Testosterone Therapy in Men Doubles the Risk for Venous Thromboembolism

Whether or not testosterone therapy in men increases the risk for venous thromboembolism (VTE) has been a debated topic and has important clinical implications. The U.S. Food and Drug Administration’s labeling for testosterone products contains a warning about VTE, yet prior studies on the topic have not been able to reach a definitive conclusion.^1,2 

Investigators from the University of Minnesota, Dr. Rob Walker and colleagues, performed a case-crossover study using commercial and Medicare claims data to identify men who had a VTE event. After excluding men without 12 months of continuous enrollment or with a diagnosis of cancer, 39,622 men with VTE were included in the analysis. The authors compared testosterone exposure by drug claims in the six months (case period) prior to the VTE event and six to 12 months (control period) prior to the VTE. Conditional logistic regression with multivariate adjustment was performed to account for hospitalizations, and outpatient emergency department visits in the case and control periods. For the analysis, subjects were stratified into those with a diagnosis code for hypogonadism and those without. In men without hypogonadism (n=36,512), use of testosterone within the case period was more frequent than the control period, resulting in an increased odds ratio (OR) ranging from 1.96 to 2.46, with the highest odds ratio identified at three months (OR, 2.46; 95% CI, 1.71-3.53). Findings were similar in men with hypogonadism (n=3,110), with OR ranging from 1.66 to 2.32 and the highest OR at six months (OR, 2.32; 95% CI, 1.97-2.74). In exploratory analyses, the risk remained similar, with testosterone exposure within three months of the VTE event. However, the OR at the three- to six-month case periods were not significant, indicating that men who have tolerated testosterone for a more prolonged period without developing VTE may have a lower risk.

This study stands out among other research on this topic due to its excellent design and the inclusion of the largest number of VTE cases examined for testosterone exposure. The case-crossover design used helps eliminate measured and unmeasured confounding, which has been a significant problem with observational studies comparing treated patients to untreated patients, owing to inherent differences in these groups.

The data from this study are consistent with that of another recent observational study, which showed an increased risk for VTE within the first six months after testosterone initiation (RR, 1.63; 95% CI, 1.12-2.37).³  These point estimates are also similar to the results of a meta-analysis of the few randomized control trials that had reported VTE outcomes (OR, 1.96; 95% CI, 0.75-5.17).⁴ 

The American College of Physicians recently published a clinical practice guideline²  on the efficacy and safety of testosterone treatment in men and noted that the available randomized control trials were not powered to assess important harms. Data from the study by Dr. Walker and colleagues were not included in the observational evidence reviewed as it had not been published at the time of the analysis.

Additional data are being collected. The TRAVERSE study (NCT03518034) is a randomized phase IV study started in 2018 with an estimated enrollment of 6,000 men with hypogonadism, and will assess long-term major adverse cardiac events in men treated with testosterone. Patients with prior VTE are excluded from enrollment. Unfortunately, the information provided on clinicaltrals.gov does not indicate whether the study will specifically evaluate VTE as an outcome, and an inquiry to the study sponsor only led to being referred back to the clinicaltrials.gov website.