Testosterone therapy linked to increased risk of venous thromboembolism

1. In this case-crossover study, use of therapeutic testosterone supplementation in men was linked with an increased short-term risk of venous thromboembolism (VTE).

2. Associated risk of VTE with testosterone therapy was demonstrated in men with and without demonstrated hypogonadism, with a trend towards increased risk of VTE in men younger than 65 years old without clinical hypogonadism.

Evidence Rating Level: 3 (Average)       

Study Rundown: Testosterone therapy is currently indicated for men with hypogonadism in order to improve sexual dysfunction, bone metabolism, and emotional dysregulation. Prescriptions of testosterone have increased substantially, especially for young men without demonstrated hypogonadism. Many of these prescriptions are made for common age related symptoms such as decreased libido, obesity, and body composition change. Complications of testosterone therapy include erythrocytosis and increased serum viscosity which can increase the risk of arterial and venous thrombotic events. The current study is a case-crossover study which sought to evaluate the risk of incident VTE among men receiving testosterone therapy, stratified by presence or absence of clinical hypogonadism. The study found that testosterone therapy increased the risk of incident VTE, regardless of presence of clinical hypogonadism. The risk appeared greatest amongst men younger that 65 years without clinical hypogonadism, although this finding was not statistically significant.

The main strengths of the study include the large number of VTE cases with testosterone exposure, the case-crossover design to account for time-invariant unmeasured confounding, and data on patients with and without clinical hypogonadism. The main limitation of the study is the dependence on administrative data, where classification of clinical hypogonadism may not be accurate.

Click to read the study in JAMA Internal Medicine

Relevant Reading: Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy

In-Depth [retrospective cohort]: This study used data from the IBM Market-Scan Commercial Claims and Encounter Database and the Medicare Supplemental Database (IBMWatsonHealth) from 2011-2017. Patients were included if they were men aged 18-99 years with at least 1 inpatient or 2 outpatient claims for VTE 7 to 184 days apart. Patients were excluded if they did not have twelve months of continuous enrollment in the database prior to the VTE, or if they had cancer. Presence of clinical hypogonadism was based on ICD-9-CM database codes. The case crossover design utilized each patient as their own control with exposure case periods of 6,3, and 1 month before the incident VTE event, with equivalent exposure control periods starting 6 months before the incident VTE event. The exposure of interest was a drug claim for testosterone prescription at the 1, 3, and 6-month time period before the incident VTE event.

Of the 39,622 patients included in the study 3110 had clinical hypogonadism. Testosterone therapy was linked with an increased risk of VTE in men with (odds ratio [OR], 2.32; 95%CI, 1.97-2.74) and without (OR, 2.02; 95%CI, 1.47-2.77) hypogonadism. In patients without hypogonadism, risk for men younger than 65 years (OR, 2.99; 95%CI, 1.91-4.68) trended higher than older men (OR, 1.68; 95%CI, 0.90-3.14), though this finding was not statistically significant (P=0.14).

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