TRAVERSE Trial: No Increased Cardiovascular Risk with Testosterone Replacement Therapy


A phase 4 trial of men with hypogonadism in the US offers an overview of the potential risk of major cardiovascular events associated with use of testosterone replacement therapy.

A. Michael Lincoff, MD | Credit: Cleveland Clinic

A. Michael Lincoff, MD
Credit: Cleveland Clinic

Results of a phase 4 trial presented at the Endocrine Society (ENDO) 2023 annual meeting could provide an end to the long-standing debate regarding the effects of testosterone replacement therapy in men.

Named the TRAVERSE study, results of the trial, which compared risk of cardiovascular events in people with hypogonadism using testosterone therapy versus placebo, indicate use of testosterone therapy was noninferior to placebo for incidence of major adverse cardiovascular events (MACE).1

“Our findings support current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events,” wrote investigators.1 “There were more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury among patients who received testosterone than among those who received placebo; these adverse events were not expected.”

Since the turn of the century, the prevalence of testosterone replacement therapy use has exploded in the US, with a 2018 JAMA study suggesting rates of use among men aged 30 years or older had tripled from 2002 to 2016. However, this increase in use was not an uninterrupted climb. According to the 2018 study, use increased from 0.52% of men in 2002 to 1.67% in 2016, but also indicate usage peaked at 3.2% in 2013 until a pair of studies purported an increase in risk for myocardial infarction and stroke associated with testosterone use.2

The current study, named the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, was launched following US Food and Drug Administration guidance on March 3, 2015 requiring manufacturers of approved testosterone products to conduct clinical trials to determine whether use is associated with an increased risk of cardiovascular events. With this in mind, the phase 4 trial was designed as a randomized, double-blind, placebo-controlled, noninferiority, event-driven trial of men aged 45-80 years of age with one or more symptoms of hypogonadism and preexisting cardiovascular disease or elevated cardiovascular risk at 316 sites in the US.1

Patients included in the trial were randomized in a 1:1 ratio to daily transdermal 1.62% testosterone gel or matched placebo gel. The primary safety endpoint of the trial was the first occurrence of a major cardiovascular event. Investigators defined major cardiovascular events as a composite of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis. Investigators pointed out Cox proportional-hazards regression model was used to estimate hazard ratios (HRs) for the primary endpoint relative to placebo therapy, with adjustment for preexisting cardiovascular disease.1

A total of 5246 patients underwent randomization in the trial, with 5204 patients included in the full analysis population. Of these 5204, 2601 were randomized to testosterone therapy and 2603 were randomized to placebo therapy. The overall population included 2847 patients with preexisting cardiovascular disease and 2357 with elevated cardiovascular risk.1

The combined treatment and placebo groups had a median baseline serum testosterone level of 227 (Interquartile range [IQR], 188-258) ng/dL. Investigators noted the mean durations of treatment and follow-up, respectively, were 21.8 (Standard deviation [SD], 14.2) and 33.1 (SD, 12.0) months in the testosterone group and 21.6 (SD, 14.0) and 32.9 (SD, 12.1) months in the placebo group. During the trial, 61.4% of those in the testosterone group discontinued treatment and 61.7% of those in the placebo group discontinued placebo use.1

Upon analysis, investigators identified182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group with a first major cardiovascular event (HR, 0.96; 95% confidence interval, 0.78-1.17; P < .001 for noninferiority). In a principal sensitivity analysis, which censored data on events occurring more than 365 days after the final dose indicated a primary endpoint event occurred in 154 patients (5.9%) in the testosterone group and 152 patients (5.8%) in the placebo group (HR, 1.02; 95% CI, 0.81-1.27; P < .001 for noninferiority).1

Investigators also called attention to results of their adverse events analyses. In these analyses, investigators found prostate cancer occurred in 12 patients (0.5%) in the testosterone group and in 11 patients (0.4%) in the placebo group (P = .87). Additionally, these analyses indicated nonfatal arrhythmias warranting intervention occurred among 134 (5.2%) of the testosterone group compared to 87 (3.3%) among the placebo group (P = .001). Further analysis demonstrated acute kidney injury occurred in 2.3% of the testosterone group and 1.5% of the placebo group (P = .04).1

“Among men with hypogonadism and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low,” investigators concluded.1


  1. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy [published online ahead of print, 2023 Jun 16]. N Engl J Med. 2023;10.1056/NEJMoa2215025. doi:10.1056/NEJMoa2215025
  2. Baillargeon J, Kuo Y, Westra JR, Urban RJ, Goodwin JS. Testosterone Prescribing in the United States, 2002-2016. JAMA. 2018;320(2):200–202. doi:10.1001/jama.2018.7999
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