Testosterone Therapy and Cardiovascular Disease: The TRAVERSE Trial

Introduction

A thorough literature review affirms that in males with testosterone deficiency (TD), testosterone therapy (TTh) improves clinical outcomes including body composition,^{1,2,3,4,5,6,7} sexual function,^8,9,10,11,12 and bone mineral density (BMD).13,14,15,16,17,18,19,20 In males with TD, TTh does not increase prostate cancer (PC)^{21,22,23,24,25,26,27} and the literature suggests that not only is TTh safe for the cardiovascular system, but it may also decrease myocardial infarction (MI) and mortality rates.^{28,29,30,31,32,33,34,35,36,37}

Between 2010 and 2014, four published studies raised concerns about TTh and cardiovascular (CV) risk. These studies suggested that TTh increased CV risk. These 4 studies received an unusual amount of media attention and provided talking points for those who believed that TTh was unnecessary or dangerous. Two studies were retrospective analyses (Vigen³⁹ and Finkle⁴⁰), 1 was a meta-analysis (Xu⁴¹), and one was a randomized controlled trial (Basaria⁴²). These 4 studies led the FDA to mandate a label change to all T products warning against possible MI and stroke. Since then, male health experts have questioned these studies’ validity, accuracy, and credibility.^{43,44,45,46,47}

There are numerous observational trials, clinical trials, and metanalyses that have not demonstrated an association between TTh and cardiovascular risk.^28-31 In fact, some studies suggest TTh may be cardioprotective,^32-35,37,38 though more studies are needed to confirm that TTh improves CAD and CV outcomes.

TRAVERSE Trial⁴⁸

Until the recently published TRAVERSE trial, there were no large, randomized, double-blind, placebo-controlled published trials (RCTs) evaluating TTh and cardiovascular outcomes. TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) was a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial that enrolled 5246 males, 45 to 80 years old, with either documented cardiovascular disease or a high risk for cardiovascular disease (> 3 cardiovascular risk factors).

All male participants had one or more testosterone deficiency symptom (decreased libido or sexual desire, decreased spontaneous erections, etc.) and 2 fasting total testosterone levels < 300ng/dL obtained between 5 AM and 11 AM using a liquid chromatography-tandem mass spectrometry assay.

Males were randomized in a 1:1 ratio to receive AndroGel or matching placebo. The patient demographics were similar in both groups. The study included 2847 males with preexisting cardiovascular disease and 2357 males with an elevated cardiovascular risk. The mean testosterone daily dose was 65mg. Dose adjustments were made to maintain serum trough total testosterone levels between 350 and 750ng/dL or to respond to a hematocrit level > 54%.

The mean treatment duration and follow-up were 21.7 and 33 months. In the treatment arm, the mean trough total testosterone levels ranged from 387-432ng/dL with mean estradiol levels of 31-32pg/mL. In the placebo arm, the mean trough total testosterone levels ranged from 230-264ng/dL with mean estradiol levels of 19-20pg/mL.

There was no statistically significant difference between the treatment arm (7.0%) and the placebo arm (7.3%) in the primary safety endpoint. The primary safety endpoint was the first occurrence of any component of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, death due to cardiovascular causes) and/or a composite of death from cardiovascular causes.

However, pulmonary embolism occurred at a higher incidence in the testosterone treatment group (0.9%) vs the placebo group (0.5%). In the treatment arm, there was also a statistically significant increase in nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury when compared to the placebo arm.

The authors concluded that in testosterone-deficient males aged 45-80 with documented cardiovascular disease or at high cardiovascular risk, testosterone-replacement therapy was noninferior to placebo with respect to major adverse cardiovascular events.

Discussion

TRAVERSE targeted a very specific male patient population. Males aged 45-80 with known cardiovascular disease or males at high risk for cardiovascular disease. AndroGel was utilized and the total testosterone ranges were trough levels similar to trough levels that have been used in previous RCTs^28-31 and observational studies^32-38 that documented improved cardiovascular outcomes.

What is concerning, and certainly needs further study, is the increased incidence, in this patient population, of pulmonary embolism, nonfatal arrhythmias warranting intervention, atrial fibrillation, and acute kidney injury when compared to the placebo arm. Therefore, until further studies are performed, caution should be used, and patients should be counselled, when considering testosterone therapy in this male population with a prior venous thromboembolic event (DVT, PE), a history of acute kidney injury, and/or a history of atrial fibrillation or other nonfatal arrhythmias.

Conclusion

TRAVERSE documented that testosterone therapy is safe and does not increase major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, death due to cardiovascular causes, or a composite of death from cardiovascular causes) in testosterone-deficient males with cardiovascular disease or in males at high risk for cardiovascular disease. Screening for thromboembolic disease, a history of acute kidney injury, and/or a history of atrial fibrillation or other nonfatal arrhythmias should allow clinicians to minimize these potential adverse events.

Moreso, it is plausible that in testosterone-deficient males without cardiovascular disease or cardiovascular risk factors, testosterone-replacement therapy is safe if serum total trough testosterone levels are maintained within a similar range.

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