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Men with significant comorbidities who receive testosterone therapy face an increased risk of cardiovascular events, according to a retrospective cohort study published in the November 6, 2013, issue of the Journal of the American Medical Association.

Investigators led by P. Michael Ho, MD, PhD, of the Veterans Administration (VA) Eastern Colorado Health Care System (Denver, CO), looked at 8,709 men from the VA Clinical Assessment Reporting and Tracking Program who underwent angiography between 2005 and 2011 and had a testosterone level below 300 ng/dL (the threshold for hypogonadism) without prior testosterone therapy.

At a median of 531 days after angiography, 14% of the men (n = 1,223) started testosterone therapy. These patients tended to be younger and have fewer comorbidities, such as congestive heart failure and cerebrovascular disease, than those who did not initiate the therapy (both P < 0.001).

Risk One-Third Higher with Testosterone

The average follow-up was approximately 27.5 months. At 3 years after angiography, the absolute rate of the composite of all-cause death, MI, and ischemic stroke (the primary outcome) was 19.9% in the no-testosterone therapy group vs. 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% CI -1.4% to 13.1%).

In analysis with standardized weighting and testosterone therapy as a time-varying covariate, testosterone use was associated with a nearly one-third increased risk of the composite outcome (HR1.29; 95% CI 1.05-1.58). There was no difference in the effect size of testosterone therapy between those with or without CAD (P for interaction = 0.41). Furthermore, the link between testosterone therapy and adverse events after adjusting for the presence of CAD remained unchanged when revascularization procedures were included as additional outcomes (HR 1.37; 95% CI 1.21-1.56).

Differences in outcomes between the arms were unrelated to differential treatment of cardiovascular risk factors or use of secondary prevention medications. For example, there were no differences between the groups in LDL levels or use of beta-blockers and statin medications at 1 and 2 years. Moreover, systolic blood pressure was similar between the arms at both 1 and 2 years, while diastolic pressure was lower in the testosterone group at 1 year and similar between the groups at 2 years.

Safety Signal Relatively New

With the exception of the TOM trial involving frail older men, which was halted prematurely, previous clinical trials have shown that testosterone therapy improves certain cardiac risk factors with no sign of harm, the authors say. However, they point out, most of the studies were small, enrolled patients of different ages, and were of variable duration. In addition, an earlier VA trial that found a 39% mortality reduction with testosterone therapy included men with a lower incidence of heart disease than the current study and used a problematic method of controlling for confounding.

The investigators suggest several possible mechanisms by which testosterone therapy may raise cardiovascular risk, including:

• Increasing platelet thromboxane A₂ receptor density and platelet aggregation
• Stimulating smooth muscle proliferation and expression of vascular cell adhesion molecule 1
• Worsening obstructive sleep apnea, a risk factor for atherosclerosis

“Our findings raise some uncertainty regarding the potential safety of testosterone use in men,” Dr. Ho and colleagues conclude. “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.”

In an accompanying editorial, Anne R. Cappola, MD, ScM, of the Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA), writes, “Perhaps the most important question is the generalizability of the results . . . to the broader population of men taking testosterone,” which includes those who receive the hormone for ‘low-T syndrome’ or anti-aging purposes and younger men taking it for physical enhancement. “Are the benefits—real or perceived—for these groups of men worth any increase in risk?” she asks.

Results ‘Hopelessly Confounded’

But in an interview with TCTMD, Sorin J. Brener, MD, of Weil Cornell Medical College (New York, NY), said the study leaves important questions unanswered, such as why the men were tested for testosterone levels in the first place and why approximately 70% of the untreated group—whose low testosterone levels appeared to qualify them for the therapy—did not receive it. Despite the investigators’ use of sophisticated methodology, the results are “hopelessly confounded,” he asserted.

Furthermore, Dr. Brener observed, over the period in which the primary outcome differed between the treated and untreated groups, the population at risk was only about 500 patients, “which means that the observation is not very robust.”

Before prescribing testosterone therapy for an older patient with a high-risk profile, a physician should consult a cardiologist, Dr. Brener advised.

“I think it’s clear that if you have advanced heart disease, you should not be on this medication,” he said, although he added that the question becomes more problematic for men with cardiovascular risk factors but no history of heart disease. Such patients should receive a stress test and if it is very abnormal, undergo catheterization to verify whether or not significant CAD is present, he said. However, “I don’t think revascularization would solve the problem because it’s the potential for plaque rupture that is the issue,” he added.

Testosterone therapy is currently being tested in the multicenter randomized, controlled Testosterone Trial, which is enrolling about 800 elderly men with testosterone levels less than 250 ng/dL. In addition to multiple efficacy endpoints, the researchers will assess plaque burden.

Study Details

Of the 1,223 patients prescribed testosterone therapy, 82.4% filled more than 1 prescription. The mean time from first to last fill was 376 days.

Sources:

1. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829-1836.

2. Cappola AR. Testosterone therapy and risk of cardiovascular disease in men [editorial]. JAMA. 2013;310:1805-1806.

Disclosures:

·         Drs. Ho and Brener report no relevant conflicts of interest.

·         Dr. Cappola reports participating in a CME presentation sponsored by an educational grant from Abbott Laboratories and serving on a data monitoring board for BioSante Pharmaceuticals.

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