Pooled Trial Data Show No Significant Increase in Major Adverse Cardiovascular Events With Testosterone Therapy

TRAVERSE Trial Reports No Rise in Major Adverse Cardiovascular Events With Testosterone Replacement Therapy

The TRAVERSE randomized controlled trial found that testosterone gel produced a similar rate of major adverse cardiovascular events as placebo. The primary composite endpoint occurred in 7.0 percent of the testosterone group versus 7.3 percent of the placebo group. Those results met the prespecified noninferiority boundary and directly address the FDA's 2015 safety communication on possible heart attack and stroke risks. This synthesis combines the trial's primary publication, its protocol registration, and the earlier regulatory document.

What this means

The data indicate that testosterone replacement therapy did not increase major adverse cardiovascular events in this specific group of middle-aged and older men. Observed rates stayed close at 7.0 percent in the testosterone arm and 7.3 percent in the placebo arm. The findings add randomized evidence to earlier mixed signals from observational studies that prompted regulatory warnings. They also note higher rates of certain secondary events in the testosterone group.

Key takeaways

• The primary MACE outcome occurred in 7.0 percent of the testosterone group versus 7.3 percent of the placebo group, with a hazard ratio of 0.96 that met the prespecified noninferiority margin [1].
• This double-blind trial enrolled 5242 men with hypogonadism and cardiovascular comorbidity. Mean treatment duration reached roughly 22 months [2].
• The 2015 FDA safety communication had required labeling changes citing possible increased heart attack and stroke risk based on evidence available at that time [3].
• Secondary signals linked to testosterone included higher incidence of atrial fibrillation, pulmonary embolism, acute kidney injury, elevated PSA levels, and erythrocytosis [1].
• The trial supplies higher-quality evidence on the primary composite endpoint after years of conflicting observational reports [1].

The TRAVERSE trial followed a rigorous protocol listed on ClinicalTrials.gov. Participants received either testosterone gel or matching placebo. Researchers tracked outcomes in a blinded fashion. This setup tested whether therapy increased cardiovascular risk beyond an acceptable margin.

Earlier regulatory statements reflected concern over observational reports and smaller studies. In 2015 the FDA reviewed available data and mandated updated labeling to highlight potential heart attack and stroke risks in men using testosterone for age-related decline. The newer trial supplies randomized evidence that speaks to that composite safety question in a higher-risk population.

Secondary safety findings diverged in some areas. Men assigned to testosterone showed increased episodes of atrial fibrillation and pulmonary embolism. Reports of acute kidney injury also rose in that arm. Laboratory changes included higher prostate-specific antigen values and greater erythrocytosis.

Limitations

Median treatment duration was 21.8 months. Longer-term cardiovascular and oncologic risks beyond three years remain less certain. The study enrolled a predominantly obese, multimorbid male population. Generalizability to younger, healthier hypogonadal men or women is limited.

Discontinuation rates approached 50 percent in both arms by study end. This may have reduced the ability to detect differences. The trial held statistical power for noninferiority on the primary MACE endpoint but carried less power for rarer secondary events such as prostate cancer or heart failure.

FAQ

What was the primary cardiovascular endpoint and its result in the TRAVERSE trial?
The endpoint combined cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. It occurred in 7.0 percent of men on testosterone versus 7.3 percent on placebo, with a hazard ratio of 0.96 (95 percent CI 0.78-1.17) that satisfied noninferiority criteria [1].

How do TRAVERSE findings relate to the 2015 FDA safety communication on testosterone products?
The 2015 FDA communication required class-wide labeling changes based on then-available evidence suggesting possible heart attack and stroke risk. TRAVERSE supplies new randomized data that did not confirm an increase in the primary cardiovascular composite within the studied population and timeframe [3].

What secondary safety signals were observed with testosterone replacement therapy?
The testosterone arm recorded higher rates of atrial fibrillation, pulmonary embolism, acute kidney injury, elevated PSA, and erythrocytosis compared with placebo [1].

In which populations do current primary sources support or limit use of TRT?
Primary sources indicate approval for men with confirmed hypogonadism who have cardiovascular disease or risk factors over the durations studied. The data do not extend to younger healthy men, women, elective use for age-related decline, or periods longer than about two years [2][3].

Sources / References

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

2. Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE Study). https://clinicaltrials.gov/study/NCT03518034

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 with use. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due-aging