Rishi Sharma (Division of Cardiovascular Research, Kansas City VA Medical Center, Kansas City, USA) and others report in the European Heart Journal that normalisation of total testosterone levels with testosterone replacement therapy is associated with a significant reduction in the risk of myocardial infarction, stroke and all-cause mortality compared with non-normalisation with testosterone replacement therapy and no therapy in men with low testosterone. These findings contradict previous studies that have suggested with testosterone replacement therapy increases the risk of cardiovascular events.
Sharma et al say that there is “growing concern” about the effect of testosterone replacement therapy on mortality and cardiovascular outcomes, given that there has been a “400% increase in the number of testosterone replacement therapy prescriptions” in the USA in the last decade. They add that the available data for the risk of mortality and cardiovascular events with the therapy is conflicting, with some studies suggesting that it increases the risk of such events and others not indicating that there is not a risk. “In light of these conflicting results and uncertainty concerning the safety of testosterone replacement therapy, we have conducted a large retrospective study long-term follow-up to address this knowledge gap,” the authors comment.
Using data from the US Veterans Health Administration, Sharma et al identified 91, 012 male patients with low testosterone levels—of whom, 43, 931 had normal testosterone levels after treatment, 25,701 did not have normalised levels despite receiving treatment, and 13,378 did not receive treatment (8,002 patients were excluded of the original 21,380 after repeat testing showed them to have normal testosterone levels). The authors then assessed baseline characteristics to create a propensity-matched cohort of 40,852 normalised-levels treated patients, 23,953 non-normalised-levels treated patients, and 11,957 untreated patients. None of the patients in this cohort had a prior history of myocardial infarction or stroke. The primary outcome was the incidence of myocardial infarction, the incidence of ischaemic stroke, and the incidence of all-cause mortality.
In the propensity-matched cohort, the risk of myocardial infarction was significantly lower in the normalised-levels treatment group compared with both the non-normalised-levels treatment group (p=0.008) and the non-treatment group (p=0.005). The risks of all-cause mortality and ischaemic stroke were also significantly lower in the normalised-levels treatment group compared with the other groups.
The authors found that the risk of all-cause mortality was significantly reduced in the non-normalised-levels treatment group compared with the untreated group, but there were no significant differences in the incidence of myocardial infarction or in the incidence of ischaemic stroke between these groups.
According to Sharma et al, their study has differences that may explain why its results differ from those of previous studies of testosterone replacement therapy. For example, they note their study population was younger (average age 64.2 years) than one that had to be stopped prematurely after an increase in cardiovascular events (soft endpoints) was observed with testosterone replacement therapy (average age 74 years). Furthermore, the authors state that—unlike some of the previous studies—they used hard endpoints (ie. myocardial infarction), repeatedly checked testosterone levels in all patients, and had a large sample size and longer follow-up.
The reasons, Sharma et al claim, as to why testosterone replacement therapy appeared to reduce the risks of all-cause mortality, myocardial infarction, or stroke in their study “remain speculative”. Listing the potential benefits of the therapy on cardiovascular outcomes, such as its anticoagulant properties, the authors also comment that there other potential mechanisms with the therapy that could increase the risk of cardiovascular events.
“In future, adequately powered, prospective, well-designed trials with a long-term follow-up will be needed to reach a conclusive agreement regarding the effect of testosterone replacement therapy on cardiovascular risk,” Sharma et al conclude.
Corresponding author Rajat S Barua told Cardiovascular News: “Our study suggests that perhaps risks/benefits of testosterone replacement therapy depend on the risk profile of the patient rather than the therapy itself. Currently there is a need for appropriate screening, selection, dosing and follow up of patients to maximise the benefit of this therapy”.