Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis.

No significant difference between TRT and placebo was observed for major adverse cardiovascular events across all included RCTs.

• Analysis included 106 studies out of 3,615 initially identified, comprising 8,126 subjects treated with TRT and 7,310 patients allocated to placebo.
• An extensive Medline, Embase, and Cochrane search was performed for placebo-controlled RCTs reporting data on TRT-related CV safety.
• The meta-analysis covered a broad range of cardiovascular outcomes including major adverse CV events (MACE).

The increased incidence of non-fatal arrhythmias and atrial fibrillation observed in the TRAVERSE trial (the only trial with CV safety as primary endpoint) was not confirmed when all other studies were considered.

• Mantel-Haenszel odds ratio for non-fatal arrhythmias across all other studies was 1.61 [95% CI: 0.84; 3.08], which was not statistically significant.
• Mantel-Haenszel odds ratio for atrial fibrillation across all other studies was 1.44 [95% CI: 0.46; 4.46], which was not statistically significant.
• The TRAVERSE trial was identified as the only RCT considering CV safety as its primary endpoint and showed an increased risk of AF.
• Results suggest the AF signal from TRAVERSE was not replicated in the broader body of RCT evidence.

No significant relationship between endogenous testosterone levels and atrial fibrillation incidence was observed after adjustment for confounders.

• Population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were included and analyzed to further examine the AF question.
• After adjustment for confounders, the association between endogenous T levels and AF incidence was not statistically significant.
• This finding from observational data corroborated the RCT-based finding that testosterone does not increase AF risk.

The systematic review and meta-analysis concluded that TRT is safe and not associated with an increased cardiovascular risk based on available placebo-controlled RCT data.

• A total of 106 placebo-controlled RCTs were included in the final analysis.
• The study population comprised 8,126 TRT-treated subjects and 7,310 placebo-allocated patients.
• The authors note that the CV safety of TRT has been 'still conflicting' prior to this updated analysis.
• The conclusion applies to both MACE outcomes and arrhythmia/AF outcomes when the totality of RCT evidence is considered.