15 December 2016Subscribe to our news feed

Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME study

Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME study

Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Maggi M, Wu FC, Jones TH, et al. Int J Clin Pract. 2016;70(10):843-852.

It is well-documented that testosterone therapy effectively restores testosterone levels in hypogonadal men and improves many health outcomes, such as quality of life 1-4, libido 4,5, metabolic parameters 5-9 and body composition.4,5,9,10

However, a few conflicting studies raised concerns about the cardiovascular safety of testosterone therapy 11,12, which in 2015 prompted the FDA to issue warnings to physicians and patients about potential cardiovascular risks of testosterone therapy. In contrast, the European Medicines Agency (EMA) acknowledged the flaws of the conflicting studies and concluded that there is no consistent evidence of harm associated with testosterone therapy, regardless of mode of delivery.13

Here we present the cardiovascular results of the notable RHYME (The Registry of Hypogonadism in Men) study, which contrary to prior clinical trials, enrolled patients with a wide range of comorbid illnesses and cardiovascular risk factors.14 The aim was to evaluate the safety of testosterone therapy in a sufficiently diverse population to reflect real-world, clinical experience.14

Key Points

  • In comparison to both untreated men and to age-matched population data, no increase in mortality or cardiovascular risk was observed with testosterone therapy, regardless of:
    • The type of testosterone administered (injectable vs. topical preparations).
    • Presence of other comorbidities.
    • Age of patients (no increased risk was seen in both younger and older hypogonadal men).
    • The type of hypogonadism being treated (primary vs. secondary).
  • These results strongly support the overall cardiovascular safety of testosterone therapy.
  • The RHYME study refutes FDA’s labelling caution for potential risks of deep vein thrombosis with testosterone therapy.

What is known

The EMA conclusion is supported by the latest testosterone therapy guidelines from the European Association of Urology (EAU) 15, International Society for Sexual Medicine (ISSM) 16, European Menopause Andropause Society (EMAS) 17, Canadian Men's Health Foundation 18 and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE).19

Examples of recent studies proving that testosterone therapy does not increase (and may actually decrease) cardiovascular risk include the respectable T-Trial 20, new database analyses in large healthcare systems 21,22,23,24, product registries 25,26 and recent systematic reviews.27,28

What this study adds

The RHYME study was a disease registry of men diagnosed with hypogonadism in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years.

Of 999 patients enrolled with diagnosed hypogonadism, 750 (75%) initiated some form of testosterone therapy. A total of 55 reported cardiovascular events occurred in 41 patients. Overall, five patients died of cardiovascular-related causes (3 on testosterone therapy, 2 untreated) and none of the deaths were related to testosterone treatment. Cardiovascular event rates for men receiving testosterone therapy were not statistically different from untreated men.

Regardless of treatment assignment, cardiovascular event rates were higher in older men and in those with increased cardiovascular risk factors or a prior history of cardiovascular events.

Commentary

The RHYME study was designed and conducted by an independent research organisation (New England Research Institutes).29 It is notable in that it enrolled a diverse population reflective of men seeking help in the real-world, and subjects were monitored for up to 36 months.20,30 This study found that predictors of new-onset cardiovascular events were age and prior cardiovascular history, not testosterone use.

The conclusion that testosterone therapy - regardless of the type of testosterone administered – does not increase mortality or cardiovascular risk, compared to both untreated men and to age-matched population data, is reassuring.

This lack of association between testosterone use and cardiovascular-related adverse events was evident in both younger and older hypogonadal men, regardless of the mode of testosterone administration (injectable vs. topical preparations). None of the cardiovascular-related mortalities were judged to be related to testosterone therapy, but were significantly associated with prior or current cardiovascular conditions. These results are consistent with results from other patient registries in the US 25,26 and Europe 7,31-33 showing relative safety of testosterone therapy in hypogonadal men with multiple illnesses and cardiovascular risk factors.

Despite FDA’s specific labelling caution for potential risks of blood clots (deep vein thrombosis) with testosterone therapy 34, this recommendation is not supported by results from recent studies, such as a large-scale medical record database review 24, the T-Trial 20, and the current findings in RHYME (presented here).14

References

1. Tong SF, Ng CJ, Lee BC, et al. Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian journal of andrology. 2012;14(4):604-611.
2. Tan WS, Low WY, Ng CJ, et al. Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. BJU Int. 2013;111(7):1130-1140.
3. Behre HM, Tammela TL, Arver S, et al. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. The aging male : the official journal of the International Society for the Study of the Aging Male. 2012;15(4):198-207.
4. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639-650.
5. Permpongkosol S, Tantirangsee N, Ratana-olarn K. Treatment of 161 men with symptomatic late onset hypogonadism with long-acting parenteral testosterone undecanoate: effects on body composition, lipids, and psychosexual complaints. The journal of sexual medicine. 2010;7(11):3765-3774.
6. Dhindsa S, Ghanim H, Batra M, et al. Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. Diabetes Care. 2016;39(1):82-91.
7. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2014;68(3):314-329.
8. Yassin A, Almehmadi Y, Saad F, Doros G, Gooren L. Effects of intermission and resumption of long-term testosterone replacement therapy on body weight and metabolic parameters in hypogonadal in middle-aged and elderly men. Clin Endocrinol (Oxf). 2016;84(1):107-114.
9. Marin P, Holmang S, Jonsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord. 1992;16(12):991-997.
10. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011-1022.
11. 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):1829-1836.
12. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805.
13. European Medicines Agency. No consistent evidence of an increased risk of heart problems with testosterone medicines, 2014.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Testosterone-containing_medicines/human_referral_prac_000037.jsp&mid=WC0b01ac05805c516f
(accessed December 29th, 2015).

14. Maggi M, Wu FC, Jones TH, et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). Int J Clin Pract. 2016;70(10):843-852.
15. Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. 2016 EAU Guidelines on Male Hypogonadism, available at http://uroweb.org/wp-content/uploads/EAU-Guidelines-Male-Hypogonadism-2016.pdf (accessed July 26, 2016).
16. Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686.
17. Dimopoulou C, Ceausu I, Depypere H, et al. EMAS position statement: Testosterone replacement therapy in the aging male. Maturitas. 2016;84:94-99.
18. Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016). CMAJ. 2015;187(18):1369-1377.
19. Goodman N, Guay A, Dandona P, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of Testosterone and Cardiovascular Risk. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015;21(9):1066-1073.
20. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624.
21. Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706-2715.
22. Anderson JL, May HT, Lappe DL, et al. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol. 2016;117(5):794-799.
23. Wallis CJ, Lo K, Lee Y, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. The lancet Diabetes & endocrinology. 2016.
24. Sharma R, Oni OA, Chen G, et al. Association Between Testosterone Replacement Therapy and the Incidence of DVT and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database. Chest. 2016;150(3):563-571.
25. Bhattacharya RK, Khera M, Blick G, Kushner H, Miner MM. Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS). Clinical interventions in aging. 2012;7:321-330.
26. Miner MM, Bhattacharya RK, Blick G, Kushner H, Khera M. 12-month observation of testosterone replacement effectiveness in a general population of men. Postgrad Med. 2013;125(2):8-18.
27. Corona G, Maseroli E, Maggi M. Injectable testosterone undecanoate for the treatment of hypogonadism. Expert opinion on pharmacotherapy. 2014:1-24.
28. Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert opinion on drug safety. 2014;13(10):1327-1351.
29. Rosen RC, Wu FC, Behre HM, et al. Registry of Hypogonadism in Men (RHYME): design of a multi-national longitudinal, observational registry of exogenous testosterone use in hypogonadal men. The aging male : the official journal of the International Society for the Study of the Aging Male. 2013;16(1):1-7.
30. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122.
31. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract. 2014;8(4):e339-349.
32. Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016:Jan 14. doi: 10.1111/and.12514. [Epub ahead of print].
33. Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. 2016;12:251-261.
34. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use 2015. Available at http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm (assessed December 8, 2016).
G.COM.GM.MH.12.2016.0437
Last updated: 2017
G.GM.MH.04.2015.0334