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

Key Insight: TRAVERSE cardiovascular hazard ratio: 0.96 -- meaning testosterone therapy showed no increase in heart attack, stroke, or cardiovascular death vs. placebo across 5,246 men followed for 4 years.

> TRAVERSE cardiovascular hazard ratio: 0.96 -- meaning testosterone therapy showed no increase in heart attack, stroke, or cardiovascular death vs. placebo across 5,246 men followed for 4 years.

Medically reviewed by licensed clinical providers · March 2026

For nearly a decade, the cardiovascular safety of testosterone replacement therapy remained one of the most contested questions in men's health. Two observational studies published in 2013 and 2014 raised concerns about heart risk -- concerns serious enough that the FDA required a large randomized controlled trial to settle the question. That trial was TRAVERSE. Published in the New England Journal of Medicine in 2023 (Lincoff et al.), it enrolled 5,246 men, followed them for up to four years, and produced what is now the definitive clinical evidence on TRT and cardiovascular outcomes. Here is what the trial found, how to interpret the results, and why they changed FDA labeling in March 2025.

Why TRAVERSE Was Ordered

The controversy began with two studies. In 2013, Vigen et al. published an observational analysis in JAMA suggesting that testosterone therapy was associated with increased risk of adverse cardiovascular events in men with coronary artery disease. In 2014, Finkle et al. reported elevated rates of myocardial infarction in older men shortly after starting testosterone prescriptions. Neither was a randomized controlled trial -- both were retrospective analyses with significant methodological limitations, including confounding variables and missing covariate data. But the headlines were enough to prompt FDA action.

In 2014, the FDA issued a safety communication requiring testosterone manufacturers to add a warning label about potential cardiovascular risk and mandating a large post-market cardiovascular outcomes trial. That requirement produced TRAVERSE.

Trial Design

TRAVERSE was a randomized, double-blind, placebo-controlled trial -- the gold standard for clinical research. Key design parameters:

  • Population: 5,246 men aged 45 to 80 with confirmed hypogonadism (testosterone below 300 ng/dL on two morning draws) and pre-existing cardiovascular disease or elevated CV risk factors
  • Intervention: Daily oral testosterone undecanoate (Jatenzo) vs. matching placebo
  • Primary endpoint: Major Adverse Cardiovascular Events (MACE) -- defined as cardiovascular death, nonfatal myocardial infarction (heart attack), or nonfatal stroke
  • Follow-up: Median 33 months; maximum 4 years
  • Design goal: Non-inferiority -- the trial was powered to determine whether testosterone therapy was no worse than placebo for MACE, not whether it was better

This population was intentionally high-risk. Men with baseline cardiovascular disease were enrolled specifically to stress-test the therapy under the most scrutiny-worthy conditions.

The Primary Result

The hazard ratio for MACE in the testosterone group vs. placebo was 0.96, with a 95% confidence interval of 0.83 to 1.12. The upper bound of the confidence interval (1.12) fell within the pre-specified non-inferiority margin, meaning non-inferiority was formally met. Testosterone therapy did not increase the rate of heart attack, stroke, or cardiovascular death relative to placebo -- even in a population selected for elevated cardiovascular risk.

This is what non-inferiority means in clinical terms: the treatment performed at least as well as placebo on the primary outcome. It is not a claim of superiority -- the trial was not designed to show that testosterone prevents cardiovascular events. It was designed to show it does not cause them. That threshold was met.

Secondary Findings Worth Knowing

The TRAVERSE investigators also tracked several secondary endpoints that are relevant for ongoing patient monitoring:

  • Atrial fibrillation: Occurred in 3.5% of the testosterone group vs. 2.4% of the placebo group. This difference was statistically significant and is now reflected in prescribing information. Men with a history of atrial fibrillation should discuss this signal with their provider before starting TRT.
  • Pulmonary embolism: Reported in 0.9% of the testosterone group vs. 0.5% of placebo -- a numerical difference that reached statistical significance in sensitivity analyses. This finding underscores the importance of monitoring and reporting symptoms such as leg swelling or unexplained shortness of breath.

Neither finding reverses the primary result on cardiovascular safety, but both are important for informed clinical decision-making and patient monitoring.

The Sub-Studies

TRAVERSE was designed from the outset to support multiple parallel investigations. Each sub-study used the same randomized cohort to examine a specific secondary question:

  • Prostate: No significant increase in prostate cancer incidence; no acceleration of low-grade disease
  • Bone density: Testosterone associated with increased bone mineral density, particularly at the lumbar spine and hip
  • Anemia: Testosterone significantly reduced incidence of anemia in hypogonadal men
  • Sexual function: Testosterone improved sexual activity and libido scores vs. placebo
  • Depression: Testosterone associated with improvement in depressive symptom scores among men with baseline low mood

These sub-studies, published separately in 2023 and 2024, provide a more complete clinical picture of what testosterone therapy does -- and does not -- affect.

How TRAVERSE Changed FDA Labeling

In March 2025, the FDA removed the black box warning on testosterone products that had required cardiovascular risk language since 2015. The agency cited the TRAVERSE trial results as the primary basis for this decision. The updated labeling no longer requires cardiovascular risk warnings as a boxed precaution, though prescribing information continues to note the atrial fibrillation and pulmonary embolism signals from the trial. Testosterone therapy remains a prescription-only medication requiring physician supervision, appropriate diagnosis (confirmed hypogonadism), and ongoing monitoring.

What This Means for Patients Considering TRT

TRAVERSE does not mean testosterone therapy is risk-free or appropriate for every man. What it does mean is that for men with confirmed hypogonadism -- testosterone below 300 ng/dL on two separate morning tests with corresponding symptoms -- the cardiovascular safety data are now the strongest they have ever been. A decade of uncertainty has been replaced by a well-designed, adequately powered, long-term randomized trial. Men in the trial averaged 66 years of age and carried baseline cardiovascular risk. The finding that testosterone was non-inferior to placebo in this population is clinically meaningful.

Physician evaluation, lab confirmation, and ongoing monitoring remain essential. But the cardiovascular question that dominated the conversation for ten years now has a clear answer.

Frequently Asked Questions

Does the TRAVERSE trial mean testosterone therapy is completely safe for the heart?
TRAVERSE demonstrated that testosterone therapy was non-inferior to placebo for major cardiovascular events (heart attack, stroke, cardiovascular death) in men with confirmed hypogonadism and elevated CV risk. It did not show superiority, and the trial identified numerical increases in atrial fibrillation and pulmonary embolism. Patients with pre-existing AF or clotting history should discuss these findings with their provider before starting TRT.

Why did the FDA remove the black box warning in March 2025?
The FDA reviewed the TRAVERSE trial results and determined that the cardiovascular risk warning added in 2015 -- based on observational studies with significant limitations -- was no longer supported by the best available evidence. The black box warning was removed; prescribing information was updated to reflect the secondary findings (AF, PE) from the trial.

Was TRAVERSE done with oral testosterone -- does that apply to testosterone spray?
TRAVERSE used oral testosterone undecanoate. The cardiovascular endpoint data are most directly applicable to that formulation. However, the FDA's labeling decision applied broadly to testosterone products, not just oral forms. Prescribers consider TRAVERSE the most relevant large-scale safety data available for the class.

Ready to Start with Clinically Supported Testosterone Therapy?

The TRAVERSE trial settled a decade of cardiovascular uncertainty. If you have been waiting for strong safety data before exploring TRT, that evidence now exists. The next step is a proper clinical evaluation -- confirming whether your testosterone is actually low and whether you are a candidate for treatment.

Keen Meds connects you with a licensed clinical team for a telehealth consultation and lab review. If your testosterone is clinically low, you receive a prescription for Testosterone Spray Rx -- delivered via Hypospray®, Keen's needle-free transdermal spray platform.

Start your Keen Testosterone Spray Program →

Medically reviewed by Licensed Clinical Providers · March 2026

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