By Brenda L. Mooney
DALLAS — When considering prescribing androgen deficiency treatment, VA physicians should take into consideration a new study finding that testosterone replacement therapy increased risks of death, heart attack or ischemic stroke in veterans who had undergone coronary angiography, the researchers advised.
The VA-funded study, published this month in the Journal of the American Medical Association, evaluated the association between the use of testosterone therapy and all-cause mortality, myocardial infarction and stroke among male veterans with low serum testosterone levels. It also looked at whether this association was modified by underlying coronary artery disease (CAD).1
“This should enter into the discussion between physicians and patients about whether patients should go on testosterone replacement therapy and this will, hopefully, help that discussion in terms of what the benefits are and what the potential risks are,” said co-author P. Michael Ho, MD, PhD, of the VA Eastern Colorado Health Care System in Denver.
Led by researchers from University of Texas Southwestern Medical Center in Dallas, the study involved 8,709 VA patients with low testosterone levels of less than 300 ng/dL who underwent coronary angiography between 2005 and 2011. Participants had high levels of coexisting illnesses, including prior history of heart attack, diabetes or CAD.
Of the patients, 14% (1,223) started testosterone therapy after a median of 531 days following angiography. After average follow-up of about two years and three-and-one-half months, the primary measured outcome for the study was a composite of all-cause mortality, heart attack, and ischemic stroke.
Results indicated that 19.9% of patients who had not used testosterone replacement therapy experienced coronary events three years after angiography compared with 25.7% in the testosterone therapy group. The groups had similar blood pressure, low-density lipoprotein levels and use of secondary prevention medications, although the control group actually was slightly older, average age 64, than the testosterone replacement group at average age of 61.
Researchers noted that, even after taking into account other factors that could explain the differences, use of testosterone therapy was associated with adverse outcomes and was consistent among patients with and without CAD.
The article noted that an estimated 2.9% of U.S. men over 40 years old are prescribed testosterone therapy, despite the lack of an extensive randomized trial examining the long-term benefits and risks.
“Rates of testosterone therapy prescription have increased markedly in the United States over the past decade,” according to background in the report. “Annual prescriptions for testosterone increased by more than five-fold from 2000 to 2011, reaching 5.3 million prescriptions and a market of $1.6 billion in 2011. Professional society guidelines recommend testosterone therapy for patients with symptomatic testosterone deficiency.”
In a video made available by JAMA, Ho pointed out that testosterone-replacement therapy “has been shown to improve muscle mass, improve insulin sensitivity, improve bone mineral density and improve sexual functions.”
The article’s background also noted that the treatment can improve lipid profiles and increase the time to ST depression during stress testing.
Writing in an accompanying editorial, Anne R. Cappola, MD, ScM, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia raised the issue of whether it can be generalized to “the broader population of men taking testosterone: men of this age group who are taking testosterone for ‘low T syndrome’ or for anti-aging purposes and younger men taking it for physical enhancement.”2
Cappola pointed out, however, that “the men who were taking testosterone in this study were slightly healthier to begin with, and surprisingly had a higher risk of catastrophic events.” She added that additional information the ongoing Testosterone Trial may provide important guidance to older men who meet current recommendations for testosterone therapy.
The “T” trial is a multicenter study of six coordinated trials of the effects of testosterone in elderly men with low testosterone on physical function, vitality, sexual function, cognitive function, anemia and cardiovascular risk. For the research, 800 men 65 or older whose serum testosterone is less than 250 ng/dL are being randomized to receive testosterone or placebo double blindly for one year. The primary end points for each trial are distance walked in six minutes, fatigue-vitality, sexual activity, delayed verbal memory, hemoglobin and coronary artery plaque burden.
The research is supported by the National Institute on Aging (NIA), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health and Human Development (NICHD), the National Heart, Lung and Blood Institute (NHLBI) and Solvay Pharmaceuticals Inc.
Until then, Cappola recommended in a Penn press release that “prescribers and patients should be wary.”
“Are the benefits — real or perceived — for these groups of men worth any increase in risk? These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men,” she wrote in the editorial.
“In light of the high volume of prescriptions and aggressive marketing by testosterone manufacturers, prescribers and patients should be wary,” she added. “There is mounting evidence of a signal of cardiovascular risk, to which the study by Vigen et al. contributes. This signal warrants both cautious testosterone prescribing and additional investigation.”
1. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36. doi: 10.1001/jama.2013.280386. PubMed PMID: 24193080.
2. Cappola AR. Testosterone therapy and risk of cardiovascular disease in men. JAMA. 2013 Nov 6;310(17):1805-6. doi: 10.1001/jama.2013.280387. PubMed PMID:24193077.
While implantable devices have shown promise in reducing rehospitalization for heart failure (HF), VA researchers sought to determine if options that are less expensive and non-invasive would have comparable results.
Legislation to prevent VA from outsourcing creation of its drug formulary and to require more input from medical professions is being considered in Congress.