Long-term TRT use reduces risk of CV events, PCa

San Diego-There is no excess risk of death, prostate cancer diagnosis, or cardiovascular events with long-term testosterone replacement therapy (TRT), Canadian researchers have found in a population-based matched cohort study.  

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TRT users with the highest exposure had reductions in the risk of all of these outcomes, although short-term use of TRT was associated with an increase in the risk of cardiovascular events, said Christopher J.D. Wallis, MD, at the AUA annual meeting in San Diego.

In 2015, the FDA required a labeling change for all prescription testosterone products to reflect a possible increased risk of myocardial infarction and stroke associated with testosterone use. This action, however, was based primarily on studies that had short follow-up and limited duration of treatment, and looked only at binary exposure (“yes” or “no”) to TRT.

“Many of these studies followed men for no more than 3 months after initiation of therapy,” said Dr. Wallis, a urology resident at the University of Toronto, working with Robert Nam, MD, and colleagues.

His group examined the relationship between short- and long-term use of TRT and rates of cardiovascular events, prostate cancer, and overall mortality. To accomplish this goal, they matched 10,311 men 66 years of age and older who were treated with TRT from 2007-2012 in Ontario, Canada to 28,029 controls. Each case was matched to up to three controls (mean: 2.7) based on age, comorbidity, history of cardiovascular events, and geographic region.

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TRT was measured according to both binary exposure and cumulative dose exposure using tertiles of TRT duration. Tertile 1 had exposure of 1 to 120 days, tertile 2 for 121 to 510 days, and tertile 3 >510 days. Median follow-up of the cohort was 5.1 years.

Next: Mortality risk drop seen in TRT users

Mortality risk drop seen in TRT users

When analyzed by binary exposure, the risk of overall mortality was decreased by 12% (p<.0001) in TRT users versus non-users. When stratified by tertile of exposure, patients in tertile 1 had an 11% increased risk of death (p=.005) but those in tertile 2 had a 10% reduction in overall mortality (p=.007) and those in tertile 3 had a 33% reduction (p<.0001).

The risk of cardiovascular events was similar in TRT users and non-users. When assessed by duration of exposure, “We again see that short durations of therapy have an increased risk, where longer durations of therapy have a significant protective effect,” Dr. Wallis said. Patients with TRT exposure in tertile 1 had a 26% increased risk of cardiovascular events (p=.002), those in tertile 2 had a 16% increased risk (p=.05), and those in tertile 3 had a 16% lower risk (p=.02).

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TRT had a protective effect on prostate cancer diagnoses in the binary model. TRT users in tertile 3 had a significant 40% reduction in the risk of a prostate cancer diagnosis compared with non-users (p=.0005).

Next: Late reduction in events with TRT use “not driven by an increase in early events"

The late reduction in events with TRT use was “not driven by an increase in early events,” he said. For each endpoint, there was a statistically significant trend for decreasing risk with increasing cumulative dose exposure to testosterone.

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A low testosterone level that has not been adequately replaced may explain the increase in some events in the short term, he believes.

“Once you adequately replace that, the risk is attenuated,” Dr. Wallis said.

The potential for a healthy user bias is one limitation of the study. Those likely to seek out and maintain TRT “are likely to be different from their contemporaries,” he said.

Although the data support the safety of long-term TRT, “Potential protective effects of TRT remain to be proven,” he concluded.

One of Dr. Wallis’ co-authors is a consultant/adviser and/or investigator for Allergan, Boston Scientific, Pfizer, Astellas Pharma, Promedon, and Merus.

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