Testosterone therapy taken for "low T" raises the risk of mortality, myocardial infarction, and ischemic stroke, according to a report published online Nov. 5 in JAMA.

The risk elevation is consistent in both men who have existing coronary artery disease and men who do not, and is not affected by differences in cardiovascular risk factors such as blood pressure or by the use of preventive medications, said Dr. Rebecca Vigen of the University of Texas at Southwestern Medical Center, Dallas, and her associates.

These findings, from what the investigators describe as the first observational study to suggest a causal link between testosterone therapy and adverse cardiovascular outcomes, "raise concerns about the potential safety of testosterone therapy." Randomized clinical trials are warranted to clarify this issue, they noted.

"Although physicians should continue to discuss the symptomatic benefits of testosterone therapy with patients, it is also important to inform patients that long-term risks are unknown and there is a possibility that testosterone therapy might be harmful," Dr. Vigen and her colleagues added.

Previous studies have shown that testosterone therapy improves sexual function and strength, as well as some cardiovascular risk factors such as lipid profiles and insulin resistance. They have not detected adverse CV effects, "but these trials were generally focused on intermediate endpoints, of short duration, and not powered for clinical endpoints," the investigators wrote.

One clinical trial that included many men with CV disorders was halted early in 2010 when the group receiving testosterone was found to have an excess of CV events, compared with the placebo group.

Dr. Vigen and her associates examined the potential CV risks of testosterone therapy in a retrospective cohort study using data from the Veterans Administration’s Clinical Assessment Reporting and Tracking (CART) program, which collects information on all procedures performed in the 76 VA cardiac catheterization laboratories across the country. They identified all men who underwent coronary angiography at these facilities in 2005-2011 (who therefore had well-characterized cardiovascular profiles) and whose medical records also showed a total testosterone level of less than 300 ng/dL.

This cohort of 8,709 men had a high burden of comorbidities: 20% had a history of MI, half had diabetes, and more than 80% had coronary artery disease. Rates of these comorbidities were approximately equal between men taking testosterone and men not taking testosterone.

A total of 1,223 of these men were taking testosterone therapy to address their low testosterone levels. Roughly 1% of them were using testosterone gel, 36% were using injections, and 63% were using patches. Men who used testosterone tended to be younger and healthier than those who did not.

During an average of 28 months of follow-up, there were 1,710 adverse events of interest: 748 men died, 443 had MIs, and 519 had strokes. The absolute risk of these events was significantly greater in testosterone users than in nonusers: 1.3% higher at 1 year, 3.1% higher at 2 years, and 5.8% higher at 3 years, the investigators said (JAMA 2013 [doi:10.1001/jama2013.280386]).

In a further, adjusted analysis of the data, testosterone use remained strongly associated with increased risk of death, MI, or stroke, with a hazard ratio of 1.29. This indicates that testosterone users were 29% more likely than were nonusers to experience these adverse outcomes.

These findings were unchanged after the data were further adjusted to account for the presence or absence of CAD and the use or nonuse of coronary revascularization procedures.

There was no significant difference in risk of adverse outcomes among the three formulations of testosterone.

The researchers noted that there are several potential mechanisms by which testosterone therapy might increase cardiovascular risk. It increases platelet aggregation, which contributes to arterial plaque formation. It enhances monocyte activation in the endothelium, which promotes atherosclerosis and is implicated in the pathogenesis of acute coronary syndromes. And it aggravates sleep-disordered breathing, another CV risk factor, they said.

This study was supported by the U.S. Department of Veterans Affairs. No financial conflicts of interest were reported.