The bottom line in one paragraph
The TRAVERSE trial (Lincoff et al., New England Journal of Medicine, June 2023) is the largest randomized cardiovascular safety trial of testosterone replacement therapy ever run — 5,246 men with hypogonadism and elevated cardiovascular risk, followed for a mean of about 33 months on transdermal testosterone or placebo. The primary finding: testosterone did not increase major adverse cardiovascular events (MACE) compared with placebo. Secondary analyses identified numerical increases in pulmonary embolism, atrial fibrillation, and acute kidney injury. For men researching whether TRT causes heart attacks, the most accurate plain-English answer the data now supports is: in middle-aged and older hypogonadal men with pre-existing cardiovascular risk, carefully monitored transdermal testosterone did not raise the rate of heart attacks, stroke, or cardiovascular death — but it did move a few narrower safety signals in the wrong direction, and it does not settle every question.
This article walks through the trial design, the headline MACE result, the secondary findings, how TRAVERSE compares with the older observational literature and the 2015 FDA label change, and what TRAVERSE does not tell us. It is educational context — not medical advice. For the broader testosterone therapy pillar guide and the companion post on hematocrit on TRT, those are the natural next reads.
Educational disclaimer:This article summarizes a published clinical trial for educational purposes. It is not medical advice, not a substitute for evaluation by a licensed physician, and not a recommendation for or against TRT. Every individual's cardiovascular risk profile is different. Decisions about starting, continuing, or stopping testosterone therapy should be made with your prescriber based on your full history, current labs, and clinical symptoms.
What the TRAVERSE trial was
TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) was a multicenter, randomized, double-blind, placebo-controlled, non-inferiority trial. It was mandated by the U.S. Food and Drug Administration as a post-marketing requirement after the agency's 2015 label change raised concerns about cardiovascular risk in men using testosterone products.
The principal investigator was Steven Nissen, MD, of the Cleveland Clinic, with A. Michael Lincoff as first author on the primary NEJM publication. The trial was sponsored by a consortium of testosterone manufacturers and conducted at 316 sites across the United States. Enrollment ran from 2018 through 2022, and the primary results were published on June 16, 2023.
Why this specific trial, and why now
Before TRAVERSE, the cardiovascular safety of TRT sat in an uncomfortable middle. Observational studies and meta-analyses had produced conflicting signals. Two high-profile studies — Vigen et al. in JAMA (2013) and Finkle et al. in PLOS ONE (2014) — reported associations between testosterone prescriptions and cardiovascular events. Other analyses, including the TOM trial of frail elderly men and the Testosterone Trials coordinated analysis, did not reproduce a clear hazard. The evidence base was too mixed to draw a firm conclusion, but alarming enough that the FDA required a randomized cardiovascular safety trial powered to detect or rule out real differences. TRAVERSE was that trial.
Why cardiovascular safety was the open question
Testosterone is unusual among chronic prescription drugs because it is prescribed lifelong in most cases and taken by otherwise-healthy men seeking symptom improvement. That framing — an elective, chronic therapy for quality-of-life symptoms — raises the bar on cardiovascular safety. Even a small absolute increase in heart attack risk becomes unacceptable if the therapy is essentially optional.
The pre-TRAVERSE arguments on both sides had biological plausibility. Arguments for increased risk included testosterone-driven rises in hematocrit (covered in depth in our hematocrit on TRT article), potential prothrombotic effects, and the possibility that aromatization to estradiol could affect coronary vasomotor function. Arguments against increased risk pointed to the well-documented association between low endogenous testosterone and adverse cardiovascular outcomes — hypogonadal men tend to have higher rates of metabolic syndrome, visceral adiposity, and cardiovascular disease — and to the counterintuitive possibility that correcting low testosterone could improve, not worsen, cardiovascular risk markers.
TRAVERSE was designed to cut through that debate with prospective, randomized, placebo-controlled data in exactly the men most likely to be concerned about heart risk.
How the trial was designed
The eligibility criteria and study protocol matter because they define the population to whom TRAVERSE results apply. Extrapolation beyond those criteria is where the debate continues.
Enrollment criteria (simplified)
- Sex and age: Men aged 45 to 80 years
- Hypogonadism: Symptomatic low testosterone with two morning total testosterone measurements below 300 ng/dL
- Cardiovascular risk: Pre-existing cardiovascular disease or high risk of cardiovascular disease (prior MI, prior stroke, peripheral artery disease, coronary revascularization, or multiple risk factors including diabetes plus hypertension plus smoking plus low HDL)
- Exclusion: Men with PSA concerns, recent cardiovascular events within 3 months, severe heart failure, and other standard TRT contraindications were excluded
Intervention and follow-up
- Testosterone arm: 1.62% transdermal testosterone gel, once daily, titrated to achieve total testosterone in the mid-normal range (350–750 ng/dL target)
- Placebo arm: Identically-appearing placebo gel, once daily
- Blinding: Double-blind — participants, investigators, and outcome adjudicators were blinded to treatment assignment
- Follow-up duration: Mean of approximately 33 months; maximum follow-up through approximately 5 years
- Endpoint adjudication: An independent clinical events committee adjudicated all primary and secondary cardiovascular endpoints, blinded to treatment assignment
Trial schematic based on Lincoff et al., NEJM 2023. Numbers per published primary analysis.
The primary endpoint: MACE non-inferiority
The primary endpoint in TRAVERSE was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke — what cardiologists call MACE. The trial was powered as a non-inferiority study: the question was not "does TRT improve cardiovascular outcomes?" but "does TRT cause unacceptably morecardiovascular events than placebo?"
Headline number
In the primary analysis, MACE occurred in 182 of 2,601 men in the testosterone group (7.0%) and 190 of 2,603 men in the placebo group (7.3%). The hazard ratio was 0.96 with a 95% confidence interval of 0.78 to 1.17. The upper bound of the confidence interval was well below the pre-specified non-inferiority margin of 1.5, so testosterone met the non-inferiority criterion.
Plain-English translation
Over roughly three years, men on transdermal testosterone were no more likely than men on placebo to have a heart attack, stroke, or cardiovascular death. The confidence interval rules out a clinically important increase in MACE at the level this trial was powered to detect.
Comparing pre-TRAVERSE hazard signals to the TRAVERSE result
The table below summarizes how the earlier signals compare to what the randomized trial found. The observational studies had methodological limits that randomization in TRAVERSE was designed to eliminate.
| Study or source | Type | Headline signal on MACE |
|---|---|---|
| Vigen et al., JAMA 2013 | Observational (VA cohort) | Associated TRT with increased MI, stroke, death (contested methodology) |
| Finkle et al., PLOS ONE 2014 | Observational (claims data) | Associated TRT with non-fatal MI in first 90 days |
| FDA 2015 label change | Regulatory action | Added warning citing "possible" CV risk |
| Testosterone Trials (Snyder et al., 2016) | RCT (n=790, short duration) | No significant MACE difference; too small to settle the question |
| TRAVERSE (Lincoff et al., NEJM 2023) | RCT, n=5,246, ~33 month follow-up | MACE non-inferior to placebo (HR 0.96, 95% CI 0.78–1.17) |
What "non-inferiority" really means: A non-inferiority result does not mean two treatments are identical. It means the trial ruled out a pre-specified difference that would have been clinically important. TRAVERSE ruled out an increase in MACE on the order of 50% with high statistical confidence. Smaller differences — a 5% or 10% relative increase — are not definitively ruled out by a trial this size. Most cardiologists interpret TRAVERSE as strong reassurance rather than proof of perfect equivalence.
Secondary findings: PE, AFib, and AKI
The primary MACE result drew the headlines, but TRAVERSE pre-specified several secondary endpoints, and a few of them moved in directions that matter clinically. These are not fatal to the overall safety signal, but honest interpretation of the paper requires covering them.
Pulmonary embolism
Pulmonary embolism occurred in 24 men (0.9%) in the testosterone group and 12 men (0.5%) in the placebo group. The absolute difference is small, but the relative difference is a doubling. Biological plausibility is real: testosterone raises hematocrit and thus blood viscosity, which is an established risk factor for venous thromboembolism. TRT prescribing information in the U.S. now carries explicit warnings about VTE risk, and this finding reinforces that labeling. Men with a prior DVT or PE, known thrombophilia, or family history of unprovoked clotting should have a documented risk-benefit discussion with their prescriber.
Atrial fibrillation
New-onset atrial fibrillation occurred in 91 men (3.5%) in the testosterone group and 63 men (2.4%) in the placebo group. The absolute difference is roughly one additional AFib case per 100 men over three years. The mechanism is not fully established; hypotheses include androgen effects on atrial electrical remodeling, sleep apnea worsening on TRT, or indirect effects via blood pressure and body mass.
Acute kidney injury and nephrolithiasis
Acute kidney injury was numerically higher in the testosterone group (2.3% vs 1.5%). Nephrolithiasis (kidney stones) was also higher (1.4% vs 0.7%). These are clinically meaningful signals that deserve flagging to patients with baseline renal dysfunction or a history of stones.
Prostate-related findings
TRAVERSE found no significant difference in incident prostate cancer between groups — an important secondary finding because prostate cancer risk is the historical worry that most men ask about when considering TRT. For a deeper look at prostate monitoring on TRT, the side effects pillar guide covers PSA surveillance protocols.
Percentages are approximate, drawn from the TRAVERSE primary and secondary outcomes reporting. MACE was the pre-specified primary endpoint; other outcomes were secondary or adverse events of special interest.
How TRAVERSE compares to older observational data
The most honest way to contextualize TRAVERSE is to compare its methodology with the studies that worried regulators in the first place.
Vigen et al., 2013 (VA cohort)
This retrospective analysis of Veterans Affairs data reported that men who filled testosterone prescriptions had higher rates of MI, stroke, and death than men with similar hypogonadism who did not fill prescriptions. The analysis drew substantial methodological criticism — the authors later corrected the data, the comparison groups differed on baseline cardiovascular risk, and the event rate characterization was disputed. It was hypothesis-generating, not hypothesis-confirming.
Finkle et al., 2014 (claims database)
This pharmacy claims analysis reported an approximately 2-fold increase in non-fatal MI in the 90 days after starting a testosterone prescription in men over 65 with pre-existing heart disease. Like any observational claims analysis, it could not adjust for unmeasured confounders, and the short 90-day window raised questions about ascertainment bias.
What observational data fundamentally cannot tell us
Men who are prescribed testosterone differ systematically from men who are not. They may have more symptoms, more comorbidities, more contact with the healthcare system (so more event detection), or different baseline cardiovascular risk. Randomization breaks those confounds. TRAVERSE is valuable precisely because it eliminates most of the selection bias that contaminated the observational literature.
The 2015 FDA label change and what it got right or wrong
In March 2015, the FDA announced that it would require testosterone manufacturers to change product labeling to reflect a possible increased risk of heart attacks and strokes, and to restrict approved indications to men with hypogonadism due to specific medical conditions — not age-related low testosterone alone. The agency explicitly cited the Vigen and Finkle analyses among the evidence base.
What the 2015 action got right
The FDA was correct to demand a randomized trial. The observational evidence was not good enough to conclude safety or harm, and the public health stakes — with testosterone prescriptions having risen sharply over the prior decade — were high. Requiring a post-marketing cardiovascular safety trial was the right regulatory move.
What the 2015 language overstated
In hindsight — now that TRAVERSE has reported — the 2015 warning language probably overstated the certainty of cardiovascular risk. The label change contributed to a sharp decline in testosterone prescribing and probably deterred some men with genuine hypogonadism from receiving appropriate treatment. A more measured interim warning, with a clearer commitment to updating once randomized data arrived, would have fit the evidence better.
Post-TRAVERSE label updates
Following the 2023 TRAVERSE publication, the FDA has updated testosterone product labeling. The revisions temper the 2015 cardiovascular language while retaining specific warnings about venous thromboembolism — consistent with the TRAVERSE pulmonary embolism signal. This is a measured, evidence-based evolution of the label.
What TRAVERSE does not tell us
This is the section most TRT commentary gets wrong. TRAVERSE is powerful for the question it was designed to answer. It is silent or uncertain on several questions that matter to real-world patients.
No injection data
TRAVERSE used transdermal gel exclusively. It did not test intramuscular testosterone cypionate or enanthate, subcutaneous injection protocols, or pellet therapy. Injections produce higher peak serum testosterone and larger hematocrit increases than gel at equivalent weekly doses, per published comparative pharmacokinetic data. Whether the cardiovascular safety signal transfers cleanly to high-peak injection protocols at supraphysiological trough testosterone is a fair open question. For a comparison of delivery methods broadly, see our TRT pillar guide and the hematocrit on TRT article.
No young men
The enrollment floor was age 45. TRAVERSE says nothing about cardiovascular outcomes in men in their 20s, 30s, or early 40s on TRT — a growing population clinically.
No low-risk men
The trial required pre-existing cardiovascular disease or high CV risk. It is silent on men with clean cardiovascular profiles, which means we cannot directly estimate whether TRT affects the baseline risk trajectory of a 50-year-old with normal blood pressure, normal lipids, and no family history of heart disease.
No supraphysiological dosing
TRAVERSE titrated testosterone into the mid-normal range. It explicitly did not test supraphysiological doses such as 200–300 mg/week protocols used by some clinics and users. Our 200mg testosterone per week article discusses where physiological replacement ends and supraphysiological territory begins.
Duration is finite
Mean follow-up of 33 months is substantial by RCT standards but short compared to the lifelong nature of TRT. Late effects — after 5, 10, or 20 years of continuous use — are not characterized by TRAVERSE.
Interpretation note:These limits do not undermine the TRAVERSE MACE result. They mean TRAVERSE should be cited as "reassuring in the studied population and route" — not as "TRT is safe for everyone." Responsible clinicians and writers use the trial to support the specific conclusion it licenses and acknowledge what remains open.
What guideline bodies say post-TRAVERSE
Major professional societies have incorporated TRAVERSE into their guidance without treating it as a blanket safety endorsement.
American Urological Association (AUA)
The AUA's 2024 amendment to its testosterone deficiency guideline acknowledges TRAVERSE as supportive evidence for cardiovascular safety in selected hypogonadal men with pre-existing cardiovascular risk. The AUA continues to recommend baseline cardiovascular risk assessment before initiating TRT and ongoing monitoring, especially for hematocrit and blood pressure. AUA guidance emphasizes individualized risk-benefit discussion rather than a protocol-level safety ruling.
Endocrine Society
The Endocrine Society's 2018 clinical practice guideline was written pre-TRAVERSE. Subsequent practice updates have incorporated the trial's findings as reassurance on MACE while retaining the 54% hematocrit threshold and continuing to urge caution in men with recent cardiovascular events or decompensated heart failure. The Society has not reversed its pre-existing caution; it has refined it.
International guidance
European Association of Urology (EAU) and several national endocrinology bodies have issued commentaries broadly consistent with the AUA and Endocrine Society interpretations — TRAVERSE supports continued, carefully monitored prescribing in appropriate candidates and does not license expansion to indications the trial did not test.
Plain-English takeaway for men researching TRT safety
If you are a man researching whether TRT causes heart attacks because you are considering therapy, here is an honest synthesis of what TRAVERSE supports.
- For the big-ticket cardiovascular outcomes — heart attack, stroke, cardiovascular death — TRAVERSE is reassuring. In middle-aged and older hypogonadal men with pre-existing CV risk, transdermal testosterone did not raise MACE compared with placebo over roughly three years.
- Venous thromboembolism (PE) is the clinically flagged safety signal. The absolute increase is small but real. Personal or family history of blood clots should prompt explicit discussion with your prescriber.
- Atrial fibrillation and acute kidney injury are secondary signals worth knowing about. They do not override the overall safety profile in most men, but they inform individual risk-benefit conversations.
- Prostate cancer incidence did not differ between arms, which is meaningful reassurance on the historical worry most men raise about TRT.
- The trial used transdermal gel at mid-normal testosterone targets. High-peak injection protocols at supraphysiological troughs are not directly characterized by TRAVERSE. That is a reason to be especially careful with monitoring on higher-dose injection regimens.
- Hematocrit monitoring did not become optional post-TRAVERSE. Guidelines retain the 54% threshold. See our hematocrit on TRT deep-dive for why.
Where this fits in the broader TRT conversation
TRAVERSE does not settle every question about TRT. It settles one important question — MACE — in a specific population using a specific delivery method. For the fuller picture of what to expect on therapy, see our TRT before and after timeline. For readers weighing non-testosterone alternatives, compare enclomiphene vs TRT and clomid vs TRT. For a terminology explainer, our HRT vs TRT post covers why the labels are often confused.
A brief scenario
Consider a 58-year-old man with controlled hypertension, a prior stent placed six years ago, symptomatic hypogonadism, and two morning total testosterone readings of 240 ng/dL. Pre-TRAVERSE, many cardiologists would have counseled against TRT on principle. Post-TRAVERSE, the conversation becomes richer. His cardiovascular event risk on testosterone is not meaningfully different from placebo, per randomized data in a population that looks similar to him. His clinical team considers hematocrit monitoring, blood pressure follow-up, and VTE history before proceeding — and often concludes that carefully monitored TRT is reasonable. This is the change TRAVERSE is driving: not a blanket green light, but a better-informed individualized discussion.
Next steps if you want to go deeper: The primary NEJM paper (Lincoff et al., 2023) is the authoritative source and is freely accessible. For what happens on the lab side, our hematocrit on TRT article walks through the single most common lab abnormality on TRT and how it interacts with the TRAVERSE PE signal. For broader safety context, the side effects pillar guide covers cardiovascular monitoring, sleep apnea risk, hematocrit, and estrogen management as an integrated framework.
Sources referenced in this article
- Lincoff AM, Bhasin S, Flevaris P, et al. "Cardiovascular Safety of Testosterone-Replacement Therapy" (TRAVERSE trial). New England Journal of Medicine. 2023;389(2):107-117.
- Bhasin S, Brito JP, Cunningham GR, et al. "Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline." Journal of Clinical Endocrinology & Metabolism. 2018;103(5):1715-1744.
- Mulhall JP, Trost LW, Brannigan RE, et al. "Evaluation and Management of Testosterone Deficiency: AUA Guideline." Originally 2018, amended 2024.
- U.S. Food and Drug Administration. Drug Safety Communication: Testosterone products labeling change regarding cardiovascular risk (March 2015) and subsequent post-TRAVERSE updates.
- Vigen R, O'Donnell CI, Barón AE, et al. "Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels." JAMA. 2013;310(17):1829-1836.
- Finkle WD, Greenland S, Ridgeway GK, et al. "Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men." PLOS ONE. 2014;9(1):e85805.
- Snyder PJ, Bhasin S, Cunningham GR, et al. "Effects of Testosterone Treatment in Older Men." New England Journal of Medicine. 2016;374(7):611-624 (Testosterone Trials).
This article was written by the TRT FAQ Editorial Team and reviewed against the published NEJM primary paper and current AUA and Endocrine Society guidance. It is educational content, not medical advice. Last content review: April 2026.
Frequently Asked Questions
What did the TRAVERSE trial actually find about TRT and heart attacks?
The TRAVERSE trial (Lincoff et al., New England Journal of Medicine, June 2023) enrolled 5,246 men with hypogonadism and pre-existing cardiovascular disease or high CV risk, randomized them to transdermal testosterone gel or placebo, and followed them for a mean of about 33 months. The primary composite cardiovascular endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 7.0% of the testosterone group versus 7.3% of the placebo group. The hazard ratio was 0.96, and testosterone met the pre-specified non-inferiority criterion. In plain English, the trial did not find that TRT increased major cardiovascular events compared with placebo in this population.
Does TRAVERSE prove TRT is safe for the heart?
TRAVERSE supports non-inferiority for major adverse cardiovascular events (MACE) in the population studied — middle-aged and older men with hypogonadism and pre-existing cardiovascular risk who received transdermal testosterone. It is the strongest randomized cardiovascular safety data to date for TRT. However, the trial identified numerical increases in pulmonary embolism, atrial fibrillation, and acute kidney injury in the testosterone group. It did not test intramuscular injection protocols, men under 45, or men without baseline cardiovascular risk. 'Non-inferior for MACE in the studied population' is the accurate summary — not 'proven safe for every man on every protocol.'
What is MACE and why does it matter in the TRAVERSE trial?
MACE stands for Major Adverse Cardiovascular Events. In TRAVERSE, the primary MACE endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (heart attack), and nonfatal stroke. Regulators and journals treat MACE as the gold-standard hard endpoint for cardiovascular drug safety because these outcomes are clear, adjudicated, and clinically meaningful. The TRAVERSE MACE result — no significant difference between testosterone and placebo — is the single headline finding that shifted the post-2015 narrative around TRT and heart risk.
Why did TRAVERSE find more pulmonary embolism and atrial fibrillation on TRT?
In TRAVERSE, pulmonary embolism occurred in 0.9% of men on testosterone versus 0.5% on placebo, and atrial fibrillation occurred in 3.5% versus 2.4%. These numerical differences did not make the primary MACE endpoint worse, but they are clinically relevant. The biological plausibility: testosterone can raise hematocrit and blood viscosity, which is a recognized risk factor for venous thromboembolism, and androgens may alter atrial electrophysiology. The trial investigators flagged these signals explicitly. Men with a history of DVT, PE, or AFib should have an explicit conversation with their prescriber about risk-benefit before starting TRT.
Does TRAVERSE apply to testosterone injections, or only to gel?
TRAVERSE used 1.62% transdermal testosterone gel, titrated to achieve mid-normal total testosterone levels. It did not test intramuscular or subcutaneous testosterone injections. Because injections produce higher peak serum testosterone and larger increases in hematocrit than gel at equivalent weekly doses, the TRAVERSE cardiovascular safety signal cannot be directly extrapolated to every injection protocol — particularly high-dose, once-weekly or every-two-week intramuscular regimens. Most guideline bodies treat TRAVERSE as reassuring but route-specific, and retain monitoring recommendations regardless of delivery method.
How does TRAVERSE change what the FDA said in 2015 about TRT and heart risk?
In 2015, the FDA added a warning to testosterone product labels about a possible increased risk of heart attack and stroke, based largely on observational studies and meta-analyses that had produced mixed signals. TRAVERSE is the randomized, placebo-controlled trial the FDA effectively asked for when it required a post-marketing cardiovascular safety study. As of early 2024, the FDA updated testosterone product labeling to reflect the TRAVERSE findings, tempering the 2015 language while retaining warnings about venous thromboembolism. TRAVERSE is the evidence base that moved the needle.
What do the Endocrine Society and AUA say about TRT and heart risk after TRAVERSE?
The Endocrine Society and the American Urological Association (AUA) have both acknowledged the TRAVERSE findings in their guidance. The AUA's 2024 guideline amendment on testosterone deficiency incorporates TRAVERSE as supportive evidence for cardiovascular safety in appropriately selected hypogonadal men with pre-existing CV risk, while retaining baseline and follow-up cardiovascular risk assessment recommendations. The Endocrine Society's clinical practice guidance similarly treats TRAVERSE as reassuring for MACE but continues to recommend hematocrit monitoring and caution in men with recent cardiovascular events or uncontrolled heart failure. Neither body treats TRAVERSE as a green light to prescribe without evaluation.