Cardiovascular Safety of Testosterone-Replacement Therapy.
Level 2 - randomized trial
Individual randomized double-blind placebo-controlled trial
PubMed 37326322 · doi:10.1056/NEJMoa2215025
What was done
In a multicenter, randomized, double-blind, placebo-controlled noninferiority trial, 5,246 men aged 45 to 80 years with symptomatic hypogonadism (two fasting testosterone levels <300 ng/dL) and preexisting or high risk of cardiovascular disease received daily transdermal 1.62% testosterone gel (dose adjusted to maintain levels between 350 and 750 ng/dL) or placebo gel. The primary cardiovascular safety end point was the first occurrence of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis, requiring an upper 95% confidence interval limit <1.5 for the hazard ratio to establish noninferiority. Mean treatment duration was 21.7±14.1 months and mean follow-up was 33.0±12.1 months.
What was found
The primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Incidence of secondary composite end points (including coronary revascularization) and individual components appeared similar between groups. A higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was observed in the testosterone group, though exact rates were not reported in the abstract.
Why it matters
This trial demonstrates that transdermal testosterone replacement therapy does not increase major adverse cardiovascular events over approximately three years of follow-up in middle-aged and older men with hypogonadism and high cardiovascular risk.
Limits
Mean treatment duration was under two years (21.7 months), leaving longer-term cardiovascular safety unmeasured. The abstract does not provide numerical counts or risk ratios for the observed increases in pulmonary embolism, atrial fibrillation, and acute kidney injury. Results reflect transdermal gel in high-risk hypogonadal men and may not generalize to other delivery routes or lower-risk populations.
Cited by
- supports The TRAVERSE trial showed that testosterone replacement therapy in middle-aged and older hypogonadal men did not increase the incidence of major adverse cardiovascular events compared to placebo.