Cardiovascular Safety Of Testosterone Replacement Therapy In Middle-Aged, Older Adults

CITATION:
Bloch M. Cardiovascular safety of testosterone replacement therapy in middle-aged, older adults. Consultant360. Published August 21, 2023. 

Increasing numbers of middle-aged and older men are being prescribed testosterone therapy for the treatment of a myriad of conditions associated with aging. While the subjective and objective benefits of testosterone therapy are fairly well established, there are limited data regarding the cardiovascular (CV) safety of this therapy. This issue was significant enough that the FDA mandated it be studied. The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE)¹ trial was designed to determine the effects of testosterone-replacement therapy on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism and either preexisting or a high risk of CV disease.

TRAVERSE was a phase 4, randomized, double-blind, placebo-controlled, noninferiority study performed at 316 clinical sites in the United States. Of note, the trial was funded and presumably designed with the input of a consortium of manufacturers of branded prescription testosterone supplements. Eligible patients were men aged 45 to 80 years with one or more symptoms of hypogonadism, established or high risk for CV disease, and a baseline testosterone level of <400 ng/dl. Exclusion criteria included congenital or acquired severe hypogonadism, a history of prostate cancer or prostate nodules, an elevated screening prostate-specific antigen (PSA) level, thrombophilia, uncontrolled heart failure, or recent CV events. Eligible patients were randomly assigned to receive daily transdermal 1.62% testosterone gel or matching placebo gel provided in metered-dose pumps. Although patients and the trial team remained blinded to treatment allocation or on-treatment testosterone levels, dose adjustment in the treatment group was undertaken by the central laboratory to maintain testosterone levels between 350 and 750 ng/dl. The primary endpoint was the first occurrence of a major CV event (death from CV cause, nonfatal myocardial infarction, or nonfatal stroke).

A total of 5246 patients were randomly assigned, about half of which had a history of established CV disease, with the other half having a high CV risk. The mean baseline serum testosterone level was 227 ng/dl and the mean duration of follow-up was just more than 21 months. After 12 months of therapy, the mean testosterone level in the treatment group was 375 ng/ml, as compared with approximately 240 ng/dl in the placebo group. Over the course of the study, the incidence of a primary CV endpoint in the active treatment group (7.0%) was non-inferior to that of the placebo group (7.3%). There was a trend toward an increased risk of atrial fibrillation (AF) and venous thromboembolism (VTE) in the active treatment group.

Overall, the TRAVERSE trial should increase our comfort level with the cardiovascular safety of testosterone repletion therapy but with a few important caveats. Certainly, there were aspects of the trial design that may have biased the results towards a null outcome, including the relatively short outcome ascertainment window and the relatively low achieved testosterone levels. Patients in this study had documented low testosterone levels (<400 ng/dl) and common symptoms of hypogonadism and were repleted to levels well less than 500 ng/dl on average. The CV safety of treating patients with less profound hypogonadism or more aggressive treatment remains unknown.  Additionally, the trend toward an increased risk of AF and VTE with testosterone therapy in this study is worthy of further investigation.  

Reference:

1. Lincoff AM, Bhasin S, Flevaris P, et al; TRAVERSE Study Investigators. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117. doi:10.1056/NEJMoa2215025