TRAVERSE Main Trial: The Definitive Cardiovascular Safety Study

TRAVERSE was the 5,246-man randomized trial that finally answered whether testosterone therapy raises cardiovascular risk in men with low-T and existing heart-disease risk factors. Over a mean 33 months of follow-up, the rate of major adverse cardiac events was statistically equivalent between testosterone gel and placebo (7.0% vs. 7.3%).[1] The trial drove the FDA's February 2025 update removing the long-standing cardiovascular warning from the Boxed Warning,[2] and a further round in June 2026 that removed the age-related hypogonadism limitation of use February 2025 had kept.[4] Both steps are set out in what the 2025 label change did.

What TRAVERSE is

TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) was the largest randomized cardiovascular safety trial of testosterone therapy ever conducted. Published in the New England Journal of Medicine in 2023 by Lincoff et al., it was the regulatory response to a decade of conflicting observational data — including the 2010 TOM trial,[3] the 2013 Vigen study, and the meta-analyses that led the FDA to add a cardiovascular warning to testosterone labels in 2015.

Read backwards, TRAVERSE was a settle-it-once-and-for-all trial: a properly powered, randomized, placebo-controlled, multi-center study designed specifically to answer whether testosterone gel raises the risk of major adverse cardiac events (MACE) — cardiovascular death, non-fatal heart attack, or non-fatal stroke — in men who already had elevated cardiovascular risk.

Trial design

The trial was multi-center, double-blind, randomized 1:1, and ran across 316 sites between 2018 and 2022. Key parameters:

• Population: 5,246 men, ages 45–80, with two morning testosterone levels <300 ng/dL plus at least one symptom of hypogonadism.
• Baseline cardiovascular risk: All participants had either established cardiovascular disease or three or more risk factors.
• Intervention: Daily 1.62% testosterone gel (AndroGel formulation) titrated to maintain serum testosterone of 350–750 ng/dL, versus matching placebo gel.
• Primary endpoint: First occurrence of MACE.
• Mean follow-up: 33 months.

Primary results

The primary endpoint was met for non-inferiority: testosterone therapy did not raise the risk of MACE versus placebo.

MACE incidence: 7.0% in the testosterone group vs. 7.3% in the placebo group. Hazard ratio 0.96 (95% CI, 0.78–1.17). The pre-specified non-inferiority margin was met (P < 0.001 for non-inferiority).[1]

For the first time in a properly designed randomized cardiovascular trial of TRT, the evidence pointed clearly: testosterone replacement, when prescribed to symptomatic hypogonadal men and titrated to physiologic levels, does not raise major cardiovascular event risk over roughly three years of follow-up.

Secondary findings

While the primary cardiovascular endpoint was reassuring, the trial flagged three secondary findings worth knowing — covered in detail in their own articles in this series:

• Atrial fibrillation: Slightly higher incidence in the testosterone group (3.5% vs. 2.4%).
• Pulmonary embolism: Numerically higher in the testosterone group (0.9% vs. 0.5%) — consistent with the wider evidence on testosterone and venous clots.
• Acute kidney injury: Numerically higher in the testosterone group (2.3% vs. 1.5%).

The nested sub-studies

TRAVERSE was not only a cardiovascular trial. Four efficacy and safety questions were answered in studies nested inside the same randomized population, and each is covered in full in the TRAVERSE sub-studies series:

• Bone and fractures — testosterone did not reduce clinical fractures; the rate ran higher on treatment.
• Sexual function — sexual activity and desire improved; erectile function did not.
• Anemia — anemia corrected in significantly more treated men, and fewer became anemic.
• Prostate safety — no significant difference in high-grade or any prostate cancer, in a screened population.

What it means for TRT today

TRAVERSE was the predicate for the FDA's 2025 label change that removed the long-standing cardiovascular warning from testosterone products.[2] For symptomatic hypogonadal men whose risk profile resembles the TRAVERSE cohort, the trial supports the position that properly dosed TRT does not raise the rate of major cardiac events.

The whole evidence arc, including the findings that sit awkwardly beside that headline, is collected in testosterone and heart health.

Limitations

Three caveats clinicians track:

1. Adherence. Roughly 60% of participants discontinued the assigned treatment by the end of follow-up.
2. Delivery method specificity. The trial used 1.62% testosterone gel only — findings aren't automatically generalizable to injections, pellets, or transdermal sprays.
3. Population. Findings apply to symptomatic hypogonadal men with elevated CV risk, not to all men considering TRT.

Bottom line

TRAVERSE is the most important cardiovascular safety study of testosterone therapy ever conducted. Its primary finding — that properly dosed TRT in symptomatic hypogonadal men does not raise major cardiac event rates — is the evidence base on which the FDA's 2025 warning removal rests. The secondary signals (AFib, VTE, AKI) are real and inform monitoring, not contraindication.

References

4 sources

1. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107–117. doi:10.1056/NEJMoa2215025 · PMID 37326322
2. U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. fda.gov
3. Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109–122. doi:10.1056/NEJMoa1000485 · PMID 20592293
4. U.S. Food and Drug Administration. Testosterone Information — postmarket drug safety information for patients and providers, including the TRAVERSE results and the June 2026 requested prescribing-information updates. fda.gov