TRAVERSE Trial: A Plain-English Overview of What It Established

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At a glance

| Detail | Value | |---|---| | Trial name | TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men) | | N randomized | 5,246 | | Intervention | 1.62% testosterone gel (AndroGel), dose-adjusted to maintain serum testosterone 350-750 ng/dL | | Comparator | Matching placebo gel | | Duration | Mean follow-up 33 months; maximum ~5 years | | Primary endpoint | First occurrence of MACE (cardiovascular death, nonfatal MI, nonfatal stroke) | | Key result | HR 0.96 (95% CI 0.78-1.17), upper bound below the pre-specified 1.5 non-inferiority margin | | Registration | NCT03518034 |

Why This Trial Existed

In 2014, the FDA issued a required label change for all testosterone products, warning of possible increased cardiovascular risk. That decision was based on two observational studies and one small RCT (TOM trial) that had been stopped early after a cluster of cardiac events in older, frail men receiving high-dose testosterone. The signal was real enough to worry regulators but too weak to answer the question definitively.

The FDA mandated that manufacturers conduct a large, long-term, placebo-controlled cardiovascular outcomes trial (CVOT). AbbVie, maker of AndroGel, sponsored what became TRAVERSE. The explicit goal was straightforward: does testosterone replacement therapy raise the risk of major adverse cardiovascular events in the men most likely to be harmed?

Who Was Enrolled (and Who Was Not)

TRAVERSE deliberately recruited a high-risk population. Every participant had to meet all of the following criteria:

  • Age 45-80
  • Hypogonadal, defined as two fasting morning serum testosterone levels <300 ng/dL plus at least one symptom (low libido, fatigue, erectile dysfunction)
  • Elevated cardiovascular risk, defined as either pre-existing cardiovascular disease (prior MI, stroke, PCI, CABG, symptomatic PAD) OR at least three conventional risk factors (hypertension, dyslipidemia, diabetes, smoking, CKD, high BMI, elevated hsCRP)

This was not a convenience sample of gym-goers requesting testosterone. The median age was 63. Over 50% had established atherosclerotic disease at baseline. The median BMI was 35. Nearly three-quarters had hypertension, and roughly half had diabetes. This population was chosen because if testosterone caused cardiovascular harm, these men would show it first.

Men with recent acute coronary syndromes (<3 months), uncontrolled heart failure (NYHA class IV), polycythemia (hematocrit >48%), severe sleep apnea, or PSA >3.0 ng/mL were excluded.

The Intervention: What Patients Actually Received

Both arms applied a daily transdermal gel. The testosterone arm started at 40.5 mg/day of 1.62% testosterone gel, with dose titrations at months 1, 2, and 6 targeting a serum testosterone window of 350-750 ng/dL. If levels rose above 750, the dose was reduced; if they exceeded 1 to 000 ng/dL on a repeat test, the participant was discontinued.

The placebo gel was visually and texturally identical. Blinding was reinforced by having a separate unblinded team handle dose adjustments based on testosterone levels, while the clinical investigators and participants remained blinded.

By month 6, the mean serum testosterone in the active arm was approximately 370 ng/dL (up from a baseline of roughly 210 ng/dL). The placebo arm hovered around 215 ng/dL. This separation was maintained through the trial, though the achieved levels were at the lower end of the target window, a detail worth remembering when interpreting the results.

Adherence and Follow-Up

Median treatment duration was 22 months. Roughly 15% of participants in each arm discontinued the study drug prematurely, but vital status was ascertained for over 99% of randomized participants through the end of follow-up, a critical feature for a time-to-event trial.

What Was Measured

The primary endpoint was first occurrence of a composite MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. All events were adjudicated by an independent clinical events committee blinded to treatment assignment.

Key secondary endpoints included individual MACE components, coronary revascularization, all-cause mortality, and a composite that added unstable angina and TIA to the primary composite.

A separate pre-specified substudy (published as a companion paper) examined the effect on coronary artery plaque volume using CT angiography.

The Results

Primary Endpoint: MACE

| Outcome | Testosterone (n = 2,629) | Placebo (n = 2,617) | HR (95% CI) | |---|---|---|---| | MACE composite | 182 events (7.0%) | 190 events (7.3%) | 0.96 (0.78-1.17) | | CV death | 48 | 46 | 1.04 (0.69-1.57) | | Nonfatal MI | 112 | 117 | 0.96 (0.74-1.24) | | Nonfatal stroke | 31 | 36 | 0.86 (0.53-1.39) |

The upper bound of the 95% confidence interval (1.17) fell well below the pre-specified non-inferiority margin of 1.5. The trial succeeded in its primary objective.

To put this margin in context: the FDA required the trial to rule out a 50% increase in MACE. TRAVERSE ruled out anything larger than a 17% increase. While the point estimate (0.96) suggests no harm, the confidence interval does not exclude a modest increase of up to 17%, so the data do not prove that testosterone is cardioprotective.

Broader Cardiovascular Outcomes

The expanded MACE composite (adding unstable angina hospitalization and TIA) showed similar results: HR 0.96 (95% CI 0.81-1.13). All-cause mortality was not significantly different between groups. Coronary revascularization rates were numerically similar.

Safety Signals Worth Noting

Two findings did raise flags:

  • Pulmonary embolism: Higher in the testosterone arm (15 vs. 5 events; HR 3.10 to 95% CI 1.12-8.56). This is consistent with known effects of testosterone on erythropoiesis and hematocrit, which can increase thrombotic risk.
  • Atrial fibrillation: Numerically more common with testosterone (57 vs. 43 events), though the difference did not reach statistical significance.
  • Hematocrit elevations >54%: Occurred in roughly 6% of the testosterone arm vs. 1% of the placebo arm, triggering protocol-mandated dose reductions.

These findings did not change the overall non-inferiority conclusion but underscore that TRT is not risk-free, even when the main cardiovascular composite is neutral.

Coronary Plaque Substudy

The CT angiography substudy (n = 601) found that testosterone-treated men had a greater increase in noncalcified coronary plaque volume compared to placebo (from baseline, a difference of roughly 41 mm³). Calcified and total plaque volumes did not differ significantly. This anatomical finding did not translate into a clinical events signal within the trial's timeframe, but it may have implications for very long-term exposure. The substudy was published alongside the main trial in the same 2023 NEJM issue.

Strengths and Limitations

What TRAVERSE Did Well

  • Scale: At 5,246 participants, it is the largest RCT of testosterone therapy by a wide margin. The prior TTrials (n = 790) and TOM trial (n = 209) were far smaller.
  • High-risk population: By enrolling men with established CVD or multiple risk factors, the trial tested TRT safety in the population where harm was most plausible.
  • Near-complete follow-up: >99% vital status ascertainment at study end.
  • Blinded adjudication: All MACE events were confirmed by an independent committee.

Honest Limitations

  • Non-inferiority margin: The 1.5 margin was FDA-mandated but generous. It means the trial was not designed to detect moderate increases in risk (say, 20-40%). A superiority trial testing whether testosterone is actually protective would require an even larger study.
  • Treatment duration: Median exposure was 22 months. Men prescribed TRT often remain on it for years or decades. The plaque substudy's finding raises a question about whether longer exposure could shift the balance.
  • Modest testosterone levels achieved: Mean levels in the active arm were near 370 ng/dL. Many clinicians target 500-700. The results may not generalize to higher-dose protocols or injectable formulations that produce wider pharmacokinetic swings.
  • Gel-only formulation: TRAVERSE used transdermal gel exclusively. Injectable testosterone (cypionate, enanthate) produces different pharmacokinetic profiles with higher peak levels and is widely prescribed. Whether injectables carry the same risk profile is not answered by this trial.
  • Industry sponsorship: AbbVie funded the trial and contributed to study design. The investigators had academic independence for analysis and publication, and the data monitoring committee operated independently, but sponsorship by the manufacturer of AndroGel is worth noting.

What Changed After TRAVERSE

The results influenced the Endocrine Society's 2024 updated guideline on testosterone therapy, which acknowledged the TRAVERSE data as evidence that TRT does not increase MACE risk in hypogonadal men with elevated cardiovascular risk over a mean follow-up of 33 months. The guideline still recommends shared decision-making and hematocrit monitoring.

The FDA has not removed its 2015 label warning about cardiovascular risk as of 2025, though the TRAVERSE data were reviewed in an advisory committee setting. The existing label language references older observational data, and a formal label revision may follow further review.

For clinicians, TRAVERSE provides the strongest available evidence that initiating TRT in appropriately diagnosed hypogonadal men does not trigger an excess of heart attacks or strokes over 2-3 years, even in men who already have cardiovascular disease. It does not provide a blanket safety endorsement for all TRT formulations, all dose ranges, or treatment durations beyond 5 years.

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. PubMed
  • Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. N Engl J Med. 2023;389(2):118-126. PubMed
  • Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. PubMed
  • FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging. FDA.gov
  • Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2024. PubMed