Elsevier

Thrombosis Research

Volume 199, March 2021, Pages 123-131
Thrombosis Research

Full Length Article
Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.thromres.2020.12.029Get rights and content

Highlights

  • In the last 3 decades, testosterone use has increased 10-fold in North America.

  • However, the cardiovascular safety of testosterone use has remained controversial.

  • Our meta-analysis of randomized trials examined the VTE risk of testosterone use.

  • We found no evidence of an increased risk of VTE with testosterone use.

  • Given the low quality of evidence, there is a need for further studies in this area.

Abstract

Introduction

The cardiovascular safety of testosterone replacement therapy (TRT) is controversial. While several studies have investigated the association between TRT and the risk of arterial thrombosis, limited information is available regarding its risk of venous thromboembolism (VTE). We aimed to compare the risk of VTE in men randomized to TRT versus placebo or active-comparator in a systematic review.

Methods

We searched Medline, EMBASE, CINAHL, CENTRAL, and clinical trial registries to identify randomized controlled trials (RCTs) comparing TRT to placebo in men aged ≥18 years. We assessed study quality using the Cochrane Risk of Bias assessment tool and the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were pooled across RCTs using random-effects models.

Results

A total of 13 RCTs (n = 5050) were included in our meta-analysis. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and TRT duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49–2.14; I2: 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes.

Conclusions

Our systematic review 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.

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

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