Table of Contents
- Key Points
- Background: Why This Study Was Needed
- How the Study Was Conducted
- Who Was Studied
- Testosterone Treatment and Dose Adjustment
- What Outcomes Were Measured
- Key Findings: Cardiovascular Results
- Other Safety Findings
- What These Results Mean for Patients
- Limitations of the Study
- Recommendations for Patients and Clinicians
- Frequently Asked Questions
- Source Information
Key Points
- In a trial of 5,246 men aged 45 to 80 with low testosterone and existing or high heart disease risk, testosterone-replacement therapy was noninferior to placebo for major adverse cardiac events.
- A primary cardiovascular event occurred in 7.0% of men taking testosterone and 7.3% taking placebo, so testosterone was noninferior to placebo for heart attack, stroke, and cardiovascular death in this group.
- Testosterone use was associated with higher rates of atrial fibrillation, acute kidney injury, and pulmonary embolism; these specific safety signals should be discussed with a healthcare provider.
- The trial had limitations: mean treatment was 21.7 months, about 61% discontinued treatment, and outcome data covered 82.7% of possible follow-up, which may dilute or bias results.
- Findings apply only to middle-aged and older men with hypogonadism and existing or high cardiovascular risk; they may not apply to younger men or those without these characteristics.
Background: Why This Study Was Needed
The cardiovascular effects of testosterone-replacement therapy in middle-aged and older men with hypogonadism (low testosterone) had not been determined before this trial. Hypogonadism is a condition in which the body does not produce enough testosterone, the primary male sex hormone.
Previous retrospective cohort studies (studies that look back at existing data) involving men receiving testosterone-replacement therapy showed conflicting results. Some studies showed increased cardiovascular risk, while others showed decreased risk. Small randomized trials also did not show a consistent association between testosterone treatment and cardiovascular risk. However, none of these trials were designed to systematically assess cardiovascular outcomes. All were inadequately powered (too small to detect meaningful differences) and had a short duration.
In response to these concerns and conflicting data, the U.S. Food and Drug Administration (FDA) issued guidance on March 3, 2015. This guidance required manufacturers of approved testosterone products to conduct clinical trials. The purpose was to determine whether testosterone-replacement therapy is associated with an increased risk of cardiovascular events.
The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to answer this question. The trial aimed to determine the effects of testosterone-replacement therapy on the incidence of major adverse cardiac events. The trial studied middle-aged and older men with hypogonadism and either preexisting or high risk of cardiovascular disease.
How the Study Was Conducted
The TRAVERSE trial was a phase 4, randomized, double-blind, placebo-controlled, noninferiority, event-driven trial. "Randomized" means patients were assigned to treatment groups by chance. "Double-blind" means neither the patients nor the researchers knew which treatment each patient received. "Placebo-controlled" means one group received an inactive gel that looked and felt like the real treatment. "Noninferiority" means the study was designed to test whether testosterone was not worse than placebo by a predefined margin. "Event-driven" means the trial continued until a specific number of cardiovascular events occurred.
The trial was conducted at 316 clinical-trial sites in the United States. The trial was funded by a consortium of testosterone manufacturers led by AbbVie. The Cleveland Clinic Coordinating Center for Clinical Research (C5Research) oversaw the trial, with support from a contract research organization (Labcorp Drug Development).
The trial protocol was designed by the executive committee and sponsor. National and institutional regulatory and ethical authorities approved the protocol. All patients provided written informed consent. An independent data and safety monitoring committee reviewed unblinded safety data. The clinical database was maintained by Labcorp Drug Development and transferred to C5Research for independent statistical analyses.
The first author wrote the first draft of the manuscript, which was reviewed and approved by all authors. The sponsor reviewed the manuscript and provided suggested revisions. However, the final decision regarding content was reserved for the academic authors, with no restrictions on the right to publish. The first and last authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and the statistical analysis plan.
Who Was Studied
Men with preexisting cardiovascular disease or elevated cardiovascular risk were eligible for the trial if they met specific criteria. They had to be 45 to 80 years of age. They had to report one or more symptoms of hypogonadism. These symptoms included decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood. Symptoms also included loss of axillary or pubic body hair or decreased frequency of shaving, or hot flashes.
Participants also had to have two fasting serum testosterone levels of less than 300 ng per deciliter (10.4 nmol per liter). Blood samples were obtained between 5:00 a.m. and 11:00 a.m. and measured at a central laboratory using liquid chromatography–tandem mass spectrometry, a highly accurate testing method.
Cardiovascular disease was defined as clinical or angiographic evidence of coronary artery disease, cerebrovascular disease, or peripheral arterial disease. Increased cardiovascular risk was defined as the presence of three or more of the following risk factors:
- Hypertension (high blood pressure)
- Dyslipidemia (abnormal cholesterol levels)
- Current smoking
- Stage 3 chronic kidney disease
- Diabetes
- Elevated high-sensitivity C-reactive protein level (a marker of inflammation)
- Age of 65 years or older
- An Agatston coronary calcium score above the 75th percentile for age and race
Exclusion criteria included congenital or acquired severe hypogonadism (testosterone level less than 100 ng per deciliter [3.5 nmol per liter]). Exclusion criteria also included a history of prostate cancer or prostate nodules. Exclusion criteria also included an elevated screening prostate-specific antigen (PSA) level. Exclusion criteria also included thrombophilia (a condition that increases blood clotting risk). Exclusion criteria also included uncontrolled heart failure. Patients could not be enrolled within 4 months after an acute coronary syndrome, stroke, or coronary or peripheral revascularization. They also could not enroll within 6 months after treatment with testosterone or androgenic steroids.
A total of 5,246 patients underwent randomization. Twenty patients were excluded from the full-analysis population owing to duplicate enrollment involving a total of 42 patient identification numbers. Of the 5,204 patients in the full-analysis population, 2,601 were assigned to receive testosterone and 2,603 were assigned to receive placebo. The safety population included 5,198 patients who had received at least one dose of testosterone or placebo (2,596 patients in the testosterone group and 2,602 in the placebo group).
The trial included 2,847 patients with preexisting cardiovascular disease and 2,357 patients at elevated cardiovascular risk. The baseline median serum testosterone level was 227 ng per deciliter (interquartile range, 188 to 258; 7.8 nmol per liter; interquartile range, 6.5 to 8.9) in the combined trial groups.
Baseline characteristics were well balanced between the two groups. The mean age was 63.3 years in both groups. Approximately 47.7% of the testosterone group and 46.5% of the placebo group were 65 years or older. The racial and ethnic distribution was similar: about 80% White, 17% Black, and 3% other races. Hispanic or Latinx patients made up 15.7% of the testosterone group and 16.9% of the placebo group.
Cardiovascular risk factors were common in both groups:
- Diabetes: 68.7% in testosterone group, 70.8% in placebo group
- Hypertension: 93.2% in testosterone group, 92.3% in placebo group
- Dyslipidemia: 90.1% in testosterone group, 89.6% in placebo group
- Current smoker: 20.3% in testosterone group, 20.5% in placebo group
- High-sensitivity C-reactive protein level ≥2 mg/dl: 61.8% in testosterone group, 61.0% in placebo group
- Stage 3 chronic kidney disease: 16.1% in testosterone group, 15.1% in placebo group
Medication use was also similar between groups. Lipid-lowering therapy was used by 84.0% of the testosterone group and 83.7% of the placebo group. Aspirin was used by 60.4% of the testosterone group and 59.5% of the placebo group. Phosphodiesterase-5 inhibitors were used by 6.5% of the testosterone group and 7.3% of the placebo group.
Testosterone Treatment and Dose Adjustment
Patients were randomly assigned in a 1:1 ratio to receive daily transdermal 1.62% testosterone gel or matching placebo gel. Transdermal means the gel was applied to the skin. The gels were provided in metered-dose pumps. Randomization was stratified according to the presence or absence of preexisting cardiovascular disease.
To avoid unblinding, the patients and trial team remained unaware of the post-baseline testosterone levels measured at the central laboratory. Dose adjustments were managed centrally by an automated algorithm. The goal was to maintain testosterone levels between 350 and 750 ng per deciliter (12.1 to 26.0 nmol per liter). Dose adjustments were also made to respond to a hematocrit (the proportion of red blood cells in the blood) greater than 54%. Patients who were randomly assigned to placebo underwent sham adjustments to maintain blinding.
Testosterone or placebo was discontinued in patients with testosterone levels that exceeded 750 ng per deciliter. Treatment was also discontinued in patients with a hematocrit that exceeded 54% even after adjustment to the lowest dose. Additionally, treatment was discontinued in patients who had a new diagnosis of prostate cancer or were deemed to be at risk for suicide. Otherwise, the assigned intervention was to be continued for the duration of the trial. Investigators received specific guidelines regarding care or referral to a urologist for patients with an elevated PSA level.
The mean duration of treatment was 21.7 months (standard deviation, 14.1 months). The mean follow-up was 33.0 months (standard deviation, 12.1 months). In the testosterone group, the mean durations of treatment and follow-up were 21.8 months and 33.1 months, respectively. In the placebo group, the mean durations were 21.6 months and 32.9 months, respectively.
A total of 61.4% of patients in the testosterone group discontinued testosterone, and 61.7% of patients in the placebo group discontinued placebo. Patients received the assigned regimen for 67.5% of the potential treatment time in the testosterone group and 67.3% in the placebo group. A total of 1,082 patients (20.8%) withdrew from the trial before end-of-trial visits began. An additional 947 patients (18.2%) did not attend their end-of-trial visit after that date. Withdrawal rates were similar in the two trial groups, and outcome data were available for 82.7% of the possible follow-up period.
What Outcomes Were Measured
The primary safety endpoint was the first occurrence of any component of major adverse cardiac events. This was a composite of death from cardiovascular causes, nonfatal myocardial infarction (heart attack), or nonfatal stroke. The primary endpoint was assessed in a time-to-event analysis.
A secondary cardiovascular endpoint was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Coronary revascularization is a procedure to restore blood flow to the heart, such as angioplasty or bypass surgery. This endpoint was also assessed in a time-to-event analysis.
Tertiary endpoints included:
- Death from any cause
- Hospitalization or an urgent visit for heart failure
- Peripheral arterial revascularization (a procedure to restore blood flow to the legs or other extremities)
- Venous thromboembolic events (blood clots in the veins, including deep vein thrombosis and pulmonary embolism)
An independent clinical-events committee whose members were unaware of the trial-group assignments adjudicated all cardiovascular endpoints. Definitions of the endpoints are provided in the Supplementary Appendix of the original article.
Key Findings: Cardiovascular Results
The trial was designed to conclude after 256 primary composite endpoint events had occurred. This number of events would provide 90% power to detect an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio (one-sided alpha level, 2.5%). At the completion of follow-up, 372 adjudicated primary endpoint events had occurred, and 306 primary endpoint events qualified for the principal sensitivity analysis.
In April 2019, blinded data from the first 2,669 patients showed a pooled primary event rate below the projected rate of 1.5% per year. Therefore, on May 31, 2019, the executive committee and sponsor discontinued enrollment of patients who qualified on the basis of cardiovascular risk factors. Thereafter, the trial enrolled only those with preexisting cardiovascular disease. Subsequently, on the basis of blinded assessments of pooled accrual rates of major adverse cardiac events, enrollment was terminated on February 1, 2022, and end-of-trial visits began after May 31, 2022.
A primary cardiovascular endpoint event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group. The hazard ratio was 0.96, with a 95% confidence interval of 0.78 to 1.17. The P value was less than 0.001 for noninferiority. This means testosterone was statistically noninferior to placebo for the primary cardiovascular safety endpoint.
In the principal sensitivity analysis, data on events that occurred more than 365 days after the last dose were censored. In this analysis, a primary safety endpoint event occurred in 154 patients (5.9%) in the testosterone group and in 152 patients (5.8%) in the placebo group. The hazard ratio was 1.02, with a 95% confidence interval of 0.81 to 1.27. The P value was less than 0.001 for noninferiority.
Similar findings were observed in sensitivity analyses in which data on events were censored more than 30 days after the last dose or after interruption of testosterone or placebo. The confirmatory analysis involving the full-analysis population also showed similar results.
For the secondary cardiovascular composite endpoint (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization), the hazard ratio was 1.02, with a 95% confidence interval of 0.86 to 1.21. This indicates no significant difference between the testosterone and placebo groups.
For the individual components of the primary endpoint, the results were as follows:
- Death from cardiovascular causes: hazard ratio 0.84 (95% CI, 0.63 to 1.12)
- Nonfatal myocardial infarction: hazard ratio 1.10 (95% CI, 0.78 to 1.56)
- Nonfatal stroke: hazard ratio 0.94 (95% CI, 0.60 to 1.49)
The incidence of secondary endpoint events and each of the events of the composite primary cardiovascular endpoint appeared to be similar in the two groups. However, the statistical analysis plan did not include a provision for correcting for multiplicity for tests of secondary or other endpoints. Therefore, results are reported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive treatment effects for secondary endpoints.
Other Safety Findings
While the primary cardiovascular safety endpoint showed noninferiority, a higher incidence of certain other adverse events was observed in the testosterone group. Specifically, the trial found a higher incidence of:
- Atrial fibrillation (an irregular heart rhythm)
- Acute kidney injury (sudden loss of kidney function)
- Pulmonary embolism (a blood clot in the lungs)
These findings were noted in the abstract and results section of the original article. The exact numbers and percentages for these adverse events were not provided in the main text of the article but are likely detailed in the Supplementary Appendix.
The trial also monitored other tertiary endpoints, including death from any cause, hospitalization or urgent visit for heart failure, peripheral arterial revascularization, and venous thromboembolic events. The results for these endpoints were not fully detailed in the main text of the article.
What These Results Mean for Patients
For men with hypogonadism and preexisting or high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. This means that testosterone therapy was noninferior to placebo for the risk of heart attack, stroke, or death from cardiovascular causes in this population.
This finding is important because previous studies had shown conflicting results about the cardiovascular safety of testosterone therapy. Some studies suggested increased risk, while others suggested decreased risk. The TRAVERSE trial was specifically designed to answer this question with adequate statistical power and duration.
However, the trial did identify specific safety signals that patients and clinicians should be aware of. The higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group means that men considering testosterone therapy should discuss these risks with their healthcare provider. Atrial fibrillation is an irregular heart rhythm that can increase the risk of stroke. Acute kidney injury is a sudden decrease in kidney function that can be serious. Pulmonary embolism is a blood clot in the lungs that can be life-threatening.
The results of this trial apply specifically to middle-aged and older men (45 to 80 years) with hypogonadism and either preexisting cardiovascular disease or high risk of cardiovascular disease. The findings may not apply to other populations, such as younger men, men without cardiovascular risk factors, or men using testosterone for other reasons.
Limitations of the Study
The trial had several limitations that should be considered when interpreting the results. First, the mean duration of treatment was 21.7 months, and the mean follow-up was 33.0 months. This may not be long enough to detect long-term cardiovascular effects of testosterone therapy.
Second, a high proportion of patients discontinued their assigned treatment. A total of 61.4% of patients in the testosterone group discontinued testosterone, and 61.7% of patients in the placebo group discontinued placebo. Patients received the assigned regimen for only about 67% of the potential treatment time. This could dilute the observed treatment effects.
Third, 20.8% of patients withdrew from the trial before end-of-trial visits began, and an additional 18.2% did not attend their end-of-trial visit. Outcome data were available for 82.7% of the possible follow-up period. This loss to follow-up could introduce bias.
Fourth, the trial enrolled only men with hypogonadism and preexisting or high risk of cardiovascular disease. The results may not be generalizable to men without these characteristics.
Fifth, the statistical analysis plan did not include a provision for correcting for multiplicity for tests of secondary or other endpoints. Therefore, the results for secondary endpoints should be interpreted with caution, and the confidence intervals should not be used to infer definitive treatment effects.
Sixth, the trial was funded by a consortium of testosterone manufacturers led by AbbVie. While the academic authors had final decision-making authority over the manuscript content, the sponsor's involvement should be considered when interpreting the results.
Recommendations for Patients and Clinicians
Based on the results of the TRAVERSE trial, the following recommendations can be made for patients and clinicians:
- For men with hypogonadism and preexisting or high risk of cardiovascular disease, testosterone-replacement therapy appears to be noninferior to placebo for major adverse cardiac events. This means testosterone therapy was noninferior to placebo for the risk of heart attack, stroke, and cardiovascular death in this population.
- Patients and clinicians should be aware of the higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism observed in the testosterone group. These risks should be discussed when considering testosterone therapy.
- Men considering testosterone therapy should have a thorough discussion with their healthcare provider about the potential benefits and risks, including the specific safety signals identified in this trial.
- Patients should also be monitored for acute kidney injury (such as decreased urine output or swelling). Patients should also be monitored for pulmonary embolism (such as sudden shortness of breath, chest pain, or coughing up blood).
- Regular follow-up with a healthcare provider is important for patients receiving testosterone therapy to monitor for potential adverse effects and to adjust treatment as needed.
- The results of this trial apply specifically to middle-aged and older men with hypogonadism and cardiovascular disease or high cardiovascular risk. Men without these characteristics should discuss their individual risks and benefits with their healthcare provider.
Further research is needed to determine the long-term cardiovascular effects of testosterone therapy. Further research is also needed to better understand the mechanisms behind the increased incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism observed in this trial.
Frequently Asked Questions
What did the TRAVERSE trial find about testosterone and heart risk?
In a randomized trial of 5,246 men aged 45 to 80 with low testosterone and existing or high risk of heart disease, testosterone-replacement therapy was noninferior to placebo for major adverse cardiac events. A primary cardiovascular event occurred in 7.0% of men taking testosterone and 7.3% taking placebo, meaning testosterone was noninferior to placebo for heart attack, stroke, and cardiovascular death in this population.
Who was eligible to take part in this trial?
Men aged 45 to 80 with symptoms of low testosterone and two fasting morning testosterone levels below 300 ng per deciliter could join if they had existing cardiovascular disease or at least three risk factors such as high blood pressure, abnormal cholesterol, current smoking, stage 3 chronic kidney disease, diabetes, elevated inflammation markers, age 65 or older, or a high coronary calcium score.
What other safety concerns were found with testosterone therapy?
Even though the primary heart safety endpoint showed noninferiority, testosterone use was associated with higher rates of atrial fibrillation (an irregular heart rhythm), acute kidney injury (sudden loss of kidney function), and pulmonary embolism (a blood clot in the lungs). These specific safety signals should be discussed with a healthcare provider when considering testosterone therapy.
What does it mean that testosterone was 'noninferior' to placebo?
Noninferiority means the trial was designed to test whether testosterone was not worse than placebo by a predefined margin. The hazard ratio was 0.96 with a 95% confidence interval of 0.78 to 1.17, and the P value was less than 0.001 for noninferiority. This indicates testosterone was statistically noninferior to placebo for the primary cardiovascular safety endpoint.
How long did patients take testosterone, and how long were they followed?
In the trial, the mean duration of treatment was 21.7 months, and the mean follow-up was 33.0 months. About 61% of patients in both groups discontinued their assigned treatment, and patients received the assigned regimen for roughly 67% of the potential treatment time. This may not be long enough to detect long-term cardiovascular effects.
What symptoms should patients on testosterone therapy watch for?
Regular follow-up with a healthcare provider is important to monitor for potential adverse effects and adjust treatment as needed.
Do these results apply to all men considering testosterone therapy?
No. The results apply specifically to middle-aged and older men (45 to 80 years) with hypogonadism and either preexisting cardiovascular disease or high risk of cardiovascular disease. They may not apply to younger men, men without cardiovascular risk factors, or men using testosterone for other reasons. Men without these characteristics should discuss their individual risks and benefits with their healthcare provider.
I'm a man with low testosterone and heart disease risk — when should I get a second opinion before starting testosterone replacement therapy?
A second opinion is worth considering when you have hypogonadism plus existing or high cardiovascular risk, since testosterone-replacement therapy was noninferior to placebo for major adverse cardiac events but was linked to higher rates of atrial fibrillation, acute kidney injury, and pulmonary embolism. A second review can confirm your testosterone levels and cardiovascular risk profile, and help weigh those specific safety signals against expected benefits. Because the trial enrolled men aged 45 to 80 with these characteristics, an independent expert can clarify whether those findings apply to you. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original Article Title: Cardiovascular Safety of Testosterone-Replacement Therapy NEJM 2023
Authors: A.M. Lincoff, S. Bhasin, P. Flevaris, L.M. Mitchell, S. Basaria, W.E. Boden, G.R. Cunningham, C.B. Granger, M. Khera, I.M. Thompson, Jr., Q. Wang, K. Wolski, D. Davey, V. Kalahasti, N. Khan, M.G. Miller, M.C. Snabes, A. Chan, E. Dubcenco, X. Li, T. Yi, B. Huang, K.M. Pencina, T.G. Travison, and S.E. Nissen, for the TRAVERSE Study Investigators
Publication: New England Journal of Medicine, July 13, 2023, Volume 389, Number 2, pages 107-117
DOI: 10.1056/NEJMoa2215025
Funding: Funded by AbbVie and others
ClinicalTrials.gov Number: NCT03518034
This patient-friendly article is based on peer-reviewed research published in the New England Journal of Medicine. The original article was published on June 16, 2023, at NEJM.org.
