TRAVERSE Trial: Confirming TRT's Cardiovascular Safety

TRAVERSE Trial: Dispelling Cardiovascular Fears, Redefining TRT Safety

Last Updated: June 2024

Untreated hypogonadism is not benign. Men with total testosterone below 300 ng/dL exhibit a 2.4 times higher cardiovascular mortality risk compared to eugonadal men (JCEM, 2018) [1]. For years, fear surrounded testosterone replacement therapy (TRT) and its potential impact on cardiovascular health, leading to widespread hesitation and a black box warning from the FDA. This caution was largely based on observational studies and smaller, often flawed trials. Clinical evidence was lacking. The medical community needed a definitive answer on TRT’s cardiovascular safety. The TRAVERSE trial has delivered it.

The Landmark TRAVERSE Trial: A Paradigm Shift

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial (NCT03518034) stands as the largest and most comprehensive cardiovascular safety study ever conducted on testosterone therapy [2]. This Phase 4 randomized, placebo-controlled clinical trial enrolled over 5,200 middle-aged and older men, all diagnosed with hypogonadism (total testosterone <300 ng/dL) and with pre-existing cardiovascular disease or a high risk for it. Participants received either topical testosterone gel or placebo for an average duration of 33 months.

The primary objective of TRAVERSE was to assess whether TRT increased the risk of major adverse cardiovascular events (MACE), a composite endpoint including cardiovascular death, nonfatal myocardial infarction (heart attack), and nonfatal stroke. The results are unequivocal.

TRAVERSE Key Findings: TRT Is Cardioprotective (or at least, non-harmful)

The TRAVERSE trial found that testosterone replacement therapy was noninferior to placebo regarding the incidence of MACE. Specifically, MACE occurred in 7.0% of men receiving testosterone and 7.1% of men receiving placebo [2]. This statistically equivalent outcome conclusively demonstrated that TRT does not increase cardiovascular risk in men with hypogonadism and established or high risk for cardiovascular disease.

This finding directly challenges and overturns the long-standing black box warning on testosterone product labels regarding increased cardiovascular events. As a direct consequence of TRAVERSE, the U.S. Food and Drug Administration (FDA) has recommended the removal of this black box warning for all testosterone products [3]. This is a monumental shift, removing a significant barrier to appropriate care for countless men.

“Testosterone replacement therapy was noninferior to placebo regarding the incidence of major adverse cardiac events,” stated the trial’s executive summary, underscoring the critical safety profile now established for TRT [2].

The New Nuance: Blood Pressure Monitoring

While TRAVERSE affirmed cardiovascular safety concerning MACE, it did identify another important consideration: blood pressure. Ambulatory blood pressure monitoring (ABPM) studies, mandated by the FDA, found a small but statistically significant increase in blood pressure in men receiving testosterone [4].

The FDA has responded by requiring a new warning on testosterone product labels about an increased risk of blood pressure elevation [4]. This is a manageable side effect. Mild fluid retention and changes in vascular tone can contribute to this. Regular blood pressure monitoring is a standard component of TRT management, and this new information reinforces its importance. Blood pressure can be controlled through lifestyle interventions or, if necessary, anti-hypertensive medications. This new warning is a shift from a potentially life-threatening MACE risk to a generally manageable physiological effect.

Reconsidering the “Normal” Testosterone Threshold

The TRAVERSE findings empower men and clinicians to focus on symptomatic hypogonadism. The conventional lower bound for “normal” total testosterone, often cited around 264-300 ng/dL, is an arbitrary and outdated standard. This threshold was derived from studies in the 1970s involving populations that included elderly, often unwell men [5]. Clinical symptoms, not just a number, define the need for treatment.

Symptoms of low testosterone — including fatigue, low libido, erectile dysfunction, decreased muscle mass, increased body fat, mood disturbances, and reduced bone density — warrant investigation regardless of where a man’s testosterone level falls within the broad “normal” range. Optimal testosterone levels for a man on TRT often fall in the range of 600-1000 ng/dL, where many men report significant symptomatic relief and improved quality of life.

Navigating TRT: Protocols and Monitoring

Effective TRT involves precise protocols and vigilant monitoring to ensure efficacy and minimize side effects.

Testosterone Formulations and Dosing

Injectable testosterone esters like testosterone cypionate and testosterone enanthate are highly effective and widely used.

• A common starting dose is 100–200mg testosterone cypionate or enanthate per week, often administered as split doses (e.g., 50–100mg twice weekly) to maintain more stable serum levels and reduce peaks and troughs. This minimizes estrogen conversion and associated side effects.

Key Laboratory Monitoring

Regular blood work is essential for safe and effective TRT.

• Total Testosterone: Aim for mid-to-high physiological range, typically 600–1000 ng/dL, measured at trough (just before the next injection).
• Free Testosterone: A crucial indicator, optimal levels are often 15–25 pg/mL.
• Estradiol (E2): While some estrogen is necessary, excessively high levels can lead to symptoms like gynecomastia, water retention, and mood swings. Target E2 levels on TRT are typically 20–40 pg/mL.
• Hematocrit: Testosterone can stimulate red blood cell production. Hematocrit levels above 50–52% (polycythemia) require monitoring and may necessitate dose adjustments or therapeutic phlebotomy.
• PSA (Prostate-Specific Antigen): Baseline PSA and regular monitoring are crucial, especially for men over 40, to screen for prostate issues. TRT does not cause prostate cancer, but it can accelerate growth in pre-existing, undiagnosed cancer.
• Lipid Panel, Fasting Glucose, HbA1c: Monitor metabolic health, as TRT can improve these markers, but overall health assessment remains important.

Ancillary Medications

• Human Chorionic Gonadotropin (HCG): Often prescribed alongside injectable testosterone to maintain testicular size and preserve endogenous testosterone production, which is crucial for fertility. Typical doses range from 500–1000 IU administered 2-3 times per week.
• Anastrozole: An aromatase inhibitor used to reduce estrogen conversion. It should be used judiciously, only if E2 is symptomatically high and outside optimal range. Prophylactic use is generally discouraged due to the risks of crashing E2 levels, which can lead to joint pain, bone density loss, and libido issues. A common dose when truly needed is 0.25–0.5mg once or twice per week.
• Enclomiphene: A selective estrogen receptor modulator (SERM) that stimulates the body’s own testosterone production. It is an alternative to exogenous testosterone injections for some men, particularly those seeking to preserve fertility, but it is typically less effective for severe hypogonadism and was not the focus of the TRAVERSE trial.

Understanding TRT Risks vs. Benefits Post-TRAVERSE

The TRAVERSE trial has significantly clarified the risk-benefit profile of TRT.