For over a decade, one question has dominated the TRT conversation: will testosterone therapy give you a heart attack? The fear was real. Two widely publicized studies in 2013 and 2014 suggested TRT might increase cardiovascular risk, and the FDA responded by slapping a boxed warning on every testosterone product in America.
Then came the TRAVERSE trial -- the largest, most rigorous cardiovascular safety study of testosterone ever conducted. It enrolled 5,246 men, ran for years, and delivered an answer that changed the landscape of TRT prescribing.
Key Takeaways
- The TRAVERSE trial (n=5,246) found TRT did not increase heart attack, stroke, or cardiovascular death risk
- The study specifically enrolled high-risk men -- those with existing heart disease or multiple risk factors
- In February 2025, the FDA removed the cardiovascular boxed warning from all testosterone products
- TRT does modestly raise blood pressure, which now requires monitoring
- Hematocrit and lipid monitoring remain important safety checkpoints during treatment
The History: How TRT Got Its Heart Warning
The cardiovascular scare around testosterone therapy didn't come from a single study. It built over several years, fueled by flawed research and media amplification.
The TOM Trial (2010)
The first alarm came from the Testosterone in Older Men with Mobility Limitations (TOM) trial. This small study of 209 men aged 65 and older was stopped early when the testosterone group showed more cardiovascular events (23 vs. 5 in placebo). The finding made headlines, but the trial had critical limitations: it was tiny, enrolled extremely frail elderly men, used high testosterone doses that pushed levels well above physiological range, and wasn't designed to measure cardiovascular outcomes as a primary endpoint.
The Vigen Study (2013)
A retrospective VA database study published in JAMA analyzed 8,709 men who had undergone coronary angiography and reported that testosterone therapy was associated with increased risk of death, heart attack, and stroke. The study was widely cited and heavily covered by media.
The problems emerged quickly. Twenty-nine medical societies worldwide called for retraction after discovering that nearly 10% of the "all-male" dataset included women, that group sizes were miscalculated by over 1,000 patients, and that the absolute event rates actually favored the testosterone group when errors were corrected. JAMA published two corrections but never retracted the paper.
The Finkle Study (2014)
A cohort study in PLoS ONE examined 55,593 men and reported doubled heart attack risk in the 90 days after a first testosterone prescription, particularly in older men and younger men with pre-existing heart disease. This study also had fundamental design flaws: it lacked a true control group, didn't confirm whether patients actually used the testosterone prescribed, and didn't account for the well-established fact that low testosterone itself is a cardiovascular risk factor.
The FDA's 2015 Response
Based on these studies, the FDA added a boxed warning to all testosterone products in 2015, stating they "may increase the risk" of heart attack and stroke. The agency simultaneously required manufacturers to conduct a large, definitive randomized trial. That requirement produced the TRAVERSE trial.
What the TRAVERSE Trial Actually Studied
TRAVERSE stands for Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men. It was purpose-built to answer the cardiovascular question definitively.
Study Design
The trial was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study conducted across 316 sites in the United States. Here are the key parameters:
| Parameter |
Detail |
| Enrollment |
5,246 men |
| Age range |
45-80 years |
| Testosterone criteria |
Two fasting levels below 300 ng/dL |
| Cardiovascular requirement |
Existing CVD or high risk (diabetes, obesity, hypertension, dyslipidemia, smoking) |
| Treatment |
Daily transdermal 1.62% testosterone gel vs. placebo gel |
| Dose adjustment |
Titrated to maintain levels of 350-750 ng/dL |
| Mean follow-up |
33 months (up to 5 years for some participants) |
| Primary endpoint |
First occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke (MACE) |
This wasn't a study of healthy young men. TRAVERSE deliberately enrolled the population most likely to show cardiovascular harm from TRT -- older men with hypogonadism who already had heart disease or were at high risk for it. If testosterone was dangerous for the heart, this trial was designed to find it.
Why This Design Matters
Previous studies that raised alarms were retrospective (looking backward through medical records) and observational (no randomization, no blinding). TRAVERSE was prospective, randomized, and double-blind -- the gold standard of clinical evidence. Neither the patients nor the doctors knew who was getting testosterone and who was getting placebo.
The trial was also powered for noninferiority, meaning it was designed to determine whether testosterone was "not worse" than placebo for cardiovascular outcomes. The predefined noninferiority margin was a hazard ratio of 1.5, and the trial had sufficient enrollment to detect clinically meaningful differences.
Primary Outcomes: The Main Event
The results were published in the New England Journal of Medicine in June 2023.
The headline finding: Testosterone replacement therapy was noninferior to placebo for major adverse cardiovascular events.
Here's what the data showed:
| Outcome |
Testosterone Group |
Placebo Group |
Hazard Ratio (95% CI) |
| Primary MACE composite |
182 events (7.0%) |
190 events (7.3%) |
0.96 (0.78-1.17) |
| Cardiovascular death |
48 |
46 |
-- |
| Nonfatal MI |
100 |
105 |
-- |
| Nonfatal stroke |
34 |
39 |
-- |
The hazard ratio of 0.96 means the testosterone group actually had a slightly lower rate of major cardiovascular events than the placebo group, though the difference was not statistically significant. The upper bound of the confidence interval (1.17) was well below the predefined noninferiority margin of 1.5.
In plain language: among 5,246 men who already had or were at high risk for heart disease, testosterone therapy did not increase heart attacks, strokes, or cardiovascular deaths over a mean follow-up of nearly three years.
Secondary Outcomes: What Else TRAVERSE Found
The trial generated a wealth of data beyond the primary cardiovascular endpoint.
Prostate Safety
One of the biggest concerns with TRT has always been prostate cancer risk. TRAVERSE addressed this directly. Among men with baseline PSA below 3.0 ng/mL, the incidence of high-grade prostate cancer was low and did not differ between groups. Rates of acute urinary retention, BPH surgery, and new medications for lower urinary tract symptoms were also similar.
Blood Pressure
This is the one area where testosterone did show a clear signal. Postmarket ambulatory blood pressure monitoring studies -- conducted separately from TRAVERSE but required by the same FDA mandate -- confirmed a modest increase in blood pressure across all testosterone products. The increase was consistent and class-wide, meaning it wasn't specific to any particular testosterone formulation.
Hematocrit and Blood Clotting
TRAVERSE found a higher incidence of pulmonary embolism in the testosterone group, though the absolute numbers were small. Testosterone is known to increase red blood cell production (erythrocytosis), which can raise blood viscosity and clotting risk. This is why regular hematocrit monitoring remains a standard part of TRT management.
Bone, Diabetes, and Other Outcomes
Testosterone-treated men did not show significantly different rates of major osteoporotic fractures compared to placebo. A substudy found that testosterone therapy did not prevent the progression from prediabetes to diabetes, which was somewhat surprising given testosterone's known effects on insulin sensitivity.
What This Means for TRT Patients
The TRAVERSE trial fundamentally changed the risk-benefit calculation for men considering TRT.
The FDA's Response
On February 28, 2025, the FDA announced class-wide labeling changes for all testosterone products based on the TRAVERSE results and completed postmarket studies. The key changes:
- Removed: The boxed warning about increased risk of major adverse cardiovascular events
- Added: TRAVERSE trial results showing cardiovascular noninferiority to labeling
- Added: Product-specific blood pressure increase data from ABPM studies
- Retained: "Limitation of Use" language for age-related hypogonadism (meaning testosterone shouldn't be prescribed solely because levels decline with age -- symptoms must be present)
This was a significant reversal. For a decade, every testosterone product carried language warning about heart risk. That warning is now gone, replaced by evidence of safety from the most rigorous trial ever conducted.
What "Noninferior" Actually Means
A noninferior result doesn't mean testosterone is good for your heart. It means testosterone didn't make cardiovascular outcomes worse compared to placebo. This is an important distinction. The TRAVERSE trial was not designed to show that TRT prevents heart attacks -- it was designed to determine whether TRT causes them. The answer was no.
Some researchers have pointed out that observational data actually suggests testosterone-deficient men who receive TRT may have lower cardiovascular mortality than untreated men. But TRAVERSE was not designed to test that hypothesis, and the evidence for a protective effect remains observational, not proven by randomized trials.
Risk Factors That Still Matter on TRT
The TRAVERSE results are reassuring, but they don't mean you can ignore cardiovascular health while on TRT. Several monitoring points remain critical.
Blood Pressure
The confirmed blood pressure increase with testosterone means you should check blood pressure regularly, ideally at home with a validated cuff. If you're already on blood pressure medication, your dose may need adjustment after starting TRT. Target is below 130/80 mmHg for most men.
Hematocrit
Testosterone stimulates erythropoiesis, pushing red blood cell production higher. When hematocrit exceeds 52-54%, blood viscosity rises, and so does the risk of clotting events. Standard TRT monitoring includes hematocrit checks at baseline, 3-6 months, and annually. If it runs high, your clinician may recommend therapeutic phlebotomy (blood donation), dose reduction, or more frequent injections to reduce peaks.
Lipid Profile
TRT can modestly decrease HDL cholesterol while having variable effects on LDL and triglycerides. These shifts are typically small and rarely clinically significant in isolation, but they matter if you already have dyslipidemia. Get lipids checked at baseline and periodically during treatment.
Sleep Apnea
Testosterone can worsen obstructive sleep apnea, which is itself a cardiovascular risk factor. If you snore heavily, feel unrested despite adequate sleep hours, or have a thick neck, get a sleep study before starting TRT.
Lifestyle Foundations
No amount of testosterone compensates for a poor foundation. The men in TRAVERSE who did well were receiving medical care, being monitored, and (presumably) addressing modifiable risk factors. Regular exercise, a reasonable diet, not smoking, and maintaining a healthy weight remain the most powerful cardiovascular interventions available -- with or without TRT.
Who Should Still Be Cautious
While TRAVERSE was reassuring, certain populations warrant extra vigilance:
- Men with recent acute coronary syndrome or stroke: TRAVERSE excluded men with events within the prior 3 months. If you've had a very recent cardiac event, discuss timing carefully with your cardiologist.
- Men with uncontrolled polycythemia: If your hematocrit is already elevated before starting TRT, testosterone will push it higher. This needs to be addressed first.
- Men with severe untreated sleep apnea: The combination of testosterone-driven erythrocytosis and apnea-related hypoxia can compound cardiovascular strain.
- Men with decompensated heart failure: Testosterone can cause fluid retention, which is problematic in heart failure. Stable, compensated heart failure was permitted in TRAVERSE, but decompensated cases require caution.
The common thread: it's not that TRT is inherently dangerous for these men, but that they need closer monitoring and potentially a phased approach to treatment.
Limitations of the TRAVERSE Trial
No study is perfect, and intellectual honesty requires acknowledging what TRAVERSE didn't answer.
Transdermal only. TRAVERSE used testosterone gel. Most men in the US use injectable testosterone cypionate or enanthate. While there's no strong biological reason to expect different cardiovascular outcomes by delivery method, the trial technically only proved safety for transdermal testosterone.
Mean follow-up of 33 months. Heart disease develops over decades. Three years of safety data is excellent, but it can't guarantee safety over 10 or 20 years of treatment.
High-risk population. The enrolled population had existing CVD or high risk. This is actually a strength for safety conclusions (if it's safe in high-risk men, it's likely safe in lower-risk men), but the specific results apply most directly to this group.
Adherence to gel. Topical testosterone has lower adherence than injections. If a meaningful percentage of the testosterone group wasn't actually using the gel consistently, this could dilute the results. The trial monitored testosterone levels and dose-adjusted, which mitigates but doesn't fully eliminate this concern.
The Bottom Line
For over a decade, the cardiovascular question hung over every TRT decision. Patients worried. Doctors hesitated. Insurance companies used it as justification for denials.
The TRAVERSE trial answered the question as definitively as a single trial can: testosterone replacement therapy does not increase the risk of heart attack, stroke, or cardiovascular death in men with hypogonadism, even those who already have heart disease.
The FDA agreed, removing the cardiovascular boxed warning in 2025. Blood pressure monitoring is now recommended, and the standard safety labs -- hematocrit, lipids, PSA -- remain part of responsible TRT management.
If you've been putting off TRT because of heart concerns, the evidence now says those concerns were based on flawed studies. The definitive trial has been done, and the results are clear.
That doesn't mean TRT is risk-free. It means the cardiovascular risk specifically -- the thing most men worry about most -- has been tested rigorously and found to be a non-issue when TRT is properly managed and monitored.
The next step is finding a clinic that takes monitoring seriously. Not every provider checks hematocrit regularly or adjusts protocols based on blood pressure trends. The quality of your care matters as much as the decision to start.
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References
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Lincoff AM, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. PMID: 37326322
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Basaria S, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. PMID: 20592293
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Vigen R, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836. PMID: 24193080
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Finkle WD, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. PMID: 24489673
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Bhasin S, et al. Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial. JAMA Netw Open. 2023;6(12):e2348692. PMID: 38150256
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Corona G, et al. Testosterone and Cardiovascular Risk: Meta-Analysis of Interventional Studies. J Sex Med. 2018;15(6):820-838. PMID: 29803351
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Bhasin S, et al. Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study. Am Heart J. 2022;245:41-50. PMID: 34871580
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FDA. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. FDA.gov