Testosterone Doesn’t Cause CV Events in High-Risk Men With Hypogonadism

Testosterone replacement therapy doesn’t lead to an excess of cardiovascular events when taken by men with hypogonadism and preexisting or high risk of CVD, according to results from the randomized, placebo-controlled TRAVERSE trial.

The results were presented today at the Endocrine Society’s annual meeting in Chicago, IL, and simultaneously published in the New England Journal of Medicine.

They bring a 13-year saga to a close: back in 2010, the US Food and Drug Administration initiated a review of testosterone products on the basis of a small placebo-controlled trial that was prematurely discontinued when its testosterone group showed a rise in CV events. In September 2014, the agency held a joint advisory committee meeting to discuss the concerns.

TRAVERSE investigator A. Michael Lincoff, MD (Cleveland Clinic, OH), who served on the FDA advisory panel back in 2014, told TCTMD that at the time, the data were very conflicting. “Some studies suggested there was benefit, some studies suggested the opposite. None of them were adequately sized or powered, none of them prospectively looked at cardiovascular events [or] men specifically at high risk for cardiovascular events,” he said.

Aiming to fill that gap, the FDA issued guidance in March 2015 that required manufacturers of approved testosterone products to conduct clinical trials. TRAVERSE, a cooperative effort by four companies, was designed to meet that request.

The news from TRAVERSE is reassuring, but shouldn’t be extrapolated too loosely, Lincoff stressed. “It shouldn’t be considered a license to go out and treat all men who are tired and not as sexually active as they’d like to be with testosterone in a willy-nilly fashion, which is happening by less-than-conscientious practitioners.”

It shouldn’t be considered a license to go out and treat all men who are tired and not as sexually active as they’d like to be with testosterone in a willy-nilly fashion. A. Michael Lincoff

Testosterone replacement therapy was initially approved by the FDA for men with hypogonadism, which can result from testicular cancer and other disorders of the testicles, pituitary gland, or brain—these patients, in particular the subset with preexisting or a high risk of CVD, were the focus of TRAVERSE.

Today, in contrast, testosterone is being used primarily “in middle-aged and older men who have declines in testosterone levels and have symptoms that could be hypogonadism but also are the symptoms of aging,” Lincoff noted. At many clinics where such patients receive testosterone, their hormone levels aren’t tested to begin with or routinely monitored thereafter.

The takeaway from TRAVERSE? For middle-age and older men with “age-related lower testosterone levels and symptoms of hypogonadism who are being monitored carefully, as they were in this trial, I think this trial provides a great deal of reassurance and confidence that their cardiovascular risk will not be elevated for the major [events like] death, stroke, and heart attack,” Lincoff specified.

TRAVERSE

Across 316 US sites, Lincoff and colleagues enrolled 5,246 men ages 45 to 80 who either had preexisting CVD or were at high risk of developing it, reported symptoms of hypogonadism, and had two fasting testosterone levels < 300 ng/dL. These participants were randomized to receive daily transdermal 1.62% testosterone gel, with the dose adjusted to reach testosterone levels of 350 to 750 ng/dL, or placebo. Mean treatment duration was 21.7 months.

At a mean follow-up of 33 months, a primary cardiovascular safety endpoint (first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke) had occurred in 7.0% of the testosterone group and 7.3% of the placebo group (P < 0.001 for noninferiority). There were no differences in each of this endpoint’s components or when coronary revascularization was added to the composite.

However, compared with the placebo group, testosterone-treated patients had more nonfatal arrhythmias warranting intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), and acute kidney injury (2.3% vs 1.5%), as well as a higher incidence of pulmonary embolism (0.9% vs. 0.5%).

Lincoff said that, going into the study, he didn’t know if it would uncover any CV safety issues. “I felt this was one of those situations where I had true equipoise,” he said, adding, “It was really an open question in my mind about whether or not there would be risk. There was clearly precedent for risk with other hormonal manipulations, such as hormone replacement for postmenopausal women, but on the other hand this is very different pathophysiology. . . . The key was to design the trial in a way that had the high-risk patients and would maximize the likelihood of seeing a safety signal if there indeed was one.”

For him, there was even a little hope that TRAVERSE would show some benefit, since some research had suggested very low levels of testosterone are linked to increased risk, Lincoff noted. He pointed out, however, that TRAVERSE wasn’t powered to show benefit and didn’t enroll men who had exceedingly low testosterone levels.

TRAVERSE’s large size is enabling researchers to pursue additional substudies looking beyond CV safety at things like “prostate safety and efficacy with regard to anemia, diabetes, sexual function, [and] bone fractures,” said Lincoff.