The first large randomised controlled trial of testosterone replacement therapy (TRT) powered to detect cardiovascular outcomes has found that TRT does not increase — and may modestly reduce — the risk of heart attack in men with clinically confirmed hypogonadism and pre-existing or high risk of cardiovascular disease, settling a decade-long controversy that had prompted FDA safety warnings and dramatically reduced TRT prescribing.

Background: A Decade of Uncertainty

Testosterone prescribing surged between 2000 and 2013 as “low T” was increasingly recognised and marketed. In 2010 and 2013, two observational studies reported increased cardiovascular events in men receiving TRT, prompting the FDA to add a cardiovascular risk warning to all testosterone products in 2015. Prescribing fell by 40% in the years following — but observational data was always methodologically limited, and the question of causality remained open.

The TRAVERSE Trial

TRAVERSE enrolled 5,246 men aged 45–80 with confirmed hypogonadism (morning testosterone <300 ng/dL on two measurements) and either established cardiovascular disease or multiple risk factors. Participants were randomised to daily transdermal testosterone gel or placebo gel and followed for a mean of 33 months for a composite cardiovascular endpoint.

Results

  • Primary MACE (major adverse cardiovascular events): 7.0% TRT vs 7.3% placebo — non-inferior (HR 0.96; 95% CI 0.78–1.17)
  • Non-fatal myocardial infarction: 2.1% vs 2.5% — 17% lower in TRT group (HR 0.83; 95% CI 0.63–1.09, directionally significant)
  • Stroke: No significant difference
  • Atrial fibrillation: Higher in TRT group (3.5% vs 2.4%; HR 1.46; P=0.02) — a safety signal warranting monitoring
  • Pulmonary embolism: Higher in TRT group (0.9% vs 0.5%; P=0.09) — a trend requiring caution

“TRAVERSE has exonerated testosterone from the charge of causing heart attacks. But the atrial fibrillation signal is real and clinicians need to factor it into prescribing decisions — particularly in older men with existing arrhythmia risk.”

— Dr. Michael Lincoff, Cleveland Clinic, TRAVERSE principal investigator

Implications for Clinical Practice

For the estimated 2.4 million American men who stopped TRT following the FDA warning, these findings — combined with TRT’s established benefits for sexual function, bone density, mood, and muscle mass — may prompt re-evaluation. However, the atrial fibrillation and pulmonary embolism signals mean that TRT should not be considered free of cardiovascular risk; it simply does not appear to increase MI risk in hypogonadal men.

⚕️ Medical Disclaimer: This article is for informational purposes only. It does not constitute medical advice. Always consult a qualified healthcare professional before making health decisions.