marks LS 20 , Ross RJ 21 , Schwartz RS 22 , Manson P 1 , Roberts S 23 , Andersen MS 24 , Magnussen LV 24 , Hernández R 25 , Oliver N 26 , Wu F 27 , Dhillo WS 26 , Bhattacharya S 28 , Brazzelli M 1 , Jayasena CN 26

Affiliations 

  • 1 Health Services Research Unit, University of Aberdeen, Aberdeen, UK
  • 2 Translational and Clinical Research Institute, University of Newcastle-on-Tyne, Newcastle Upon Tyne, UK
  • 3 Departent of Medicine, Harvard Medical School, Boston, MA, USA
  • 4 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • 5 University of Melbourne Austin Health, Heidelberg, VIC, Australia
  • 6 Division of Gerontology, Boston, MA, USA
  • 7 Deartment of Endocrinology, Fiona Stanley Hospital, WA, Australia
  • 8 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  • 9 Department of Geriatrics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
  • 10 Department of Psychiatry, Leiden University Medical Centre, The Netherlands
  • 11 Department of Men's Health, Aston University Medical School Birmingham, Birmingham, UK
  • 12 Department of Chemical Pathology, University Hospitals Birmingham, Birmingham, UK
  • 13 Division of Internal Medicine, Section of Endocrinology, University Hospital of North Norway, Tromsø, Norway
  • 14 Department of Medicine, University of Colorado, Boulder, CO, USA
  • 15 Department of Endocrinology, University Medical Centre, Ljubljana, Slovenia
  • 16 Western University and Omega Fertility Center, London, ON, Canada
  • 17 Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
  • 18 School of Medicine, Taylor's University, Petaling Jaya, Malaysia
  • 19 Department of Urology, University College London, London UK
  • 20 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  • 21 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
  • 22 Division of Geriatric Medicine, University of Colorado, Boulder, CO, USA
  • 23 Centre for Biostatistics, Manchester Academic Health Science Centre, Division of Population Health, Health Services, Research and Primary Care, University of Manchester, Manchester, UK
  • 24 Department of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
  • 25 Health Economics Research Unit, University of Aberdeen, Aberdeen, UK
  • 26 Faculty of Medicine, Hammersmith Hospital, Imperial College London, London, UK
  • 27 Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
  • 28 School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
Lancet Healthy Longev, 2022 Jun;3(6):e381-e393.
PMID: 35711614 DOI: 10.1016/S2666-7568(22)00096-4

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: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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