TRAVERSE
Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (Lincoff et al., NEJM 2023)
Evidence grade 5 of 5, Settled. Read how the Atlas grades evidence.
1 human trial, about 1 studies, ~5,246 participants men, 316 sites, United States and Puerto Rico. The written rationale for this grade is still being prepared.
- FDA
- FDA-mandated post-marketing safety trial (results 2023)
Reference only. Not medical advice.
What can go wrong
TRAVERSE is reassuring on hard cardiac events but introduced new caution: significantly more atrial fibrillation, pulmonary embolism, and acute kidney injury were seen in treated men, and a later fracture sub-study found MORE fractures with testosterone. Findings apply only to physiological gel replacement in genuinely hypogonadal men with monitoring.
This is something to take to a clinician. The Atlas can tell you what is known about traverse in general. It cannot tell you what is happening in your body, and the difference matters most for exactly the symptoms that bring people to this page.
TRAVERSE was a randomized, double-blind, placebo-controlled noninferiority trial of transdermal testosterone gel in middle-aged and older men with hypogonadism and pre-existing or high risk of cardiovascular disease. Mandated by the FDA after the 2015 boxed-warning controversy, it enrolled roughly 5,246 men and found testosterone noninferior to placebo for major adverse cardiac events (MACE). It is the largest dedicated CV-safety RCT of testosterone to date, but it surfaced unexpected signals for atrial fibrillation, pulmonary embolism, and acute kidney injury, and it studied gel only.
The trial that answered the FDA's 2015 cardiovascular safety question for TRT.
What people take it for
What it is taken for. Approval, where it exists, covers only some of these.
- CV safety of TRT
- Provided the pivotal randomized data the FDA required to reconsider the class CV warning
- High-CV-risk hypogonadal men
- Population was deliberately enriched for established or high-risk cardiovascular disease
How it works
TRAVERSE tested whether restoring serum testosterone to the mid-normal range with topical gel increases the rate of hard cardiovascular events versus placebo in men already enriched for cardiovascular risk. The design was noninferiority: the goal was to rule out an unacceptable increase in MACE rather than to demonstrate cardiovascular benefit.
What TRAVERSE did NOT prove
Noninferiority is not proof of safety in every dimension. TRAVERSE did not show cardiovascular BENEFIT, did not study injectable or pellet testosterone, excluded men seeking fertility, used a relatively short mean treatment exposure (~22 months) that may be too brief for atherosclerotic endpoints, and had high discontinuation and incomplete follow-up. The atrial-fibrillation, pulmonary-embolism, and fracture signals were secondary/unadjusted and hypothesis-generating, not definitively established. It also enrolled men with genuine hypogonadism, so its reassurance does NOT extend to recreational or supraphysiological anabolic use.
Safety in detail
This intervention involves significant physiological effects and requires evaluation and monitoring by a qualified physician. Self-administration without medical oversight carries documented health risks. TRAVERSE findings apply to physiological gel replacement in diagnosed hypogonadism, not to supraphysiological or recreational use.
Replacement is not the same as a cycle
TRAVERSE titrated to the MID-NORMAL physiological range. Its reassurance about major cardiac events does not extend to supraphysiological or anabolic dosing, where polycythemia, hypertension, and thrombotic risk are materially higher and uncharacterized by this trial.
What people get wrong
Often saidTRAVERSE proved testosterone is good for the heart
ActuallyIt proved testosterone gel was NOT WORSE than placebo for major cardiac events (noninferiority) - it showed no cardiovascular benefit, and flagged new afib, clot, and fracture signals.
Often saidThe 2015 heart-attack scare about TRT was confirmed
ActuallyTRAVERSE largely did not confirm an excess of heart attacks or strokes; it softened that specific concern while raising different ones.
Who profits, and who pushes back
Editorialists in JACC: Advances
By underplaying its limitations, the trial risks giving false reassurance, especially since real-world use often involves higher doses and longer durations than were studied.
Critics of trial adherence/retention
Over 60% of participants discontinued treatment and roughly 1 in 5 withdrew before end-of-trial visits, weakening confidence in the long-term safety conclusion.
Conflict-of-interest skeptics
Funding by a consortium of testosterone manufacturers, though overseen by an academic coordinating center, warrants caution in how broadly the reassuring headline is generalized.
How we got here
After observational studies (2013-2014) suggested possible cardiovascular harm from testosterone, the FDA in 2015 required a boxed-style warning and mandated a dedicated CV-safety trial. TRAVERSE, sponsored by AbbVie and coordinated through the Cleveland Clinic Coordinating Center for Clinical Research, was the answer. Enrollment ran 2018-2022; primary results were presented at ENDO 2023 and published simultaneously in the New England Journal of Medicine.
- 2013-2014Observational studies suggest possible CV harm from TRT
- 2015FDA mandates CV warning and a dedicated safety trial
- 2018-2022TRAVERSE enrolls ~5,246 men
- 2023Primary MACE results published (noninferior) in NEJM
- 2024Fracture sub-study shows higher fracture rate with testosterone
Set against the alternatives
TRAVERSE is by far the largest and only adequately powered dedicated cardiovascular-safety RCT of testosterone, which is its central advantage over the trials that preceded it. The earlier TOM trial was stopped early after an excess of cardiovascular events, igniting the safety debate, but it was small, used a different population with mobility limitations, and was not designed as a CV-outcomes study. The T-Trials demonstrated modest benefits in sexual function and other domains in older men but were underpowered for hard CV endpoints and raised a noncalcified coronary plaque signal. T4DM showed testosterone could reduce progression to type 2 diabetes but, like the others, was not a cardiovascular-safety trial. TRAVERSE therefore resolved the headline MACE question that the others could not, while studying only transdermal gel titrated to the mid-normal range, leaving injectable and supraphysiologic regimens untested.
| Trial | Population | Primary aim | Key result |
|---|---|---|---|
| TRAVERSE (2023) | ~5,246 hypogonadal men, high CV risk | CV safety (MACE noninferiority) | Noninferior; AFib/PE/AKI signals |
| TOM (2010) | Older men, mobility limitation | Physical function | Stopped early; excess CV events |
| T-Trials (2016) | ~790 men >=65, low T | Sexual/physical/other benefit | Modest benefit; coronary plaque signal |
| T4DM (2021) | ~1,000 men, prediabetes/T2DM risk | Diabetes prevention | Reduced T2DM; not a CV-safety trial |
What the trials could not show
Limits of the studies themselves, as distinct from limits of the treatment.
- Noninferiority design (cannot claim benefit); gel-only (no injectables/pellets); ~22-month mean exposure likely too short for atherosclerotic outcomes; high dropout and missing data; population enriched for CV risk limits generalizability to healthy men; secondary safety signals were not pre-specified primary endpoints.
What we do not know
- Are the afib/PE/fracture signals causal or chance?
- Do injectable or pellet formulations carry the same profile?
- Would a longer exposure reveal atherosclerotic effects?
What could change
Secondary analysesOngoing reports on fracture, prostate, sexual function, anemia, and diabetes endpoints from the cohort.Signal investigationFollow-up work probing the AFib, pulmonary embolism, and AKI safety signals.Next-generation trialsCalls for a successor RCT testing injectables, longer duration, and higher-dose real-world regimens.Guideline updatesProfessional societies revising TRT cardiovascular-safety guidance in light of the results.
At a glance
- Design
- Randomized, double-blind, placebo-controlled, noninferiority
- N randomized
- ~5,246
- Agent
- 1.62% transdermal testosterone gel (AndroGel) titrated to mid-normal range
- Mean age
- ~63 years
- Mean follow-up
- ~22 months (treatment); ~33 months total
- Primary endpoint
- First MACE (CV death, nonfatal MI, nonfatal stroke)
What this entry does not yet cover
What follows is unfinished work on our side, not a finding about TRAVERSE. A short entry is not a safe entry.
- Cost and market. We have not documented what it sells for or who sells it.
- Supply chain. We have not mapped where it is made.
- Who uses it. We have not documented the user groups.
- Children and teenagers. We have not checked what is known about younger people.
Sources
The studies below are named and described, but not linked. You cannot open them from here and check our reading against them, which means this page is our summary of the literature rather than a document you can verify. Weigh it accordingly until the links exist.
The studies that matter
TRAVERSE primary CV results (Lincoff et al., NEJM)2023
Testosterone gel noninferior to placebo for MACE; HR ~1.07 (95% CI ~0.85-1.33). Secondary signals: more atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone arm
TRAVERSE fracture sub-study (Snyder et al., NEJM)2024
Unexpectedly, clinical fracture incidence was HIGHER in the testosterone group (~3.5% vs ~2.5%), contradicting the assumption that TRT reduces fractures
TRAVERSE sexual function / hematocrit secondary analyses2023-2024
Modest sexual-function benefit; expected rise in hematocrit and small PSA increase