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

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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 every clinician now works 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 carried either 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, collectively referred to 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 is a meaningful result. For over a decade, prescribers operated under genuine uncertainty, partly because a 2010 RCT by Basaria and colleagues in frail elderly men was stopped early due to excess cardiovascular events, and because the FDA issued a 2015 safety communication cautioning about using testosterone products for low testosterone due to aging, citing the possibility of increased risk of heart attack and stroke (FDA Drug Safety Communication). TRAVERSE was designed precisely to address that regulatory ambiguity, and its non-inferiority finding is the strongest prospective evidence we have had.

The 2018 Endocrine Society Clinical Practice Guideline on testosterone therapy acknowledges the cardiovascular uncertainty directly, recommending that clinicians "not prescribe testosterone therapy to men who have had a myocardial infarction or stroke within the previous 6 months" and stating that "the long-term cardiovascular safety of testosterone therapy has not been established" (Bhasin et al., JCEM 2018). The guideline's lead author, Shalender Bhasin, has described the cardiovascular question as one requiring a specifically powered outcomes trial. TRAVERSE was that trial.

Three statistics anchor the findings:

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, consistent with non-inferiority but not with a clear protective effect (Lincoff et al., NEJM 2023).

Second, and less discussed in post-trial commentary, TRAVERSE found a statistically significant higher incidence of pulmonary embolism in the testosterone group (0.9% vs. 0.5%, p=0.03) and atrial fibrillation (3.5% vs. 2.4%, p<0.001) (Lincoff et al., NEJM 2023). These were secondary endpoints, and the trial was not powered to declare superiority or inferiority on them as standalone outcomes. They are signals, not verdicts. But they are not nothing.

Third, the FDA's 2015 labeling action covered all approved testosterone products and was triggered in part by pharmacoepidemiological studies suggesting elevated MI risk in the year following TRT initiation. The FDA's position as of that communication was explicit: "the benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man's symptoms seem related to low testosterone." That language has not been fully rescinded, and the current boxed warning still addresses abuse potential and secondary exposure risks (FDA).

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-CV-risk population. It was not a study of average-risk middle-aged men seeking TRT for fatigue and low libido. The trial enrolled men who already had, or were at high risk for, cardiovascular events. 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 and plaque destabilization driven by lipid shifts, polycythemia-related viscosity changes, or hemostatic pathway alterations may operate on timescales longer than two years. The Endocrine Society guideline was written before TRAVERSE and acknowledges that "long-term cardiovascular safety has not been established." TRAVERSE does not change that language in our reading, because "long term" typically implies at least five years of follow-up in cardiovascular outcomes trials, the standard set by trials like ACCORD, ADVANCE, and ORIGIN in the metabolic disease space.

Crossover contamination is the other underreported design issue. In TRAVERSE, 16.9% of placebo-arm participants discontinued and an unstated proportion sought testosterone therapy outside the trial. Intention-to-treat analysis preserves randomization but dilutes the observed treatment effect in direct proportion to crossover. If TRT carries any modest adverse effect on a secondary endpoint like atrial fibrillation (and the data suggest it might), crossover in the control arm would attenuate the apparent hazard ratio toward 1.0, exactly mimicking non-inferiority. This is not our assertion that TRAVERSE's conclusion is wrong. It is a mechanistic reason why the non-inferiority margin should not be read as a clean bill of health.

The atrial fibrillation signal deserves separate attention. A hazard ratio for AF of approximately 1.47 in the testosterone arm, with a p value of less than 0.001, is not background noise. AF is not a component of the MACE composite used in this trial, so it did not affect the primary endpoint. Yet AF contributes materially to stroke risk, embolic events, and hospitalizations. The atrial fibrillation finding in TRAVERSE is consistent with prior mechanistic data showing testosterone's effects on cardiac ion channel expression and atrial remodeling. Waving it off because MACE was non-inferior misreads the trial's actual risk profile.

The FDA's boxed warning history reflects a regulatory agency reacting to real-world pharmacovigilance signals that preceded TRAVERSE. We do not think TRAVERSE retroactively nullifies those signals. It adds important prospective evidence. The two bodies of evidence coexist, and the reconciliation between them is a clinical judgment call, not a simple hierarchy.

Our position

The HealthRX 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 CV disease should revisit that blanket restriction. The trial's primary finding justifies a more individualized conversation about risk and benefit, particularly when the 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, however, interpret TRAVERSE as removing the requirement 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), fasting lipids, and a conversation specifically 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 rendering them unnecessary.

We are also explicit that we are extending clinical judgment beyond the strict RCT support on the following point. The 21.9-month median follow-up is insufficient 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 that it covers roughly two years, and that the monitoring schedule we use is a response to that residual uncertainty, not to excessive caution.

For men with prior AF, we consider the AF signal from TRAVERSE a material factor in shared decision-making, not merely a secondary finding to footnote. This position is not supported by a head-to-head trial in AF patients. It is our clinical judgment, and we name it as such.

The clinical implication that most changes our practice after TRAVERSE is not about who we screen out. It is about counseling. Before TRAVERSE, the honest answer to "is TRT safe for my heart?" was "we don't have a well-powered RCT." Now the honest answer is "the best trial we have, 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 we don't yet know what five or ten years looks like." That is a better-informed conversation. It is not a simpler one.

What would change our mind

We would revise our screening position if any of the following evidence emerged.

A minimum five-year follow-up extension of the TRAVERSE cohort, or a comparable independently powered trial, showing no increase in AF incidence, atrial fibrillation-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 in TRAVERSE was confounded by baseline AF risk imbalance between arms, rather than a pharmacological effect of testosterone, would also update our position. The randomization appeared balanced on baseline characteristics, but AF risk prediction tools were not specifically used for stratification, and residual confounding is possible.

Finally, if the Endocrine Society or a comparable guideline-issuing body formally revised its cardiovascular screening recommendations post-TRAVERSE and provided a transparent rationale for removing any specific monitoring element, we would treat that as signal worth incorporating. We do not dismiss guidelines as bureaucratic scaffolding. We read them as a synthesis of evidence we may have weighted differently, and we update when the 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 substantially forward. It did not close the question.

Frequently asked questions

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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/
  • U.S. Food and Drug Administration. FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging. FDA Drug Safety Communication. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-about-using-testosterone-products-low-testosterone-due
  • 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/