Increased VTE Risk With Testosterone Therapy

By Will Boggs MD

November 13, 2019

NEW YORK (Reuters Health) - Men with and without hypogonadism have an increased risk of venous thromboembolism (VTE) with testosterone therapy, according to a case-crossover study.

"While testosterone therapy can have great benefits for men, cardiovascular risk needs to be kept in mind and monitored for at least 6 months after a man's last prescription," said first author Rob F. Walker of the University of Minnesota School of Public Health, in Minneapolis.

"Not only VTE, but stroke and heart attack have been found to be associated with testosterone therapy, and giving a prescription to patients should be done after careful consideration and assessment," he said.

The findings were published online November 11 in JAMA Internal Medicine.

Baseline testosterone levels are not associated with an increased risk of VTE. But exogenous testosterone therapy can increase hematocrit levels, and the associated increase in blood viscosity might increase the risk of subsequent VTE events. Studies addressing this concern, however, have yielded conflicting results.

Walker and colleagues investigated whether exposure to testosterone therapy is associated with an increased risk of incident VTE among more than 39,000 men, including 3,110 diagnosed with hypogonadism and 36,512 without hypogonadism.

Men in the case periods (one, three and six months before the VTE events) were compared with themselves in the control periods (one, three and six months before the case period).

Among men without hypogonadism, testosterone therapy was associated with 96% higher odds of VTE when using the one-month case period, 2.46-fold higher odds of VTE when using the three-month case period, and 2.02-fold higher odds of VTE when using the six-month case period, compared with the equivalent control periods.

Similarly, among men with hypogonadism, testosterone therapy was associated with 66%, 2.28-fold and 2.32-fold increases in the odds of VTE, respectively. All risk increases were statistically significant.

Among men without hypogonadism, the VTE risk in the three-month case period was higher for men younger than 65 than for older men, but this interaction was not statistically significant, and there was no similar interaction among men with hypogonadism.

Associations between testosterone therapy and VTE risk did not differ by the route of testosterone therapy (transdermal or intramuscular).

"For men with hypogonadism, there is an inherent need for testosterone therapy," Walker said. "A man with hypogonadism may require a more careful eye from clinicians regarding VTE risk, including other factors like weight, smoking status, race, etc."

"For men without hypogonadism, however, they might be needlessly putting themselves at a higher risk for a deep vein thrombosis or pulmonary embolism with these therapies, especially younger men," he said. "Other medications or even 'prescribed' lifestyle changes could be beneficial while carrying less of a risk for this group of men, but if testosterone therapy is deemed appropriate, I think clinicians may also want to carefully watch for VTE triggers, risk factors, and warning signs."

"More research assessing risk for high-risk subgroups of men, such as risk by race, geography, or urban/rural divide, would help further inform clinicians about testosterone prescription decisions, and we hope to continue researching this very important topic," Walker added.

Dr. Damon E. Houghton of Mayo Clinic, in Rochester, Minnesota, who in a recent systematic review and meta-analysis (https://bit.ly/34XT0d4) found little evidence to support an association between testosterone therapy and VTE, told Reuters Health, "This study pushes the discussion of testosterone and risk of VTE from whether it is a risk factor, to how much of a risk factor and what physiologically is driving this process. This study adds solid evidence that testosterone supplementation is a risk factor for VTE and that the highest risk occurs within the first several months after drug initiation."

"The driving mechanism behind this association remains unclear," he said. "A better understanding of why this is occurring and what groups would be at the highest risk may lead to more nuanced discussions of risk and possibly even ways to minimize risk if and when testosterone supplementation is truly necessary."

"Risk of VTE with testosterone should now be a standard part of shared decision making discussions prior to testosterone supplementation," Dr. Houghton said.

Dr. Charles J. Glueck of the Cholesterol, Metabolism, and Thrombosis Center, in Cincinnati, Ohio, who has reported a link between testosterone therapy, thrombophilia and VTE (https://bit.ly/2QmqOfV), told Reuters Health by email, "We have very recently published that the greatest density of thromboembolic events was at 3 months after starting testosterone, with a rapid decline by 10 months. The data (in the new report) showed the exact same finding. Previous population studies which focused on thromboembolic events after 6-12 months probably missed the testosterone-thromboembolism relationship because of this time course."

"Testosterone therapy should be given only to men with documented hypogonadism, with antecedent warning of thromboembolic risk, and optimally, with pre-testosterone therapy screening for thrombophilia," he said.

"Testosterone should not be given to patients with documented familial and acquired thrombophilia, particularly if they are heterozygous for the Factor V Leiden mutation and/or have the Lupus Anticoagulant," added Dr. Glueck, who like Dr. Houghton was not involved in the new study.

SOURCE: https://bit.ly/2CAKUe3

JAMA Intern Med 2019.

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