CHICAGO — Testosterone-replacement therapy was noninferior to placebo in the occurrence of major adverse cardiac events among men with hypogonadism and established or high risk for cardiovascular disease, the randomized TRAVERSE trial showed.

At a mean follow-up of 33 months, the primary cardiovascular endpoint — first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke — occurred in 7% of patients in the testosterone group compared with 7.3% of those in the placebo group (HR 0.96, 95% CI 0.78- 1.17, P

However, testosterone-replacement therapy compared with placebo was associated with increased risks of atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), and pulmonary embolism (0.9% vs 0.5%), according to the findings, which published simultaneously in the New England Journal of Medicine.

“Controlled trials have shown that the use of testosterone in older men improves sexual function, increases volumetric and areal bone mineral density, corrects unexplained anemia, and moderately reduces depressive symptoms,” Lincoff and colleagues wrote.

“However, because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has weighed on treatment decisions by clinicians and patients,” they added. “Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism.”

Bradley Anawalt, MD, of the University of Washington in Seattle, told MedPage Today these results were “important,” noting that the FDA requires a black box warning that testosterone might increase the risks of stroke and heart attacks, “and that’s been a long-standing warning for almost 10 years.”

“And it’s also important to note that this was done in a cohort of men that had what we would call bona fide, confirmed testosterone deficiency,” he said.

But “the study doesn’t actually give a stamp of approval to run off and take testosterone without considering the potential risks,” he added.

He pointed out that the study showed there was an increased risk of heart arrhythmia, which can increase the risk of strokes. “We’ve known for a long time that testosterone has direct effects on the heart and rhythm. But we’ve never actually seen in a conclusive fashion that there is this arrhythmia,” he said.

“And the other finding was one that showed there was increased risk of blood clots that go to the lungs,” he continued. “If you’re at high risk for blood clots, then we need to be careful about prescribing testosterone to that group of men.”

Maria Stamou, MD, of Mass General Brigham in Boston, told MedPage Today that the TRAVERSE study will change the way she manages patients considering testosterone-replacement therapy.

“Advertisements touting testosterone products have become very popular,” she said. “We do see a lot of patients who are being evaluated for low testosterone. So this study is actually very exciting because it answers a question that has not been answered before.”

Stamou also said that patients on testosterone-replacement therapy should have their prostate-specific antigen (PSA) levels regularly tested to make sure that increasing testosterone is not affecting the prostate or fueling prostate cancer.

“For every patient we see at the clinic, we need to evaluate a lot of different factors,” she noted.

For the multicenter, double-blind TRAVERSE trial, Lincoff and team enrolled 5,246 men ages 45 to 80 who had pre-existing or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng/dL from May 2018 to February 2022.

Mean patient age was 63, 80% were white, and 17% were Black. Over 50% had pre-existing cardiovascular disease; the others were considered at increased risk. Most with pre-existing cardiovascular disease had a history of coronary artery disease. Common cardiovascular risk factors included diabetes, hypertension, dyslipidemia, and current smoking. Only 15 patients had previously been on testosterone therapy.

Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel, a dose that was adjusted to maintain testosterone levels between 350 and 750 ng/dL, or placebo gel.

The primary cardiovascular safety endpoint was assessed in a time-to-event analysis. The researchers set a noninferiority criterion requiring an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.

A secondary cardiovascular endpoint that added coronary revascularization to the composite of outcomes included in the primary endpoint also occurred in a similar number of patients in the testosterone and placebo groups.