Reviewed Research
The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was a phase 4, randomised, double-blind, placebo-controlled, non-inferiority, event-driven multicentre trial (with an inaccurate acronym).
The study was designed to determine the effects of testosterone replacement therapy on the incidence of major adverse cardiac events in middle-aged and older men with hypogonadism. The trial was mandated by the US FDA because of uncertainty about the risk of heart attack and stroke in men treated with testosterone for symptomatic relief of low levels arising from comorbidities associated with aging.
Outcomes
Although primarily a safety trial, TRAVERSE included efficacy sub-studies of sexual function, depression, bone fracture, diabetes and anaemia.
Participants
Intervention
Participants were randomised to treatment with either transdermal testosterone gel or placebo. The testosterone treatment group was titrated to maintain plasma testosterone levels between 12.1-26.0 mmol/l while the placebo group received a sham dose adjustment.
The average duration of treatment was 22 months for both groups, and follow-up averaged 33 months.
Discontinuation rates were 61.4% and 61.7% in the testosterone and placebo groups, respectively; higher than anticipated (30-40%). Participants used testosterone gel or placebo for just over two-thirds of the eligible time.
The median rise in serum testosterone levels (at 12 months) was 5 nmol/l (interquartile range, 1.2 to 10.8) in the testosterone group, and 0.5 nmol/l (IQR, -0.7 to 1.9) in the placebo group.
The median serum testosterone level in the testosterone group at this time was 12.9 mmol/l (IQR, 9 to 18.2). Many men (at least 25%) on testosterone treatment failed to reach the serum testosterone target range.
Results
The occurrence of the study’s primary endpoint was not different between testosterone and placebo groups (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17). Secondary endpoints also occurred at similar rates.
Higher rates of atrial fibrillation, acute kidney injury and pulmonary embolism occurred in the testosterone group than in the placebo group.
In the sexual function sub-study, the primary outcome – increased sexual activity – was higher in the testosterone group than in the placebo group.
The secondary endpoints of sexual function and libido improved more with testosterone than with placebo. Erectile function was not different between groups.
Prespecified subgroup analyses in the sexual function sub-study showed that testosterone increased sexual activity in men with (but not without) prior cardiovascular disease, in men aged over (but not under) 65 years, and in White (but not Black) men.
Conclusions
The TRAVERSE study “provides critical safety information for patients and providers who are faced with making decisions about testosterone treatment” for men who share the characteristics of those enrolled in the trial.
