BACKGROUND
The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined.
METHODS
In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.
RESULTS
The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group.
CONCLUSIONS
In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034. opens in new tab.)
The cardiovascular effects of testosterone-replacement therapy in middle-aged and older men with hypogonadism have not been determined. Retrospective cohort studies involving men receiving testosterone-replacement therapy have shown conflicting results, with some showing increased and others decreased cardiovascular risk.1-5 Small randomized trials similarly have not shown a consistent association of testosterone treatment with cardiovascular risk, although none were designed to systematically assess cardiovascular outcomes and all were inadequately powered and had a short duration.6-10
In response to concerns and conflicting data regarding the cardiovascular safety of testosterone-replacement therapy, the Food and Drug Administration (FDA) issued a guidance on March 3, 2015, that required manufacturers of approved testosterone products to conduct clinical trials to determine whether testosterone-replacement therapy is associated with an increased risk of cardiovascular events.11 The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was designed to determine the effects of testosterone-replacement therapy on the incidence of major adverse cardiac events among middle-aged and older men with hypogonadism and either preexisting or a high risk of cardiovascular disease.
Methods
TRIAL DESIGN AND OVERSIGHT
We conducted this phase 4, randomized, double-blind, placebo-controlled, noninferiority, event-driven trial at 316 clinical-trial sites in the United States (see the Supplementary Appendix, available with the full text of this article at NEJM.org). The trial design has been published previously.12 The trial was funded by a consortium of testosterone manufacturers led by AbbVie and was overseen by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) with support from a contract research organization (Labcorp Drug Development). The trial protocol, available at NEJM.org, was designed by the executive committee and sponsor. National and institutional regulatory and ethical authorities approved the protocol, and all the 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 the authors. The sponsor reviewed the manuscript and provided suggested revisions, but 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.
TRIAL POPULATION
Men with preexisting cardiovascular disease or an elevated cardiovascular risk were eligible if they were 45 to 80 years of age; reported one or more symptoms of hypogonadism, including decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood, loss of axillary or pubic body hair or decreased frequency of shaving, or hot flashes; and had two fasting serum testosterone levels of less than 300 ng per deciliter (10.4 nmol per liter) in blood samples obtained between 5:00 a.m. and 11:00 a.m. and measured at a central laboratory with the use of liquid chromatography–tandem mass spectrometry.
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, dyslipidemia, current smoking, stage 3 chronic kidney disease, diabetes, elevated high-sensitivity C-reactive protein level, age of 65 years or older, or an Agatston coronary calcium score that was above the 75th percentile for age and race.
Exclusion criteria included congenital or acquired severe hypogonadism (testosterone level, <100 ng per deciliter [3.5 nmol per liter]), a history of prostate cancer or prostate nodules, an elevated screening prostate-specific antigen (PSA) level, thrombophilia, and uncontrolled heart failure. Patients could not be enrolled within 4 months after an acute coronary syndrome, stroke, or coronary or peripheral revascularization or within 6 months after treatment with testosterone or androgenic steroids. Detailed eligibility criteria are provided in the Supplementary Appendix.
TRIAL INTERVENTION
Patients were randomly assigned in a 1:1 ratio to receive daily transdermal 1.62% testosterone gel or matching placebo gel 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 to maintain testosterone levels between 350 and 750 ng per deciliter (12.1 to 26.0 nmol per liter) or to respond to a hematocrit greater than 54% were managed centrally by an automated algorithm (additional details are provided in the Supplementary Appendix). 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 or with a hematocrit that exceeded 54% even after adjustment to the lowest dose, as well as 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. The investigators received specific guidelines regarding care or referral to a urologist for patients with an elevated PSA level.
END POINTS
The primary safety end point was the first occurrence of any component of major adverse cardiac events, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization in a time-to-event analysis. Tertiary end points included death from any cause, hospitalization or an urgent visit for heart failure, peripheral arterial revascularization, and venous thromboembolic events. An independent clinical-events committee whose members were unaware of the trial-group assignments adjudicated all cardiovascular end points. Definitions of the end points are provided in the Supplementary Appendix. Effects of testosterone therapy on noncardiovascular outcomes in this trial are not reported in this article (see Table S1 in the Supplementary Appendix).
STATISTICAL ANALYSIS
In this noninferiority trial, we used a Cox proportional-hazards regression model to estimate the hazard ratio and its two-sided 95% confidence interval for a primary end-point event with testosterone as compared with placebo, with adjustment for preexisting cardiovascular disease. The trial was designed to conclude after 256 primary composite end-point 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%). Because the statistical analysis plan did not include a provision for correcting for multiplicity for tests of secondary or other end points, 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 end points.
The full-analysis population consisted of all the patients who had undergone randomization, and the safety population consisted of all the patients who had undergone randomization and had received at least one dose of testosterone or placebo. The primary analysis involved the safety population and was repeated in a supportive analysis involving the full-analysis population. The principal sensitivity analysis included major adverse cardiac events that occurred during the period from randomization to 365 days after the last dose, with censoring of data on events that occurred more than 365 days after the last dose. Additional sensitivity and supportive analyses based on different event censoring times and a restricted mean survival time at 3 years are described in the Supplementary Appendix.
Under the assumption of an annual event rate for the primary end point of 1.5% in the placebo group, with an accrual period of 3.5 years and an annualized loss to follow-up rate of 2%, the sample size was estimated to be approximately 5400 patients to observe the required 256 events. However, to achieve similar power for the principal sensitivity analysis, the required sample size was estimated to be approximately 6000 patients, on the assumption of a testosterone or placebo discontinuation rate of 20% in the first year and 10% in each subsequent year. To reach the intended event rate for the primary end point, the protocol allowed the executive committee and sponsor to limit enrollment in the cohort with cardiovascular risk factors if that cohort exceeded 70% of the total enrollment or if the pooled primary event rate fell below projections. All statistical analyses were performed with the use of SAS software, version 9.4.
Results
PATIENTS
The first patient was enrolled on May 23, 2018. A total of 5246 patients underwent randomization, and 20 patients were excluded from the full-analysis population owing to duplicate enrollment involving a total of 42 patient identification numbers (Fig. S1). Of the 5204 patients in the full-analysis population, 2601 were assigned to receive testosterone and 2603 were assigned to receive placebo. The safety population included 5198 patients who had received at least one dose of testosterone or placebo (2596 patients in the testosterone group and 2602 in the placebo group).
In April 2019, blinded data from the first 2669 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 and thereafter 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. At the completion of follow-up, 372 adjudicated primary end-point events had occurred, and 306 primary end-point events qualified for the principal sensitivity analysis.
Table 1.
Baseline Characteristics of Patients in the Full-Analysis Population.
Baseline characteristics are summarized in Table 1. The trial included 2847 patients with preexisting cardiovascular disease and 2357 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. The demographic characteristics were representative of the population of middle-aged and older men with hypogonadism and a high risk of cardiovascular events (Table S2).
The mean (±SD) durations of treatment and follow-up, respectively, were 21.8±14.2 and 33.1±12.0 months in the testosterone group and 21.6±14.0 and 32.9±12.1 months in the placebo group. A total of 61.4% of the patients in the testosterone group discontinued testosterone, and 61.7% of the patients in the placebo group discontinued placebo (Fig. S2); patients received the assigned regimen for 67.5% and 67.3% of the potential treatment time in the testosterone and placebo groups, respectively. A total of 1082 patients (20.8%) withdrew from the trial before end-of-trial visits began, and 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 time (observed person-time divided by total person-time, on the assumption of no withdrawals)13 in the testosterone group and 81.7% of the possible follow-up time in the placebo group.
TRIAL END POINTS
Figure 1.
Median Serum Testosterone Levels and Changes in Serum Testosterone Levels over Time.
The mean (±SD) daily dose of testosterone was 65±22 mg. Serum testosterone levels that were measured approximately 24 hours after the patient had received a dose of testosterone or placebo over the course of the trial are shown in Figure 1 and Table S3. At 12 months, the median increase from baseline in serum testosterone levels was 148 ng per deciliter; interquartile range, 34 to 312 (5.1 nmol per liter; interquartile range, 1.2 to 10.8) in the testosterone group, as compared with a median increase of 14 ng per deciliter; interquartile range, −21 to 56 (0.5 nmol per liter; interquartile range, −0.7 to 1.9) in the placebo group. Estradiol levels are summarized in Table S4.
Figure 2.
Time-to-Event Analysis for the Primary and Secondary Cardiovascular Safety End Points.
Table 2.
Adjudicated Cardiovascular End Points in the Safety Population.
A primary safety end-point event (the first adjudicated major adverse cardiac event) occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval [CI], 0.78 to 1.17; P<0.001 for noninferiority) (Figure 2A and Table 2). In the principal sensitivity analysis (with censoring of data on events that occurred >365 days after the last dose), a primary safety end-point event occurred in 154 patients (5.9%) in the testosterone group and in 152 patients (5.8%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.81 to 1.27; P<0.001 for noninferiority) (Figure 2B). 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, in the confirmatory analysis involving the full-analysis population, and among prespecified subgroups; analysis of the restricted mean survival time at 3 years met the criteria for noninferiority (Figs. S3 and S4 and Table S5).
No apparent clinically meaningful differences in the incidence of secondary cardiovascular end-point events were observed between the trial groups (Table 2 and Figure 2C through 2F). A higher incidence of pulmonary embolism, a component of the adjudicated tertiary end point of venous thromboembolic events (Table 2), occurred in the testosterone group than in the placebo group (0.9% vs. 0.5%).
ADVERSE EVENTS
Table 3.
Investigator-Reported Adverse Events.
Prostate cancer occurred in 12 patients (0.5%) in the testosterone group and in 11 patients (0.4%) in the placebo group (P=0.87); these cases were adjudicated as high-grade prostate cancer (Gleason score, 4+3 or higher, indicating an intermediate or higher risk of progression) in 5 patients and 3 patients, respectively (P=0.51). The increase in PSA levels from baseline was greater in patients in the testosterone group than in those in the placebo group (0.20±0.61 ng per milliliter vs. 0.08±0.90 ng per milliliter, respectively; P<0.001). The change in mean systolic blood pressure from baseline through 6 months was 0.3 mm Hg (95% CI, −0.3 to 0.9) in the testosterone group and −1.5 mm Hg (95% CI, −2.0 to −0.9) in the placebo group (P<0.001) (Table S6). Investigator-reported adverse events are summarized in Table 3. Nonfatal arrhythmias warranting intervention occurred in 134 patients (5.2%) in the testosterone group and in 87 patients (3.3%) in the placebo group (P=0.001); atrial fibrillation occurred in 91 patients (3.5%) and 63 patients (2.4%), respectively (P=0.02), and acute kidney injury occurred in 60 patients (2.3%) and 40 patients (1.5%), respectively (P=0.04).
Discussion
We conducted this randomized, placebo-controlled trial to address uncertainty as to whether testosterone-replacement therapy in middle-aged and older men with hypogonadism increases the risk of cardiovascular events. We included men with established cardiovascular disease or multiple cardiac risk factors who would be most vulnerable to an increased risk of adverse cardiovascular outcomes. Among 5198 patients who received testosterone or placebo for a mean duration of 22 months, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. The hazard ratio for a primary end-point event was 0.96 (95% CI, 0.78 to 1.17), a noninferiority finding that was confirmed in sensitivity analyses with adjustment for the influence of interruptions or discontinuations of testosterone or placebo.
The FDA initiated a review of the cardiovascular safety of testosterone products in 2010 after a small placebo-controlled trial was prematurely discontinued because of an increased incidence of cardiovascular events among patients who received testosterone therapy.14 However, subsequent meta-analyses showed variable results and most, including a recent patient-level meta-analysis,15 did not confirm these findings. Cardiac events in those trials were not uniformly adjudicated, definitions were broad and inconsistent, and the trials were not adequately powered for cardiovascular outcomes. Retrospective observational studies, which were limited by potential confounding and selection bias, also showed conflicting findings,1-5 although one analysis from a large health care database suggested that an age of 65 years or older or preexisting cardiovascular disease might be important modifiers of increased risk with testosterone-replacement therapy.2 Nearly half the patients enrolled in the current trial were 65 years of age or older, and more than half had preexisting cardiovascular disease. The 372 adjudicated primary end-point events that occurred in this trial were greater in number than those in all previous randomized trials of testosterone combined.
The incidence of pulmonary embolism was higher with testosterone than with placebo. Although most reported cases of thrombosis associated with testosterone therapy have been in men with underlying thrombophilia,16 a meta-analysis of randomized trials did not show an association between venous thromboembolic events and testosterone use in wider populations.15 Our findings support current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events.17 There were more cases of nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury among patients who received testosterone than among those who received placebo; these adverse events were not expected. A cohort study suggested that normalization of low testosterone levels by testosterone-replacement therapy was associated with a decrease in the incidence of atrial fibrillation.18 In the current trial, the small increase in blood pressure observed in the testosterone group was similar to that reported previously with other testosterone formulations.19
Our trial design specified that noninferiority testing for cardiovascular safety be performed in the population of all patients who had undergone randomization and who had received at least one dose of testosterone or placebo. This modified intention-to-treat analysis preserves the integrity of randomization but may attenuate differences between trial groups and bias toward noninferiority when patients are not adherent to or discontinue their assigned testosterone or placebo. We therefore planned three on-treatment sensitivity analyses and specified that the trial would not conclude until accrual of at least 256 primary end-point events that met the criteria for the principal sensitivity analysis. By considering only those end-point events that occurred while patients were receiving testosterone or placebo or within a time frame of physiologic effect after discontinuation of testosterone or placebo, on-treatment analyses can strengthen safety signals by providing more specific accounting of outcomes related to testosterone therapy. These sensitivity analyses provided support for the noninferiority conclusions.
The incidence of adherence and of retention was lower in this trial than in most cardiovascular outcome studies. Similar levels of adherence and retention have been reported in other trials of testosterone20,21 as well as other therapies for symptomatic conditions such as menopause,22,23 obesity,24,25 and chronic pain.26 These findings reflect the challenge of retaining patients who have persistent symptoms and choose to switch medications or discontinue trial participation. The consistency of the results derived from the intention-to-treat and on-treatment sensitivity analyses suggests that the noninferiority conclusions were unlikely to have been influenced by nonadherence. The effect of nonretention, however, is more difficult to quantify, and the possibility of bias due to informative censoring cannot be ruled out despite a similar incidence of nonretention in the two trial groups. It is somewhat reassuring that of the patients who discontinued trial participation, nearly half did so after end-of-trial visits began, and outcome data were available for more than 80% of the potential person-time follow-up.
Controlled trials have shown that the use of testosterone in older men improves sexual function,27-29 increases volumetric and areal bone mineral density,30 corrects unexplained anemia,31,32 and moderately reduces depressive symptoms.33 However, because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has weighed on treatment decisions by clinicians and patients.17 Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism.
Among men with hypogonadism and established cardiovascular disease or multiple risk factors for incident cardiac events, testosterone-replacement therapy was noninferior to placebo with respect to the occurrence of major adverse cardiac events during a mean 22-month follow-up, and the overall incidence of adverse events was low.
Increased risk for fractures observed with testosterone
In addition to CV safety data, researchers presented findings from five substudies to analyze the effects of testosterone therapy on prostate safety, anemia, diabetes, sexual function and fractures.
Participants in TRAVERSE were asked if they had a fracture during each trial visit. Reported fractures were adjudicated before being labeled as confirmed, unconfirmed or uncertain.
There were 154 confirmed fractures in the testosterone group compared with 97 in the placebo group. Men receiving testosterone had a higher risk for sustaining a clinical fracture compared with men receiving placebo (HR = 1.43; 95% CI, 1.04-1.97; P = .03). The risk for all fractures was also higher in the testosterone group compared with placebo (HR = 1.52; 95% CI, 1.13-2.05; P = .006).
Findings from the fracture substudy were surprising, according to Peter J. Snyder, MD, professor of medicine at the University of Pennsylvania and medical director of the Penn Pituitary Center.
“If testosterone improves bone quality, why does it increase the risk for fracture?” Snyder said. “We can speculate about the possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism.”
No differences in prostate cancer risk, progression to diabetes
In the prostate safety substudy, researchers analyzed the incidence of high-grade prostate cancer among men receiving testosterone vs. placebo. Men were considered for a urological referral and possible biopsy if they had a confirmed prostate-specific antigen test increase of more than 1.4 ng/mL above baseline in the first year of treatment, a confirmed test of more than 4 ng/mL at any time, or a prostate nodule or induration.
The researchers found no difference in prostate cancer or prostate event rates compared with placebo. The overall incidence of prostate cancer was low in the full cohort, with 12 men in the testosterone group and 11 in the placebo group diagnosed with prostate cancer. There was no difference in lower urinary tract symptoms between the groups.
Shalender Bhasin
“It is possible that the viewing of video and shared decision-making played a role in low rates of prostate biopsy and overall low rates of cancer detection,” Shalender Bhasin, MD, professor of medicine at Harvard Medical School, director of the research program in Men’s Health: Aging and Metabolism and director of the Boston Claude D. Pepper Older Americans Independence Center at Brigham and Women’s Hospital, said during the presentation.
Another substudy analyzed the rate of progression from prediabetes to diabetes in TRAVERSE participants. The substudy included 607 men in the testosterone group and 568 in the placebo group who had prediabetes at baseline. In the study, there was no difference in the rate of men who progressed to diabetes between the two groups at any timepoint. There was slightly lower HbA1c among men with prediabetes receiving testosterone compared with placebo at 48 months, but the difference was not deemed to be clinically meaningful, according to Bhasin.
In an analysis of data from 1,917 men in the testosterone group and 1,963 men in the placebo group with diabetes at baseline, the percentage of men who had diabetes remission was similar between the two groups.
Testosterone corrects anemia, improves sexual function
In the anemia substudy, researchers collected data from men who had anemia at baseline to analyze the prevalence of anemia correction. There were 390 men receiving testosterone and 425 men receiving placebo with anemia at baseline. Men in the testosterone group were more likely to have anemia correction at 6, 12, 24 and 36 months compared with placebo.
In an analysis of men who did not have anemia at baseline, the testosterone group had a lower risk for incident anemia at 6, 12 and 24 months compared with placebo.
Researchers also analyzed the effect of testosterone on sexual activity and hypogonadism symptoms. Using the Psychosexual Daily Questionnaire – Question 4 survey, men receiving testosterone reported more sexual activities than those receiving placebo (P = .011). Men in the testosterone group who completed the Hypogonadism Impact of Symptoms Questionnaire reported fewer hypogonadism symptoms than men receiving placebo (P < .001).
“Testosterone treatment was more efficacious than placebo in improving overall sexual activity in middle-aged and older men with hypogonadism who had low libido,” Bhasin said. “The improvements in sexual activity over 1 year were maintained over 2 years of treatment.”
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