- The TRAVERSE clinical trial is the largest randomized controlled trial involving 5,204 hypogonadal patients with cardiovascular disease or at risk of it, who received either TRT or placebo.
- Findings revealed no significant differences in any of the primary cardiovascular outcomes between the treatment and placebo groups.
- The most notable adverse events observed were an increased risk of non-fatal arrhythmias, venous thromboembolic events, and fractures in the testosterone group compared to the placebo group.
- The TRAVERSE study provides welcome clarity on the role of TRT on cardiovascular risk; however, further research is necessary to explore safety concerns.
Rationale for TRAVERSE
The impact of testosterone replacement therapy (TRT) on cardiovascular risk remains a highly debated topic in the medical community. Conflicting evidence from randomised controlled trials and meta-analyses has raised concerns about the potential risks associated with TRT, particularly in individuals with a high risk of cardiovascular disease. While some highly controlled studies report no effect or even improvements in cardiovascular health, others have led to a concern over arterial plaque progression and cardiovascular events that has stopped the trials early.1,2,3
Experts have called for more high-quality evidence to clarify the potential harms of TRT. Though recent guidelines from the Society of Endocrinology suggest that the best scientific evidence does not reveal any association between testosterone treatment and cardiovascular or cerebrovascular events, positive or negative, a report by the American College of Physicians stated that TRT’s long-term safety in older men with low testosterone levels is currently "unknown".4,5
The TRAVERSE clinical trial is the largest randomised controlled trial to evaluate the cardiovascular risk associated with TRT.6
The TRAVERSE clinical trial
The TRAVERSE trial aimed to investigate the relationship between TRT in the form of a 1.62% testosterone gel on cardiovascular events. A total of 5,204 patients were enrolled with 5,198 receiving at least one dose of TRT or placebo, referred to as the safety population of interest. A total of 2,596 were randomised to receive TRT and 2,602 a placebo gel.
To ensure optimal efficacy of TRT, the researchers established a target testosterone range of 350 to 750 ng/dL, with dose adjustments made to maintain these levels. Patients' median baseline testosterone levels across groups were 227 ng/dL before the initiation of TRT or palcebo began.
The primary outcome of the trial was the first occurrence of any component of a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke, assessed via time-to-event analysis. The trial was designed to conclude after 256 primary composite end-point events had occurred.
Trial duration and changes in testosterone levels
The mean treatment duration for testosterone was 21.8 months with a median follow-up of 32.9 months, compared to 21.6 months and 32.9 months for placebo, respectively.
Testosterone levels were recorded during check-ups at a clinic throughout the treatment duration – recorded 24 (±2) hours after the last dose. The median testosterone levels throughout the study ranged between 300–400 ng/dL, with the median increase at 12 months of 148 ng/dL in the testosterone group compared to 14 ng/dL in the placebo group. The mean daily dose of testosterone administered was 65 mg.
No differences observed in major cardiovascular events
Over the treatment and follow-up period, there were no significant differences in all primary cardiovascular outcomes between the treatment and placebo groups. The number of recorded events in the safety population (182; 7%) was comparable to the placebo group (190; 7%), with differences reported as statistically non-inferior (hazard ratio [HR] = 0.96, P<0.001 for non-inferiority). The testosterone group experienced a non-signicarficant 16% lower incidence of death due to cardiovascular causes (HR 0.84; 95% CI, 0.63–1.12).
Although treatment did not significantly change the primary endpoint, patients receiving TRT observed a significant:
- 46% increased risk of venous thromboembolic events (44 patients, 1.7% vs 30 patients, 1.2%; P=0.001)
- Increase in non-fatal arrhythmias warranting intervention (134 cases, 5.2% vs 87 cases, 3.3%; P=0.001)
- Increase in atrial fibrillation (91 patients, 3.5% vs 63 patients, 2.4%; P=0.02)
The safety data suggests the relationship between TRT in patients with or at risk of cardiovascular disease, may depend on the cardiovascular measure of interest. Future research designed to measure these safety concerns may be necessary. Importantly, there were no significant differences in major cardiovascular events.
Surprisingly, patients receiving TRT also observed an increased risk of acute kidney injury (60 patients, 2.3% vs 40 patients, 1.5%; P=0.04) and fractures compared to placebo. The authors stated in the supplementary data that fracture outcomes will be explored in more detail and published as a separate paper.
Discontinuation rates were high
Poor long-term adherence is a persistent challenge associated with TRT. The TRAVERSE study further emphasises this challenge, revealing that 1,553 patients (59.8%) discontinued their testosterone treatment by month 48. This finding underscores the ongoing difficulty in maintaining patient adherence to their medications. Similar discontinuation rates were observed for placebo.
Our thoughts, at TRTed
The TRAVERSE study provides welcome news for the medical community, as it did not find a significant difference in major cardiovascular events between patients in the testosterone group and placebo group. Going forward, this data, together with expert analysis, can be used to support the hypothesis that TRT does not increase the risk of a major cardiovascular event in patients at risk of or with existing cardiovascular disease.
However, some degree of caution is warranted when interpreting the TRAVERSE study. While differences in the incidence of major cardiovascular events were not statistically significant, results revealed an increased risk of non-fatal arrhythmias and venous thromboembolic events in the testosterone group. We therefore acknowledge and support current guidelines that testosterone should be used with caution in patients with a history of thromboembolic events, and this may now extend to patients with a history of arrhythmias. Further prospective research is needed to explore these markers further. It remains possible that the follow-up period of 32.9 months in the TRAVERSE clinical trial was not long enough to reliably measure cardiovascular outcomes with testosterone exposure, and longer-term exposure of TRT may lead to different outcomes. Ideally, well-controlled prospective research may be necessary to capture these long-term outcomes.
Nevertheless, the TRAVERSE study provides valuable insights into the cardiovascular safety of TRT in patients at risk of or with existing cardiovascular disease, this data may prompt a review of the current guidelines.
Dr. Steven Nissen, an author of the TRAVERSE trial, told Cleveland Clinic
- '’The question we were asking was were there more cardiovascular events in men who were getting testosterone compared to men who were getting a placebo. The answer is there were not, there were almost an identical number of events in the placebo group and in the men taking testosterone. Although we showed that in men with low testosterone levels and symptoms, that treatment of testosterone is safe, we do not want the results of the TRAVERSE trial to be used as a justification for the widespread treatment of men who are ageing unless they really are well documented to have low testosterone.’’
- ‘’There were also some safety concerns in the trial, there was a higher rate of clots in the legs, and in fact, the current guidelines suggest that men who have had clots in their legs should not be treated with testosterone. My advice is that men should go to an established medical centre where there are urologists or endocrinologists who are familiar with the data on the effects of testosterone who can evaluate them carefully and decide whether or not they should be treated.’’
- Aversa A, et al. J Sex Med 2010;7(10):3495–503.
- Budoff M, et al. JAMA 2017;317(7):708–716.
- Basaria S, et al. N Eng J Med 2010;363(2):109–22.
- Jayasena CN, et al. Clin Endocrinol 2022;96:200–219.
- Diem SH, et al. Ann Intern Med 2020;172(2):105–118.
- Lincoff AM, et al. NEJM 2023. DOI: 10.1056/NEJMoa2215025.