January 31st, 2014
On January 31st, 2014, the U.S. Food and Drug Administration (FDA) released a statement saying that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. Additional major updates to this topic are presented below in chronological order.
“We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. We are providing this alert while we continue to evaluate the information from these studies and other available data, and will communicate our final conclusions and recommendations when the evaluation is complete.
At this time, the FDA has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death. Patients should not stop taking prescribed testosterone products without first discussing any questions or concerns with their health care professionals. Health care professionals should consider whether the benefits of FDA-approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed.”
The first publication that prompted FDA to reassess the cardiovascular safety of testosterone therapy was an observational study of older men in the U.S. Veteran Affairs health system published in the Journal of the American Medical Association (JAMA) in November 2013.1 The men included in this study had low serum testosterone and were undergoing imaging of the blood vessels of the heart, called coronary angiography, to assess for coronary artery disease. Some of the men received testosterone treatment while others did not. On average, the men who entered the study were about 60 years old, and many had underlying cardiovascular disease. This study suggested a 30 percent increased risk of stroke, heart attack, and death in the group that had been prescribed testosterone therapy.
A second observational study reported an increased risk of heart attack in older men, as well as in younger men with pre-existing heart disease, who filled a prescription for testosterone therapy.2 The study reported a two-fold increase in the risk of heart attack among men aged 65 years and older in the first 90 days following the first prescription. Among younger men less than 65 years old with a pre-existing history of heart disease, the study reported a two- to three-fold increased risk of heart attack in the first 90 days following a first prescription. Younger men without a history of heart disease who filled a prescription for testosterone, however, did not have an increased risk of heart attack.
In September, an expert panel recommended for the FDA to impose stricter stricter limitations on the prescription guidelines for testosterone for treating low testosterone. Specifically, the panel recommended that the FDA tighten labels for the medicines so they are not prescribed to men who only have problems related to aging, such as low energy and libido. While, the FDA is not obligated to act on the recommendations of the expert panel, it often does act on the advice of these panels. The FDA has yet to redefine prescribing guidelines.
A new meta-analysis (Testosterone Therapy and Cardiovascular Risk: Advances and Controversies) in the Mayo Clinic Proceedings says there is no evidence of increased cardiovascular risks with testosterone therapy. This meta-analysis is the largest to date, and it revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. This analysis contradicts the findings of the two studies that led the FDA to begin a review of the risk of cardiovascular diseases with testosterone therapy.
On March 3rd, 2015, the FDA released a follow-up statement to its initial January 31st, 2014 statement to state that testosterone replacement therapy is only for men with low testosterone levels due to certain medical conditions. It also requires manufacturers to add labeling to inform patients about the possible increased risk of heart attacks and stroke in patient taking testosterone. The statement includes the following summary.
“The U.S. Food and Drug Administration (FDA) cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone. We are requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications. We are also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone. Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.”
1. 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.
2. Finkle, WD, Hoover, RN, et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PONE. January 29, 2014