Another Study Links Testosterone Therapy to MI Risk

January 30, 2014

LOS ANGELES, CA (updated) — Men, especially older men, thinking about testosterone therapy might want to be aware of the potential cardiovascular risks, according to the authors of a new study[1]. New data published online January 29, 2014 in PLoS One showed that men treated with testosterone are significantly more likely to have an MI in the first 90 days after starting the medication.

In the three months after the start of testosterone therapy, the risk of MI overall was increased by 36%. For those aged 65 years and older, the risk of MI was more than twofold higher in the 90 days after filling the prescription.

"Our findings are consistent with a recent meta-analysis of placebo-controlled randomized trials of testosterone therapy lasting 12 or more weeks among mainly older men, which reported that testosterone therapy increased the risk of adverse cardiovascular-related events, as well as serious adverse cardiovascular-related events, which included myocardial infarction along with other conditions," report Dr William Finkle (Consolidated Research, Los Angeles, CA) and colleagues.

In that previous study, the risk of serious adverse cardiovascular events, including MI, was increased 61%. Other studies, including those reported by heartwire , have also highlighted potential risks, including one National Institutes of Health-sponsored study investigating a testosterone gel that was discontinued given adverse cardiovascular outcomes. A study in the Veterans Affairs healthcare system showed that treatment with testosterone therapy led to an excess of cardiovascular events and death.

Testosterone therapy is currently approved by the Food and Drug Administration for the treatment of low testosterone levels. The ubiquitous "low-T" marketing campaign by makers of testosterone therapies point out that symptoms of low levels include fatigue, loss of sexual interest, and loss of energy.

To heartwire , Dr Steven Nissen (Cleveland Clinic, OH), said he has been concerned about the use of testosterone therapy for some time. He said Proctor & Gamble applied to the FDA in 2004 for an approval of a testosterone patch for women with low libido but was unanimously turned down because there were insufficient data to support long-term safety. Nissen was a member of the FDA advisory committee that recommended against approval and voiced his concerns at that time. In particular, he was concerned about the use of testosterone on the risk of cardiovascular events, including MI and stroke.

Testosterone therapy, added Nissen, is heavily marketed with direct-to-consumer advertising, the drug branded as "a fountain of youth" to treat low energy levels and improve sexual function in men. As a result, he believes that millions of men might be taking testosterone therapy, and yet the long-terms risks, including cardiovascular risks, have never been fully characterized.

"Testosterone is involved in nearly every tissue in the body," said Nissen, noting that it also affects lipids, "and yet we don't what the long-term consequences are."

More Than 50 000 Patients Studied

This latest analysis included 55 593 men who received a new prescription for testosterone therapy, and these men were compared with 167 279 who filled a prescription for phosphodiesterase type 5 (PDE5) inhibitors (sildenafil [Viagra, Pfizer] and tadalafil [Cialis, Lilly]). The PDE5 inhibitors were selected as a comparator arm because many indications for use are similar to testosterone therapy and these agents are not associated with an increased risk of cardiovascular events.

To assess the effect of testosterone therapy, the researchers compared the rate of MI incidence in the 90-day postprescription interval with the incidence rate in the preprescription interval.

The pre- to postprescription relative risk of MI for all patients was 1.36 (95% CI 1.03–1.81). For men 65 years and older, the relative risk of MI 90 days after starting testosterone therapy was 2.19 (RR 1.27–3.77). For those younger than 65 years, there was only a trend toward a higher risk of MI. In the comparator arm, those treated with PDE5 inhibitors had similar rates of MI in the period before they filled their prescription, but there was no signal of risk in the postprescription period, even in the older patients.

When investigators stratified patients into two groups—those with existing coronary heart disease and those without—they found testosterone therapy in those aged younger than 65 years was associated with a twofold increased risk of MI. For those of the same age but without heart disease, there was no signal of risk. In older patients, regardless of heart-disease history, treatment with testosterone increased the risk of MI.

To heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said the nonrandomized design of the study is suitable for detecting the effect size observed in this study, that being a relative risk >1.5 or 2.0. "They have used sophisticated statistical tools to reliably adjust for bias and confounding and ensure validity of results," he added. "The use of a concurrent control [PDE5-inhibitor prescription] is particularly clever because it suggests that the results are not confounded by behavioral or other factors associated with prescription."

With the supportive observations from other studies, the biological plausibility of the findings, and temporal trend of increased risk observed within 90 days of starting the prescription, Kaul said the "overall quality and quantity of data provides credible evidence" linking testosterone therapy to an increased risk of cardiovascular events in vulnerable patients, such as those identified in this paper.

These observations (Kaul was not involved in the study) were echoed by the researchers themselves.

"Given the rapidly increasing use of testosterone therapy, the current results, along with other recent findings, emphasize the urgency of the previous call for clinical trials adequately powered to assess the range of benefits and risks suggested for such therapy," according to Finkle et al. "Until that time, clinicians might be well advised to include serious cardiovascular events in their discussions with patients of potential risks, particularly for men with existing cardiovascular disease."

A clinical trial is needed to characterize the risk of testosterone therapy, added Kaul. "Until then, physicians should exercise clinical judgment and weigh the comparative risks and benefits of [testosterone therapy] on a case-by-case basis," he said.

The study was funded the National Cancer Institute. Finkle is the owner of Consolidated Research, a company that develops statistical methods and software. Disclosures for the coauthors are listed in the paper.





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