Commentary

Will Testosterone Replacement Therapy Kill Your Patient?

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The second trial that seemed to cast doubt on the safety of TRT suffered from an even worse design. It was a retrospective cohort study of 8,709 veterans aged 60 to 64 years with low testosterone levels who were undergoing coronary artery angiography. The authors reported in the Journal of the American Medical Association that those receiving testosterone therapy had a higher risk of experiencing a composite outcome of all-cause mortality, myocardial infarction (MI), or cerebrovascular accident than did those who had not received testosterone therapy (hazard ratio [HR] = 1.29; 95% confidence interval [CI]: 1.04-1.58).2 Right off the bat, you should be very wary of any HR emanating from a retrospective study that shows a small increase in risk of 29%; it’s only when a HR is 2.0 or more that it’s likely you’re looking at a real phenomenon. But to add insult to injury, the percentage of actual adverse outcomes was actually SMALLER in those taking testosterone than in those who did not get any! The authors had used such an incredibly tortured series of risk adjustments for a variety of comorbidities that they actually managed to stand the raw numbers on their head.

The third study, which had seamed at first blush to demonstrate cardiovascular toxicity of TRT, was a much larger retrospective cohort study of 55,793 men who had received replacement testosterone.3 The authors reported an increase in the relative risk of MI in the first 3 months after starting testosterone compared with the risk of MI in the same men in the prior year (relative risk [RR] = 1.36). However, the much more important absolute risk increase was very, very low, with only an additional 1.25 cases of MI seen over 1,000 patient-years. Apart from the fact that a RR of 1.36 is most unimpressive in a retrospective study, the simple fact that the men were older by a few months after TRT is probably more than adequate to explain this tiny increase in apparent risk.

The FDA has monitored these studies closely and has chosen not to make a determination that there is an increased risk of cardiovascular events associated with TRT. That is not at all the same as saying that it has been proven to be completely free of cardiovascular risk; rather it is a common-sense acknowledgment that there is not any convincing evidence to date of such a risk.

Thus, the conscientious clinician is left to conclude that TRT is a reasonable option in symptomatic patients who have been shown to have low levels of free testosterone. It has not been conclusively demonstrated that TRT will have significant beneficial effects, but neither has it been proven to have any true cardiovascular toxicity. It is a therapy worth trying in those symptomatic patients who understand that they will be receiving therapy of uncertain benefit, if any, and with the possibility of uncertain risk, if any.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of
Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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