The TRAVERSE Study Helped Answer a Key Question: Is Testosterone Safe for the Heart?
TRAVERSE followed more than 5,000 men with low testosterone and existing heart disease or serious cardiovascular risk factors to determine whether testosterone therapy increased their risk of cardiac events.
Testosterone prescriptions have climbed for years, and so has a nagging question. Does replacement therapy raise a man’s risk of heart attack or stroke? The TRAVERSE trial, the largest randomized study ever built to answer that question, finally gave doctors and patients firm ground to stand on. Its results carry weight for anyone weighing hormone therapy against cardiovascular risk.
Published in the New England Journal of Medicine in 2023, TRAVERSE followed more than 5,000 men with low testosterone who already had heart disease or serious risk factors for it. Investigators wanted to know whether adding testosterone to that vulnerable group would tip them toward a cardiac event. The answer, arriving after years of conflicting smaller studies, is now reshaping how doctors talk about hormone therapy.
How the TRAVERSE study worked
TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled trial. Researchers enrolled 5,246 men between the ages of 45 and 80 who either had cardiovascular disease or were at high risk for it. Every participant reported symptoms of hypogonadism and had two fasting testosterone readings below 300 ng per deciliter.
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Half received a daily transdermal 1.62% testosterone gel, with doses adjusted to keep testosterone between 350 and 750 ng per deciliter. The other half received a placebo gel. The primary safety endpoint tracked the first occurrence of cardiovascular death, nonfatal heart attack or nonfatal stroke. Mean treatment lasted 21.7 months, with a mean follow-up of 33 months.
The trial was designed as a noninferiority study, meaning testosterone would clear the bar only if it did not push cardiovascular risk meaningfully higher than placebo.
Why the testosterone and heart findings matter
A primary endpoint event occurred in 182 patients, or 7.0%, in the testosterone group. In the placebo group, 190 patients, or 7.3%, hit that endpoint. The hazard ratio landed at 0.96, meeting the trial’s noninferiority threshold with a P value below 0.001.
For a class of drugs that had spent years under a cloud, the numbers offered relief. “These findings provide reassurance about the cardiovascular safety of testosterone therapy over the typical duration of treatment in men in whom it is indicated,” said coprincipal investigator A. Michael Lincoff, MD.
The study exists because of a 2015 Food and Drug Administration mandate. Regulators, alarmed by mixed observational data, required manufacturers of approved testosterone products to run trials on cardiovascular safety. Lincoff, who served on the FDA advisory committee behind the requirement, noted that no adequately powered prospective study had answered the question before TRAVERSE.
What the trial did not settle
The reassurance came with fine print. Researchers observed higher rates of atrial fibrillation, acute kidney injury and pulmonary embolism in the testosterone group. Pulmonary embolism struck 0.9% of testosterone recipients compared with 0.5% of placebo recipients.
Study chair Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart, Vascular and Thoracic Institute, urged caution. “This study should not be used as a justification for the widespread prescription of testosterone to aging men,” he said.
The population studied is narrow. TRAVERSE enrolled men with clinically confirmed low testosterone and documented symptoms. Its results were not meant to endorse testosterone for men who obtain the hormone from “low T clinics” without a clear medical indication.
What cardiologists are watching next
Cardiologists have integrated the results into how they counsel patients, though not without qualifications. Rasi Wickramasinghe, MD, PhD, chief of cardiology at Houston Methodist Sugar Land Hospital, told Cardiology Advisor that “the conversation around testosterone and cardiovascular risk really changed with the seminal TRAVERSE trial.”
He flagged two signals worth watching. Pulmonary embolism appeared more often in the testosterone arm, prompting him to think twice before prescribing therapy to men with prior venous thromboembolism or a known thrombophilia. Atrial fibrillation is the other concern. Higher rates of nonfatal arrhythmias in the testosterone group, combined with observational data suggesting a 27% increased AF risk over five years, point to what he described as “a real biological effect, not just an artifact.”
Dr. Mohit Khera of Men’s Health Urology framed TRAVERSE as “a beacon for future research in testosterone replacement therapy and cardiovascular health,” while noting that the safety signals flagged in the trial deserve deeper examination. Identifying which patients benefit most, and which face the highest risk, remains the next task for researchers building on the trial’s foundation.
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