No Increase in Major Cardiac Events With Testosterone-Replacement Therapy, MedPage Today, June 16, 2023.

[cujoe]

This is a post I started a week ago - and Patrick's post earlier today on Supraphysiological Androgens effects on tumor suppression has given me the impetus to complete it. It is based on a MedPage Today article on the TRAVERS trial that seems to debunk most of the former concerns over cardiac issues related to TRT. This should give some relief to those with known cardiac issues considering the possible use of BAT. (Note that there was an unexplained increase in the incidence of fractures in the TRT group? Maybe, as speculated, they felt better and were more active?)

The MedPage article is reproduced in its entirety below:

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Testosterone-Replacement Therapy — Men with hypogonadism and heart disease or risk factors saw no increased risk vs placebo, by Ed Susman, Contributing Writer, MedPage Today June 16, 2023

CHICAGO -- Testosterone-replacement therapy was noninferior to placebo in the occurrence of major adverse cardiac events among men with hypogonadism and established or high risk for cardiovascular disease, the randomized TRAVERSE trial showed.

At a mean follow-up of 33 months, the primary cardiovascular endpoint -- first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke -- occurred in 7% of patients in the testosterone group compared with 7.3% of those in the placebo group (HR 0.96, 95% CI 0.78- 1.17, P<0.001 for noninferiority), reported A. Michael Lincoff, MD, of the Cleveland Clinic in Ohio, during ENDO 2023opens in a new tab or window, the annual meeting of the Endocrine Society.

However, testosterone-replacement therapy compared with placebo was associated with increased risks of atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), and pulmonary embolism (0.9% vs 0.5%), according to the findings, which published simultaneously in the New England Journal of Medicine.

"Controlled trials have shown that the use of testosterone in older men improves sexual function, increases volumetric and areal bone mineral density, corrects unexplained anemia, and moderately reduces depressive symptoms," Lincoff and colleagues wrote.

"However, because testosterone deficiency is not a life-threatening condition, uncertainty about cardiovascular outcomes has weighed on treatment decisions by clinicians and patients," they added. "Our findings regarding the cardiovascular safety of testosterone may facilitate a more informed consideration of the potential benefits and risks of testosterone therapy among middle-aged and older men with hypogonadism."

Bradley Anawalt, MD, of the University of Washington in Seattle, told MedPage Today these results were "important," noting that the FDA requires a black box warning that testosterone might increase the risks of stroke and heart attacks, "and that's been a long-standing warning for almost 10 years."

"And it's also important to note that this was done in a cohort of men that had what we would call bona fide, confirmed testosterone deficiency," he said.

But "the study doesn't actually give a stamp of approval to run off and take testosterone without considering the potential risks," he added.

He pointed out that the study showed there was an increased risk of heart arrhythmia, which can increase the risk of strokes. "We've known for a long time that testosterone has direct effects on the heart and rhythm. But we've never actually seen in a conclusive fashion that there is this arrhythmia," he said.

"And the other finding was one that showed there was increased risk of blood clots that go to the lungs," he continued. "If you're at high risk for blood clots, then we need to be careful about prescribing testosterone to that group of men."

Maria Stamou, MD, of Mass General Brigham in Boston, told MedPage Today that the TRAVERSE study will change the way she informs patients considering testosterone-replacement therapy.

"Advertisements touting testosterone products have become very popular," she said. "We do see a lot of patients who are being evaluated for low testosterone. So this study is actually very exciting because it answers a question that has not been answered before."

Stamou also said that patients on testosterone-replacement therapy should have their prostate-specific antigen (PSA) levels regularly tested to make sure that increasing testosterone is not affecting the prostate or fueling prostate cancer.

"For every patient we see at the clinic, we need to evaluate a lot of different factors," she noted.

In findings from nested substudies, there appeared to be no significant increased risk of prostate cancer among men taking testosterone compared with placebo, and the same was true for urinary tract infections.

Of note, those in the testosterone group were more likely to have corrected anemia and an increase in sexual functioning. However, testosterone-replacement therapy also resulted in an increase in fractures when compared with placebo (HR 1.43, 95% CI 1.04-1.97, P=0.03), reported Peter Snyder, MD, of the University of Pennsylvania in Philadelphia.

"This study was not designed to look at the reasons for fractures -- most of which occurred due to falls," he said in response to questions from the audience. "Because this was an unexpected finding, I am sure there is a reason to explain this, but we don't know what it is."

He also noted that centrally adjudicated fractures were observed in 154 patients in the testosterone group compared with 97 confirmed fractures in the placebo group. Audience and panel members speculated that the excess falls might be due to increased physical or sexual activity, or it might have been related to obesity, since most participants in the study were obese.

For the multicenter, double-blind TRAVERSE trial, Lincoff and team enrolled 5,246 men ages 45 to 80 who had pre-existing or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng/dL from May 2018 to February 2022.

Mean patient age was 63, 80% were white, and 17% were Black. Over 50% had pre-existing cardiovascular disease; the others were considered at increased risk. Most with pre-existing cardiovascular disease had a history of coronary artery disease. Common cardiovascular risk factors included diabetes, hypertension, dyslipidemia, and current smoking. Only 15 patients had previously been on testosterone therapy.

Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel, a dose that was adjusted to maintain testosterone levels between 350 and 750 ng/dL, or placebo gel.

The primary cardiovascular safety endpoint was assessed in a time-to-event analysis. The researchers set a noninferiority criterion requiring an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.

A secondary cardiovascular endpoint that added coronary revascularization to the composite of outcomes included in the primary endpoint also occurred in a similar number of patients in the testosterone and placebo groups.(emphasis added throughout.)

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Link to MedPage Article:

medpagetoday.com/meetingcov...

Here is a link to the Abstract of the NEJM (full article is behind paywall):

Cardiovascular Safety of Testosterone-Replacement Therapy, published on June 16, 2023, at NEJM.org

nejm.org/doi/pdf/10.1056/NE...

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As a postscript, I note that slowly, but surely, Dr. Abraham Morgenthaler's view on TRT is being recognized by the mainstream medical community. (See the linked interview below for a summary of his research and clinical experience with TRT - and equally important how that research and use has been viewed by his peers.) His "Saturation Model" still remains somewhat controversial, but there can be little doubt of TRT's significant QOL benefits (esp. for older men) and limited SE risks. IMO, this video should be viewed by all PCa patients (and their urologist/MO):

Testosterone Therapy in Clinical Medicine: Interview with Abraham Morgentaler, MD, FACS, by GRU contributing editor Neil H. Baum, MD, circa Feb 2023.

youtube.com/watch?v=Nemzbt6...(Not working as expected?)

Stay S&W, Ciao - Kaptin K9

[Scout4answers]

Can anyone recommend an urologist or MO willing to administer BAT

[pca2004]

Hi Cujoe,

TRT might lower the risk of PCa in hypogonadal men, particularly the risk of aggressive PCa. imo

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From what I have heard about traditional TRT, doctors would consider it only if a man had T below 300 ng/dL AND symptoms. The therapy would be designed only to raise T above 300 ng/dL. I doubt that there would be much risk of anything untoward with that protocol.

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When I began using T against PCa in 2006, I was using androstenedione as a precursor, and chrysin to inhibit conversion to estradiol. Within a couple of years, my integrative doc was prescribing 5mg Androderm patches with Arimidex. In both cases, T was kept above 1,000 ng/dL (i.e. high-normal) and I reckoned that I was producing >500 ng/dL myself - I had not been on ADT at that time.

Perhaps the doctor advised me to check hematocrit levels. They were always in the middle of the range.

A few years later, when I was alternating between ADT (3 months) & T (3 months), my red blood cells [RBCs] would fall to near anemia, but rise again to mid-range.

Hematocrit is the proportion of RBCs in the blood. U.S. TRT guidelines generally exclude men with hematocrit > 50% (>54% in Europe). My doctor told me that he had two patients whose levels kept rising along with T (erythrocytosis). This is by no means a natural event, but should be monitored.

Erythrocytosis may be due to polycythemia [1].

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I have always been surprised that Denmeade makes no mention of hematocrit in his study papers. After all, his target T is 2,000 ng.dL - twice high-normal.

Men on BAT should check hematocrit periodically. imo

-Patrick

[1] en.wikipedia.org/wiki/Polyc...