Use of testosterone in middle-aged and older men with hypogonadism and pre-existing heart disease or with risk factors for heart disease did not increase the risk of major adverse cardiac events compared to placebo, according to the TRAVERSE trial published in the New England Journal of Medicine.¹ These findings were also presented at ENDO 2023, the ongoing Annual Meeting of the Endocrine Society.

A total of 5246 men, ages ranging from 45 to 80 years (mean age 63 years), were recruited for this multicenter study from May 2018 to February 2022. More than half of the selected participants had either pre-existing heart disease, while the remaining were at high risk of heart disease with presence of risk factors such as hypertension, diabetes, dyslipidemia or active smoking. They also had symptoms of hypogonadism and fasting testosterone levels <300 ng/dL on two separate occasions. The study subjects were randomized to daily treatment with transdermal testosterone gel 1.62% or a placebo gel for a period of 21.7 months (mean). The testosterone levels were maintained between 350 and 750 ng/dL. The mean follow-up was 33.0 months.

After a mean follow-up of 33 months, the primary cardiovascular safety endpoint, which was the first episode of any component of a composite of cardiac-related mortality, nonfatal myocardial infarction or nonfatal stroke was comparable between the two groups; 7.0% in the testosterone group vs 7.3% in the placebo group (hazard ratio 0.96). The secondary endpoints, which had components similar to the primary endpoint, but additionally included coronary revascularization, were also similar between the two groups. However, the incidence of atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%) and pulmonary embolism (0.9% vs 0.5%) was higher in patients on testosterone compared to those receiving placebo.

These much-awaited results show that testosterone replacement therapy was non-inferior to placebo with regard to the first occurrence of acute cardiac events in men with hypogonadism with diagnosed heart disease or those who are at high risk of developing heart disease. But the risk of atrial fibrillation and pulmonary embolism was increased in the testosterone group. The US FDA has cautioned about the use of testosterone replacement therapy in aging men with low testosterone levels. It also requires a warning about the increased risk of acute cardiac events such as heart attack and stroke associated with the use of testosterone. The findings of the present study are reassuring, but they do not totally refute the current guidance about exercising caution when prescribing testosterone. Nonetheless, they do enable a more informed decision making after taking into consideration the potential risks and benefits.

Reference

1. Lincoff AM, et al; TRAVERSE Study Investigators. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023 Jun 16. doi: 10.1056/NEJMoa2215025.