Testosterone Replacement Therapy (TRT) is a treatment used for men diagnosed with hypogonadism, a condition characterized by low testosterone levels and associated symptoms like reduced libido, fatigue, and decreased muscle mass. For years, the medical community and patients have been divided over the cardiovascular safety of this therapy. The long-standing controversy was driven by conflicting results from smaller studies and observational data, creating uncertainty about whether TRT increased the risk of serious heart problems. The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men, or TRAVERSE, trial was specifically designed as a large-scale, randomized study to definitively address this major safety question.
The Historical Safety Concerns Leading to TRAVERSE
The need for a large safety trial like TRAVERSE arose from a tumultuous period of conflicting data and heightened regulatory scrutiny in the 2010s. Earlier observational studies and retrospective analyses suggested a possible link between TRT and an elevated risk of heart attack or stroke, causing significant alarm among prescribers and patients. These reports, despite being methodologically limited, led the US Food and Drug Administration (FDA) to issue a warning in 2015 requiring manufacturers to conduct a comprehensive cardiovascular outcomes trial.
This regulatory action highlighted a critical gap in the scientific literature: a lack of robust, long-term, randomized, placebo-controlled data focused on major adverse cardiovascular events (MACE). Previous studies were too small, too short, or not specifically designed to track hard cardiovascular outcomes, making definitive safety conclusions impossible. The TRAVERSE trial was mandated as a phase 4 study to fill this void and guide safe prescribing practices.
Primary Findings on Cardiovascular Safety
The TRAVERSE trial was structured as a noninferiority study, meaning its primary goal was to demonstrate that testosterone replacement therapy was not worse than placebo in terms of cardiovascular risk. The study randomized over 5,200 men aged 45 to 80 who had confirmed hypogonadism and were already at high risk for cardiovascular disease (CVD) or had established CVD. Participants were treated with transdermal testosterone gel or a matching placebo gel for a mean duration of 21.7 months, with a mean follow-up of 33 months.
The primary safety endpoint was a composite outcome of MACE, including nonfatal myocardial infarction, nonfatal stroke, or death due to cardiovascular causes. The incidence of MACE was comparable between the two groups, occurring in 7.0% of the testosterone group and 7.3% of the placebo group. This finding established that TRT was noninferior to placebo, meaning it did not increase the risk of major adverse cardiovascular events in this population.
Secondary Outcomes and Efficacy Results
Beyond the primary safety outcome, the TRAVERSE trial investigated multiple secondary outcomes, including efficacy and non-MACE safety signals. The efficacy results demonstrated that testosterone therapy provided significant clinical benefits for the men with hypogonadism. Men receiving TRT experienced measurable improvements in sexual function, particularly libido, as well as changes in mood, physical function, and anemia markers.
The trial also identified several non-MACE safety signals that require careful consideration. The testosterone group had a statistically higher incidence of certain adverse events compared to the placebo group. Researchers noted an increased risk of atrial fibrillation, acute kidney injury, and venous thromboembolic events, such as pulmonary embolism and deep vein thrombosis.
Implications for Clinical Practice
The TRAVERSE results offer significant reassurance regarding the cardiovascular safety of testosterone replacement therapy when used appropriately. The finding that TRT does not increase the risk of MACE removes a major concern that previously complicated treatment decisions for men with hypogonadism and existing heart disease risk. This evidence supports the use of TRT strictly in men who meet the established criteria: clinical symptoms of low testosterone and laboratory confirmation of low serum testosterone levels, typically below 300 ng/dL.
The trial’s findings do not support the widespread use of testosterone for men who lack a medical indication, such as for age-related decline without symptoms. Clinicians must now balance the proven MACE safety with the observed increased risks of atrial fibrillation, acute kidney injury, and venous thromboembolism. These non-MACE risks suggest that men with a history of these conditions may need to use TRT with greater caution and under closer monitoring.
The study also had limitations, including the exclusion of men who had a heart attack or stroke within the six months prior to the trial. This means the safety profile in extremely high-risk, recently destabilized patients remains uncertain. Prescribing guidelines will continue to emphasize careful patient selection, ongoing monitoring of testosterone levels, and discussion of both the benefits and the specific non-MACE risks identified by TRAVERSE.