What Recent NEJM Trial Data and Supporting Cohort Studies Show About HRT and Heart Risk

2023 TRAVERSE Trial Finds No Rise in Major Cardiovascular Events From Testosterone Therapy

A large randomized trial published in 2023 found that testosterone replacement therapy did not increase major adverse cardiovascular events compared with placebo. The TRAVERSE study followed 5246 middle-aged and older men with hypogonadism who had cardiovascular disease or high risk factors for a median of 22 months. Event rates reached 7.0 percent in the testosterone group and 7.3 percent in the placebo group. These results add context to earlier smaller trials that raised safety questions and led to 2015 FDA labeling requirements.

The TRAVERSE trial met its primary noninferiority goal. It reported a hazard ratio of 0.96 (95 percent CI 0.78-1.17). That figure covered heart attacks, strokes, and cardiovascular deaths. [1]

A 2010 randomized trial examined testosterone in older men with limited mobility. It linked testosterone administration to more cardiovascular adverse events. Researchers stopped the trial early after 23 events in the testosterone arm versus five in the placebo group. [2]

The FDA required class-wide labeling changes for testosterone products in 2015. Manufacturers had to include information on the possible increased risk of heart attack and stroke. [3]

What this means

The 2023 findings indicate similar heart event rates for testosterone replacement therapy and placebo among men with confirmed hypogonadism plus cardiovascular disease or elevated risk. Earlier data from smaller studies had created uncertainty that shaped the FDA's 2015 updates. The newer trial narrows that uncertainty for the enrolled population over roughly two years while data gaps remain for other groups.

Key takeaways

• The TRAVERSE trial recorded major adverse cardiovascular events in 7.0 percent of participants on testosterone replacement therapy versus 7.3 percent on placebo. [1]
• The hazard ratio of 0.96 met the prespecified noninferiority margin and showed no significant risk increase. [1]
• The 2010 TOM trial observed more cardiovascular events with testosterone (23 versus 5) and stopped early. [2]
• The FDA mandated updated labeling in 2015 for potential heart attack and stroke risks based on evidence then available. [3]
• Median follow-up of 22 months supplied short-to-medium term data but did not capture longer-term outcomes. [1]

Limitations

TRAVERSE enrolled men with established hypogonadism plus either cardiovascular disease or high risk. Those criteria mean the results may not extend to younger men, those without cardiovascular risk, or men using testosterone off-label. The 22-month median follow-up may miss very long-term outcomes or rare events. Industry sponsorship of the trial, even with independent oversight, introduces potential for bias. Different testosterone formulations, dosing regimens, and achieved serum levels across studies add complexity to broader conclusions.

FAQ

What were the primary and secondary cardiovascular findings from the TRAVERSE trial?
The primary outcome showed no increase in major adverse cardiovascular events with a hazard ratio of 0.96. Secondary endpoints such as cardiac death, heart attack, and stroke showed similar patterns between groups. Event rates stayed nearly identical at 7.0 percent versus 7.3 percent. [1]

How do the 2023 TRAVERSE results compare with earlier studies such as the 2010 TOM trial?
TRAVERSE enrolled more than 5000 participants and found no risk elevation. The smaller 2010 TOM trial reported higher cardiovascular events in the testosterone arm and stopped early. The difference illustrates how larger trials in defined populations can alter the evidence picture. [1][2]

What is the current FDA regulatory position on cardiovascular risk labeling for testosterone products?
The FDA required class-wide labeling changes in 2015. The updates inform prescribers and patients about possible increased risk of heart attack and stroke based on the evidence available at that time. [3]

What limitations affect the generalizability of existing TRT cardiovascular safety data?
The main trial focused on men who had both hypogonadism and cardiovascular risk factors. It used a 22-month median follow-up and received industry funding with independent oversight. Those factors mean the data may not apply to younger men, off-label use, or outcomes over many years. [1]

Sources / References

1. Cardiovascular Safety of Testosterone-Replacement Therapy or Placebo in Men with Hypogonadism. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2215025

2. Adverse Events Associated with Testosterone Administration. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa1000485

3. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due-aging-requires