TRAVERSE Showed TRT Non-Inferiority for MACE. That Is Not the Same as Cardiovascular Safety.

The evidence base

The TRAVERSE trial, published by Lincoff and colleagues in the New England Journal of Medicine in June 2023, is the reference point most clinicians now work from when discussing testosterone therapy and cardiovascular outcomes. The trial enrolled 5,246 men aged 45 to 80 with hypogonadism (defined as two morning testosterone levels below 300 ng/dL) who also had pre-existing cardiovascular disease or a high risk of it based on standard risk factors. Participants were randomized to a 1.62% testosterone gel or placebo and followed for a median of 21.9 months. The primary endpoint was a composite of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke, known as MACE. The hazard ratio for MACE was 0.96 (95% CI, 0.78 to 1.17), meeting the prespecified non-inferiority margin of 1.5, with p<0.001 for non-inferiority (Lincoff et al., NEJM 2023).

That result matters. For over a decade, prescribers operated under genuine uncertainty, in part because a 2010 randomized trial by Basaria and colleagues in frail elderly men was stopped early after excess cardiovascular events appeared in the testosterone group (Basaria et al., NEJM 2010), and in part because the FDA issued a 2015 safety communication about testosterone products and age-related low testosterone. The communication's core message was that neither the cardiovascular benefit nor the cardiovascular safety of these products had been established for that use, regardless of whether a patient's symptoms seemed connected to low testosterone (a 2015 FDA safety communication). TRAVERSE was designed to address that regulatory uncertainty directly, and its non-inferiority finding is the strongest prospective evidence available to date.

The 2018 Endocrine Society Clinical Practice Guideline on testosterone therapy, published before TRAVERSE, took a cautious position: it recommended against starting TRT within six months of a heart attack or stroke, and it noted that testosterone's long-term cardiovascular safety was still unproven at that time (Bhasin et al., JCEM 2018). TRAVERSE is the specifically powered outcomes trial that guideline effectively called for.

Three findings from the trial matter most for this discussion:

First, the MACE incidence rate was 7.0% in the testosterone group versus 7.3% in the placebo group over the median 21.9 months of follow-up. That is consistent with non-inferiority, not with a clear protective effect (Lincoff et al., NEJM 2023).

Second, and less discussed in post-trial commentary, the testosterone group had a higher incidence of pulmonary embolism (0.9% vs. 0.5%, p=0.03) and atrial fibrillation (3.5% vs. 2.4%, p<0.001) (Lincoff et al., NEJM 2023). Both were secondary endpoints, and the trial was not powered to declare superiority or inferiority on either one individually. They are signals, not verdicts. They are also not nothing: a statistically significant difference in a common arrhythmia, in a trial this size, is worth naming plainly rather than folding into the headline non-inferiority result.

Third, the FDA's 2015 labeling action applied to all approved testosterone products and was informed in part by pharmacoepidemiological studies suggesting elevated myocardial infarction risk in the year after TRT initiation. That communication has not been formally withdrawn, and testosterone labeling still carries warnings that predate TRAVERSE (per the agency's 2015 communication).

Decision framework: what TRAVERSE changes and what it doesn't

This is not a general risk calculator. It is a summary of what the trial evidence above actually supports for specific situations, and what it leaves open.

What the data does and does not show

Here is where we part ways with the headlines.

TRAVERSE established non-inferiority for MACE over roughly two years in a specific, pre-selected high-cardiovascular-risk population. It was not a study of average-risk middle-aged men seeking TRT for fatigue or low libido. Generalizing the non-inferiority finding to a broader hypogonadal population requires an inferential step the trial data do not directly support.

The median follow-up of 21.9 months is a real limitation. Atherosclerotic progression, polycythemia-related viscosity changes, and hemostatic pathway effects may operate on timescales longer than two years. The Endocrine Society guideline's own conclusion, that long-term safety remained unproven, predates this trial, and in our reading it still holds. Researchers running cardiovascular outcomes trials typically define long term as five years or more of follow-up, the standard set by trials such as ACCORD, ADVANCE, and ORIGIN in the metabolic disease space.

Crossover contamination is another design issue worth naming, though the exact figures need confirmation against the trial's published supplementary data before we would cite them as precise. A meaningful share of men randomized to placebo stopped their assigned treatment during the trial, and some pursued testosterone therapy outside the study protocol. Intention-to-treat analysis preserves randomization, but any real crossover in the placebo arm dilutes the observed difference between arms in direct proportion to that crossover. If TRT carries even a modest adverse effect on a secondary outcome like atrial fibrillation, placebo-arm men who obtained testosterone elsewhere would pull the placebo group's event rate toward the treatment group's, making the trial look closer to a clean safety result than the underlying biology might support. This is not an assertion that TRAVERSE's conclusion is wrong. It is a mechanistic reason not to read the non-inferiority margin as a full safety clearance.

The atrial fibrillation finding deserves separate attention. A jump from 2.4% to 3.5% incidence, a relative increase of roughly 50% in an already common condition, with a p value under 0.001, is not background noise. AF was not part of the MACE composite, so it did not affect the primary endpoint. But AF contributes materially to stroke risk, embolic events, and hospitalizations, and the finding is consistent with prior mechanistic work on testosterone's effects on cardiac ion channel expression and atrial remodeling. Setting it aside because MACE was non-inferior understates the trial's actual risk profile.

The FDA's warning history reflects a regulatory agency responding to real-world pharmacovigilance signals that predate TRAVERSE. We do not think TRAVERSE retroactively nullifies those signals. It adds important prospective evidence, and the two bodies of evidence now have to be reconciled through clinical judgment, not through a simple hierarchy where the newest trial automatically overrides everything before it.

Our position

The HealthRX.com Medical Team holds the following position, explicitly.

TRAVERSE provides credible evidence that TRT does not meaningfully increase MACE risk in hypogonadal men with elevated cardiovascular risk over approximately two years of treatment. Clinicians who previously avoided TRT in all men with cardiovascular disease should revisit that blanket restriction. The trial's primary finding supports a more individualized conversation about risk and benefit, particularly when hypogonadism is symptomatic and biochemically confirmed by two separate morning measurements below 300 ng/dL, as the Endocrine Society guideline specifies (Bhasin et al., JCEM 2018).

We do not read TRAVERSE as removing the need for careful pre-treatment cardiovascular evaluation. Our screening before TRT initiation includes a baseline ECG (given the AF signal), a hematocrit and hemoglobin (polycythemia is dose-dependent and well documented outside this trial), fasting lipids, and a specific conversation about prior venous thromboembolic events given the pulmonary embolism signal. None of this is new. It is what the 2018 guideline already recommended. TRAVERSE reinforces those screens rather than making them unnecessary.

We are extending clinical judgment beyond the strict trial data on one point: the roughly two-year median follow-up is not enough to characterize the long-term trajectory of TRT's effects on atrial fibrillation burden, thromboembolic risk, or downstream cerebrovascular events. We tell patients that the non-inferiority finding is reassuring but time-limited, and that our monitoring schedule responds to that remaining uncertainty rather than to excessive caution.

For men with prior AF, we treat the AF signal from TRAVERSE as a material factor in shared decision-making, not a footnote. This is our clinical judgment applied to a secondary endpoint, not a conclusion drawn from a head-to-head trial in AF patients, and we name it as such.

What changes most in our practice after TRAVERSE is the counseling, not the screening. Before this trial, the honest answer to "is TRT safe for my heart" was that a well-powered trial did not exist. The honest answer now is that the best available trial, over about two years, did not show a significant increase in heart attack, stroke, or cardiovascular death, but did show higher rates of atrial fibrillation and pulmonary embolism, and that longer-term data are not yet available. That is a better-informed conversation. It is not a simpler one.

What would change our mind

A minimum five-year follow-up extension of the TRAVERSE cohort, or a comparably powered independent trial, showing no increase in AF incidence, AF-related stroke, or thromboembolic events would move us toward a lighter screening protocol. The five-year threshold is not arbitrary. It reflects the standard used in other cardiovascular outcomes trials and the plausible latency period for clinically significant atrial remodeling.

Mechanistic data showing that the observed AF signal was driven by a baseline imbalance in AF risk between arms, rather than a pharmacological effect of testosterone, would also update our position. Randomization appeared balanced on baseline characteristics as reported, but AF-specific risk stratification was not used, so residual confounding cannot be ruled out from the summary data available to us.

If the Endocrine Society or a comparable guideline body formally revised its cardiovascular screening recommendations after TRAVERSE, with a transparent rationale for removing a specific monitoring step, we would treat that as evidence worth incorporating. We read guidelines as a synthesis of evidence we may have weighted differently, and we update when that synthesis is compelling.

Until that evidence arrives, we do not read a two-year non-inferiority trial as answering the long-term cardiovascular question. TRAVERSE moved the field forward substantially. It did not close the question.

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Frequently asked questions

›Does TRAVERSE mean any symptomatic hypogonadal man can start TRT without a cardiovascular workup?

No. TRAVERSE demonstrated non-inferiority for MACE over roughly two years in a high-cardiovascular-risk population specifically, and it found statistically significant higher rates of atrial fibrillation and pulmonary embolism in the testosterone arm. A baseline ECG, hematocrit, and lipid panel remain standard before initiation.

›What does the FDA currently say about testosterone and cardiovascular risk?

The FDA's 2015 safety communication cautioned against using testosterone products for age-related low testosterone, stating that benefit and safety had not been established for that use. TRAVERSE provides substantial new prospective data since then, but the underlying caution has not been formally withdrawn as of this article's publication date. Readers should check the FDA's current labeling for the most up-to-date language.

›What was the atrial fibrillation finding in TRAVERSE?

Atrial fibrillation occurred in 3.5% of testosterone-treated men versus 2.4% of placebo-treated men, a statistically significant difference (p<0.001). AF was a secondary endpoint and was not part of the MACE composite. Its significance for individual patients, particularly those with prior AF or elevated stroke-risk scores, remains a matter of clinical judgment rather than direct trial evidence.

›How does the 2018 Endocrine Society guideline interact with TRAVERSE?

The 2018 guideline predates TRAVERSE and states that long-term cardiovascular safety of testosterone therapy had not been established at the time. TRAVERSE provides the most powerful prospective data yet on the MACE question specifically. The guideline's other screening recommendations, including caution after recent MI or stroke and monitoring for polycythemia, remain clinically sound given TRAVERSE's own secondary endpoint findings.

References

• Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. https://pubmed.ncbi.nlm.nih.gov/37326322/
• Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. https://pubmed.ncbi.nlm.nih.gov/29562364/
• Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109-122. https://pubmed.ncbi.nlm.nih.gov/20592293/