Arq. Bras. Cardiol. 2024; 121(3): e20230558
Cardiovascular Safety of Testosterone-Replacement Therapy: Critical Appraisal of a Currently Published Clinical Trial
Isabela Tramontini Muller
, Sérgio Renato da Rosa Decker, Regis Goulart Rosa, Guilherme Rollin
Introduction
In the last edition on June 16 of the New England Journal of Medicine, A. Michael Lincoff et al. published a non-inferiority trial, entitled “Cardiovascular Safety of Testosterone-Replacement Therapy”, aiming to determine the safety outcomes of testosterone replacement therapy in middle-aged and older men with hypogonadism and pre-existing cardiovascular disease. The inclusion criteria for hypogonadism were symptoms and two fasting serum testosterone levels of less than 300 ng/dL in blood samples obtained between 5:00 a.m. and 11:00 a.m. The intervention was daily transdermal 1.62% testosterone gel with adjustments to maintain testosterone levels between 350 and 750 ng/dL or to respond to a hematocrit greater than 54%.
The baseline characteristics were men, with a mean age of 63 years, 80% were white, with a mean body-mass index of 35, and 55% had preexisting cardiovascular disease. The median testosterone level was 227 ng/dL in both groups, and the median increase from baseline was 148 ng/dL in the testosterone group, as compared to a median increase of 14 ng/dL in the placebo group. The study concluded non-inferiority for major adverse cardiac events (MACE) by comparing testosterone replacement to placebo, and a prespecified non-inferiority margin of 1.5. The final results showed a hazard ratio for the primary end-point of 0.96 (95% confidence interval, 0.78-1.17; p-value for non-inferiority <0.001). However, we have concerns regarding this claim of non-inferiority mainly because of two points: the margin of non-inferiority and the choice of a three-point MACE over a five-point MACE.,
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