Cardiovascular Safety of Testosterone Replacement Therapy: Take 2

Cosmetic medicine and a study that tells us nothing

This is the second time I am posting about the NEJM article Cardiovascular Safety of Testosterone-Replacement Therapy, the TRAVERSE Study from June 16th, 2023. I posted what we will now call a first draft of this article on June 23rd, 2023.

I am updating my previous post for two reasons. First, I heard a story on NPR that had me yelling at the radio. I was going to pitch the TRAVERSE study as an article to cover on This Fortnight in Medicine, but before I emailed the group, I checked whether we had already covered the study. I found that I had already written about it. Second, after reading my early version, I realized I had learned something since my first writing, so now I’ve got even more to criticize.

An aspect of primary care medicine that never excites me is what I (disparagingly) call cosmetic medicine. For me, this is the type of medicine practiced when a doctor gives a fancy medical name to a symptom that is part of the human condition (fatigue, achy muscles, grief, loss of libido, dysthymia…) and medicalizes it, offering a treatment, usually without evidence that it even helps. Of course, any of these symptoms could be a symptom of a serious medical condition that requires treatment — I shamelessly refer you to chapter 18 of Symptom to Diagnosis: Fatigue. This is not what I am talking about. I am talking about pharmacologic therapy for just plain old “I wish I had more energy; I felt better when I was 26 than I do now at 56.”

Enter testosterone replacement therapy. Androgen deficiency is a real problem that needs to be evaluated and treated. It can be caused by failure of the testes to produce testosterone or by a problem further up the “pituitary-hypothalamic axis.” It has a defined differential diagnosis and evaluation. This is not what I am writing about.

Over the last couple of decades, testosterone has been aggressively marketed. You’ve almost certainly seen an advertisement encouraging you to “Ask your doctor about low T.” These commercials are aimed at people with an array of non-specific symptoms – fatigue, decreased libido, decreased energy, fewer spontaneous erections, low or depressed mood. I imagine that the companies behind these ads know that if every man with these symptoms gets tested, many will be found to have slightly low testosterone with no apparent cause. If you understand the normal distribution and how we define a normal blood test result, and are, or know, a man over 45, you realize this is an ENORMOUS market.

Now you might say, “Whatever, what’s the harm? If the guy’s testosterone is a little low, replete it. Maybe he feels a bit better, even if it is just the placebo effect.” Well, this might sound OK if you are OK with over-treatment and mild ethical lapses, but what if testosterone repletion is associated with harm? There is reason to be concerned that testosterone repletion might be harmful, associated with cardiovascular events, and prostate cancer.¹

That introduction brings us to the NEJM article Cardiovascular Safety of Testosterone-Replacement Therapy, the TRAVERSE Study. This study was done because the FDA demanded safety data from the companies that were making money selling testosterone (and no doubt funding all those damn low-T ads). The study was “supported by AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals, and Upsher–Smith Laboratories.”

Patients

The study enrolled men, 45 to 80 years old, with cardiovascular disease or elevated cardiovascular risk. The men had at least one symptom of testosterone deficiency (decreased sexual desire or libido, decreased spontaneous erections, fatigue or decreased energy, low or depressed mood, loss of axillary or pubic hair or decreased frequency of shaving, or hot flashes) and had two fasting serum testosterone levels of less than 300 ng per deciliter. The lower limit of normal in our lab is 180. Patients with very low testosterone levels (< 100) were excluded, as were men with prostate cancer or an elevated PSA.

Intervention and Endpoints

The participants were randomized to testosterone gel or a placebo, and a system to allow for dose adjustments without causing unblinding was established. This was designed as a non-inferiority study. The primary endpoint was the first occurrence of a component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Results

5246 men were randomized. The study's headline was that testosterone treatment was not associated with an increase in cardiovascular events. A primary endpoint occurred in 7.0% of people in the testosterone group and 7.3% in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for non-inferiority).

Limitations

What I have come to appreciate more since I first wrote about this article is that it was inappropriate to design this trial as a non-inferiority study. Vinay will cover this in depth in one of our upcoming videos. Non-inferiority studies are most appropriate when testing treatments whose primary benefit is decreasing treatment burdens, costs, or harms relative to an existing standard. A well-done non-inferiority trial assures us that we are not sacrificing efficacy in switching to a substitute treatment.

This is not the case here. These are patients who (supposedly) had symptomatic hypoandrogenemia. We should be testing if treatment, with its associated harms and benefits, is better than no treatment. An appropriate study would have been powered for both benefits and harms. This is one of those studies designed more to sell a product than to help patients.

The banal results of the study (you remember, primary endpoint 7.0% in the testosterone group and 7.3% in the placebo group) are not the whole story. There is at least a signal (a term I generally hate) for injury associated with testosterone therapy. There was about a 1% increase in AFIB and acute kidney injury in the treated group in a study with a mean follow-up of less than 3 years.

Most importantly, the results of this study are essentially meaningless. First, the increase in testosterone levels in the treated group was remarkably small. While the placebo group maintained levels of about 250, the treatment group peaked at a mean of about 350. The design of the study had the testosterone dose titrated to levels of 350-750. Underlining the fact that patients were under-treated, 61.4% of patients in the testosterone group stopped therapy, almost identical to the 61.7% of patients who stopped placebo. About two-thirds of people on treatment and placebo thought, “This is doing nothing, it's not worth taking.”

What prompted me to rewrite this article was neither my newfound irritation regarding the misuse of non-inferiority studies nor my continued antipathy to cosmetic medicine; it was the NPR story. On this report, one of the authors of the TRAVERSE study seemed shocked, shocked I tell you, that their article — one supported by drug companies to get a warning label removed — would be used to increase sales. He said:

We used the drug in a very specific way, and we have a very reasonable answer. But I would not feel good if our study resulted in the unrestrained use of testosterone in ways that we didn't study.

Conclusion

This study tells us that homeopathic doses of testosterone — ones that barely change blood levels of testosterone (the process measure) and have so little effect on how people feel that 60% of them stop the medicine — are sort of safe. These results do nothing to reassure anyone that using testosterone for “cosmetic medicine” is safe. In practice, when we (I use the first-person plural pronoun liberally here) treat low testosterone, we titrate the dose up every 2-4 weeks until there is a response in target symptoms, elevated testosterone levels, or other abnormal blood test results. This is clearly not what was done in this study.

I expect that this study was designed to satisfy the FDA while minimizing the chance of discovering adverse effects. I am not sure how an author can be surprised that the results of a study funded by pharma would be used to sell more pharmaceuticals. If you play in the mud, you should be prepared to get dirty.

1. Leave aside the fact that treating older men with low testosterone attributed to the “andropause” (or the more maddeningly termed manopause) is analogous to giving estrogen to every woman in menopause. You might remember that we once did that.