TRAVERSE Trial 2023: History, Design, and Why It Resolved the TRT Safety Debate

Written by Keen Meds  ·  Reviewed by Licensed Clinical Providers  ·  March 1, 2026

Key Insight: TRAVERSE enrolled 5,246 men across 316 clinical sites in 22 countries, with a median follow-up of approximately 3.2 years — the largest cardiovascular outcomes trial ever conducted specifically for testosterone therapy.

The history of testosterone replacement therapy includes a fifteen-year period, roughly 2008 to 2023, during which cardiovascular safety was the central unanswered question in the field. The concern was not new in 2008 -- small studies and observational analyses had raised it periodically for decades -- but it became clinically acute following the TOM Trial in 2010 and the observational publications of 2013 and 2014 that prompted the FDA's 2015 black box warning.

Clinicians and researchers recognized throughout this period that the question could only be definitively answered by a specific type of study: a large, randomized, placebo-controlled trial with enough participants, a long enough follow-up, and a high-risk enough population to detect any increase in cardiovascular events if one existed. That study was TRAVERSE.

Why TRAVERSE Was Necessary: The Gap in the Evidence

The TOM Trial, published in 2010, had found a significantly elevated rate of cardiovascular adverse events in testosterone-treated men compared to placebo -- 23 events versus 5 -- leading to early stopping. The population enrolled was older men with confirmed mobility limitations and high cardiovascular risk. The result created a credible safety signal, even if the generalizability to typical TRT candidates was questionable.

The observational studies from 2013 to 2014 -- Vigen et al. in JAMA and Finkle et al. in PLoS ONE -- generated media coverage and FDA scrutiny despite significant methodological limitations. Observational analyses could produce signals and hypotheses; they could not establish causation. Multiple subsequent observational datasets contradicted the Vigen and Finkle findings, adding to the uncertainty rather than resolving it.

The TTrials' cardiovascular sub-study, published in 2017, found that testosterone therapy was associated with increased coronary artery noncalcified plaque volume over one year compared to placebo in approximately 170 older men. This was a surrogate endpoint finding in a small population, and its implications for actual cardiovascular events were unclear.

The FDA's 2014 safety communication included a requirement that manufacturers conduct a clinical trial to address cardiovascular safety. This regulatory requirement became the direct mandate for TRAVERSE.

TRAVERSE Design: Purpose-Built to Answer the Question

The formal design of the TRAVERSE trial was published by Bhasin et al. in the American Heart Journal in 2022, before the results were available. The pre-registration of the protocol and publication of the design paper are standard practices for major clinical trials.

TRAVERSE enrolled men between 45 and 80 years of age with confirmed hypogonadism -- defined as two testosterone levels below 300 ng/dL measured on separate mornings -- and either pre-existing cardiovascular disease or an elevated cardiovascular risk profile. The use of a population with established cardiovascular risk was deliberate: if testosterone therapy increases cardiovascular event rates, the effect would be most detectable in a population where events occur at meaningful rates.

Participants were randomized 1:1 to receive testosterone undecanoate 200 mg/day (a daily oral capsule formulation) or matching placebo. The primary outcome was MACE: a composite of cardiovascular death, nonfatal myocardial infarction (heart attack), and nonfatal stroke. The trial was designed as a non-inferiority study, meaning it was testing the hypothesis that testosterone was not worse than placebo for MACE. The pre-specified non-inferiority margin was a hazard ratio upper bound of 1.50.

The Primary Result: Non-Inferiority Confirmed

The primary results of TRAVERSE were published by Lincoff et al. in the New England Journal of Medicine in June 2023. After a median follow-up of approximately 3.2 years, the primary MACE outcome occurred in 7.0% of men in the testosterone group and 7.3% in the placebo group, yielding a hazard ratio of 0.96 (95% confidence interval 0.83 to 1.12).

This result satisfied the pre-specified non-inferiority criterion. The upper bound of the 95% confidence interval, 1.12, was well below the 1.50 non-inferiority margin. The headline finding was clear: testosterone therapy in men with hypogonadism and elevated cardiovascular risk did not increase the rate of major cardiovascular events compared to placebo over a median of 3.2 years.

Secondary Findings: Atrial Fibrillation and Pulmonary Embolism

The TRAVERSE publication also reported on pre-specified secondary safety endpoints, two of which showed statistically significant differences between the testosterone and placebo groups.

Atrial fibrillation occurred in 3.5% of men in the testosterone group compared to 2.4% in the placebo group (hazard ratio 1.35). Pulmonary embolism occurred in 0.9% of the testosterone group versus 0.5% in the placebo group (hazard ratio 1.72). Both findings were statistically significant.

These were not primary endpoints, and neither finding altered the primary MACE non-inferiority conclusion. However, they represent meaningful signals that have been incorporated into clinical guidance. The FDA's March 2025 labeling changes, while removing the cardiovascular black box warning, retained language about the potential for increased atrial fibrillation and called for monitoring in patients at elevated risk.

The Sub-Studies: Comprehensive Outcome Assessment

One of the distinguishing features of the TRAVERSE program was the breadth of pre-planned sub-studies examining outcomes beyond cardiovascular events.

The prostate sub-study, published in JAMA, found no significant difference in the rate of high-grade prostate cancer between the testosterone and placebo groups.

The bone sub-study found that testosterone therapy significantly increased bone mineral density and estimated bone strength in the TRAVERSE population, consistent with the TTrials bone findings.

The anemia sub-study replicated the TTrials finding that testosterone therapy corrects unexplained anemia at substantially higher rates than placebo.

The sexual function sub-study found significant improvements in sexual activity and desire in testosterone-treated men compared to placebo.

The depression sub-study found improvement in depressive symptoms in men with elevated depression scores at baseline who received testosterone therapy.

The diabetes sub-study found that testosterone therapy reduced new-onset type 2 diabetes in men with prediabetes, and improved glycemic control in men with existing diabetes.

The FDA Response: Black Box Warning Removed March 2025

The primary TRAVERSE result was the central evidence basis for the FDA's March 2025 decision to remove the cardiovascular black box warning from all FDA-approved testosterone products. The FDA's determination was that TRAVERSE provided a level of evidence -- a large, adequately powered, randomized controlled trial in a high-risk population -- that the prior observational studies could not match and that resolved the cardiovascular safety question.

The removal of the black box warning does not mean that testosterone therapy is without any cardiovascular considerations. The atrial fibrillation and pulmonary embolism signals remain in updated prescribing information, and individual patient cardiovascular risk assessment remains part of clinical practice.

What TRAVERSE Does Not Answer

TRAVERSE used a single testosterone formulation: oral testosterone undecanoate. While the results are relevant to understanding the cardiovascular safety of testosterone therapy broadly, they were generated with this specific formulation and delivery method.

TRAVERSE had a median follow-up of approximately 3.2 years. Long-term outcomes beyond this window -- including cancer risk, sustained bone effects, or cardiovascular effects over decades -- were not assessed.

TRAVERSE enrolled men with confirmed hypogonadism and elevated cardiovascular risk. The degree to which results generalize to younger men, men without cardiovascular risk, or men with testosterone levels in the borderline range is not established by the trial.

Understanding Your Testosterone Today

TRAVERSE is the most rigorous cardiovascular outcomes trial ever conducted for testosterone therapy, and its conclusion -- that testosterone does not meaningfully increase the rate of major cardiovascular events in men with hypogonadism and elevated cardiovascular risk -- represents the highest standard of evidence available in clinical medicine. For appropriately evaluated patients, this evidence base supports informed clinical decision-making about testosterone therapy.

Keen Meds connects you with licensed clinical providers for a telehealth evaluation and lab review. If your testosterone is clinically low, you may qualify for a prescription for Testosterone Spray Rx -- a needle-free transdermal testosterone program.