Testosterone Therapy Raises Risk of VTE Early but Not Beyond 6 Months

A new population-based study suggests that the duration of testosterone replacement therapy is an important factor to consider when assessing the risks of venous thromboembolism (VTE) associated with treatment.

In a large analysis of patients treated at 370 primary care clinics in the United Kingdom, testosterone use was associated with a significantly increased risk of VTE in the first 6 months of treatment, but the risk declined following this initial period. The early rise in VTE risk within 6 months of starting treatment was observed among patients with and without hypogonadism and patients with and without a clinical risk factor for VTE.

“It’s a small but significant increase,” senior investigator Alexander Cohen (Guy’s and St. Thomas NHS Foundation Trust, London, England), told TCTMD. “I don’t think this study elicits panic,” he added, noting the absolute number of events with therapy was small.

Regarding the immediate clinical implications, Cohen said physicians should have conversations with patients taking testosterone therapy so that they’re aware about the signs and symptoms of VTE. “Well, you can hardly say don’t go on testosterone, but as part of informed consent, they should be aware of the symptoms, such as swollen legs, chest pain, and shortness of breath,” he advised. “At least educate the patient.”

The study was published November 30, 2016, in the BMJ.

Ongoing Debate, Little Resolution So Far

Debate over the cardiovascular risks of testosterone therapy has been ongoing for several years, and the issue is particularly relevant given the dramatic increase in use. For example, in the United States, there was a 10-fold increase in testosterone use from 2000 to 2011. In Canada, when internet pharmacies were included in the estimate, researchers suggested use increased 40-fold during the same time period.

At least educate the patient. Alexander Cohen

The increased uptake is typically for unproven indications, such as diminished libido and/or decreased energy levels. In 2015, concerns over the risks of MI and stroke with testosterone therapy led the US Food and Drug Administration (FDA) to require manufacturers to change the product label in order to clarify that testosterone is indicated only as replacement therapy in men with conditions associated with a deficiency in endogenous testosterone, such as primary or hypogonadotropic hypogonadism.

In this latest analysis, which was led by Carlos Martinez, MD (Institute for Epidemiology, Statistics, and Informatics, GmbH, Frankfurt, Germany), the researchers identified 19,215 patients with confirmed VTE between 2001 and 2013 from the UK Clinical Practice Research Datalink and 909,530 age-matched controls. Patients were stratified into three exposure groups: currently taking testosterone, recent (but not current) treatment, and no treatment in the past 2 years.

Compared with the no-treatment group, the risk of VTE was not significantly higher among those currently taking testosterone (adjusted rate ratio 1.25; 95% CI 0.94-1.66). In the first 6 months, those taking testosterone had a relative 63% higher risk of VTE compared with the no-treatment group, a difference that was statistically significant. This corresponded to 10 additional VTEs per 10,000 person-years. Beyond 6 months, and after treatment was stopped, the risk of VTE was not significantly elevated among testosterone users.

Earlier this year, a Canadian study published in the Lancet Diabetes and Endocrinology also found a link between duration of treatment and the risk of death and cardiovascular events.

To TCTMD, Cohen flagged the rising use of testosterone therapy in the UK and Europe. “We’re seeing, from a clinical point of view, testosterone and testosterone-like products, such as androgen, used in a lot in men, and it’s not for any other reason than general lassitude, sexual dysfunction, and perhaps wanting to feel a bit more youthful,” he said.

Cohen noted that some immune-modulated therapies, which are now being used to treat some cancers, such as melanoma, can cause a general immune reaction that results in hypopituitarism and diminished testosterone levels.

Paucity of Data  

Robert Kloner, MD (Huntington Medical Research Institutes, Pasadena, CA), who was not involved in the study but who authored a state-of-the-art review in the Journal of the American College of Cardiology earlier this year, said the analysis has a number of strengths, including a large number of study subjects, a validated VTE algorithm, matched controls, long duration of follow-up, and an attempt to take into account comorbidities. 

The current paper is unlikely to change the FDA label, he said, but it does strengthen the warning. “There really has been a paucity of data in this area, and not all studies have shown an association between testosterone and VTE,” he told TCTMD.

In 2014, the FDA required manufacturers to include a general warning about the risk of VTE with testosterone products. Prior to the change, the label did include a warning about the risk of VTE but only as a possible consequence of polycythemia, which is an abnormal increase in red blood cells.

The seemingly “transient” increased risk of VTE is “interesting,” added Kloner, but given the observational nature of the study, which includes the potential of unmeasured or residual confounding variables, nothing definitive can be drawn from the conclusions. “What we really need to resolve the testosterone controversy is a large randomized, placebo-controlled trial that is blinded and in which cardiovascular endpoints are primary endpoints,” he said. “Without such a study the testosterone controversy will continue.”

It would be a huge study, and a lot of men would love to be in it. Stephen Kopecky

Stephen Kopecky, MD (Mayo Clinic, Rochester, MN), one of the co-authors of the JACC review, said similar transient risks have been observed with estrogen replacement therapy, with women who have taken the hormone for extended periods of time not having the same risk of cardiovascular events as shorter-term users. He said more research is needed to identify the type of patient at risk for developing VTE with testosterone therapy and agreed that a randomized controlled trial is needed. Logistically, though, such a study would be a tough undertaking.

“The big issue is who you include in the trial,” Kopecky said. “There’s the FDA indication—patients with hypogonadism—but there aren’t that many true patients like that out there. So, to find a vascular event like this, which doesn’t occur that frequently—the absolute numbers are not that large—you’d need tens of thousands of patients. They’d likely have to expand it to patients with chemical hypogonadism, or close to it, and [who also] have some lethargy, fatigue, or erectile dysfunction. It would be a huge study, and a lot of men would love to be in it.”