Cardiovascular Safety of Testosterone-Replacement Therapy.

Testosterone-replacement therapy was noninferior to placebo for the primary composite cardiovascular endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

• A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group.
• Hazard ratio was 0.96 with a 95% confidence interval of 0.78 to 1.17; P<0.001 for noninferiority.
• Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio.
• The trial was a multicenter, randomized, double-blind, placebo-controlled, noninferiority design enrolling 5246 men aged 45 to 80 years.

The incidence of secondary cardiovascular end-point events and each individual component of the primary composite endpoint appeared similar between the testosterone and placebo groups.

• The secondary cardiovascular end point was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
• The incidence of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups.
• Sensitivity analyses censoring data at various times after discontinuation of testosterone or placebo showed similar findings to the primary analysis.

A higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was observed in the testosterone group compared to placebo.

• These three safety signals — atrial fibrillation, acute kidney injury, and pulmonary embolism — were identified as adverse outcomes with higher incidence in the testosterone group.
• These findings were noted despite the overall cardiovascular noninferiority result.
• The trial was designed to assess cardiovascular safety in men with preexisting or high risk of cardiovascular disease.

The study enrolled men with hypogonadism defined by two fasting testosterone levels of less than 300 ng per deciliter and symptoms of hypogonadism.

• Participants were 45 to 80 years of age with preexisting or a high risk of cardiovascular disease.
• Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel, with dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter, or placebo gel.
• A total of 5246 men were enrolled in the trial.
• The mean duration of treatment was 21.7 ± 14.1 months and the mean follow-up was 33.0 ± 12.1 months.