Long Way to Go Before Testosterone Warnings Reach Older Men?

Liam Davenport

December 28, 2018

Men with coronary artery disease (CAD) are continuing to use testosterone, often off-label, despite warnings from the US Food and Drug Administration (FDA) that it can be associated with potential cardiovascular harm, as well as having unproven benefits in many populations, warn researchers.

Nancy E. Morden, MD, MPH, The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, and colleagues examined Medicare data on millions of men aged at least 50 years between 2007 and 2016.

They found that as many as 7% of men used the hormone in certain parts of the United States, with the majority of prescriptions for off-label use. And spending on testosterone has been increasing annually, almost quadrupling from just over $100 million in 2007 to around $400 million in 2016.

The research, which was published online today in JAMA Internal Medicine, also shows that testosterone use is consistently higher among men with CAD than those without.

"Persistently higher testosterone use among patients with CAD suggests the need for more effective dissemination of label changes," the team writes.

"A robust prior authorization process could also help, as could rigorous evidence-based safety-review processes, richer shared-risk contracts, and patient education."

Morden underlined to Medscape Medical News that the study figures apply only to Medicare patients, and so these are a "very conservative" estimate of overall spending on testosterone in the United States.

"That's just for the drug, we're not talking about the cost of any events," that might arise. "So this is a public payer reimbursing medications of unknown efficacy and unknown harms in the population that is [almost] entirely off-label."

RCT of Testosterone Will Provide Answers but Is Moving at a Snail's Pace

The publication of two articles linking testosterone therapy with stroke and myocardial infarction in 2013 and 2014 prompted the FDA to issue a safety communication and a requirement for a warning on the product label, which was echoed by the Endocrine Society. In 2015, the FDA revised testosterone labels to highlight the lack of evidence of efficacy for age-related hypogonadism and added a warning about potential increased cardiovascular risk.

The Endocrine Society issued new guidance on testosterone prescribing earlier this year.

Morden, who led the current study, told Medscape Medical News that it is at least "helpful" that direct-to-consumer advertising of off-label testosterone was withdrawn voluntarily in 2014. "We were sending out messages that were misleading and certainly didn't communicate any potential risk, and so the end of that is good," she said.

However, she believes much more work is needed to "develop policies and practice standards that make sure patients are informed that we do not understand efficacy and that safety is unclear."

"That would be the lowest bar to clear, in my mind," she added.

But it would be preferable, for testosterone in particular, that a precautionary principle be adopted in terms of regulation, she stressed to Medscape Medical News.

"This is a particularly complex example...[this] is about sex, this is about aging, this is about natural processes being medicalized."

Moreover, Morden would like to see more evidence of the potential benefits as weighed against the harms of testosterone use, which should be forthcoming once an FDA-mandated randomized controlled trial on the hormone is completed.

"That has been, in my opinion, very slow to move. When we very first submitted this article for consideration [in 2018], recruiting of patients had not started yet. The FDA made its announcement in 2015," after an initial 2010 publication hinted at potential harms.

Morden continued: "That [FDA] trial is not expected to be completed until 2022. So, a full 12 years after the first signals of harm came out, we will finally see the results of this randomized trial."

"It is a long time...for potential harms to be done and, over this time...more and more men are crossing that threshold of 65 years of age...and an aging population means that we are potentially putting more and more men at risk for an unknown benefit."

Reimburse Only Those With a Proven Indication for Testosterone?

To examine the changing patterns of testosterone use, Morden and colleagues collated a random 40% sample of Medicare fee-for-service data from 2007 to 2016.

From this, they created annual cohorts of men aged at least 50 years, with and without a CAD diagnosis in the same year, examining testosterone prescription fills, adjusted for national and regional rates.

The annual cohorts ranged in size from 1.8 to 3.1 million men, representing 10% to 12% of the fee-for-service Medicare population aged ≥ 50 years. The mean age was 71.2 years.

The annual CAD cohorts ranged from 629,823 to 1,017,484, representing approximately one third of the overall CAD cohort.

Between 0.2% and 0.3% of men included in the study received an on-label prescription for testosterone. Off-label prescriptions reached a peak in 2013, at 3.2% of the CAD cohort and 2.4% of those without CAD.

Throughout the study period, testosterone use was higher among men with CAD than those without. In 2016, for example, the respective percentages were 2.0% and 1.6%.

There were large regional variations in testosterone use, however.

For example, in 2016, the percentage of men using the hormone ranged from 4.4% to 7.0% in four regions with high use versus 0.5% and 1.0% in 14 regions with low use.

And reiterating the increase in annual testosterone spending observed in this study, from $108 million in 2007 to $402 million in 2016, Morden said it might be wise to consider instituting a policy, for example, "to only reimburse testosterone use for patients with a documented, proven indication for it."

Other studies have shown a decline in testosterone prescriptions in recent years. For example, one which assessed use in employed American men covered by a large US insurer, published in July in JAMA, as reported by Medscape Medical News, showed prescriptions for testosterone started to drop from 2013 onwards.

The study was funded by a grant from the Agency for Healthcare Research and Quality (AHRQ) Comparative Health System Performance Initiative. Lisa M. Schwartz and Steven Woloshin reported serving as medical experts in testosterone litigation and being cofounders of Informulary, which ceased operations in December 2016.

JAMA Intern Med. Published online December 28, 2018. Abstract

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