Making Sense of the TRAVERSE Trials

Geoffrey Hackett, MD
Geoffrey Hackett, MD Sudarshan Ramachandran, PhD
Sudarshan Ramachandran, PhD

Geoffrey Hackett, MD, Aston University Medical School, Birmingham
Sudarshan Ramachandran PhD, University Hospitals Birmingham NHS Foundation Trust

Introduction

TRAVERSE (1) is multicentre randomized, double-blind, placebo-controlled, noninferiority trial of testosterone therapy, enrolling 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis.

For the diagnosis, subjects required two fasting testosterone levels of less than 10.4 nmol/l. Patients were randomly assigned to receive daily transdermal 1.62% testosterone or placebo gel for a mean 27.1 months.

The study was commissioned at the request of the FDA(2) , following the Testosterone in Older Men (TOM) (3 )and Vigen (4) studies , which led to a black box warning on all testosterone products. In contrast the European Medicines Agency (EMA) (5), found no cause for concern.

Recently, seven papers from TRAVERSE have been published addressing cardiovascular safety (1), diabetes (6), prostate (7), anaemia (8), bone (9) depression (10), somatic symptoms and sexual function (1) have been published. The implications for clinical practice are discussed below.

Cardiovascular Safety

The initial publication from Lincoff et al addressed cardiovascular safety. Reassuringly, in men with hypogonadism and pre-existing or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events (the Primary Study Endpoint). There was a small non-significant reduction in cardiovascular mortality (Hazard Ratio 0.84 [95% confidence interval 0.63-1.12]) in the testosterone group (1).

Prostate Safety

Also, there was no increase in prostate cancer or prostate related events, strongly supporting the view that routine Digital Rectal Examination (DRE) is not required unless clinically indicated for other clinical indications. This has been supported by a recent meta-analysis which concluded that DRE as a screening tool for prostate cancer was similar to PSA in terms of the positive predictive value (PPV) and cancer detection rate (CDR) but with a significantly lower CDR. Furthermore, the combination of DRE and PSA did not enhance the screening efficacy in comparison to PSA alone. (12)

Diabetes and Pre-Diabetes

TRAVERSE shows a possible reduction in diabetes progression which led to closer analysis data on incident diabetes (6). In the original NEJM paper (1), 189 men in Testosterone therapy (TTh) and 213 on placebo developed incident diabetes which is recorded as 7.3 and 8.2% and non-significant.

Importantly, 70% in both cohorts had diabetes at baseline. As clearly patients with baseline diabetes cannot develop incident diabetes, these percentages need to be based on the circa 30% without baseline diabetes. As 607 men on testosterone v 568 on placebo had pre-diabetes at baseline the calculation for progression is therefore 189/607 (31%) on TTh v 213/558 (40%) on placebo, which equates to a 22.5% reduction (p= 0.029 by Chi-square) in progression to new onset diabetes. The authors conceded that 25% of patients failed to reach the normal range of testosterone and the median increase was 9.3 to 12.9 nmol/l, suggesting that patients were undertreated. In addition, a total of 61.4% of the patients on testosterone and 61.7% on placebo group discontinued placebo.

In contrast the T4DM study (13) involved 1007 men with pre-diabetes and a baseline testosterone <14 nmol/l treated with 12 weekly Testosterone Decanoate injections (or placebo) achieving trough level increases from 13.4 to 16.8 nmol/l on active therapy and a significant 41% reduction in incident diabetes. As the treatment levels in TRAVERSE failed to reach even the pre-treatment levels (7) in T4DM, it is likely that TRAVERSE patients with greater co-morbidities were undertreated in terms of diabetes prevention, but still achieved a significant 22.5% reduction.

Bone and Fracture

Paradoxically, the fracture incidence (8) was numerically higher among men who received testosterone (3.5%) than among those who received placebo (2.5%). This was a surprising finding as fractures were largely fall related and occurred too early to be related to T therapy. The JAMA editorial on TRAVERSE suggested a mechanism which is likely to be related to increased activity in an otherwise vulnerable group which may have led to falls. However, it is important to note that the primary end-point of this sub-study was “clinical fractures” regardless of the type of trauma that caused the fracture. Non-high impact clinical fractures, which would be analogous to the more commonly used term “fragility fractures”, did not increase significantly (hazard ratio 1.32 [0.94-1.86]) in testosterone group. The study did not include assessment of bone mineral density (BMD) pre and post treatment, which has been found to significantly improve with TRT to the normal range over time in other studies (14).

Anaemia

Testosterone therapy corrected anaemia (detected in 815 of 5204 or 15.7%) and energy levels in a significantly greater proportion of testosterone-treated than placebo-treated men at 6 months (9) (143 of 349 [41.0%] vs 103 of 375 [27.5%]. This is in line with the T Trial (15) where anaemia was found in 15-20% and correction of anaemia occurred with TRT even in patients with an alternative clinical diagnosis and treatment. TRAVERSE was the first study to demonstrate that functional symptom improvement is closely related to correction of anaemia. It is worth noting that anaemia is an established cardiovascular risk factor (16). In TRAVERSE, among participants without anaemia, a significantly smaller proportion of testosterone-treated men developed anaemia than placebo-treated men. Improved haemoglobin levels were associated with beneficial changes in energy level (9).

Only six participants, whose haematocrit level exceeded 54% at the lowest (20.25 mg) testosterone dose, had their study medication discontinued (9). Time-dependent Cox hazards models did not show an association between change in haematocrit and the risk of Major Adverse Cardiac Events (MACE) (HR, 0.97; 95% CI, 0.92-1.02) or Veno Thrombo-Embolism (VTE) (HR, 0.94; 95% CI, 0.84-1.05) . Of the 6 patients who developed raised haematocrit above 54% and there was no association between haematocrit and risk of CV events. The authors stress that these findings apply only to the protocol of this study and that the findings might not apply to short-acting self-administered injection regimes.

Depression and Somatic Symptoms

Depression was recorded in 50% of the men with hypogonadism and was mild to moderate but 10% were severe. Modest improvement in depression and Aging Male Symptom Scores (AMS) scores were found in mild to moderate cases. The authors suggest a strategy of screening for depression in hypogonadism (10). Treatment with TRT was demonstrated to improve the depressive symptoms and patients should now be informed of these findings.

Sexual Function

There was a significant increase in sexual desire and sexual frequency but not improvement in erectile function, which is not surprising in a population of mean age 65yrs, 70% of whom had diabetes plus multiple cardiovascular co-morbidities (11). Erectile Dysfunction (ED) in these patients was most likely related to endothelial dysfunction, or diabetic neuropathy rather than hormonal factors. Only 8% were taking ED medications at any stage and in T4DM only 4% (13). These findings support the British Society of Sexual Medicine Guidelines (17) recommendation for routine daily use of PDE5 inhibitors in hypogonadal men with ED. A recent observational study based on healthcare claims and national death index data of men with erectile dysfunction and cardiovascular risk factors, supports additional cardiovascular benefits and protection with phosphodiesterase type 5 inhibitors (18).

Adverse Events

A surprising finding was an increase in diagnosis of atrial fibrillation (AF) (1) pointing to 91 v 63 cases in the 5200 patients (p=0.02) non-fatal arrythmias (p=0.001) and 60 v 40 cases of Acute Kidney Injury (p=0.04). These had not been reported in other RCTs.

Previously low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men (19)

Recent metanalyses had suggested that TTh to therapeutic levels decreased incident cases of AF, but only after 5 years or longer (20).

Conclusions

As this study was conducted at the request of the FDA, these positive findings should aid the lifting of the cardiovascular “Summary of Product Characteristics” warning on testosterone products. Additionally, the lack of an association of a raised haematocrit with cardiovascular risk is reassuring.

It does seem that every positive testosterone study comes with caveats and in this case, it is the report of a small increase in fracture rate, atrial fibrillation, and acute kidney injury where other studies have no such links. This raises the possibility that increased vitality and physical activity before therapeutic benefits might have been contributary (14). This might justify caution in frail patients in the early stages of treatment, and the need for appropriate advice.

The publication of multiple papers potentially leads to underestimation of the combined health benefits as specialists might not refer to evidence beyond their subject area. TRAVERSE should provide physicians reassurance, enabling them to manage symptomatic testosterone deficiency without the seemingly inevitable conclusion that “more studies are required”.

References

  1. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone replacement therapy. N Engl J Med 2023; 389:107-17 DOI: 10.1056/NEJMoa2215025
  2. U.S. Food and Drug Administration. FDA drug safety communication. FDA cautions about using testosterone products for low testosterone due to aging; requires labelling change to inform of possible increased risk of heart attack and stroke with use. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm [PubMed]
  3. Basaria S et al. Adverse Events Associated with Testosterone Administration. N Engl J Med 2010; 363:109-122 DOI: 10.1056/NEJMoa1000485
  4. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310(17):1829-36
  5. No consistent evidence of an increased risk of heart problems with testosterone medicines | European Medicines Agency (europa.eu)
  6. Bhasin S, Lincoff M et al Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism A Substudy of the TRAVERSE Randomized Clinical Trial. JAMA Intern Med. doi:10.1001/jamainternmed.2023.7862 February 5, 2024.
  7. Bhasin S et al. Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism. A Randomized Clinical Trial JAMA Network Open. 2023;6(12):e2348692. doi:10.1001/jamanetworkopen.2023.48692
  8. Snyder PJ et al. Testosterone Treatment and Fractures in Men with Hypogonadism N Engl J Med 2024;390:203-11. DOI: 10.1056/NEJMoa2308836
  9. Pencina KM et al. Efficacy of Testosterone Replacement Therapy in Correcting Anaemia in Men With Hypogonadism JAMA Network Open. 2023;6(10):e2340030. doi:10.1001/jamanetworkopen.2023.40030
  10. Bhasin S et al. Depressive Syndromes in Men with Hypogonadism in the TRAVERSE Trial: Response to Testosterone Replacement Therapy. The Journal of Clinical Endocrinology & Metabolism, dgae026, https://doi.org/10.1210/clinem/dgae026
  11. Pencina KM et al. Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism The Journal of Clinical Endocrinology & Metabolism, 2023, 00, 1–12 https://doi.org/10.1210/clinem/dgad484
  12. A. Matsukawa, T. Yanagisawa, K. Bekku et al., Comparing the performance of Digital Rectal Examination and Prostate-specific Antigen as a Screening Test for Prostate Cancer: A Systematic Review and Meta-analysis, Eur Urol Oncol (2024), https://doi.org/10.1016/j.euo.2023.12.005
  13. Wittert G et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. https://doi.org/10.1016/S2213-8587(20)30367-3.
  14. Grossmann M et al. Breaking News — Testosterone Treatment and Fractures in Older Menn Engl j med 390;3 nejm.org January 18, 2024 J Am Heart Assoc.
  15. Dos Santos, MR & Bhasin, S. Benefits and Risks of Testosterone Treatment in Men with Age-Related Decline in Testosterone. S. Annu. Rev. Med. 2021.72:75-91
  16. Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN, Levey AS, Sarnak MJ. Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol. 2005 Nov;16(11):3403-10. doi: 10.1681/ASN.2005030226. Epub 2005 Sep 14. PMID: 16162813
  17. Hackett G et al. The British Society for Sexual Medicine Guidelines on Male Adult Testosterone Deficiency, with Statements for Practice ISSN: 2287-4208 / eISSN: 2287-4690 World J Men’s Health 2023 Jul 41(3): 508-537 https://doi.org/10.5534/wjmh.221027
  18. Kloner R et al. Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data.The Journal of Sexual Medicine, Volume 20, Issue 1, January 2023, Pages 38–48, https://doi.org/10.1093/jsxmed/qdac005
  19. Tanja Zeller, Renate B Schnabel, Sebastian Appelbaum, et al, Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women – results from the FINRISK study, European Journal of Preventive Cardiology, Volume 25, Issue 11, 1 July 2018, Pages 1133–1139, https://doi.org/10.1177/2047487318778346
  20. Sharma R et al. Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation 2017 May 9;6(5): e004880. doi: 10.1161/JAHA.116.004880

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