Testosterone-replacement therapy noninferior to placebo for preventing cardiovascular events

1. In this randomized controlled trial, in adults with hypogonadism and cardiovascular risk factors, testosterone did not reduce the incidence of major adverse cardiac events (MACE) compared to a control.

2. Arrhythmias, atrial fibrillation, acute kidney injury, and pulmonary embolism occurred more frequently in the testosterone group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Male hypogonadism is a chronic health condition mainly affecting middle-aged and older patients where testosterone is not produced in sufficient quantities, resulting in impaired quality of life, sexual function, and metabolic health. Topical testosterone-replacement therapy has seen increased use, although its impact on cardiovascular risks, either positive or negative, has not been clearly characterized. The Food and Drug Administration has required manufacturers to study this association. The current study was a multicenter trial comparing topical testosterone gel and placebo for the risk of MACE among male adults 45 to 80 years of age with hypogonadism who were at risk of cardiovascular disease. It was found that a composite primary outcome of MACE occurred at similar frequencies between the testosterone and placebo groups, as did the individual components of the composite primary outcome. Although the study reported appreciable nonadherence and non-retention rates, sensitivity analyses yielded similar conclusions to the primary analyses. These results suggested that for men with hypogonadism and an elevated risk for cardiovascular disease, testosterone-replacement therapy did not increase this risk any further when compared to placebo.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This study was a randomized, double-blinded, placebo-controlled, noninferiority trial assessing the cardiovascular safety of topical testosterone-replacement therapy compared to placebo. Male participants between 45 and 80 years of age who had symptomatic hypogonadism with low serum testosterone levels and had pre-existing cardiovascular disease or risk factors were included. Exclusion criteria were severe hypogonadism, history of prostate cancer or high prostate-specific antigen level, history of MACE, or testosterone therapy. Overall, 5,204 participants were randomized 1:1 to receive daily transdermal 1.62% testosterone gel or a matching placebo. The primary outcome was the first occurrence of any components of MACE. Secondary outcomes included the first occurrence of individual MACE or coronary revascularization. After a mean treatment period of 21.7 months and a follow-up period of 33.0 months, the primary outcome event occurred in 182 participants (7.0%) in the testosterone group and in 190 participants (7.3%) in the placebo group (hazard ratio, 0.96; 95% Confidence Interval [CI], 0.78 to 1.17; p<0.001 for noninferiority). Death from any cause, hospitalization for heart failure, and benign prostatic hyperplasia were reported at similar rates between the groups. Conversely, pulmonary embolism, nonfatal arrhythmia, atrial fibrillation, and acute kidney injury occurred rates significantly higher rates among participants in the testosterone group. These results indicated that testosterone-replacement therapy was noninferior to placebo in cardiovascular safety for male adults with hypogonadism and at high risk for cardiovascular disease.

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