Testosterone Therapy Linked With Adverse CVD Events

November 05, 2013

DENVER, CO — The use of testosterone therapy in men is associated with an increased risk of death, MI, or ischemic stroke, according to the results of a new study[1]. The increased risk, which was about 30% higher in men treated with testosterone than in those who did not receive it, was observed in a cohort of Veterans Affairs (VA) patients with multiple comorbidities undergoing coronary angiography.

"We found an association; it's not causal, given the observational nature of the study," senior investigator Dr Michael Ho (Veterans Affairs Eastern Colorado Health Care System, Denver) told heartwire . "It does provide some evidence that testosterone therapy may be associated with some increased risk of adverse cardiovascular outcomes. For patients who are starting therapy or who are currently on therapy, this might warrant a discussion with their physicians about the potential benefits of the therapy vs the potential risk. I think that decision should be individualized for each patient."

For Dr Anne Cappola (University of Pennsylvania Perelman School of Medicine, Philadelphia), who wrote an editorial accompanying the study[2], one of the more important questions currently is whether or not the findings would apply to a broader patient population than those observed in the VA analysis.

In the US, nearly 3% of men over 40 years of age are prescribed testosterone therapy, and many men take the drug for "low-T syndrome," antiaging purposes, or "physical enhancement," according to Cappola.

"Does the 29% increased risk of myocardial infarction, ischemic stroke, or mortality apply to these groups? Are the benefits—real or perceived—for these groups of men worth any increase in risk?" she asks. "These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men."

Risk Is One-Third Higher With Testosterone

Published in the November 6, 2013 issue of the Journal of the American Medical Association, the study included 8709 men with low testosterone levels, defined as <300 ng/dL, undergoing coronary angiography between 2005 and 2011. Of these men, 1223 started testosterone-replacement therapy. The individuals included in the analysis had a high rate of comorbidities, with 20% having a prior history of MI, 50% having diabetes, and more than 80% having coronary artery disease.

After a median follow-up of 27 months, 748 individuals died, 443 had an MI, and 519 had a stroke. Regarding the combined end point of adverse cardiovascular outcomes, which included death, MI, and ischemic stroke, the absolute rates at one year were 10.1% in those who did not receive testosterone and 11.3% among those who did. At two years, the absolute rates were 15.4% and 18.5%, respectively, and at three years, the absolute rates were 19.9% and 25.7%, respectively.

Overall, the use of testosterone therapy was associated with a 29% increased risk of death, MI, or ischemic stroke (p=0.02), and this risk was unchanged after adjustment for the presence of coronary artery disease. There was no significant difference in risk by testosterone formulation, although the study was underpowered to detect differences between the routes of administration.

Not the First Study to Suggest Harm

To heartwire , Ho said that previous studies analyzing the association between testosterone use and cardiovascular risk showed mixed results. There were a lot of unknowns, he added, because many of these studies were small in size or short in duration. In one recent observational study, men with hypogonadism who took testosterone for 5 years showed improvements in lipids, blood pressure, and blood glucose levels. But another study, theTestosterone in Older Men with Mobility Limitations (TOM) trial, was stopped early because of an increased risk of cardiovascular events in patients treated with testosterone. That trial, said Ho, led investigators to analyze data from the VA healthcare system.

At present, not much is known about the possible underlying mechanism that might contribute to the increased risk of cardiovascular events in testosterone-treated patients, but Ho said testosterone can increase hematocrit levels, affect platelet aggregation, and worsen sleep apnea. Further studies are needed to address the possible mechanism, as well as randomized, controlled trials to validate these results and properly characterize the risk in men.

In the editorial, Cappola said there is "mounting evidence of a signal of cardiovascular risk" with testosterone, and patients and prescribers need to be wary, given the large number of prescriptions written in the US and the aggressive marketing by the drug companies that manufacture testosterone-replacement therapy. There is little information in the VA database about whether testosterone was prescribed appropriately, such as those with a clinical problem related to testosterone deficiency, and whether testosterone levels were monitored properly, she adds.

Funding and support for the study was provided by grants from the Veterans Affairs. Ho and coauthors have no conflicts of interest. Cappola reports participating in a continuing medical education (CME) presentation sponsored by Abbott and serving on a data monitoring board for BioSante Pharmaceuticals.

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