madman
Super Moderator
Re: Cardiovascular Safety of Testosterone-Replacement Therapy
www.sciencedirect.com
Experts’ summary: Lincoff et al. conducted a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial to evaluate the risk of cardiovascular and thromboembolic events with testosterone gel therapy among hypogonadal men with preexisting cardiovascular disease or risk factors. The primary endpoint was death from a cardiovascular event or nonfatal myocardial infarction or stroke. The authors hypothesized that testosterone therapy would be non-inferior to placebo with regard to cardiovascular risk. They found similar rates of primary cardiovascular endpoints in the testosterone and placebo groups and concluded that testosterone therapy was non-inferior to placebo in terms of major adverse cardiac event (MACE) incidence.
Experts’ comments: The authors should be commended for conducting this trial to investigate the cardiovascular risk of testosterone therapy, as previous studies were often retrospective and small and contradicted one another. While this study provides robust evidence, several questions remain regarding the real-world safety of testosterone in the absence of close monitoring.
Patients had serum testosterone measurements and dose adjustments several times within the first year and every 6–12 mo thereafter to check that their level remained in the range of 350–750 ng/dl. These measurements were more frequent in the first year than the American Urological Association guidelines [1], which recommend checking serum testosterone once within 2–4 wk and then every 6–12 months thereafter. Studies assessing follow-up found that 50% of men receiving testosterone have follow-up serum testosterone checked within 1 yr [2]. Furthermore, median testosterone levels in the experimental arm remained between 350 and 400 ng/dl throughout the study, with the 75th percentile never exceeding 550 ng/dl. This reflects close monitoring and dose titration, but such tight control of serum testosterone would be difficult to replicate in the real world. In addition, dose titration based on a hematocrit >54% at regular intervals may have contributed to the non-inferiority demonstrated by the trial. Given the dose-response relationship between testosterone therapy and erythropoiesis[3] and the risk of MACE for patients on testosterone therapy with a hematocrit >52% [4], higher serum testosterone could have precipitated a greater risk of MACE. Outcomes for study participants with a sustained hematocrit > 54% are not reported. Finally, the varying effects of different testosterone formulations on hematocrit should be considered, as the study only investigated gel, while intramuscular formulations cause greater increases in hematocrit [5].
In conclusion, this study addresses many concerns regarding the cardiovascular safety of testosterone therapy. The close monitoring may have played a key role in the noninferiority conclusions, and providers should remain wary of prescribing testosterone without regular follow-up and monitoring.
