The TRAVERSE Study suggests TRT in hypogonadal men may not increase risk of heart attack or stroke

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

The trial was designed to end after the occurrence of 256 primary end-point events, which were a composite of:

• Death from cardiovascular causes
• Non-fatal heart attack
• Non-fatal stroke

A secondary endpoint was a composite of the primary end-point events with the addition of coronary revascularisation.

Tertiary end-points were:

• Death from any cause
• The need for urgent care or hospitalisation for heart failure
• Peripheral arterial revascularisation
• Venous thromboembolism

Although primarily a safety trial, TRAVERSE included efficacy sub-studies of sexual function, depression, bone fracture, diabetes and anaemia.
 

Participants

Recruitment of study participants was deliberately made from a population of men aged 45-80 years at higher-than-normal risk of the study’s endpoints, with:

• Pre-existing coronary artery disease
• Pre-existing cerebrovascular disease
• Peripheral arterial disease
• Hypertension
• Dyslipidaemia
• Tobacco smoking
• Chronic kidney disease
• Diabetes
• Elevated high-sensitivity C-Reactive protein level
• Elevated coronary calcium score, or
• Age over 65 years

Inclusion criteria for the study were:

• Serum testosterone <10.4 nmol/l (300 mg/dl), and
• One or more of the following symptoms of testosterone deficiency:
  • Decreased sexual desire
  • Decreased spontaneous erections
  • Low energy or fatigue
  • Low or depressed mood
  • Loss of body hair or reduced need to shave, or
  • Hot flushes
     

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. “However, the safety of longer-term therapy, the implications of supplementation to reach higher testosterone levels, and the adverse effects that appear to be associated with this therapy must be better understood.”