Full Length ArticleTestosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials☆
Introduction
Testosterone replacement therapy (TRT) is prescribed for the management of low testosterone levels when hypogonadism [1] interferes with health or quality of life [2,3]. TRT use has increased 10-fold in North America [4] over the last 30 years, with a 12-fold increase in worldwide sales from $150 million to $1.8 billion during this period [4]. However, the use of TRT declined in recent years [5] following the publication of cardiovascular safety studies [[6], [7], [8], [9]] and a subsequent safety warning surrounding this issue from the US Food and Drug Administration (FDA) [10]. This warning was based on evidence that TRT can increase the risk of coronary artery dilation and potentially rupture an unstable plaque, resulting in myocardial infarction [11].
While much attention has focused on TRT and the risk of arterial thrombosis, the effect of TRT on the risk of venous thromboembolism (VTE) remains poorly understood [12]. The US FDA [13] issued a labeling change in the product information of all approved TRT products regarding the risk of VTE. However, this change was based on limited evidence, consisting only of a case series of patients with VTE [[14], [15], [16]]. The lack of a reference group renders these data difficult to interpret. Moreover, the FDA positional statement on the benefits and safety of TRT in older men stressed the lack of conclusive data for this potential adverse drug effect [10].
There exists both a strong biological rationale and emerging evidence that supports a potential association between TRT and VTE. TRT is hypothesized to interact with previously undiagnosed thrombophilia-hypofibrinolysis, leading to VTE [17]. In addition, several animal [18,19] and human [20,21] studies support the thrombogenic potential of TRT [15,22,23]. A number of randomized controlled trials (RCT) reported VTE as an adverse event of TRT; however, these trials were individually underpowered to examine this safety endpoint, resulting in imprecise estimates. Three previous observational studies have examined this association, reporting heterogeneous findings [[23], [24], [25]]. The association has also been examined in three previous systematic reviews, which reported a disparate risk of VTE in men treated with TRT [12,26,27]. However, these previous systematic reviews had several important limitations, including the exclusion of potentially relevant studies. Consequently, there remains a need to synthesize the totality of the evidence regarding the risk of VTE with TRT. The objective of this systematic review and meta-analysis of RCTs was therefore to determine if TRT, compared with placebo or an active comparator, is associated with the risk of VTE among men ≥18 years.
Section snippets
Methods
The protocol for this study was written following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 checklist (Appendix 1) [28], and the study is reported according to the PRISMA guidelines (Appendix 2) [29]. The study involved aggregate, publicly available data and thus did not require research ethics approval.
Search results
A total of 5014 articles were identified from our search of six databases and two clinical trial registries (Supplementary Table 1). After removing duplicates, 4019 publications underwent title/abstract screening, 418 underwent full-text review, and 13 were included in this meta-analysis (Fig. 1).
Study characteristics
Table 1 describes the characteristics of the included RCTs. The 13 RCTs included 5050 men, 2636 of whom were randomized to TRT and 2414 to placebo or active comparator. The sample size of included RCTs
Discussion
This systematic review and meta-analysis of RCTs was designed to determine the risk of VTE associated with the use of TRT among men. When study-specific estimates were pooled across 13 RCTs, we found no evidence of an increased risk of VTE with TRT. Similar results were obtained for DVT and PE and across several sensitivity analyses. We observed a high risk of bias and an overall low quality of evidence. While no evidence of an increased risk was observed, our estimates were accompanied by wide
Conclusions
Our systematic review and meta-analysis of RCTs suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out. Despite the limitations of the available evidence, the findings of this systematic review and meta-analysis contribute to the evolving body of evidence regarding the cardiovascular safety of TRT.
The following are the supplementary data related to this article.
CRediT authorship contribution statement
HTA designed the study, conducted screening, extracted data, assessed quality, conducted the statistical analyses, and drafted the manuscript. VCB performed screening, data extraction, quality assessment, interpreted data, and critically reviewed the manuscript. KBF, CR, and VT contributed to study design and protocol development, interpreted data, and critically reviewed the manuscript for important intellectual content. KBF is the guarantor.
Declaration of competing interest
The authors declare no competing interest.
Acknowledgments
We thank Andrea Quaiattini, a medical librarian at McGill University, for her help on the development of our search strategies and relevant articles identification.
Sources of funding
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. KBF is supported by a senior salary support award from the Fonds de recherche du Québec – Santé (FRQS; Quebec Foundation for Research - Health) and a William Dawson Scholar award from McGill University. HTA is supported by an FRQS Postdoctoral Training Award. VCB holds a Doctoral Training Award from the FRQS and a Drug Safety and Effectiveness Training (DSECT) Program Award
References (53)
- et al.
European Association of Urology position statement on the role of the urologist in the management of male hypogonadism and testosterone therapy
Eur. Urol.
(2017) - et al.
Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials
BMC Med.
(2013) - et al.
Testosterone therapy, thrombophilia, and hospitalization for deep venous thrombosis-pulmonary embolus, an exploratory, hypothesis-generating study
Med. Hypotheses
(2015) - et al.
Testosterone, thrombophilia, thrombosis
Transl. Res.
(2015) - et al.
Risk of venous thromboembolism in men receiving testosterone therapy
Mayo Clin. Proc.
(2015) - et al.
Testosterone therapy and venous thromboembolism: a systematic review and meta-analysis
Thromb. Res.
(2018) - et al.
Differential risks in men and women for first and recurrent venous thrombosis: the role of genes and environment: comment
J. Thromb. Haemost.
(2015) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Int. J. Surg.
(2010) - et al.
Testosterone supplementation and sexual function: a meta-analysis study
J. Sex. Med.
(2014) - et al.
Random-effects model for meta-analysis of clinical trials: an update
Contemp Clin Trials
(2007)
Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the veterans administration database
Chest
An update on the role of testosterone replacement therapy in the management of hypogonadism
Ther. Adv. Urol.
ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males
Int. J. Impot. Res.
Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse
Med. J. Aust.
Testosterone prescribing in the United States, 2002–2016
JAMA
Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels
JAMA
Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men
PLoS One
Adverse events associated with testosterone administration
N. Engl. J. Med.
Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action
Clin Sci (Lond)
Testosterone treatment and cardiovascular and venous thromboembolism risk: what is ‘new’?
J. Investig. Med.
Food and Drug Administration (FDA)
FDA Adding General Warning to Testosterone Products About Potential for Venous Blood Clots
Hospitalization for pulmonary embolism associated with antecedent testosterone or estrogen therapy in patients found to have familial and acquired thrombophilia
BMC Hematol.
Thrombophilia in 67 patients with thrombotic events after starting testosterone therapy
Clin. Appl. Thromb. Hemost.
Cited by (15)
Coagulation profiles during and after anabolic androgenic steroid use: data from the HAARLEM study
2023, Research and Practice in Thrombosis and HaemostasisHemostatic considerations for gender affirming care
2023, Thrombosis ResearchWhy do patients with hypopituitarism still present an increased mortality?
2023, Annales d'Endocrinologie62-Year-Old Man With Abdominal Pain
2023, Mayo Clinic ProceedingsEffects of 12 Months’ Treatment with Testosterone Undecanoate on Markers for Erythropoietic Activity and Safety Aspects in Transgender and Cisgender Hypogonadal Men
2024, Journal of Applied Laboratory Medicine
- ☆
The poster of this manuscript was presented at the 36th International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE 2020) on September 16th, 2020.