Elsevier

The American Journal of Medicine

Volume 132, Issue 9, September 2019, Pages 1069-1077.e4
The American Journal of Medicine

Clinical Research Study
Cardiovascular and Cerebrovascular Safety of Testosterone Replacement Therapy Among Aging Men with Low Testosterone Levels: A Cohort Study

https://doi.org/10.1016/j.amjmed.2019.03.022Get rights and content

Abstract

Purpose

We assessed the risk of ischemic stroke, transient ischemic attack, and myocardial infarction associated with testosterone replacement therapy (TRT) among aging men with low testosterone levels.

Methods

Using the UK Clinical Practice Research Datalink, we formed a cohort of men aged 45 years or older with low testosterone levels and no evidence of hypogonadotropic or testicular disease, between 1995 and 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) of a composite of ischemic stroke/transient ischemic attack and myocardial infarction were estimated using time-dependent Cox proportional hazards models, comparing current use of TRT with nonuse.

Results

The cohort included 15,401 men. During 71,541 person-years of follow-up, 850 patients experienced an ischemic stroke/transient ischemic attack/myocardial infarction (crude incidence rate 1.19 [95% confidence interval (CI), 1.11-1.27] per 100 persons per year). Compared with nonuse, current use of TRT was associated with an increased risk of the composite outcome (HR 1.21; 95% CI, 1.00-1.46). This risk was highest in the first 6 months to 2 years of continuous TRT use (HR 1.35; 95% CI, 1.01-1.79), as well as among men aged 45-59 years (HR 1.44; 95% CI, 1.07-1.92).

Conclusions

TRT may increase the risk of cardiovascular events in aging men with low testosterone levels, particularly in the first 2 years of use. In the absence of identifiable causes of hypogonadism, TRT should be initiated with caution among aging men with low testosterone levels.

Introduction

Testosterone replacement therapy (TRT) is used for the treatment of male testosterone deficiency, or hypogonadism.1 While the rates of hypogonadism have remained stable, TRT prescriptions have increased by over threefold from 2001 to 2011 in the United States,2, 3 and by almost 90% from 2001 to 2010 in the United Kingdom.4 Thus, TRT may be increasingly prescribed to relieve nonspecific symptoms of aging, such as fatigue and declining sexual function. While endogenous testosterone levels are known to decrease modestly with age, the clinical benefits of TRT in late-onset hypogonadism are moderate, at best.5 Consequently, TRT is not indicated among aging, but otherwise healthy, men.6, 7

In addition to the unclear benefits of TRT among aging men with testosterone decline, concerns have emerged as to the cardiovascular and cerebrovascular safety of these medications. While randomized controlled trials (RCTs) have not been sufficiently powered to detect differences in the rates of adverse vascular events comparing testosterone with placebo,8 observational studies have generated conflicting findings. Indeed, some have reported an increased risk of stroke or myocardial infarction associated with TRT,9, 10 whereas others have reported the opposite association, with testosterone having a strong protective effect.11, 12 Given these uncertainties, different federal and regulatory agencies have also adopted different standpoints. For example, the US Food and Drug Administration and Health Canada have issued warnings as to the potential risks associated with TRT, while the European Medicines Agency has found no consistent evidence for such risks.6, 7, 13 The US and European Endocrine Society recently acknowledged a lack of conclusive evidence and the need for additional information about the cardiovascular safety of TRT.14, 15

In light of the ongoing uncertainty about the cardiovascular safety of these medications, the objective of this population-based study was to evaluate the association between TRT and the risk of ischemic stroke/transient ischemic attack and myocardial infarction, in aging men with low testosterone levels.

Section snippets

Data Source

This study was conducted using the Clinical Practice Research Datalink (CPRD). This database contains electronic medical records of more than 15 million patients enrolled in over 700 primary care practices in the UK.16, 17, 18 The information collected includes demographic data and lifestyle habits, diagnoses, and referrals to specialists and hospitals. Data related to medical diagnoses, procedures, and services are coded using the Read classification scheme,19 while prescriptions are recorded

Results

After applying all exclusion criteria, our final cohort comprised 15,401 hypogonadal men (Figure 1) with a mean age of 60.4 years (standard deviation [SD] 9.6 years) (Table 1). TRT was prescribed to 4485 patients (29.1%) on at least one occasion during a mean follow-up time of 4.7 years (SD 3.7 years), with a majority of patients initiated on testosterone gels/creams (56.8%) and injections (33.6%).

Overall, 850 patients experienced an ischemic stroke/transient ischemic attack or myocardial

Discussion

In this population-based cohort study of aging men with low testosterone levels, current exposure to TRT was associated with an increased risk of ischemic stroke/transient ischemic attack/myocardial infarction. This association was highest in the first 2 years after treatment initiation, as well as among middle-aged patients, although a similar increased risk in older patients is possible. Conversely, current use of TRT was associated with a decreased risk of mortality and past use with an

Acknowledgments

LA holds a Chercheur-Boursier Senior Award from the Fonds de recherche du Québec – Santé and is the recipient of a William Dawson Scholar award from McGill University. OHYY holds a Chercheur-Clinicien Junior 1 Award from the Fonds de recherche du Québec – Santé.

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  • Cited by (0)

    Funding: This study is supported, in part, by funding from the Canadian Institutes of Health Research.

    Conflict of Interest: None declared.

    Authorship: All authors had access to the data and a role in writing the manuscript.

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