Testosterone Replacement and Heart Health: No Increased Risk, But Watch for Side Effects

A large study in the New England Journal of Medicine investigated if testosterone replacement therapy (TRT) harms the hearts of men with hypogonadism and existing cardiovascular risk. Over 5,000 men received either TRT or placebo gel. The main finding is that both groups had similar rates of major heart events like heart attacks and strokes, showing TRT isn't riskier in this population. However, TRT was linked to more cases of atrial fibrillation, kidney issues, and blood clots in the lungs. While encouraging heart safety, longer studies are needed, and potential side effects require careful consideration with your doctor before starting TRT.

Key findings:

This study investigated the cardiovascular safety of testosterone replacement therapy (TRT) in middle-aged and older men with hypogonadism and pre-existing or high-risk cardiovascular disease.

• Non-inferiority of TRT: The primary outcome measure was the occurrence of major adverse cardiac events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The study found no significant difference between the TRT and placebo groups in the rate of these events, demonstrating the non-inferiority of TRT regarding cardiovascular safety.

• Similar secondary outcomes: Similar results were observed for a broader range of cardiovascular events, including coronary revascularization.

• Potential side effects: TRT was associated with a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism compared to placebo.

• Limitations: The study duration was relatively short, and longer-term effects require further investigation.

Additional information:

• The study involved over 5,000 participants, making it a large and statistically robust analysis.

• The participants received daily transdermal testosterone gel with dosage adjustments to maintain a specific testosterone level range.

• The study was funded by AbbVie and others, which raises potential concerns about bias, although the findings were published in a reputable medical journal.

Overall:

This study provides encouraging evidence regarding the cardiovascular safety of TRT in men with pre-existing cardiovascular risk factors. However, it is crucial to consider the potential side effects and discuss them with a healthcare professional before making any treatment decisions. Additionally, more research is needed to assess the long-term effects of TRT on cardiovascular health.

Testosterone replacement therapy (TRT) has been a subject of considerable debate regarding its cardiovascular effects in middle-aged and older men with hypogonadism. While some retrospective cohort studies have suggested an increased cardiovascular risk associated with TRT, others have shown conflicting results. Similarly, small randomized trials have failed to provide consistent evidence regarding the cardiovascular safety of testosterone treatment. To address these concerns, the Food and Drug Administration (FDA) mandated clinical trials to evaluate the cardiovascular risks of TRT. The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to determine the effects of TRT on major adverse cardiac events among men with hypogonadism and either preexisting cardiovascular disease or a high risk of cardiovascular events. This randomized, placebo-controlled trial investigated whether testosterone-replacement therapy increases cardiovascular risk in men with hypogonadism. 5198 men with established cardiovascular disease or risk factors received testosterone or a placebo for 22 months. The study found no increased risk of major cardiac events in the testosterone group compared to the placebo group. Pulmonary embolism was higher in the testosterone group, and more cases of nonfatal arrhythmias, atrial fibrillation, and acute kidney injury were observed. However, the overall incidence of adverse events was low. This study suggests that testosterone therapy may be safe for men with hypogonadism and cardiovascular risk, but caution should be used in those with a history of blood clots. The findings may help inform treatment decisions for men with low testosterone.

Trial Design and Oversight

The TRAVERSE trial was a phase 4 randomized, double-blind, placebo-controlled, noninferiority study conducted at 316 clinical trial sites in the United States. Funded by a consortium of testosterone manufacturers led by AbbVie, the trial was overseen by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) with support from a contract research organization (Labcorp Drug Development). The trial protocol was approved by national and institutional regulatory and ethical authorities, and all patients provided written informed consent. An independent data and safety monitoring committee reviewed safety data throughout the trial.

Trial Population

The trial enrolled men aged 45 to 80 with preexisting cardiovascular disease or an elevated cardiovascular risk. Eligible participants reported symptoms of hypogonadism and had low serum testosterone levels. Cardiovascular disease was defined as clinical or angiographic evidence of coronary artery disease, cerebrovascular disease, or peripheral arterial disease. Increased cardiovascular risk was determined by the presence of three or more specific risk factors, including hypertension, dyslipidemia, smoking, chronic kidney disease, diabetes, elevated C-reactive protein level, age 65 or older, or an elevated Agatston coronary calcium score.

Trial Intervention

Participants were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel in a 1:1 ratio. Randomization was stratified based on the presence or absence of preexisting cardiovascular disease. Dose adjustments were made centrally to maintain testosterone levels within a specified range. The trial protocol outlined criteria for discontinuation of testosterone or placebo based on testosterone levels, hematocrit, new diagnoses of prostate cancer, or suicide risk.

Endpoints

The primary safety endpoint was the occurrence of major adverse cardiac events, including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints included additional cardiovascular events, all-cause mortality, heart failure hospitalizations, peripheral arterial revascularizations, and venous thromboembolic events. Adjudication of cardiovascular events was performed by an independent clinical events committee.

Statistical Analysis

The trial utilized a noninferiority design, with the primary analysis conducted on the safety population. Cox proportional-hazards regression models were used to estimate hazard ratios and 95% confidence intervals for primary endpoint events. Sensitivity analyses were performed to assess the robustness of the findings, including adjustments for interruptions or discontinuations of testosterone or placebo.

Results

Among the 5198 patients included in the trial, testosterone replacement therapy was found to be non-inferior to placebo in terms of the incidence of major adverse cardiac events over a mean follow-up duration of 22 months. The hazard ratio for primary endpoint events was 0.96 (95% CI, 0.78 to 1.17). However, the incidence of pulmonary embolism was higher with testosterone than with placebo, suggesting caution in men with previous thromboembolic events.

To Summarize

1. Trial Participants: 5246 men aged 45 to 80 years with preexisting or high-risk cardiovascular disease participated in the study.

2. Treatment Duration: The mean duration of treatment was 21.7 months, with a mean follow-up of 33.0 months.

3. Primary Endpoint: 7.0% of patients in the testosterone group and 7.3% in the placebo group experienced primary cardiovascular events, demonstrating non-inferiority.

4. Secondary Endpoint: A similar incidence of secondary endpoint events was observed between the two groups.

5. Sensitivity Analyses: The consistency of findings across sensitivity analyses strengthens the reliability of the results.

6. Adverse Events: The testosterone group exhibited a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism.

7. Conclusion: Testosterone-replacement therapy in men with hypogonadism and cardiovascular disease was non-inferior to placebo regarding major adverse cardiac events.

Conclusion

The TRAVERSE trial provides valuable insights into the cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism. While TRT was not associated with an increased risk of major adverse cardiac events, careful consideration is warranted, especially in individuals with a history of thromboembolic events. These findings contribute to a more informed understanding of the risks and benefits of testosterone therapy in this patient population.

Reference Article

Lincoff, A. M., Bhasin, S., Flevaris, P., Mitchell, L. M., Basaria, S., Boden, W. E., Cunningham, G. R., Granger, C. B., Khera, M., Thompson, I. M., Jr, Wang, Q., Wolski, K., Davey, D., Kalahasti, V., Khan, N., Miller, M. G., Snabes, M. C., Chan, A., Dubcenco, E., Li, X., … TRAVERSE Study Investigators (2023). Cardiovascular Safety of Testosterone-Replacement Therapy. The New England journal of medicine, 389(2), 107–117. https://doi.org/10.1056/NEJMoa2215025

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Testosterone Replacement Therapy (TRT): Everything You Need to Know | Healthnewstrend

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