Association between testosterone replacement therapy and cardiovascular events in men: a retrospective propensity-weighted analysis.

TRT was associated with a 27% increased risk of MACE in propensity-weighted analyses.

• Among 6949 men who received TRT and 415,837 controls, HR 1.27 (95% CI: 1.16-1.39) in weighted analyses.
• MACE occurred in 9.95% of TRT users versus 5.56% of controls.
• A Cox proportional hazards model was used to assess time to first MACE.
• Stabilized inverse propensity treatment weighting was applied using a logistic regression model including age, socioeconomic status, index year, diabetes, hypertension, dyslipidemia, and renal disease.

Men diagnosed with testosterone deficiency (TD) also showed a 27% increased risk of MACE compared to matched controls.

• Among 7306 men diagnosed with TD and 442,602 matched controls, HR 1.27 (95% CI: 1.16-1.39).
• The magnitude of increased MACE risk was identical for TRT users and men with TD diagnosis.
• This parallel finding raises the question of whether cardiovascular risk is driven by TRT itself or the underlying condition of TD.

Median time to first MACE was longer in TRT users than in controls despite a higher event rate.

• Median time to MACE was 2828 days in the TRT group and 2707 days in controls.
• MACE was defined as the first occurrence of myocardial infarction, coronary revascularization, ischemic stroke, or hospitalization for heart failure.

The study used a large population-based retrospective cohort design spanning over two decades of provincial health administrative data.

• Data were drawn from provincial health administrative databases covering April 1, 1995, to December 31, 2018.
• Men were eligible if they had no prior TRT use or MACE and maintained at least one year of provincial health coverage.
• TRT was defined as having at least two prescriptions filled within one year for testosterone products (capsules, gels, patches, or injections).
• Total cohort included 6949 TRT users and 415,837 controls for the primary analysis.

Testosterone deficiency affects a substantial proportion of middle-aged Canadian men, providing context for the public health relevance of TRT cardiovascular risk.

• TD affects up to 25% of Canadian men aged 40 to 60.
• TRT has been in clinical use for over seven decades.
• The relationship between TRT and MACE has remained unclear prior to this study.

The study acknowledged potential unmeasured confounding that could influence the observed cardiovascular risk associations.

• Unmeasured confounders include obesity, smoking, and physical activity levels.
• Diagnostic coding limitations may affect TD case identification.
• These limitations mean independent causal attribution of MACE risk to TRT versus underlying TD cannot be definitively established.