Cardiovascular Safety of Testosterone-Replacement Therapy
- Testosterone therapy in middle-aged and older men with hypogonadism compared to placebo does not increase major cardiovascular events.
- The incidence of pulmonary embolism, nonfatal arrhythmia, atrial fibrillation, and acute injury was higher in subjects who received testosterone replacement therapy.
- Adherence and retention in this trial was lower than in most cardiovascular outcomes, but similar to other trials in symptomatic conditions.
Does testosterone replacement therapy in middle-aged and older men with hypogonadism cause increased overall cardiovascular risk?
A total of 5,246 men aged 45-80 years with pre-existing or high risk of cardiovascular disease, symptoms of hypogonadism, and testosterone levels <300 ng/dL were enrolled. They were assigned to receive testosterone gel or placebo gel. The primary endpoint was first occurrence of nonfatal stroke, death from cardiovascular cause, nonfatal myocardial infarction, or nonfatal stroke. A secondary endpoint was the first occurrence of any component of death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A noninferiority analysis was performed.
The mean duration of treatment was 21.7 ± 14.1 months. Mean follow-up was 33 ± 12.1 months. The primary endpoint occurred in 7% of the testosterone group and in 7.3% of the placebo group. The incidence of the secondary endpoint appeared to be similar in the two groups. Of note, a higher incidence of pulmonary embolism, acute kidney injury, and atrial fibrillation was noted in the testosterone group.
Testosterone therapy in middle-aged and older men with hypogonadism and low testosterone levels was not associated with increased overall cardiovascular risk, when compared to placebo. However, a higher incidence of pulmonary embolism, acute kidney injury, and atrial fibrillation was noted in the testosterone group.
There has been longstanding concern that testosterone replacement therapy may increase cardiovascular risk, as well as the risk of thromboembolic disease. The TRAVERSE trial, reviewed here, was performed as a response to the Food and Drug Administration’s requirement in 2015 that manufacturers of testosterone replacement therapy conduct such trials.
The results are very reassuring in that testosterone replacement does not increase overall cardiovascular risk in this group of patients with symptomatic hypogonadism and low testosterone level. It is concerning, however, that there was a higher incidence of pulmonary embolism, atrial fibrillation, and acute kidney injury in the testosterone therapy group; this finding certainly warrants further evaluation. With this, it may be prudent to avoid usage of testosterone replacement in men with prior thromboembolic events, and perhaps even with those with paroxysmal atrial fibrillation or prior renal insufficiency.
This study does not address testosterone’s safety in otherwise normal people who take it solely to build muscle or for other reasons—it just applies to patients with symptomatic hypogonadism and low testosterone levels. The study had a relatively low rate of adherence and retention, which is not uncommon in studies of symptomatic conditions. It was felt that this issue did not significantly affect the results, as over half of those who discontinued trial participation did it after the end-of-trial visits began and outcome data were available for >80% of the person-time follow-ups.
In summary, testosterone therapy appears generally safe from an overall cardiovascular standpoint but may come with risks that must be weighed in balance with its potential benefits on an individual patient whose hypogonadism may be affecting their overall quality of life.
Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine
Keywords: Acute Kidney Injury, Aged, Arrhythmias, Cardiac, Atrial Fibrillation, Hypogonadism, Middle Aged, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Primary Prevention, Pulmonary Embolism, Renal Insufficiency, Risk Factors, Stroke, Testosterone, Thromboembolism, Vascular Diseases
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