Testosterone Therapy Ups VTE Risk, Even When Indicated

Testosterone therapy, no matter how it is delivered, raises the 6-month risk of venous thromboembolism (VTE) regardless of whether the men who take it have low levels of the hormone, a new observational study suggests. Among men without hypogonadism, however, the risk appears to be higher in those younger than 65 years than in older men.

“These findings suggest that caution should be used when prescribing testosterone therapy,” Rob F. Walker, MPH (University of Minnesota, Minneapolis), and colleagues write, noting that there are several reasons why the therapy might raise VTE risk, such as elevated hematocrit levels that increase blood viscosity.

Despite some evidence of harm and little evidence of benefit, testosterone use skyrocketed more than 300% from 2001 to 2013, they point out. Thanks to a 2014 warning from the US Food and Drug Administration about potential stroke and MI risks with testosterone therapy, prescriptions decreased and then plateaued. As of 2016, approximately 1.15 million US men older than 30 years (1.6%) were prescribed the therapy.

The researchers explain that the main clinical indication for testosterone therapy is hypogonadism, a condition in which serum testosterone levels dip low enough to cause sexual dysfunction, changes in bone metabolism and body composition, and heightened emotions. Causes can include genetic disease as well as complications from surgery, infection, and medications.

But many men are simply hoping to stave off aging, even in the absence of low testosterone levels that might merit treatment.

Stephen Kopecky, MD (Mayo Clinic, Rochester, MN), said that the current study is consistent with its predecessors in showing the risks of testosterone. Commenting for TCTMD, he drew parallels to data on the hazards of estrogen use in women. “Ten, 12, 15 years ago, everybody thought estrogen was going to be the answer to menopause and women’s risk of heart disease going up after menopause,” Kopecky said. But similar to the situation with testosterone, women experienced a rise in thromboembolic risk, particularly just after initiating estrogen.

The bottom line in both situations is that hormone therapy is okay if needed but shouldn’t be taken lightly, he stressed.

VTE Risk Before and After Testosterone

For their case-crossover study, published online November 11, 2019, in JAMA Internal Medicine, Walker et al culled data from the IBM MarketScan Commercial Claims and Encounter Database as well as the Medicare Supplemental Database on 39,622 men (mean age 57.4 years) who experienced VTE between 2011 and 2017 but were free of cancer. Within this group, 7.8% had evidence of hypogonadism based on diagnostic codes and 73.7% were below age 65.

In the hypogonadism group, 42.8% had been prescribed testosterone in the year prior to their VTE. For men without the condition, the prescription rate was 1.0%.

By design, individuals served as their own controls. Adjusted for patient age, VTE risk was doubled in the 6 months after starting testosterone for men with hypogonadism (OR 2.32; 95% CI 1.97-2.74) and for men without the diagnosis (OR 2.02; 9% CI 1.47-2.77) compared with the risk during the 6 months prior.

Without hypogonadism, there was a trend toward greater VTE risk on testosterone in those younger than 65 years (OR 2.33) compared with older individuals (OR 1.41; P for interaction = 0.11). Among patients with hypogonadism, however, no age-based difference was seen. Across the board, there were no differences in risk according to whether the route of testosterone therapy was transdermal or intramuscular.

For both groups, VTE risk was most elevated in the first 3 months of testosterone therapy.

“Men younger than 65 years who begin testosterone therapy early to deter common health symptoms potentially associated with aging may be exposing themselves to greater risk of early-onset cardiovascular disease outcomes, especially if there is no clinical indication for starting therapy,” the investigators caution, advising that men experiencing the “symptoms that result from natural aging,” such as low libido and fat redistribution, should assess their CVD risk with their physicians before starting therapy.

What to Tell Patients

Asked whether most cardiologists would be aware of patients’ testosterone use, Kopecky urged clinicians to routinely ask about every pill or capsule they swallow and every injection or paste they put on their skin, whether prescribed or over the counter. “Now, that doesn’t mean they always tell us about them. They don’t always put it down, especially things like testosterone and . . . anabolic steroids that some men will take to build muscle. [W]e sometimes find it in lab testing and have to ask them about it,” he pointed out.

In terms of what might be done to mitigate the VTE risk, Kopecky said that there is no easy answer. “We don’t have a pill that negates it,” he observed, adding that any remedy might carry its own side effects.

Instead, “we need to be very judicious and very careful with who we give testosterone to. And if your testosterone levels are normal, it doesn’t really help to have more. . . . Your body doesn’t really need more,” stressed Kopecky.

The absolute risk is quite low, he acknowledged, “but the point is, ‘If it happens in you, it’s a big deal in you.’” On a population scale, too, once a drug is used by millions of people, this translates into an observable impact on public health, he explained.

Worth remembering is that the relative risks carried by smoking, unhealthy foods, and lack of exercise are even larger than what’s seen with hormone therapy, Kopecky noted. “If you are going on testosterone for whatever legitimate reason, if you’re hypogonadal, then try to improve your lifestyle as much as you can.” He advised eating a diet based on fruits and vegetables with less red meat and processed foods as well as getting more aerobic exercise, even in small intervals.