Arq. Bras. Cardiol. 2024; 121(3): e20230558

Cardiovascular Safety of Testosterone-Replacement Therapy: Critical Appraisal of a Currently Published Clinical Trial

Isabela Tramontini Muller ORCID logo , Sérgio Renato da Rosa Decker, Regis Goulart Rosa, Guilherme Rollin

DOI: 10.36660/abc.20230558i

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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Cardiovascular Safety of Testosterone-Replacement Therapy: Critical Appraisal of a Currently Published Clinical Trial

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