How to Read the TRAVERSE Trial: What a Cardiovascular Safety Study Can and Cannot Tell You

The TRAVERSE trial asked one narrow question: in men with symptomatic hypogonadism who already had cardiovascular disease or were at high risk for it, does testosterone therapy raise the risk of a major cardiac event compared with placebo? The answer it reported was no measurable increase in the primary composite of cardiovascular death, nonfatal heart attack, and nonfatal stroke. That is a safety finding, not a proof of benefit, and it applies to the specific population studied. Reading it well means separating what the design could establish from what a headline or a label change might imply.

What TRAVERSE actually tested

Published in the New England Journal of Medicine in 2023, TRAVERSE randomly assigned 5,246 men aged 45 to 80 to a transdermal testosterone gel or a matching placebo gel. Every participant reported symptoms of hypogonadism and had low measured testosterone, and every participant either had established cardiovascular disease or carried a high risk of it. The enrolled group skewed older and sicker than the average person searching this topic online: mean age around 63, high average body-mass index, and a large share with type 2 diabetes. Participants were treated for a mean of roughly 22 months.

The primary endpoint was time to the first event in a composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. This is a standard cardiovascular-safety composite, and the choice of endpoint matters for how far the results can travel.

Why this was a noninferiority trial, and what that changes

TRAVERSE was designed as a noninferiority trial. That distinction is easy to skim past and central to interpretation. A superiority trial asks whether a treatment is better than the comparator. A noninferiority trial asks whether a treatment is not unacceptably worse, within a pre-specified margin. The regulatory motivation here was history: earlier observational reports and one stopped trial had raised concern that testosterone might increase cardiovascular events, and the U.S. Food and Drug Administration had required a dedicated safety study.

So the question was defensive. Does testosterone, given under monitored conditions, avoid crossing a defined harm threshold? In the primary result, first events occurred in 7.0 percent of the testosterone group and 7.3 percent of the placebo group, with a hazard ratio of 0.96 and a confidence interval that stayed within the pre-specified noninferiority margin. That satisfies the safety question as posed. It does not demonstrate that testosterone protects the heart, and the trial was never built to show that.

The signals that did not disappear

A clean primary result does not mean a clean trial. TRAVERSE reported several secondary safety signals that a careful reader should hold alongside the headline. The testosterone group showed higher rates of atrial fibrillation, acute kidney injury, and pulmonary embolism, and an increase in venous thromboembolism. There was also an unexpected increase in fractures. These were secondary endpoints, which means the trial was not powered to confirm or refute them with the same confidence as the primary composite. That cuts both ways: it means the numbers are hypothesis-generating rather than definitive, and it means they should not be waved away simply because the primary endpoint was met. A safety trial that clears one bar can still surface questions on others.

What the 2025 FDA label change did and did not do

On February 28, 2025, the FDA announced class-wide labeling changes for testosterone products. Drawing on TRAVERSE and required postmarket studies, the agency removed the boxed warning language about increased cardiovascular risk, added the trial results to product labeling, retained the existing limitation-of-use language for age-related hypogonadism, and required new blood-pressure warning information for products with completed monitoring studies.

Here is the part that headlines tend to compress. A label change is a legal and regulatory act describing what the evidence now supports, not a recommendation to take a drug and not a declaration that a product is safe for everyone. Removing a boxed warning about a specific cardiovascular risk means the agency judged that the earlier warning was not supported by the trial data for the studied indication. It does not extend an all-clear to men outside that indication, it does not address the secondary signals, and the retained limitation-of-use language is itself a signal that the label still does not endorse testosterone for low levels that are simply age-related. Describing that mechanism is different from praising or criticizing the decision or the officials behind it.

A short checklist for reading any safety trial

The same questions that clarify TRAVERSE apply broadly. Who was actually enrolled, and do you resemble them? What was the exact endpoint, and is it the outcome you care about? Was the design built to show benefit or only to rule out harm within a margin? How long was follow-up, and does that match the timescale of the risk? Were the alarming numbers primary endpoints or secondary signals? For TRAVERSE, the honest summary is that it answered a specific cardiovascular-safety question for an older, higher-risk, treated-under-monitoring population over about two years, it left efficacy and longer-term outcomes open, and it raised secondary questions that remain under study.

None of this tells any individual what to do. Whether testosterone therapy is appropriate is a personal decision made with a clinician who knows the full clinical picture, weighing measured hormone levels, symptoms, competing risks, and the secondary signals the trial surfaced. This article is educational and is not medical advice.