PDF: TRAVERSE
(2023)Objective
Evaluate the cardiovascular safety of testosterone replacement therapy compared to placebo in men with hypogonadism and high cardiovascular risk.
Study Summary
Intervention
Multicenter, randomized, double-blind, placebo-controlled trial. N=5246 men aged 45–80 years with hypogonadism and either established cardiovascular disease or multiple cardiovascular risk factors. Randomized to: • Daily transdermal testosterone gel (dose titrated to achieve normal levels) • Placebo gel Median follow-up: 33 months. Primary endpoint: composite of cardiovascular death, nonfatal MI, or nonfatal stroke.
Study Design
Arms: Array
Outcome
• Secondary outcomes:
- Atrial fibrillation: higher with testosterone (HR 1.50)
- Acute kidney injury: HR 1.45
- Pulmonary embolism: HR 2.00
- No significant difference in prostate cancer, death from any cause, or fracture
• Testosterone improved sexual function, energy, and mood measures modestly
Bottom Line
Testosterone-replacement therapy was noninferior to placebo concerning major adverse cardiac events in middle-aged and older men with hypogonadism and cardiovascular disease or high cardiovascular risk. However, it was associated with higher incidences of atrial fibrillation, acute kidney injury, and pulmonary embolism.
Major Points
- 5246 men (45 to 80 years of age) with hypogonadism and preexisting or high cardiovascular risk were randomized (2601 to testosterone, 2603 to placebo).
- Mean duration of treatment was 21.7±14.1 months, and mean follow-up was 33.0±12.1 months.
- A primary cardiovascular end-point event (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 7.0% (182 patients) in the testosterone group and 7.3% (190 patients) in the placebo group (Hazard Ratio [HR], 0.96; 95% CI, 0.78 to 1.17; P<0.001 for noninferiority).
- Similar findings were observed in sensitivity analyses and among prespecified subgroups.
- The incidence of secondary end-point events (composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) or individual components of the primary composite endpoint appeared similar in both groups.
- A higher incidence of investigator-reported atrial fibrillation (3.5% vs 2.4%, P=0.02), nonfatal arrhythmias warranting intervention (5.2% vs 3.3%, P=0.001), and acute kidney injury (2.3% vs 1.5%, P=0.04) was observed in the testosterone group.
- Pulmonary embolism, a component of venous thromboembolic events, was also higher in the testosterone group (0.9% vs 0.5%).
- Prostate cancer occurred in similar proportions in both groups (0.5% vs 0.4%, P=0.87), including high-grade cases.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, noninferiority, event-driven trial (Phase 4)
- Randomization
- Yes
- Blinding
- Double-blind (patients and trial team unaware of post-baseline testosterone levels; sham adjustments for placebo to maintain blinding).
- Sample Size
- 5246
- Follow-up
- Mean 33.0±12.1 months
- Centers
- 316
- Countries
- United States
Primary Outcome
Definition: First occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 190 patients (7.3%) | 182 patients (7.0%) | 0.96 (0.78 to 1.17) | <0.001 (for noninferiority) |
Limitations & Criticisms
- The incidence of adherence and retention was lower than in most cardiovascular outcome studies, although consistent with other symptomatic condition trials. While sensitivity analyses supported noninferiority, the possibility of bias due to informative censoring cannot be entirely ruled out.
- The trial was designed as a noninferiority study, meaning it was powered to show that testosterone is not worse than placebo, not necessarily to show superiority or a significant benefit.
- The trial discontinued enrollment of patients who qualified based on cardiovascular risk factors once the pooled primary event rate fell below projections, potentially affecting the patient mix.
- Some adverse events, such as nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury, were not expected and had a higher incidence in the testosterone group, requiring further investigation despite the overall low incidence of adverse events.
- The study did not evaluate effects of testosterone therapy on noncardiovascular outcomes, limiting a comprehensive understanding of the overall benefit-risk profile.
Citation
N Engl J Med 2023;389:107-17.