Literature
Clinical Pearls & Morning Reports
Published July 12, 2023
Did testosterone-replacement therapy increase the risk of major adverse cardiac events in the trial by Lincoff et al.?
Lincoff et al. conducted a double-blind, placebo-controlled, noninferiority trial that evaluated 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 cardiovascular disease. Read the NEJM Original Article here.
Clinical Pearls
Q: What is known about the cardiovascular effects of testosterone-replacement therapy in middle-aged and older men with hypogonadism?
A: The cardiovascular effects of testosterone-replacement therapy in middle-aged and older men with hypogonadism have not been determined. Retrospective cohort studies involving men receiving testosterone-replacement therapy have shown conflicting results, with some showing increased and others decreased cardiovascular risk. Small randomized trials similarly have not shown a consistent association of testosterone treatment with cardiovascular risk, although none were designed to systematically assess cardiovascular outcomes and all were inadequately powered and had a short duration.
Q: Did testosterone-replacement therapy increase the risk of major adverse cardiac events in the trial by Lincoff et al.?
A: The primary safety end point of the trial was the first occurrence of any component of major adverse cardiac events, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority).
Morning Report Questions
Q: How did the incidence of pulmonary embolism compare in the two groups in this trial?
A: The incidence of pulmonary embolism was higher with testosterone than with placebo. Although most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia, a meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations. The authors state that their findings support current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events.
Q: What were some of the other adverse events that were more common with testosterone therapy than with placebo?
A: Nonfatal arrhythmias warranting intervention occurred in 134 patients (5.2%) in the testosterone group and in 87 patients (3.3%) in the placebo group (P = 0.001); atrial fibrillation occurred in 91 patients (3.5%) and 63 patients (2.4%), respectively (P = 0.02), and acute kidney injury occurred in 60 patients (2.3%) and 40 patients (1.5%), respectively (P = 0.04). These adverse events were not expected. A small increase in blood pressure observed in the testosterone group was similar to that reported previously with other testosterone formulations. The increase in prostate-specific antigen levels from baseline was greater in patients in the testosterone group than in those in the placebo group (0.20±0.61 ng per milliliter vs. 0.08±0.90 ng per milliliter, respectively; P<0.001).