Testosterone treatment is not associated with risk of adverse cardiovascular events – RHYME study
15 December 2016
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 life1-4, libido4,5, metabolic parameters 5-9 and body composition.4,5,9,10
However, a few conflicting studies raised concerns about the cardiovascular safety of testosterone therapy11,12, 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
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 Foundation18 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-Trial20, new database analyses in large healthcare systems21,22,23,24, 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.
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 US25,26 and Europe7,31-33 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 therapy34, this recommendation is not supported by results from recent studies, such as a large-scale medical record database review24, the T-Trial20, and the current findings in RHYME (presented here).14